Lesley King: Hi. I’m Lesley King
and I’m a part of the Sickle Cell Unit team.
And I will be guiding you
through the first session this morning.
I hope everybody had a good sleep
and is now refreshed and ready for day two.
Day one, we know was exciting, lots of information.
And I expect that day two is going to be much of the same.
Another packed day, so we’re going to start 8:33 a.m.
We’re already a little bit late.
And this morning, we’re going to start off with a welcome
from Professor Marshall Tulloch-Reid,
who is the director of CAIHR, Caribbean
Institute for Health Research.
It is a tape, as he’s unable to be here in person.
So, over to IT.
Marshall Tulloch-Reid: Good morning,
ladies and gentlemen, conference attendees.
My apologies for not being present at today’s meeting
due to people’s obligation. But once again, I’m pleased,
on behalf of the Caribbean Institute for Health Research,
to welcome you to this year’s Sickle Cell in Focus meeting.
We at the Caribbean Institute for Health Research
are once again pleased to partner with the National Heart,
Lung, and Blood Institute of NIH in staging this annual meeting.
As you may already be aware,
the Caribbean Institute for Health Research
is a regional institute of the University of the West Indies,
and that means that it has branches in more
than one of the university’s campuses.
In the case of the Caribbean Institute for Health Research,
we have campuses located in Jamaica and Barbados.
Three of those in Jamaica
are the Tropical Metabolism Research Unit,
which is the oldest unit comprising the institute;
the Epidemiology Research Unit;
and, of course, the Sickle Cell Unit,
which is today’s focus.
In Barbados, we have the George Alleyne
Chronic Disease Research Center,
which became part of the institute
a couple of years after it was formed in 1999.
Each unit focuses on different aspects of health research
or focus, of course,
is a lot around issues related to the health conditions
that are of importance to the region.
Particularly, non communicable diseases, their determinants,
working on surveillance of these conditions,
interventions that may help to change the natural history
of these conditions, nutrition,
child development research, climate, and health,
and then of course, sickle cell disease.
So, as you may already be aware of,
the Sickle Cell Unit, founded by Professor Graham Serjeant,
is now headed by Professor Monika Parshad-Asnani.
They have a strong tradition of research and service
to people living with sickle cell disease
in Jamaica and around the world.
It operates the Sickle Cell Unit,
one of the largest clinics in the region,
providing training and clinical support to clinicians,
not only in Jamaica but the Caribbean.
It’s also a part of the CAIHR unit
that supports the island wide newborn screenings
you’ve been discussing at your meeting.
And works with other Caribbean islands
to support their screening services as well.
We’ve been part of a number of innovative clinical trials,
including studies of hydroxyurea and other curative measures
which are being used now to address issue
of chronic of sickle cell disease.
So, members of the unit are integrally involved
in a lot of translational work
and work closely with the ministries of health
as well as persons living with sickle cell disease
to implement a number of policies
which are evidence based to help to improve quality of life.
We hope that you enjoy the next few days
and the continued deliberations that you have.
We wish you all the best as you continue to exchange
and discuss current issues
which are critical to the care of the patients that we manage.
And we wish you all the best for another successful conference.
[applause]
Lesley King: Great. Thanks, Professor Tulloch-Reid.
All right. Still missing some people,
but we must press on. Okay.
So, our next speaker is going to speak to us
about Improving Hydroxyurea
Adherence: Understanding Barriers and Enablers.
Dr. Monika Asnani is a professor of Family Medicine
and Epidemiology
and the director of the Sickle Cell Unit
of the Caribbean Institute for Health Research
at the University of the West Indies in Jamaica.
Professor Asnani, over to you.
Monika Parshad-Asnani: Thank you, Lesley.
This is probably for best.
You know you don’t want to have to speak after Russell Ware.
[laughter]
Why did you agree so quickly?
[laughter]
Okay. Here goes. Morning, everyone.
Everybody had a very good time yesterday.
I think that’s where we are a little short
waking up this morning. But here goes.
We’re going to be speaking to use of hydroxyurea in Jamaica,
barriers that we are identifying.
I’m not sure if there are enablers,
but we can suggest some. Let me try this.
Okay. All right.
So, Jennifer spoke to some of this.
And you would know that this is where you guys all are.
You know, right, where you are?
Where is this going? Right here in Jamaica.
So, the Caribbean region, a tiny region here,
44.2 million population, with all of us together,
which is just about .54 percent of the world’s population.
But yet, the incidence of sickle cell disease
is second highest in the Caribbean region,
second only to Sub-Saharan Africa.
And the prevalence of the sickle trait
is 8 to 10 percent in most territories.
If you look at -- just to provide some context.
My first couple of slides, I thought,
I’ll provide context to our setting,
you know, to really understand.
Because, you know, that is important for use
of any strategies that we are using in any diseases.
So, from the -- from some of the data,
this is -- the next couple of slides
are from Global Burden of Disease data
where sickle cell disease numbers were presented.
And this was published last year in The Lancet Haematology.
If you look at it overall, there has been --
and this is looking at data from 2000
and comparing it to 2021, there’s been a 13.7 percent
rise in global numbers of the disease.
Now we estimate about almost half a million people
are being born --
half a million babies are being born annually
with sickle cell disease.
And really, this increase has been massive
in Sub-Saharan Africa.
And the only other region, the only other GBD super region
that has shown an incline in numbers,
is Latin America and the Caribbean.
All the other regions are actually showing a decline.
All right. This is the next slide.
And looking at the birth incidence,
the overall global birth incidence
is about 382 per 100,000 live births,
highest in Sub-Saharan Africa,
followed by Latin America, and the Caribbean.
And if you look at Jamaica’s number in the blue --
sorry for all my colors.
This makes -- you know, it’s easy for me --
I’m a little blind -- to point out things to you.
Jamaica is probably the largest, or one of the largest,
or the highest incidents, at 573 per 100,000.
It’s actually closer to about 650
based on our more precise numbers.
These two pointers, you know, is killing me.
So, looking at this sickle cell disease in Jamaica,
10 percent sickle cell trait, and 5 percent of the population
has some other trait for some other abnormal hemoglobin.
One in 150 live births are born with sickle cell disease,
and we estimate about 19,000 people in Jamaica
are living with the disease.
Median survival is about 42 years,
which is three decades
lower than the national life expectancy.
Maternal mortality ratio is about 378 deaths
per 100,000 live births.
And fortunate, it’s about four times
that in non-sickle births in Jamaica.
And there really hasn’t been any change over the last two
decades in this. But our win is --
Jennifer said this yesterday -- the childhood mortality.
So, deaths under five no different than that
in the non-sickle cell children with provision
of newborn screening and early childhood care.
Marshall spoke to this quite a bit.
So, I’ll just say the Sickle Cell Unit
is one of the four units within the Caribbean
Institute for Health Research,
which is a department within the University of the West
Indies, a regional university.
And our mission is improving lives for persons
living with sickle cell diseases
through research, education, and clinical care.
The unit is one of the largest comprehensive care clinics
in the region. We have more than 10,000 people
registered in our database historically.
Now, currently, numbers have fallen a bit,
definitely during the pandemic, and thereafter.
We have about 2,800 patients annually who come to the clinic
making up close to 9,000 visits, 30 to 40 visits.
That number is a little bit down.
I think -- I don’t think we see 50 most days now.
Thirty to 40 patients are being seen every day.
And of course, you would have heard many times
over the last -- yesterday and today,
that is staffed primarily by primary care physicians,
pediatricians, and family physicians.
Currently, we have no hematologist on staff.
And we do provide expert consultations,
not only for patients who come to us,
but others in the island being managed
by other healthcare providers, as well as in the region.
And the Jamaica sickle cell cohort study -- and that’s Prof.
Serjeant and Mrs. Searjent. We are missing them today.
They live right here in Kingston, as you know.
The Jamaica sickle cell cohort study,
which was led by Prof. Serjeant, is one of the oldest birth
cohort studies on sickle cell disease.
And this is just a quick map. This is a map of Jamaica.
And that big green bunch up here is Kingston, where we are,
where the Sickle Cell Unit is located.
And just to show each dot,
whether it’s red or yellow or green, is a patient,
represents a patient of the clinic.
So, you can see that these are patients.
Our clinic does see patients from around the island,
which is not necessarily a best thing.
Our model of care is a comprehensive, integrated,
and continuing care,
including provision of social support.
We follow the chronic care model
because it’s ideal to manage such a chronic disorder.
And our aim is really to provide equitable access
to quality services
wherever people living with sickle cell disease
living in Jamaica. Okay.
And we do engage -- to affect our aims --
we do engage closely with patient support groups
as well as policy makers.
Through our work and that of other critical stakeholders
in the Ministry of Health of Jamaica’s 2013
to 2018 National Strategic Plan for Prevention
and Control of Non-communicable Diseases,
sickle cell disease made its entry for the first time.
And here the aim at that time
was really to strengthen management
of sickle cell disease
with the main targets being set for newborn screening
and training of healthcare providers.
The Sickle Cell Technical Working Group,
which has been mandated by the chief medical officer,
is led by Ministry of Health and Wellness,
but with members from Sickle Cell
Unit, Sickle Cell Support Foundation of Jamaica,
from the four regional health authorities,
and the National Public Health.
These are all members of this technical working group.
And it leads, for now,
especially provision of newborn screening
and early childhood care.
We have had universal newborn screening
since 2015 in the island,
which was quite delayed for a country
that where the benefits of newborn screening
for sickle cell disease were first identified, you know.
On the other hand, the National Health Fund
is a drug subsidy program that covers medicines
for 17 common chronic diseases in Jamaica.
And it’s a statutory body
that has been appointed by the MOHW in 2003.
Sickle cell disease, through a lot of advocacy,
was added to this list in 2015.
So, these are some of the areas. The picture on the right --
because you’ve heard about newborn screening
and the NHF already.
Now this is our second edition of our Clinical
Care Guidelines that have been written by Sickle Cell Unit.
And we have copies for you to view at our little table
to just show you Sickle Cell
Unit, because most of you have not been able to visit us.
And I’m going to see if next year,
next time, if ever John,
we end up being in Jamaica for the conference,
I think we should have a day where whoever wishes to visit
the unit will be happy to welcome them.
But these guidelines are used
by the Ministry of Health and Wellness.
They are adopted for use in their primary
health care system throughout Jamaica.
And there are many other countries in the region
who employ our Clinical Care Guidelines.
So, how do we manage sickle cell disease in Jamaica,
specifically, the treatments being used here?
Chronic transfusion programs are not employed.
A large part of why that is so
is because blood products are limited in availability.
We have no BMT, bone marrow transplantation facilities
available for sickle cell disease in Jamaica
or in the wider region.
Only three through overseas links
that we might be able to send patients for that.
Gene therapies, of course, are not available here though,
through the trial with Cincinnati in Punam Malik,
the Aruvant gene therapy trial, we were one of the major sites.
Seven of their treated patients came from us.
So, we’ve had three individuals from our unit
who have gotten gene therapy.
I think the oldest is -- I mean,
the first one is seven years -- going seven years.
She did make seven years in July. So, doing fairly well.
And if you look at the sickle cell,
other sickle cell disease treatments,
the disease modifying treatments,
the only DMT available in Jamaica is hydroxyurea.
Though the unit has participated in trials
for both crizanlizumab and voxelotor,
they are not licensed for use here.
L-glutamine is only available in the health stores
as a supplement.
The situation is pretty similar to this
for the rest of the Caribbean.
And if you just look at the average cost of hydroxyurea
here on the top --
oh, this thing keeps disappearing.
Then with the NHF, the National Health Fund subsidy
for an average 25 milligram per kilogram per day dose,
for an average 60 kilogram adult,
the cost would be about equivalent of about us $20.
And that’s really not a huge cause. It’s pretty reasonable.
But what’s the current use of hydroxyurea
at the sickle cell unit? As of about a week ago,
795 patients had used hydroxyurea.
The first case was in 2002 when we really started working
and thinking of using hydroxyurea in the clinic.
Most of those were SS.
I just want to highlight that 24 of those have been SC.
And the discussions yesterday were very interesting.
I think we really do need to take a closer look
at what our SCs are doing, have been doing.
And look at their numbers
and see how hydroxyurea has gone in them.
If you look at numbers from January 1, 2003,
last year January 1 to now,
we’ve had a total of 2,589 patients
who have visited the clinic.
Of those, 631 are on hydroxyurea.
That’s a good number, 24.4 percent.
But if you look at even just two years ago, September 2022,
less than 10 percent of our clinic population
was taking hydroxyurea.
That number was 15.7 percent in March of last year.
So, we are right now at 24.4 percent.
And this figure is very nice.
Thanks to Lesley for this figure.
Where you can see how many persons
have started hydroxyurea per year,
and you can see the sharp incline
in the last two to three years.
Don’t worry about this dip in 2024
because we haven’t completed the year yet.
So, numbers are going up.
But do remember that this is a specialized center
providing comprehensive care for sickle cell disease.
This is another set of data.
And this is looking at the National Health
Fund, which, as I said earlier, is a drug subsidy program,
and where sickle cell was added
to the formulary in June of 2015.
Data as at March of 2024 is that --
remember, I said that we estimate about 18
to 19,000 persons in Jamaica
are living with sickle cell disease.
Just a little over 3,000 of these individuals
are actually enrolled on the NHF
for their sickle cell disease status.
And something we recommend that every person living
with this chronic disorder should be registered.
Total claims over a one year period
from April ‘23 to March 2024 have been only 3,676.
This is not hydroxyurea.
The last bullet is on hydroxyurea for that time period
where total HU claimants
have just been 292 and total hydroxyurea
claims have just been about 1,438.
That’s just about five claims per individual.
I just wanted to say, though that --
remember I said 631 of our patients are taking hydroxyurea.
But here, it shows the claimants as only 292.
This just represents prescriptions
that are being filled in the private pharmacies,
because hydroxyurea can be accessed free of cost
in the public system. We are awaiting that data.
But we certainly don’t expect it to be huge numbers,
much bigger numbers than that.
So, Jamaica does have universal health care,
which means in the public system,
persons living in Jamaica can access free health care.
But numbers are subpar still.
So, why the under use of hydroxyurea?
What factors have been identified generally --
we’re not talking about Jamaica here --
leading to the under use of hydroxyurea?
These factors are thought to be related to provider issues,
patients or caregiver issues, or system level issues,
poor availability of the drug, as well as widespread access.
You know, where can you access the drug?
Even if it is available,
is it available in different parts of your country,
you know, or just at one or two pharmacies?
In many LMICs, liquid preparations,
for example, are unavailable. Access to laboratory
testing that is needed for monitoring may be limited.
Provider and patient factors may include low self-efficacy,
low awareness of its benefits,
lack of medical advice and concerns about side effects,
both at the provider level as well as the patient
and caregiver level.
Providers might have their own biases.
They might perceive that patients will not be compliant
with daily medications or may not be able to keep
the more frequent visits that are required,
and definitely might not be too willing to do labs.
You know, patients want -- even when they start,
might have poor adherence to use of hydroxyurea.
And you know, that’s not a good thing.
That’s not -- we don’t -- we want our patients
to be taking this drug on a daily basis.
And this adherence issues may be worse
when you have complex dosing schedules.
So, not everywhere do you have preparations
that allow for easier dosing. And what can be done?
What might work to improve this underutilization
training of healthcare providers,
along with provision of clear clinical care guidelines,
which might need to be adapted for various settings?
You know, what works in Jamaica
might not work in Barbados and vice versa.
Improving provider benefits and attitudes
and reducing their biases to respond
to some of the patient and caregiver issues.
Partnering with peer support networks
to strengthen the messages.
Improving their ability for shared decision
making could all help.
Improving access and affordability of drugs
and wider availability of the drug within communities
can also lessen barriers to uptake.
So, our study that we initiated early last year
aimed to understand barriers to hydroxyurea
use across Jamaica at the provider,
patient and caregiver and health systems level.
Some of that health system I presented in the slides earlier,
we are conducting a mixed method study,
including desk reviews of key policy documents
and in depth interviews with key stakeholders.
I’ll present some initial results today.
Starting with the parent or caregiver arm.
One hundred seventy two caregivers,
mostly mothers, have been surveyed,
and a subset have had in depth interviews of the group.
Only 36 percent have an NHF card.
27 percent a little over a quarter,
have never heard of hydroxyurea.
57.6 percent have been advised for their child
to take hydroxyurea.
Of these, about 68 percent have started it.
It’s good news here that almost all
who have started it have continued using it.
Barriers identified the parents and caregivers
have been both via the survey and through the interviews,
is that they need more information on hydroxyurea.
Almost 40 percent have stated this.
36 percent worried about costs of medications and of labs.
And over a quarter worried about side effects
and the increased frequency of visits and laboratory testing.
This table looks a little deeper at those 68 percent
who were actually advised
or who remember being advised to take hydroxyurea.
Because our current guidelines have our own inclusion criteria
or criteria for initiation of hydroxyurea.
So, we thought taking a look at those who had been advised
to take it, comparing barriers in those
who actually began and those who didn’t.
Inadequate knowledge, availability of hydroxyurea,
and not wishing their child to take additional medications
were some of the significant barriers,
especially knowledge if you look at those numbers.
Moving to the adults.
And again, I mean, we didn’t try for this,
but we have almost a similar number that we surveyed.
We have done some in depth interviews as well.
One hundred seventy four adults living with sickle cell disease,
and these are people over the age of 18.
73 percent who are female,
just over a half have an NHF card.
So, I don’t know why Lesley that you know more adults
have a NHF card than kids do.
But here, 36 percent have never heard of hydroxyurea.
That’s over a third. 43.7 percent have been counseled
read the need to take hydroxyurea.
Again, two-thirds of those who were counseled
actually ever started it.
And only half of those tanks are currently taking it.
Barriers identified over a half state
that they don’t know enough about the drug.
A third over a third state cost as a barrier,
but near 30 percent again worry about side effects,
such as low --
the drug lowering their ability to fight infections,
damaging their children if they are to have children,
and cancer risks.
Over a quarter don’t want to have to do frequent blood tests,
and nearly a quarter not interested in a drug
to take daily.
We got to survey 54 healthcare providers to date,
that includes 46 physicians and eight nurses.
Surveys in pharmacies --
and pharmacists because we do hope to reach out
to pharmacists as well, haven’t reached far yet.
Practice sites for the HCPs included family medicine,
emergency room, pediatrics.
The lowest frequency was for hematologists.
63 percent of these surveyed
managed both adults and children.
Median years in practice was 15 years.
Whereas, 16.7 percent were very comfortable.
Part of this group is individuals,
doctors and nurses who work at the sickle cell unit.
About 8 to 9 of these 54
are people who work at sickle cell units,
16.7 percent who are very comfortable
managing sickle cell disease.
Just a little under half are just somewhat comfortable.
20 percent are not comfortable managing sickle cell disease.
I thought this was an interesting figure down below.
Comfortable managing acute pain.
Just over a half, but less than a quarter are comfortable
managing chronic pain.
Two-thirds of the surveyed individuals
said they have no patients taking hydroxyurea.
And 44 percent were uncomfortable in using it,
with only 25, 28 percent saying they have some level of comfort
in using hydroxyurea.
The criteria they identified for use of hydroxyurea pretty low.
Just over 30 percent would use it for frequent pain
being managed in hospital,
but very few of those would use it
if these pain events occurred at home.
26 percent said yes for stroke, said yes for stroke,
and a quarter for acute chest syndrome.
Providers feel families decline hydroxyurea
because of worry about side effects
and not wanting frequent labs or visits.
Whereas important considerations for them are patients,
anticipation of side effects, patients’ adherence,
adherence to labs, possibility of pregnancy.
Over a quarter said that they don’t have --
they lack the resources to counsel.
20 percent didn’t know whether hydroxyurea
could be effective in managing pain.
I’ll move on to the next one.
So, what have we seen?
We have identified various patient and provider barriers.
Many are similar to other studies,
mainly in the U.S. and certain parts of Africa.
They’re not a lot of studies,
but definitely studies from these regions.
Barriers are greater in adults.
Provider barriers are also similar.
44 percent of them are uncomfortable prescribing.
And they are personal biases that we have identified
in just even this small group
that we have reached out to so far.
Striking for us also is the low registration
with the National Health Fund.
What can we do?
We clearly need to enable better understanding of hydroxyurea
use and efficacy among providers and patients.
Enhanced tools could assist with providers,
use of peer support networks, social media,
and use of patient navigators.
We’ll hear our nurses in clinic say,
"You know, I’ll have a mommy who is there --
whose child has been taking hydroxyurea
speak to this one that you want to go on hydroxide.
That’s always a win.
But to do it in a more determined way
could possibly help patients and caregivers
in their decision making process.
Improving registration with NHF could reduce cost burden,
but maybe increase visibility of access
to this critical medicine as well.
So, the study was mainly
within the southeast region of the island,
which is where the Sickle Cell Unit is.
We do have patients from other parts.
And we did reach out to some patients
for in the Northeast and the western region.
But we do still need more robust data from other regions,
where especially ambulatory care sites for adults are limited.
We also need to enable identification of persons
with sickle cell disease who are eligible for hydroxyurea use,
because, you know that could be a targeted group
to have them enrolled for care.
Further work to get a deeper understanding of these areas
and possible solutions
is ongoing as we look at these results.
So, that’s it. This is my last slide.
I want to end by acknowledging
and thanking members of the study team in the blue.
Our partners, the Sickle Cell Technical Working Group,
the parish teams, and the Ministry Of Health and Wellness
for seed funding for this study.
Thanks to Lesley King and Zachary Ramsay
for helping with the slides and the data in the slides,
and Mrs. Dawson Shaw from the National Health Fund,
who partners well with us. Thank you all for listening.
[applause]
Lesley King: Okay. Thanks very much, Prof.
Asnani for a great presentation.
Are there any questions from the audience?
The mic is coming.
Female Speaker: Thank you.
It went by a little too fast for me.
But I noticed that one of the reasons
why physicians didn’t use hydroxyurea
or didn’t recommend it was they didn’t believe it worked.
But I didn’t see the percent.
Are there still physicians who don’t think it works?
Monika Parshad-Asnani: That was a low percent.
That was about 20 percent
who weren’t sure about this efficacy.
So, then I don’t think we had anybody
who said I don’t believe it works.
Female Speaker: That was great. I’m sorry [unintelligible] late.
But what I was going to say was,
even when I was in the U.K., before I came to the U.S.,
the [unintelligible] hydroxyurea is pretty low.
Even though it’s available,
even though we counsel them many,
many times, I think there was -- maybe now it has improved.
I have to ask Daniel here, who’s just joined the King’s College.
Perhaps, you know, this apprehension number
is being, you know,
[unintelligible] use for cancer treatment.
I think that has a lot to do with it among the patients.
Monika Parshad-Asnani: I was happy to see in this study,
the data that we have to date, you know,
that was not a huge worry. Even in the in depth interviews,
a few that we have done so far, that that was not a huge worry.
Now, this data is on the background of,
you know, COVID was good in some ways.
It allowed us to have so many Zoom meetings.
It taught us for the first time,
to reach out in really good ways.
You know, Lesley leads the clinical care team
through the Office Sickle Cell Technical Working Group.
We have done a lot of training sessions.
We have done a whole echo series on hydroxyurea use.
So, I think the cancer thing is low,
but we really need some more data.
You know, the drug has --
that’s why I thought it was important to present numbers
for what’s the health system doing?
Because Jamaica is passionate about using hydroxyurea,
but we’re not quite there.
Even at our own unit, I think we are not there at all.
Only 20 something percent of our patients are taking it,
[inaudible]
Yes, definitely.
And among the women in Jamaica and the Caribbean,
you know, and like other parts of the world,
fertility is a big issue.
Most of these young people want to have a child.
So, if you are not able to say to them,
that’s why I really want to hear what Russell has to say next,
that you know, you might not be able to have kids,
or you have to stop it. And then, you know, pregnancy,
we have shown in our slides -- in our numbers here,
is really a high risk pregnancy in our women.
So, do they stop it and get in trouble, et cetera?
So, those are concerns, but I do believe that person --
we are not sending messages that we need to.
That’s what this is showing, right? So, we need to learn.
We need to collaborate with communication people.
How do we spread these messages in a good way?
How do we enable shared decision making?
Because so many of them are saying
that they’ve never heard of this drug.
And a lot of these patients surveyed are ones
who are coming to the unit or have access to,
you know, communication or Instagram page, et cetera.
So, we need to build better communication channels
to spread the information that we need to.
Female Speaker: Hi, I’m over here. Great talk.
How much of an issue is it for moms to get childcare
for, say, the well --
the children that don’t have sickle cell disease back at home
and leave those kids and bring their child
with sickle cell disease to the clinic.
That’s one question.
And then another question is just, what do females
that want to have children do for treatment,
for the sickle cell pain? Do they do nothing?
Monika Parshad-Asnani: You have such wonderful questions.
That’s an excellent question about,
what do they do with the children?
I wonder. Lesley, you want to take that on?
Mind you, our clinic opens in in, in working hours,
meaning 8:30 a.m., to 4:30 p.m. So, most of them do come.
But we have to identify these barriers.
We did not get that.
We’ve only done about 25 in depth surveys,
and we did talk about transportation.
This is part of a larger study looking at access to care.
Transportation was not much of a barrier.
And you know, reaching the clinic,
whether getting time off from work or so.
But Jamaica, the social system, has a good network
even though most of these individuals
we surveyed were mothers.
But a lot of times, grandmothers will bring children.
They have extended family.
But I’m just kind of guessing on the background of what I know.
Your second bit was --
do you have something to add to that, Lesley?
Lesley is the head of our clinical services,
and she’s a pediatrician. Keep going?
[laughs] What was the second bit you were saying?
Right. What do women who want to get pregnant do?
We advise them -- they get pregnant, yes.
And after that, they said, "Oh, my God, you’re pregnant.
You need to come off your hydroxyurea if you’re on it.
Because we still don’t let them carry it through,
and that’s something we need to talk through.
Yeah.
Lesley King: All right. Great, yep, I think that’s it.
There are two questions here in the --
but I’ll probably just take them quickly.
So, there are two questions here from Dr. Sinque
[phonetic sp] in the chat.
She’s asking about the difficulty
in getting labs done on HU
and can you give your minimum labs needed?
And so, what I think is I think Russell’s talk
may help us with that,
in trying to give us a better idea
of what are the minimum labs that we need to do.
Because that has always been a barrier.
And certainly, what formulation of HU do you use for children?
And we really only have tabs available in Jamaica
at this time.
But a number of our pharmacists will --
can make it into a suspension for our children.
All right. Okay. So, thanks, Prof. Asnani.
Great talk and great discussion so far.
So, now we are going to move back
to our original first presentation
from Dr. Russell Ware
on revisiting hydroxyurea use in sickle cell disease.
So, Russell really needs no introduction,
and I already introduced him. So, over to you, Russell.
And we’re seeing your slides now but we haven’t heard you.
Are you saying anything yet?
Russell Ware: I just got unmuted, so I --
Lesley King: Great. All right, go ahead.
Russell Ware: Thank you.
And let me offer my apologies for not being there
and in person due to personal reasons.
But I’m very happy to have a chance to speak.
This was the title that I was given,
revisiting hydroxyurea use.
Although, based on Professor Asnani’s data,
maybe it should be introducing hydroxyurea use.
It seems like a remarkable statistic
that so many adults would have never heard of hydroxyurea.
But nevertheless, I asked what revisiting meant --
and if I can advance the slide.
I’m not able to advance so I might need some assistance.
These three topics were suggested.
Talk about dosing, talk about use in pregnancy,
and talk about et cetera.
So, dosing, I’ll spend about 8 or 10 minutes
talking about why we think this matters.
Certainly, if you use too little drug,
you won’t get a benefit,
and that might be why patients don’t think that it works.
If you use too much, you can be toxic,
and that’s not good for anyone, providers, families,
or patients themselves. We like an optimal dose.
The second topic I’ll spend a little time on is,
what do we know and not know about its use in pregnancy,
and specifically, is it safe?
And then in the last five minutes,
I decided et cetera would be a follow on to pregnancy
and talk about what we know about moms
who wish to breastfeed.
So, dosing first. We know a lot about dosing.
This drug has been around a long time.
And here is my now 40-year timeline
that is spilling over the edge left
and right, that shows a wide array of studies
that have been performed over the years.
The ones in green are phase one two trials,
many of them funded by the NHLBI.
Reddish ones are phase three trials.
Again, many of them funded by NIH.
And the purple boxes at 1997 and 2017 represent the dates
at which the US FDA
approved hydroxyurea for use, first in adults
and then 20 years later, in children.
What it shows, collectively,
despite all the theoretical concerns
and naysayers and hate mail, is that the drug really is safe
and effective in all ages, from infancy to adulthood.
There’s a lot of nuances, of course.
But I think that the overwhelming compendium
of evidence supports this statement.
And the other is that the dose matters.
As I said, too little, too much is not good.
But it’s not uncommon to have drugs
with what we call a therapeutic window
where we try to get the right dose.
And I’m going to use the term occasionally, MTD,
maximum tolerated dose as a marker.
Because it’s in the literature, but it’s really a misnomer.
We’re not trying to push the patient to a toxic level.
It really should be called the optimal dose.
It’s the one at which you get the greatest benefits
without any toxicity.
And I’m going to start by talking about a study
long ago from 1992. This one is -- was published in
Blood over 30 years ago. It was led by Sam
Suresh, a great leader in the use of hydroxyurea
and also the architect of the phase three MSH trial.
This study is probably the best article
in the medical literature on this topic
that I’ve ever seen.
It covers everything about hydroxyurea,
and I’ve listed all of the things on the left column.
It’s really a rich study. It’s well written.
It’s as if Professor Suresh is telling a story to us.
So, I would encourage you to dig back into your PubMed
and find this article and read it,
and you’ll learn a lot about hydroxyurea, including dosing.
The two stories that I’m going to tell you about dosing.
One represents a -- well, they’re both prospective trials,
but one prospectively looked at the dosing,
and the other one has a way to look at it.
So, trial number one is called No Harm.
This is a study that I was fortunate to join
with Chandy John on the left, from Indiana,
who’s a malaria expert; and Robert Opoka,
a pediatrician and physician scientist in Uganda.
And they were interested in using hydroxyurea.
Professor Opoka was
but there was a lot of reluctance,
because it was in a malaria endemic region.
And some data from Inserm [phonetic sp]
had shown that while hydroxyurea might have solitary benefits
on sickle cell, it also increased adhesion
molecule expression on endothelium,
and these might serve as docking proteins for malaria.
So, it might make your sickle cell better
but make you more risk -- at risk for malaria severity.
And so, we were able then -- together with the three of us,
to create a protocol that would look at hydroxyurea
in the setting of Sub-Saharan Africa,
but the primary endpoint would be malaria infections.
And so, this was published in 2017
but it really started back in 2013, 2014
and it was a double blind placebo controlled trial.
So, you wouldn’t think that you could do many more placebo
controlled trials with hydroxyurea.
But in this case, it was for 12 months based on the fact
that the primary endpoint was malaria.
And the ethics committee agreed to this,
or actually recommended it, as long as with --
there was no signal of danger that all of the patients
could roll over to open label hydroxyurea.
And that is what happened.
Two hundred children, very young, age one to four,
were enrolled quickly.
You can see the enrollment curve on the right.
Very brisk enrollment over about a four month period.
And so, the treatment was fixed dose hydroxyurea
of 20 milligrams per kilogram per day.
It showed no risk of -- no increased risk of malaria.
If anything, it was higher in the placebo arm.
We had all of the treatment benefits.
And surprisingly, equivalent dose limiting toxicities.
There were plenty of DLTs,
as we call them, on the placebo arm,
and the equivalent number to the study treatment.
So, then what we had were children
who had been on hydroxyurea or placebo for 12 months.
And per the Ethics Committee, they all got put on open label.
And you can see a very simple figure here
on the right that shows that
although there was a difference of about a gram,
a gram and a half of hemoglobin during year one,
hydroxyurea placebo,
this quickly rectified. And by --
in year two, they all had the same higher hemoglobin.
So, everyone was taking their medicine,
and this was 20 milligrams per kilogram,
so a reasonable dose.
But what we realized then was we had a unique opportunity
to prospectively ask the question,
does it matter if you go up to MTD?
Does it matter if you stay at 20
or go up to 30 milligrams per kilogram?
What would be the risks and benefits of higher dosing?
And our prediction was that you would have more laboratory
and clinical benefits at MTD,
but you’d also have more toxicities.
And it would be a shared decision
making or a weighted discussion of whether it was better
to stay safe and lower or to push the dose up.
So, what happens surprised us.
Here on the left, you can see -- the top left, here’s the dose.
The fixed dose stayed at about 20
for the duration of the 18 months.
And the dose went up to 30 in the escalation arm.
So, it did what it was supposed to do.
And you can see on the lower left
that almost all of the clinical events
were significantly reduced on the higher treatment arm.
Now this is not treatment versus placebo.
This is 30 milligrams versus 20 milligrams.
And the dose limiting toxicities, to our surprise,
was equal or equal.
And so, the reason it was only 18 months
was that the primary endpoint was met.
The safety thresholds were not crossed.
And so, the study was halted early by the DSMB.
And so, this was one of the two publications
that I’m going to show you
that actually show dose escalation mattered
and seemed safe and seemed worthy of doing it.
Now the second trial started almost the same way,
but it was not placebo controlled.
It was an open label -- is an open label called REACH.
And this was to use hydroxy in four countries, Angola,
DR Congo, Uganda and Kenya, fixed dose for six months,
then a dose escalation with 600 children across the four sites.
And here are the PIs of that. And this is funded by the NHLBI.
And in the original report,
all of the events that were relevant to us at the time,
sickle events, vaso-occlusive pain, acute chest,
this is all compared to the screening pre-treatment period.
And this was also published in New England Journal.
And there’s Professor Tshilolo,
who presented it at ASH in a plenary session,
the first African author to ever present at ASH
in a plenary session.
So, what happened after that?
Well, this children have been on treatment
now for about eight years.
We have a terrific retention over that time.
And the other thing that we’ve done is slowly increase the dose
from what an initial conservative MTD call
to what we’ll call an optimized dose.
And you can see that the dose is about 25
to 30 across all the sites.
And this is almost exactly what we see in the U.S.
other high resource settings,
that the dose for children is about 25 to 30,
well tolerated at that.
But this also gave us the opportunity to look at
what happened during the fixed dose,
what happened during the escalation,
and more importantly, what happened after we reached MTD,
and what we’ll call the optimization.
And there are thousands of patient years here,
so we really have a good opportunity.
And what I’m going to show you here next
is the comparison between the fixed dose,
which was about 17.5, to this MTD optimal dose,
which is about 27.
So, this is analogous to the no harm data
that I just showed you.
And this was just published in The Lancet Haematology
and shows once again,
that although being on any hydroxyurea
is far better than untreated and better than placebo,
there is still a significant benefit that you can get
by increasing the dose toward mild myelosuppression.
And so, I would encourage you to consider,
if you’re going to do the investment
of treating your patients,
that you try to use an optimal dose,
that you try to get a small amount of myelosuppression.
Neutrophil count of 2,000, 3,000 and this will give you
the best bump in hemoglobin, hemoglobin F.
And as you can see,
significantly better than a lower dose.
So, some of the reluctance to use hydroxyurea in terms of,
it doesn’t work, it doesn’t help me
is likely to be due to not having a sufficient dose.
Okay. Topic 2, hydroxyurea during pregnancy.
So, 10 years ago, I had the chance encounter with a woman.
I was in the Middle East at a conference
and she was from the Maldives archipelago off India.
And she told me she has sickle thalassemia,
essentially beta zero thalassemia we since learned.
She said, "I was pregnant in 2005. I was told --
I started hydroxyurea in 2003, became pregnant,
was told I had to stop.
I became so sick and I miscarried.
So, I was determined not to let that happen again.
In 2008, I was again told
I had to stop at about 8 weeks, 10 weeks.
I was sick, almost died, delivered in term infant.
What should I do in my next pregnancy?"
And I said, well, there really isn’t very good data.
I gave her some recommendations. I spoke --
I sent some things to her OB but said ultimately,
it was her decision with her own providers.
And in fact, she was probably talking
because she intended to get pregnant.
And announced that in late 2013.
Once again, she was told she had to stop.
Within about two to four weeks,
she had more crises and decided to start again.
And she stayed on through the end of the first
trimester -- second and third trimester.
So, why are we worried about this?
Well, here’s what the hydroxyurea package insert says.
It says there are no adequate, well controlled studies.
I’ve highlighted the parts I’m going to read to you --
potential harm to the fetus.
You should avoid becoming pregnant.
And it classifies the drug as Category D.
And for decades, the FDA classifies drugs
according to their risk and what’s known about it,
A, B, C, D and X.
X being the only truly contraindicated one.
And then it adds that for nursing mothers,
hydroxyurea is excreted in human milk.
And a decision should be made to either discontinuing nursing
or discontinue the drug, taking into account
the importance of the drug to the mother.
So, that’s an interesting little recommendation at the end.
So, what is Category D?
Well, very similar to what I just read you.
Positive evidence of human fetal risk.
But the potential benefits from the use of the drug
in pregnant women may be acceptable,
despite its potential risks if the drug is needed in a life
threatening situation or serious disease.
So, this is where we should think about hydroxyurea
and sickle cell.
Do we really think that sickle cell
is a serious enough disease that people need to be treated?
Curious, if only 25 percent
of the Jamaican sickle cell population is on it.
Because without blood transfusion support,
that means 75 percent of people are not even on any disease
modifying or symptom modifying therapy.
So, they’re basically untreated.
I think it is a life threatening disease,
and there are data from Jamaica that talk about this,
particularly in the maternal context.
So, here’s a review from Dr. Asnani, et.
al., talking about the maternal risk of being pregnant
and in Jamaica.
And the maternal mortality ratio was about 10 times higher
than in the rest of the island. And then she also mentioned
Professor Serjeant’s cohort study.
This was published a few years back.
Again, a large number of pregnancies
and a large number of women,
this would, of course, have no hydroxyurea or transfusion,
just the risk of being pregnant on the island.
You can see more abortions, fewer live births,
higher risk of retained placenta.
And actually, five of the 71 women died.
So, much higher mortality rate than the Sickle Cell Unit one.
So, sickle cell and pregnancy are high risk in Jamaica,
but it’s also high risk around the world.
This is a meta-analysis that was published in Blood 2015
that said, "Overall, six times the mortality ratio,
but also a lot of morbidity for the mother and the baby."
And a U.S. study that was published last year
showed that there was a much higher mortality risk,
even in the U.S.
So -- and also morbidity with stroke and thromboembolism.
So, pregnancy is high risk.
Pregnancy in sickle cell is very high risk.
And so, we should consider this a serious disease.
So, why are we worried?
Well, there are studies in the toxicology
that hydroxyurea can harm fetuses.
Here’s one in the rat fetus using 200
to 1,000 milligrams per kilogram.
Now that’s a very high dose. And of course, mice and rats
don’t metabolize hydroxyurea the same way.
But at that dose, it was teratogenic.
But the mice and the rats were dead
because they had aplastic marrow.
So, they were clearly treated with very, very high doses.
Here’s another study that used up to 150 milligrams.
This was done with guidance
by the U.S. Environmental Protection Group.
And they put in their discussion
that strategies are needed in the animal literature
to establish clinically relevant exposures.
And I was part of an invited review a few years ago
with a bona fide card
carrying environmental toxicologist Steve Dertinger.
And we reviewed all of the data that was available.
And there, I think, an interesting findings
about what hydroxyurea does and what it doesn’t do based
on a large amount of preclinical animal and human data.
All right. The EPA also has this sort of infamous statement
that toxicity, you document it in animals,
but safety, you need to try it in humans.
So, what’s the experience?
Well, the MSH trial followed 300 participants,
150 females, and reported 94 pregnancies.
And there’s a summary, some of the people in the audience
probably are part of this, said that exposure of the fetus
to hydroxyurea does not cause teratogenic changes.
A large study from Europe,
the ESCORT-HU looks at almost 2,000 patients,
about 100 women with pregnancy and rights.
Pregnancy outcomes after hydroxyurea exposure in patients
are rather reassuring when compared to the risks
of maternal and perinatal complications
related to sickle cell disease itself.
So, again, it goes back to that phraseology
in the package insert
that referred to the seriousness of the disease itself
versus the potential risks of the treatment.
However, there was a more recent article in 2022
that talked -- it was a self-report.
So, probably a little less in terms of documentation.
Again, several of the authors are probably at this audience
that said for mothers who were taking hydroxyurea
when they got pregnant,
that didn’t seem to cause a problem.
But if they kept going during pregnancy,
then they had a higher rate of miscarriage.
So, it’s possible that there are some risks to take it during.
Now, interestingly, ASH has a pocket handbook about it.
I don’t know where this bullet point comes from.
I’ve asked the people who wrote it, they don’t remember.
But it said some women choose to stop taking hydroxyurea
early in their pregnancy
and then started again in the third trimester.
Presumably to help their own health,
maybe improve blood flow for the baby,
maybe to improve birth weight and so on.
So, best is what’s out there.
So, how are we going to do it?
Monika said we need more data, and we absolutely do.
And there are two clinical trials
that we’ve been associated with in the Caribbean,
one in Dominican Republic, called Sacred,
one in Jamaica Extend.
And this took youngsters who were on --
who benefited from hydroxyurea for stroke prevention.
And they’ve been treated for more than five years,
some up to almost 10 years.
And they’re now older teens entering child-bearing age,
and we can now ask the questions about long term risks.
And so, they -- all of these youngsters
are going to enroll
in a surveillance study known as SAFE,
which is a serial assessment of fertility experiences.
And we’re going to do quarterly visits
as they’re on their medication and ask questions
and gather data about their fertility potential
and reproductive outcomes.
We don’t know whether we’ll get many or any pregnancies.
We’re certainly not advocating yet.
But while they’re on hydroxyurea,
we do want to capture that information.
And so, we’re grateful to both of these cohorts
and their leaders to enroll the patients.
All right. Last quick topic, the et cetera is --
well, if you get through your pregnancy
and you wish to breastfeed, what about that?
Well, why does the package insert say that it’s unsafe?
It references this article. So, you pull this article.
You find out that it is exactly one patient, a case report.
And it’s a 29 year old Woman with chronic leukemia.
She was taking hydroxyurea three times a day.
She had breast milk collected two hours after the last dose.
It was detected in the milk.
And the conclusion was, hydroxyurea does enter the milk.
So, women should not lactate cut and dried.
But as you know, mothers with sickle cell anemia
really wouldn’t take the drug that way.
They would take it once a day,
a higher dose with a shorter half-life.
Most of it should be gone from the serum.
Most of it is excreted in the urine.
Does it go into the breast milk? Does it accumulate?
Does it go in? Does it go out? Really wasn’t known.
So, with the help of our clinical pharmacology group
at Cincinnati Children’s,
we designed a prospective trial to study in lactating women
whether hydroxyurea goes into the blood
and the urine and the breast milk.
And can we measure it, and can we create population profiles?
And I was pretty skeptical
that lactating women would sign up for this,
but I was very wrong. Women were very eager.
Most of them didn’t have sickle cell.
We did allow a few who were pregnant
to lactating women with sickle cell to join at the end.
But these were normal, healthy women.
And so, what we found was that, in fact,
it does go into the milk.
You can see, here’s four examples of plasma levels
as well as milk levels.
There’s a very easy passage, if you will,
from plasma into milk.
But then it’s two way street.
So, if you wait a few minutes, it actually drops in the milk.
And because it sort of equilibrates with the plasma,
so you get this initial amount that’s in the milk.
But as time goes by, and that time is in minutes,
not hours, as the drug gets excreted from the plasma,
the equilibration goes back,
and the drug actually leaves the milk.
So, it does not accumulate, not like urine,
where it can’t go backward.
And so, at the lower right, you can see that
after a single thousand milligram hydroxyurea dose.
A total of 2.2 milligrams would be transferred.
But this is if you count and add up all the milk
that was like at 30 minutes and 60 minutes and 90 minutes.
But that’s not the way women breastfeed.
If you were to do it at three hours, six hours,
nine hours, it’s about half that one milligram.
So, 1 milligram out of 1000. Is that safe? Is it not safe?
So, WHO gives some guidance
called the relative infant dosage.
And it’s the fraction of the dose in milligrams per kilogram
relative to what the mother’s dose.
And if the relative infant dose is less than 10 percent,
most medications are quite safe.
And so, for hydroxy, it’s 3.4 percent
and that’s if you fed every 30 minutes after your dose.
If you wait three hours, it’s half that.
So, about 1 to 1.5 percent.
And so, based on these WHO recommendations,
you would conclude that hydroxyurea is not
contraindicated because it’s in the safe levels.
Again, based on whether you think
the drug is important for that mother
to have versus having untreated sickle cell disease.
So, maybe it’s time to not ignore the theoretical risks
but use the human data for safety and incorporate them
into our clinical decision making.
Here’s the mom who delivered her hydroxy treated child,
who is now 10 years old and the smartest child in her class.
And this mother has always offered herself as a guidepost
and likes to talk to women who need to make their choices.
And so, with that, I’ll end and happy to take any questions.
Thank you.
Lesley King: Thanks, Russell.
Okay. So, another great presentation.
Are there any questions from the floor?
Okay. So, Prof.
Knight-Madden has a question here for you.
Jennifer Knight-Madden: Hello.
Russell Ware: Hello.
Jennifer Knight-Madden: Okay.
Hi. Hey, Russell. Great talk as usual. Question.
So, the study that’s going on in Dom Rep and Jamaica,
what will happen when the -- if the girls get pregnant?
What advice would they be given at that point in time?
Russell Ware: It’s a great question.
Remember, this is a surveillance study.
So, there’s no guidance about even birth control
or sexual activity.
This is handled by the physicians,
which I think in this transition age,
is probably some combination of the pediatric
and the adult group.
Angela Rankine-Mullings, I think, is there.
And maybe Professor Reid can answer more about that.
The information would be captured.
And I don’t know if they would insist
that the young lady come off treatment
and whether they would restart it later or use transfusions.
I don’t know what the practice
is now of pregnant women in Jamaica.
Jennifer Knight-Madden: So, it would be based
on the standard of care
in the clinic is what you’re saying.
Russell Ware: That’s right.
Jennifer Knight-Madden: Okay. Thank you.
Lesley King: Go ahead first.
Okay. So, one, and then you [unintelligible]. Go ahead.
Cheryl Stucky: Hi, Dr. Ware.
This is Cheryl Stucky. Great presentation.
I work on animal models of sickle cell disease
using the mouse models.
And I was wondering if it would be beneficial
to do a mouse study where we use the dose
equivalent of your higher 30 milligrams per kilogram dose
in the mice and sickle mice and control mice.
Do long term treatment with the dams,
then let them get pregnant.
Then thoroughly analyze the pups for any sort of deficits
and the breast milk as well see how they develop
and let them also then have pups themselves.
Would that be a valuable study?
Russell Ware: I think so.
And I’d be happy to talk with you further about it.
I think the mouse model is an imperfect version
for humans in part
because, remember, any affected pups
are going to have sickle disease
all through their gestation, right?
There is no fetal.
I don’t know, maybe your mouse model is different.
But yes, there needs to be some animal data.
We also need the human data.
We need to do surveillance and reporting.
And I’m pleased to say that our colleagues
in Caribbean part of the [unintelligible]
network have some examples. Maybe 10 or 15 women
who are receiving hydroxy exposure during pregnancy.
Professor Joe [unintelligible]
is in the process of writing that up.
So, we’ll get more information over time.
Cheryl Stucky: That’s great. Thank you so much.
Lesley King: Prof. Thein has a question. Go ahead.
Swee Lay Thein: Hi, Russell.
Sorry to not be able to see you in person.
It’s Swee Lay here.
I think it was great that you did this study
on the lactating, you know, where they’re safe to lactate.
But you know, many mothers, they collect their milk
because they store them in the fridge for communion time.
So, given what you’ve done and from the studies,
when do you think is the best time window to collect the milk?
Russell Ware: That one’s pretty --
has a clear answer, Swee Lay. Thank you for the question.
The mother should finish breastfeeding infants
and then take the medicine.
So, then for the next two or three hours,
there’s no milk transfer to the baby.
And then there’s a process called pump and dump.
If you’re worried about that first three hour feeding,
then you would just throw that one away.
And then pump again at six hours or feed again at six hours.
So, as long as you’re a few hours out from that first one,
the amount of hydroxy in the milk is really miniscule.
Swee Lay Thein: So, if it’s not convenient,
they can actually collect the milk
and feed it the baby a bit later.
Russell Ware: Oh, sure.
That’s what breastfeeding women do all the time.
They pump and freeze for months.
Lesley King: All right. Okay. Great. Russell, thanks.
Another great talk as usual,
and I’m sure we’ll see you here in Jamaica sometime soon.
All right.
Russell Ware: I’m sorry for the inconvenience.
Lesley King: Not a problem. Take care.
Happy that you were able to participate.
Okay. So, we are maybe about -- running about five minutes late.
So, we’re going to go on now to our third speaker,
who is Dr. Luisanna Sanchez.
And she is a pediatric hematologist-oncologist
at the Indiana Hemophilia & Thrombosis Center.
And she’s going to speak to us on clinical and hematopoietic
profiles associated with sustained response.
Luisanna Sanchez: Good morning, everyone.
My name is Luisanna Sanchez.
And I’m a pediatric hematologist and sickle cell doctor
at the Indiana Hemophilia & Thrombosis Center.
I thank the organizers for the invitation here today.
This is my second time in Kingston.
And I can’t believe that it was almost 10 years ago
when I was here presenting at the 2016
[unintelligible]
Conference when I was only a medical student
hoping to become a hematologist one day.
So, it’s a privilege to be here today as a junior faculty,
sharing the room with so many people
who are an inspiration for me
and having an inspiration so far in my career.
Today, I would like to talk to you
about the research study that I participated on
when I was a fellow at Texas Children’s Hospital.
It’s titled Clinical and Hematopoietic
Profiles Associated with a Sustained Hydroxyl Response
for Patients with Sickle Cell Disease.
I do not have any disclaimers, but after going to talk after
Dr. Russell Ware and Dr. Monika Asnani,
I would like to say that I love hydroxyurea.
[laughter]
And despite what you’re going to hear in this presentation,
I’m a true believer in hydroxyurea.
Especially because I was born
and raised in Dominican Republic,
where we share some of the limitations
and access barriers that were discussed by Monika earlier on.
And now that I have been practicing
and to have my own group of sickle cell patients,
I’ve seen how children who were studied on hydroxyurea
when they were infants, and now are 11, 12 years old,
they have never experienced a sickle cell crisis
in their lives, and that’s something amazing.
And so, I do believe that hydroxyurea improves
the lives of individuals with sickle cell disease.
But now that hydroxyurea has been around
for over two decades, we’re seeing some heterogeneity
in long term response to the therapy.
Patients may experience a decline
on their F levels over time, despite being compliant.
Some authors have reported that sickle cell --
or individuals with sickle cell disease
have well documented changes in their bone marrows,
specifically when talking about hematopoietic
stem and parenteral cells or HSPCs.
So, we wonder in this context
if perhaps the impact of hydroxyurea
in the HSPCs of pediatric patients during treatment
could at least be partially responsible
for the declining F that we’re seeing over time.
To answer this question, we first wanted to determine
if this was a true phenomenon and what was the clinical impact
of declining hydroxyl response in pediatric patients.
And second, we wanted to characterize
the HSPC profiles associated with hydroxyl response.
We started by screening a large cohort of pediatric patients
seen in Texas Children’s Hospital from 2011 to 2021.
Individuals who were SS or HbS beta-thalassemia genotypes,
had these genotypes and were on hydroxyurea
for more than five years were eligible for the study.
We used mean corpuscular volumes and absolute neutrophil counts,
as well as number of hydroxyurea prescriptions
and outpatient notes, has surrogates of compliance.
If an individual was felt to be eligible for the study,
then we use the hemoglobin F to be able to --
has a response to hydroxyurea to categorize them
in one of two subgroups.
First the sustained response group,
if after starting hydroxyurea,
they had an initial F induction of more than 20 percent
that remained above 20 percent
throughout their treatment history.
The second option was to be part of the decreased response group
when they had an appropriate initial response
but then decreased to less than 10 percent over time.
We proceeded to collect clinical and laboratory
data longitudinally for each individual patient
over the course of 10 years of treatment.
Now, in the present time when they came to clinic,
we collected whole blood samples from these patients
that sent to our lab
to isolate peripheral blood mononuclear cells.
We identified HSPC populations using flow cytometry.
And then a subset of the samples
was done for single cell RNA sequencing.
Two hundred eight children with SS or HbS
beta-thalassemia were included in the study.
71 percent of them were part of the sustained response group,
and 29 percent was -- were categorized as having
a decreased response to hydroxyurea.
As you can see in the table, their demographic
characteristics were very homogeneous.
And the only thing to highlight here
is that the median age of start of hydroxyurea
in the sustained response group
was four years old compared to two years old
in the decreased response group.
In the interest of time, we’re going to focus mainly
on the F values of these patients.
As you can see in green,
patients with a sustained response,
their baseline F levels were about 26 percent
at the start of treatment and remain above 20 percent
throughout their treatment history.
In red, we’re seeing those patients categorized
as having a decreased response.
They started as well with high F values, above 24 percent.
But these values decreased to less
than 10 percent of our time.
When we looked at the mean corpuscular volumes
and absolute counts of these patients,
we’re seeing that they share the macrocytosis
and myelosuppression at least for the first eight years.
They were very similar.
When we subdivided or when we adjusted for age,
their F values, something very interesting happened.
Here we see in the right upper corner
the patients who had a sustained response.
In dark green, you can see that individuals
that were at the time of the transitional cut off
when we were analyzing data,
they were between 15 and 21 years old.
And they had been on hydroxyurea for 10 years at least.
So, they were started when they were already older.
And so, we were thinking that if someone was started
on hydroxyurea when they were older,
perhaps their F response was not going to be as robust.
But we saw that actually,
these patients maintain levels up of 20 percent over 10 years.
The opposite in the right lower corner,
when you have a decreased response group in children
who were started earlier on on hydroxyurea,
even those that were at the present time ages
between five and nine years old,
had a decreased response and were less than 20 percent.
In this slide, we’re presenting the clinical outcomes
of age-matched patients.
Age-matched patients between the two groups.
We’re seeing that between the groups,
they had similar number of office visits.
But the sustained response group had a higher incidence --
sorry, a decreased incidence in sickle cell events
requiring hospitalizations, transfusions, and procedures.
This data is expressed in number of events per 100 patient use.
So, this was speaking to the protective --
to the protection of fetal hemoglobin
in the sustained response group.
At this point, we were thinking, well, having patients
that are experiencing a decreased response
to hydroxyurea is a true phenomenon.
And second, this is leading to significant
clinical repercussions in our patients.
So, we decided to take a look at their cells.
But before doing that, let’s just go through
this figure as a reminder for all of us
that we have been talking about HSPCs.
This is essentially this four subgroups here
that we are seeing on the far right
when we’re seeing stem cells, multiple temporary cells,
committed progenitors and recursive cells.
But all of them start from this small group of cells
in the top middle of the screen.
They’re called hematopoietic stem cells.
These are a subgroup of cells that are subdivided
in long term HSCs and short term HSCs.
Their main characteristic is that they maintain
their ability to self-renewal, or self-regenerate over time.
The short term HSCs then eventually generate
the multiple temporary inter cells.
They will eventually go down the path
and lose their generation capacity
and give rise to all the cells in the body,
including erythroid cells.
We use specific antibodies to target cell
surface markers in the cells
and to be able to characterize each compartment
that we saw in the prior slide.
We found out that patients with a sustained response
here in green had a higher number of multipotent cells
and hematopoietic stem cells.
While the decreased response group
had a higher number of multipotent progenitor cells
in general and megakaryocyte erythroid progenitor cells.
So, what does this mean? Let’s go back to the figure.
And essentially, what we’re saying
is that the sustained response group
had a higher number of cells
that maintained their regeneration capacity,
while the decreased response group had more cells
that already committed to become erythroid cells.
Now, let’s talk about single cell RNA sequencing.
We randomly selected four different patients,
two from each group, sustained response group
and decreased response group.
Here, each patient had been on hydroxyurea
for at least five years and had similar hydroxyurea doses
by the time that the sample was collected.
As you can see, these patients had their F level values
that were expected for the group that they belong to.
For example, patient sample number
three had an F value of 10.5 percent.
Across the four samples there or [unintelligible]
microcytosis and myelosuppression.
We proceeded to select C 34+ Lin-
cells that were selected to flow cytometry and cell sorting.
And then use 10 x genomics technology
to perform single cell
sequencing of approximately 10,000 cells
for these four different patients.
On the right, you can see the clustering
of these different cells. Each dot represents a cell,
and each cluster or color represents cells
that are related to each other by their gene expression.
We found that this cluster right here in the middle
seems to have cells that are more
HMC like or hematopoietic multipotentials.
And that actually 30 percent of this cluster
belonged to the sustained response group,
while only 3.5 percent of them
were part of the decreased response group.
On the other hand, we saw a cluster of cells right here
in the right lower corner with a C34+ --
sorry, C33+ myeloid signature.
We know that this is a cell server antigen
that is absent from multipotent hematopoietic stem cells.
We found that only patients with a decreased response group --
in the decreased response group had these cells.
In terms of gene expression, when we look at the results,
we found that nearly 200 genes with over two full gene
expression between the two groups.
72 percent --
72 of these genes were enriched in the decreased response group.
The most interesting aspect of all of this
is that 13 of the 72 genes were in the NF Kappa B1 pathway.
When we look at the expression of the NF Kappa B
across the cluster profiling on our single cell,
similar to the slide before on the right,
we see how the highest expression is identified
in patients who had a decreased response.
NF Kappa B is a pathway known to promote differentiation
and loss of cell renewal in response to inflammation.
We think that this is maybe part of the difference
why we’re seeing patients lose a response --
or like lose their ability
to response of hydroxyurea over time.
So, in summary, we found that almost 30 percent of children
with sickle cell disease who are taking hydroxyurea
eventually will have a decreased response
based on their F levels.
We saw both by flow cytometry and single cell
RNA sequencing of HSPCs,
that patients with a decreased response
will have a lower amount of cells
that are hematopoietic, multipotent cells.
And had more cells that are C33+ myeloid
that were committed to become erythroid cells.
I do want to highlight that we saw again in this study,
just like many other studies in the 40 years
that hydroxyurea has been around to protect our slides,
that F values or F levels are protected.
Hydroxyurea is protective of patients.
And I do want to acknowledge that it’s possible
that increasing hydroxyurea doses for these patients
may restore some of this F induction.
But at the same time, our findings are suggesting
that premature aging of the hematopoietic system
plays an important role in long term hydroxyurea response.
So, where are we going to go next?
One of the important questions is,
is this the chicken or the egg?
So, are these changes that we’re seeing related
to an individual susceptibility to lose fetal induction,
or are we seeing this as a consequence
of fetal of hydroxyurea related effects?
So, we would like to add more patient samples
to our flow cytometry experiments,
as well as single cell RNA sequencing.
We would like to add a control samples for patients who are --
who have sickle cell disease and who are not on hydroxyurea.
And we would like to know more about how age
is playing a role here,
and how we can use this data to hopefully,
patients who are known to have a decreased response phenotype,
we can’t offer them personalized
strategies to enhance F induction.
And perhaps facilitate early selection of alternative
treatments for sickle cell disease.
Thank you very much to the NHLBI
and Sickle Cell in Focus Conference organizers,
to the Texas Children’s Hematology Center,
Flanagan Lab, our collaborators
and, of course, the participants that --
patients that participated in the study.
I would like to also thank the financial support
of the American Society of Hematology
and National Brain Disorders Foundation.
Thank you very much.
[applause]
Lesley King: Okay. Great presentation, Dr. Sanchez.
And I see a number of hands here already.
I think this is quite interesting,
what she’s talking about.
Because just doing a quick review of some of our patients,
this is something that I’ve actually noticed,
is that we do get that initial response.
But that sustained response, we see the F levels dropping.
And the question is, you know, why?
Well, okay. So, we’re going to start off.
Male Speaker: That was fantastic.
Thanks for sharing the RNA seq data
which is really provocative. So, I wondered,
did you do a heat map looking at the inflammasome?
And were there more than NF Kappa B
elevated in the second part of that was --
I think it’d be really interesting
to look at the same study
and those getting regular transfusions to see
if the signature can be changed,
particularly in the non-responding group.
Luisanna Sanchez: Thank you very much for the question.
We are still analyzing our RNA sequencing data.
And we have not explored other pathways yet.
But it’s certainly something that we would like
to add as a next step.
And we hope to add within those control groups,
patients were also on chronic transfusions,
who were on purpose, did not include in the study.
Thinking that made that a confounding factor.
But indeed, it’s something that we’re going to start looking at.
Thank you.
Deepika Darbari: Great presentation and great study.
And this is such a big problem for many of our patients,
as we see, as they grow and response is not as much.
How do you determine the compliance in these patients?
Because many times we just blame, you know,
maybe it’s they’re not taking the medication.
Luisanna Sanchez: Great question, Dr. Darbari.
So, this is, in part, a retrospective review study
with a prospective arm in the sense
of we reviewed thousands of charts.
And took into consideration that MCV values
and absolute interval counts,
as well as counting the prescriptions.
That in their outpatient notes,
where providers will typically write in their assessments
if they thought there was a compliance issue.
So, that’s why we only select the patients
who we felt met criteria being compliant in both arms.
Those 200 patients are part of like 2,000 patients
that we looked at, that we felt were compliant
and had their F values pertaining to each category.
But it’s certainly something that I would like
to acknowledge, that even if we push them
a little bit more with their hydroxyurea,
having higher doses, reaching to optimal doses,
I think that we could see a little bit more of F,
especially in the decrease response group.
But I do not think that the findings
that we’re seeing in the RNA sequencing
are going to change significantly.
So, I do think this is a true phenomenon
that many of us have experienced and looked at over time,
and particularly in our patients.
And perhaps, we have not investigated deep enough yet.
Male Speaker: Really interesting talk.
Do you -- very nice work. Do you think that --
or is there any way to look back at the data originally?
I don’t know if you did RNA seq at baseline
to see if there are signals or predictors
for who might continue to respond or who might not.
And that might help us understand
who should be on hydroxyurea long term
and who maybe -- who shouldn’t.
Luisanna Sanchez: That is amazing --
an amazing question. We did not.
This was part of my fellowship project
founded by ASH and National Bleeding Disorders Foundation.
So, we were limited in the amount of resources
that we could use for RNA sequencing.
But now we’re going to add more patients.
And one of the main criteria was to be on hydroxyurea
for at least five years before drawing the sample.
So, I wonder if we can do that in patients
who are nine months of age.
And we can just -- at least have a few patients
that have never been on hydroxyurea in that way.
Male Speaker: Yeah. Really nice work.
Female Speaker: Fantastic study.
I’m so glad you accepted the invitation
to come and talk here.
Because when I saw your ASH presentation,
I said, "I want to know more."
And this is a problem that I treat adults, okay.
And when I see adults,
they become so sensitive to the dose.
300 milligrams, and they already hit,
you know, very low ANC [phonetic sp].
And the other thing, which I couldn’t explain
is when we restart them, they no longer response.
So, I think all your future directions to look at,
I think, is probably premature aging
and the hematopoietic stem cells.
But I really look forward to your RNA seq data
and more to discuss with you. But one thing I noticed, though,
even in those with sustained response,
you use less than 10 percent [unintelligible].
But you look at those with sustained response,
that was slowly declining. Right?
From 30 down to like just above 20.
So, maybe you observe over another 10 years,
you will go down.
Luisanna Sanchez: That is true. Yes.
Thank you very much, [unintelligible].
Lesley King: All right. One final question.
Male Speaker: Yes. Also really impressed by these data.
I’m wondering how growth curves factor into dosing over time.
Because you know the sustained response
and the non-sustained response were in different age groups.
So, I wonder how tightly controlled the dosing
was per kg over the growth of those individuals,
and whether the non-sustained response
reflected a lower milligram per kilogram dosing
because of not keeping up with their growth.
Have you looked at that?
Luisanna Sanchez: Yes. We use --
we make sure to write down the milligrams of hydroxyurea
that each patient was on throughout that 10 year period.
And that’s why I made that acknowledgement at the end,
that there is some work to do
still to push them a little bit higher.
So, I do think, in part,
some of that decrease could be related to that.
But regardless the changes, that wouldn’t change necessarily
what we saw on flow cytometry and RNA sequencing.
But I do think that that’s a component.
Thank you.
Lesley King: All right.
[applause] Luisanna Sanchez: Thanks.
Lesley King: Okay, great.
And certainly, look forward to some future work
coming out from you, Dr. Sanchez.
All right. So, we’re doing not too badly on time right now.
Our last presentation for this session
will be by Dr. Lauren Merz
on reexamining the utility of absolute neutrophil count
as MTD in the context of Duffy status.
Dr. Merz is currently a fellow in hematology-oncology
at Dana-Farber Cancer Institute
[unintelligible] Brigham. Okay. Welcome.
[applause]
Lauren Merz: Hi, everyone. It’s so great to be here.
Thank you for the invitation. It’s a huge honor to be here
among such giants in sickle cell.
So, thank you for having me.
So, we’re going to talk about the Duffy null phenotype today.
We’re first going to start with looking at
how the Duffy null phenotype impacts healthy people
and what we can expect.
We’re then going to look at the impact of sickle cell disease
and ANC, and then how Duffy null status plays into that.
We’re also then going to examine what we know about
Duffy null status and hydroxyurea MTD.
And then we’re going to spend time with --
talking about gaps in knowledge and next steps,
which there are many.
And there is lots of work to be done.
So, we have to start with neutrophil development.
So, our neutrophils mature in the bone marrow.
It takes about 7 to 10 days to complete.
And then once we have mature neutrophils,
these circulate throughout the body
in places where they’re most needed.
I think one of the important things to emphasize
is that only 1 to 5 percent of mature neutrophils
are circulating in the periphery at any one time.
And they only remain there for 3 to 24 hours.
The other 95 percent of our mature Neutrophils
are in other reservoirs, like the bone marrow,
the liver, the lungs, and the spleen.
So, this means that when we obtain our CBC with differential
and we look at the absolute neutrophil count,
what we’re seeing is a very brief snapshot
that can fluctuate throughout time.
And we’re also looking at an imperfect proxy
for the value that really matters in health
and disease of total body neutrophil counts.
When we look at how we define normal,
which is what we often look at with our reference intervals,
there’s a lot of variation worldwide.
So, when we look at the African continent,
we see that normal, absolute nature fill counts
are anywhere from 500 to 5,400 in Togo,
900 to 3,800 in Uganda,
or 950 to 7,600 in the United Arab Emirates.
We also have a lot of variation
in normal ANC in the United States.
So, as mentioned, I work at the Dana-Farber Cancer Institute,
as well as Brigham Women’s Hospital,
which are physically connected institutions
that are across the street from each other,
and yet there are dramatically different reference intervals
that are used by each of these institutions.
But Dana-Farber have a lower limit of normal of 2,200
compared to Brigham Women of 1,900.
When we look at large data sets within the United States
that are broken down by race,
we do see that there are differences in normal
ANC among healthy people.
Where people who self-identify as Black or African American
have cells that are about 700 cells
lower than people who identify as white race.
And when we look at that threshold of neutropenia,
which we’ve defined for decades as an ANC of 1,500,
we see that 4.5 percent of healthy black people
will be called neutropenic,
will be told that they have a disease,
compared to only .79 percent of white people.
So, I have to emphasize here that race is a social construct.
It’s not a biologic fact, and there is much more
genetic variation within race than between race.
But we still have to ask the question
of why are there observed differences in ANC
between white and black populations?
And surprisingly, given the title of my talk,
we got the answer in the early 2000s
with the Duffy null phenotype.
This is a T to C substitution on chromosome 1
on one of the gene transcription initiation sites.
And the homozygous polymorphism C/C results
in the lack of the ACKR1
or DARC expression on erythrocytes.
So, this is the Duffy null phenotype.
We still see ACKR1 in other cells,
especially endothelial cells and lymphoblasts.
We think that the Duffy --
the lack of the Duffy protein was protective against malaria.
You take away one of the docking proteins
for the malaria parasite to bind to and enter the red blood cell.
When we account for the Duffy null phenotype,
we no longer see any differences
in absolute neutrophil counts by race.
So, we have a complete explanation
for the differences in absolute neutrophil
count with the Duffy null phenotype alone.
Unsurprisingly, we see the frequency
of the Duffy null phenotype where it be most beneficial
and most protective against plasmodium vivax.
So, in West Africa, we see 80 to 100 percent of the population
that will be Duffy null.
This is backed up by some other recent studies,
and things like Clozapine,
where, when you actually tested it
was near 100 percent Duffy null phenotype.
In the Arabian Peninsula, we see about 50 to 80 percent
of the population that’ll be Duffy null.
And then in the United States and the Caribbean,
among people who self-identify as Black or African American,
we see about two in every three people
who will have the Duffy null phenotype.
So, I’ve been talking a lot about a red blood cell antigen,
but how does this impact neutrophils?
The short answer is we don’t really know for sure.
We have some ideas that we’ve seen in mouse models.
We also have some theories based on what we know
about cytokine regulation, but we don’t really know.
And the one of the models that I think is the most compelling
is the one that was put down by [unintelligible]
here, where there is ACKR1 mediated interactions
with hematopoietic stem cells in the bone marrow.
And when we take away that ACKR1 expressions,
we have neutrophils that have altered markers
and an increased propensity to leave the circulation.
These scientists are very clever and tagged the neutrophils
and looked at all those reservoirs,
like liver, lung, spleen.
And really we only saw that the neutrophils
that lacked ACKR1 expression went to the spleen.
And so, this emphasizes and tells us
that total body neutrophil count is unchanged,
but localization is altered.
So, that leaves us with what is a normal neutrophil count.
I apologize that I’m an adult hematologist,
so we’ve mostly looked at this in adults.
But we do have pediatric data that is in the works right now
to look at this as well. But we looked at black patients
who are coming for primary care in Boston,
and we asked permission to add on Duffy status
as well as an absolute neutrophil count.
And we found that patients who are Duffy null,
which are seen in the blue --
on the graph had a median ANC of 2,820
compared to 5,000 which we found in the Duffy non- null patients.
There was no significant difference
in our institutional reference
ranges between Duffy non-null and institutional,
but there was a significant difference
in our Duffy null population.
And I specifically like to call out that 10 percent
of these healthy primary care patients
would have been called neutropenic
because they had an ANC of less than 1,500.
We then expanded this to try to think
about what a normal reference interval should be.
And our data found that there are reference intervals
better at a lower limit of normal of 12,000 which again,
is a closer replication of what we see in the African continent
than what we’re used to seeing here in the United States.
The last thing I really want to talk about
before we get into sickle cell
is thinking about the impact of the Duffy antigen and cytokines.
If you’ve heard of the Duffy antigen before,
you’ve probably heard about it in the context of neutrophils.
But there’s a lot of really unexplored data
or interesting things
to think about with cytokine regulation as well.
The Duffy antigen is a pretty promiscuous receptor.
It’s a decoy receptor.
There is a lot of CXC and CC class chemokines
that it regulates,
and it seems to have a really important impact
in cytokine circulation and leukocyte trafficking.
And when you look at the adult oncology literature,
there’s also some very interesting suggestions
about things like tumor control and angiogenesis
in people who are Duffy null versus Duffy non null.
So, a really untapped and under explored area
that we’ll get back to as well
in the context of sickle cell disease.
So, let’s think about how we should apply this
to sickle cell disease, and specifically hydroxyurea.
I will just say that we don’t know much,
but we’ll kind of review what we do know.
So, first, let’s think about the impact of the Duffy
null genotype
on absolute neutrophil count in white blood cells.
There was a study that looked at HUSTLE,
SWiTCH and TWiTCH.
HUSTLE is more of an observational
study on hydroxyurea.
SWiTCH and TWiTCH, we’re looking at stroke prevention.
So, sicker patients that were hemoglobin SS
as part of the criteria.
They reported that the mean white blood cells
were different by Duffy status.
With those who were Duffy null of 13.5 compared to Duffy
non null of 14.6, they also looked at mean ANC.
And there was also a significant difference in what mean
ANC was by the cohort with Duffy null being 72,000
and Duffy non null being 8,500. And this results
in a mean difference about 1.1 for white blood cells
and 1,300 for our absolute neutrophil counts.
There are a couple more recent pieces of data.
It’s very exciting that has just come out as well.
This is a retrospective cohort from Nationwide Children’s
that we’ll look at first.
They had 187 patients with sickle cell disease.
This was all genotypes that were included.
They reported 78.6 percent of their population is Duffy null.
And they did not
reach statistical significance in baseline ANC.
But they got very close and reported that baseline ANC.
This is at the one year visit before hydroxyurea
was a meeting of 2.9 in your Duffy null cohort,
compared to 4.1 in your Duffy non-null cohort.
St Jude actually, around the same time,
put out some similar data. This is only an abstract form,
so it’s a little bit more bare bones
than our Nationwide Children’s data.
But they had 250 patients with sickle cell disease
of which 72 percent were Duffy null.
And they found similarly that in our Duffy
null patient population, there was a median --
or mean ANC of 3,800 and non-null of 4,700.
They did reach statistical significance,
which is different than Nationwide Children’s.
And so, from this in our pediatric patients
with sickle cell disease,
we can say that there is a difference in baseline
ANC by Duffy status.
We have a lot less on this and the adult population.
There was one study that came out in 2023
that that looked at it --
this in a slightly different lens,
but I think it’s very clever.
They looked at how variants and absolute neutrophil count
could be contributed or attributed
to different genomic variants, including sickle cell.
And so, they use three large adult cohorts,
the CSSCD, GEN-MOD, Mondor/Lyon which has over 2,000 patients.
And then healthy controls
were obtained from BioMe in the UK Biobank.
They found in our non-sickle cell disease individuals --
so, again,
like healthy people kind of living their everyday life,
that variation in neutrophil count can be explained
about 18 to 24 percent by the Duffy null phenotype.
This was associated with a mean --
white blood cell mean reduction of 1.9
and an ANC mean reduction of 1,600.
In contrast, our patients with sickle cell disease,
there was a weak or non-significant impact
of the Duffy null phenotype on ANC variants.
There was, you know, some slight variation with white blood cell
mean reduction of .76 and an ANC mean reduction of 840.
But a significantly lower impact of the Duffy null genotype
on what we can expect
in variation of absolute neutrophil counts.
This is a great example of epistasis,
which is when the expression of one gene like Duffy null
is modified by the expression of another gene
like sickle cell disease.
I thought this graphic explained things pretty well.
So, the top two lines,
the red and pink are patients with sickle cell disease.
The pink line is those who are Duffy null.
So, we are seeing that there is a difference
in absolute neutrophil count by Duffy status.
But the lines are a lot closer together
than our bottom two lines, which are healthy,
non-sickle cell disease patients by Duffy status.
Where the gray on the bottom is our Duffy null patients
and the blue on the top is the Duffy non-null.
The authors, actually, from this data,
found that Duffy null has a twofold weaker effect
on absolute neutrophil counts in sickle cell patients
than in non-sickle cell disease patients.
We also did look at this in sickle cell trait,
and did not find any impact like this.
And so, we can comfortably put our sickle cell
trait patients in the healthy, non-sickle cell disease bucket,
and there doesn’t seem to be an intermediary
or any interaction between those two things.
So, why is this?
Why are we seeing that there’s less impact of Duffy on ANC
and our patients with sickle cell disease?
There are two hypotheses that I think could be playing --
could be at play here,
and I think it might be a little bit of both.
The first is the reality is a splenic atrophy.
This reduces the reservoir that we hypothesize is
where most of the Neutrophils are localized.
So, when you take away that reservoir,
you’re going to have to have the neutrophils
circulate other places, like the periphery.
And so, that might be one of the reasons we’re not really seeing
that the difference is a smaller effect size.
The second potential thing is the cytokine theory.
Again, we know in patients who are healthy and Duffy null
that if they’re sick, if they are given steroids,
if they’re given any sort of other inflammatory impetus,
you have neutrophils come out into the periphery.
And it starts to mirror what we see in Duffy
non null people with sickle cell.
It’s a very pro inflammatory disease,
and so you may just have these elevated levels of cytokines
and inflammation all the time.
And so, mitigates a lot of the effect
that we would otherwise see
with the Duffy null phenotype in healthy people.
But the long and short of it, so we don’t really know.
And this is something too that we should work on
from a mechanistic standpoint.
So, let’s pivot to how this might impact
things like hydroxyurea.
It was amazing to hear these talks beforehand
that really emphasized how important things like MTD
is for having good outcomes in sickle cell.
And I think there’s a lot of questions in this space as well
when you when you consider Duffy status.
So, as a quick review,
in our phase 1 and 2 trials for hydroxyurea,
which was done in like the late 80s, early 90s.
Initially, toxicity criteria were defined
as an ANC of less than 3,000.
And then given that so many people
were hitting that threshold, it was reduced to 2000.
Unsurprisingly, the authors reported the most
common toxicity of was neutropenia at 73 percent.
However, they did emphasize that there was no difference
or no increase in the number of infections or unusual infections
while they were getting ready to understand hydroxyurea
for these patients.
So, when you look at guidelines on how to do MTD escalation,
most of them will say,
"Oh, you can increase your hydroxyurea
and ANC of 1,500 to 3,000
by doing polls of what we do in Boston."
And then also talking to some of you all,
most high volume sickle cell centers will use 1,500
if not massage that a little bit lower.
Because patient looks good and let’s keep going up.
We don’t want to reduce it, which is dramatically different
than what is actually in the package insert.
So, the package insert says that acceptable ranges and increasing
really should only happen when ANC is greater than 2,500
and you do not increase the dose when the ANC is less than 2,000.
Which raises some questions on what is done by experts
in high volume centers versus what is maybe done with people
who have one to five sickle cell patients
and aren’t that familiar with hydroxyurea
within the United States or worldwide.
So, there’s been a few small, single center studies
that looked at Duffy null and hydroxyurea.
The first two studies I’m going to mention
look at just prescriptions.
So, this first one was in adults with SS at Duke and UNC
in the early 2000s and they found that 73.4 percent
of sickle cell patients were Duffy null.
And they did find a difference
in initiation of hydroxyurea by Duffy status.
They didn’t really go into that anymore, by what was going on,
if it was neutrophils, infections,
but they just reported this.
Again, with the Nationwide Children’s paper
that just was released, they did not find any difference
in initiation of hydroxyurea by Duffy status.
And they also looked at what was happening a year
after hydroxyurea initiation,
and they found also no difference in hydroxyurea
at one year after initiation.
The Nationwide Children’s also looked a little bit deeper
at things like at hydroxyurea initiation.
What was going on with the neutrophils?
What were the prescribed HU doses?
And really did not find any difference
by these two parameters.
And then similarly, at one year of hydroxyurea therapy,
they did not find any difference in median ANC
or prescribed hydroxyurea doses by Duffy status.
Although I will point out that meeting
ANC seems to be opening up a little bit
when you compared to an initiation.
But again, it’s hard to know if that’s a small sample size
or if there might be something there or not.
And so, from this, we can say that Duffy status
was not associated with differences
in mean hydroxyurea doses or differences in ANC
while prescribed hydroxyurea.
In the HUSTLE, SWiTCH and TWiTCH,
we actually get some similar information.
They also found 71 percent of their patients were Duffy null.
And they found that higher hydroxyurea
MTD was associated
with higher pre-treatment white blood cells and ANC
but was not associated with Duffy status.
So, again, it was kind of where you were at
when you first started,
rather than Duffy status alone, that seemed to drive it.
Again, these two things are interconnected,
but it seems like the stats magic
that a lot of our biostatisticians
can do kind of emphasize that it seemed
to be the baseline neutrophil and white blood cell count,
rather than Duffy status, that was the big driver.
St. Jude found something very similar, that there was
no significant difference in MTD by Duffy status.
And Duffy status did impact time to MTD,
but again, only indirectly, via baseline ANC.
They did have this interesting extra bit
where they said that people with Duffy
null had more frequent episodes of an ANC of less than 1,500.
Again, our artificial kind of random threshold
that we’ve been using for decades to think about toxicity.
And they did not report anything about infection
or hospitalization
or other myelosuppression things that would actually matter.
Just really, did they cross that threshold?
That we’ve drawn a line in the sand yes or no of 1,500.
They found that people with Duffy null were 1.2 versus
.5 in Duffy non-null.
And so, again, from this, we can say that Duffy status
was not associated with differences in mean
MTD in pediatric patients with sickle cell disease.
So, we’re going to last bit is think
about how Duffy might impact sickle cell disease outcomes.
Again, there’s a lot of mysteries
around some of the cytokine homeostasis and milieu.
And so, some people have tried to look at that to see
if there’s anything there.
I will warn you, the data is quite mixed,
but we’ll at least report what we know.
First, there was some basic science literature
that first kind of prompted this too.
That irreversible sickle RBCs had a 17 fold higher amount
of sickling in Duffy null RBCs compared to Duffy non-null RBCs.
And so, then from this, there’s a lot of questions
on what’s going on with outcomes in humans.
So, in the adult literature, there was one study from the UK
that found that there were no differences in complications
except for leg ulcers.
But again, those numbers are really small.
We’re saying, you know, 5 out of 15 and 25,
out of 133 with a P value of 04.
Another study in the USA found no difference
in the complications, including leg ulcers.
But they did find that there were some differences
in proteinuria that was higher among those
that were Duffy null compared to Duffy non-null.
And then a final study from the French West Indies
found that there were no differences
in any complications whatsoever.
Hard to know what to do with that.
Pediatrics, similar things, St. Jude
looked at the frequencies of vaso-occlusive crises
or acute chest syndrome.
Within two years, hydroxy initiation found no differences.
There was another -- the HUSTLE,
TWiTCH and SWiTCH studies did find
that Duffy positive status
seemed to be protected against Albuminuria [phonetic sp].
Again, reminiscent of what the USA study and adults found,
but no other complications or associations.
And there was a study that was released literally less
than a week ago on [unintelligible]
that also looked at complications by Duffy status,
as well as a couple other things,
And found that there was no association with Duffy status
with three plus pain crises,
stroke priapism or acute chest syndrome.
So, from this, there’s no clear or consistent differences
in sickle cell disease complications by Duffy status
but more work to be done.
So, what do we know? We know that age, genotype,
disease severity, hydroxyurea use,
Duffy status, all impact absolute neutrophil count
in sickle cell disease. We know that sickle cell disease
has an epistatic effect on the Duffy null genotype.
Baseline
ANC is higher in all patients with sickle cell disease.
And although you do see a separation by Duffy status,
the effect size is much smaller than what we see in our healthy
non-sickle cell disease patients.
We know that 70 to 80 percent of patients
with sickle cell disease have the Duffy null phenotype.
If you remember, by people who just identify as Black
or African American,
that number was closer to two and three in the United States.
So, we see a higher prevalence of the Duffy null phenotype
in those with sickle cell disease.
This also means that all those trials
that have been referred to included patients
with the Duffy null phenotype.
So, trials and medications were approved
and built with these populations.
This is very different from what we’re struggling with
in cancer clinical trials and other clinical trials.
Right now, where we have very low black recruitment
and enrollment,
which means that we likely have very low
Duffy null phenotype representation as well.
So, that’s reassuring that we’ve been inclusive
of these patients.
There are still questions of why are we choosing an ANC of 1,500?
It’s an arbitrary number, and should we be using a number
that’s a little bit different for MTD or toxicity thresholds.
Duffy status does not seem to impact
hydroxyurea prescription in pediatrics;
does not seem to impact MTD in pediatric patients;
and there’s no clear impact of Duffy status
on sickle cell disease complications,
except maybe some proteinuria or leg ulcers
that should be explored. So, where are our gaps?
We really need to look at adults with sickle cell disease
and look at prescription and MTD by Duffy status.
Again, we have one study,
single center from the early 2000s
that suggests that maybe there’s lower initiation of hydroxyurea.
But a lot of work to be done in that space.
We need to confirm some of these different --
that there’s no differences in hydria use of MTD
by Duffy status in pediatrics and larger data sets.
And specifically, I want to look at those lower center,
low volume sickle cell disease centers.
I’m not worried about St Jude and Nationwide Children’s,
but I am worried about the centers that, you know,
maybe it’s a general hematologist that only sees,
you know, a few patients with sickle cell disease every year.
Are they following the package insert
and is that resulting any disparities
or are we still doing okay?
We need to better understand mechanisms
of elevated white blood cell count in ANC,
in adverse events in sickle cell disease.
There’s a lot of literature that shows
that high white blood cells, high ANC, bad,
but it doesn’t seem like again, we know the chicken or the egg.
Is it that elevated ANC is a marker of severe disease,
or is it a cause of inferior outcomes,
or maybe it’s a little bit of both?
And that’s an important question to answer.
And factoring in Duffy status to that
is also going to be an important question as well.
And then finally, we need to assess for differences
in sickle cell disease complications in adults
and pediatrics by Duffy status.
And again, keeping in mind both the impact on neutrophil levels
as well as some of these cytokine regulations
and homeostasis,
how is it impacting things like response
to transplantation or response
to some of the complications or response to hydria?
So, a lot of questions here,
and a lot of richness to be uncovered.
So, with that, I thank you for your attention,
and I’m looking forward to any questions.
Female Speaker: Dr. Merz, that was a great presentation.
You know, I heard you and ASH. [laughs]
I want to know more about this Duffy and hydroxyurea
[unintelligible].
So, I concur with you about your last three summary
about pediatrics.
The adult study, which you mentioned in the U.K.
was done by our group.
Lauren Merz: Oh, I didn’t know.
Female Speaker: We found, in fact,
that when patients with sickle cell disease
go into sickle crisis,
they can mobilize a white cell count,
just as those who are deafly known now.
And the late ulcers incidence was not high,
but it did take longer for the late ulcers to heal.
But it didn’t seem to impact sickle complications.
Lauren Merz: Yeah.
Female Speaker: So, then, when I came here,
we just recently did a retrospective audit
of our NIH patients.
The incidence of Duffy now is similar
to the African American population.
It did not impact the MTD dose
in those who are taking hydroxyurea.
But you look at the reverse when you look at MTD dose,
the MT come with the same. So, I think you know,
as you pointed out in your very first slide,
that most of the neutrophils stay in the bone marrow.
And they can mobilize the neutrophils when it’s needed.
But I also can confirm that when we look
at the sickle cell populations now
and non-now and the difference is much narrower
than those without sickle cell disease.
And I think maybe it’s the background
inflammation that’s mobilizing the --
Lauren Merz: No, I very much -- great.
I’m looking forward to seeing that data
out of your group as well.
Female Speaker: I want to discuss more with you.
Thank you so much.
Lauren Merz: That would be great.
And, you know, I think we see that
in non-sickle cell disease patients as well,
that there’s been a lot of studies, you know.
Back when we were calling it benign ethnic neutropenia.
We would, you know, do things like give steroids.
And we saw great mobilization, which, again,
was reassuring that no infections,
no issues with bone marrow,
no issues with neutrophil function.
It just seems to be where they live.
And then what we’re measuring in the blood.
Female Speaker: One question. In your very first slide,
you did show that the Caucasians,
there was a very small percentage.
I mean, you know, there’s a big racial mixture
in the American population.
So, could you actually check these Caucasians?
Whether they do have the they will actually definitely so
Lauren Merz: So, in that data, where it showed that,
you know, there was by race
who had an ANC of less than 1500 that was from NHANES,
which is like one of our big observational studies
that we get in the States.
And they really didn’t have granular data.
They don’t have genomic issues.
So, I use that as a suggestion that, you know,
the Black patients mostly probably had
the Duffy null phenotype,
and you don’t see this much in white patients.
The one thing I will say, and one of the many reasons
that it’s important to move away from race based medicine
and towards biologic facts like Duffy,
is that a lot of people of Middle Eastern descent
will identify as white. It was actually only this year
that the Middle Eastern North African designation
was added to census.
So, in the past and a lot of our like hospital registries,
you’re going to have Middle Eastern patients
that will identify as white.
They also have, you know, over 50 percent will have Duffy null.
And so, you may have that as well.
And then, of course, there’s other natural variations in ANC.
Those with autoimmune neutropenia.
You name it, like other things going in there as well.
But it’s really important to recognize normal,
predictable changes by, you know, a biologic variant,
which is one of our big crusades right now.
Francine Baker: Hi.
I’m Francine Baker from the University of Maryland.
That was a very great talk.
And I’m just really curious specifically,
as it relates to penicillin prophylaxis in your results.
Because just whether or not that might have an impact
on any of the data that you presented,
and were the patients on penicillin --
was everybody on penicillin?
And what was the use of penicillin in the data?
Lauren Merz: That’s a great question.
My memory of the papers is that none of them reported
if the people are using penicillin or not.
I will have to go back and triple check that.
But I don’t remember that being there
because I was looking for things like, did you report infections?
Did you report prophylaxis? Was prophylaxis different?
And so, that’s not something that I saw reported
in the data that’s available. But an interesting question,
do you mean it from like infection prevention
or more does it have an impact on the ANC?
Francine Baker: Yeah.
Would it have an impact on the ANC?
Lauren Merz: My understanding is that penicillin
shouldn’t have a significant impact
on absolute neutrophil counts.
And so, you know, it wasn’t reported,
and it’s not one that that I thought about.
But again, one of the other many studies
that we probably should look at
and have a better explanation and a better grasp of.
Male Speaker: Real quick question, really nice talk.
Do you -- the mechanism looking at splenectomy --
or, sorry, looking at [unintelligible] is interesting.
I’m curious if you’ve looked at,
or people have looked at Duffy null in splenectomized patients
or compared it in more mild forms of sickle cell disease,
like S beta plus, right, and looked this over time.
It’s probably not, but I’m curious.
Lauren Merz: I’m actually trying to do that study right now.
It’s very hard to find a good data
set of people who have had a splenectomy.
And I’m trying to pick splenectomy for trauma,
not splenectomy for like, you know,
ITP, or some other sort of like, lymphoma, things like that.
Not many people get splenectomies,
especially that’s, like, reported in like, a UK Biobank.
All of us, I tried to work with, like, the trauma surgeons.
But they really only care about the first 30 days.
And I want to see, you know, ANC before,
and then, like, a year after, when it’s regulated.
And even if I do have that,
it’s very hard to find the genomic data.
So, if anyone’s aware of a data
set that has all those components, that would be great.
So, I think that’s an important question.
Male Speaker: It might be interesting
looking for older Thalassemia patients could be a population.
Lauren Merz: The problem is my understanding too
is thalassemia patients have alterations
in their absolute integral count as well.
So, again, isn’t like the perfect cohort,
but we’ve got to start somewhere.
And it’s a question that, again,
can get at the mechanistic aspect from the human side,
and I’m looking to all the basic scientists
to help me with the more like mouse
and basic science aspect of it. So, we can bring it to humans.
Male Speaker: The VA probably have a good database
on this too, for splenectomy patients.
Lauren Merz: That is our best lead so far,
and it’s just cracking into that system [laughs]
-- Male Speaker: Yeah.
Lauren Merz: -- which we’re working on.
Lesley King: All right. I’m going to --
we’re right on time right now,
and we’re going to -- it’s 10:40 a.m.
So, we’re already five minutes running late.
So, I’m going to ask anybody who has any questions,
Doctor Merz is here.
So, you can just please have a one-on-one with her,
and so that we can try and stick to time as much as possible.
Because we have another packed session.
[applause]
All right? So, thank you, everybody.
We have a quick 10-minute break
Angela Rankine-Mullings: Session two focuses
on the ongoing challenges
in the management of sickle cell disease.
And our first speaker, Dr. Lydia Pecker,
will be joining us remotely,
and she will be presenting on fertility and pregnancy.
Dr. Pecker is an associate professor of medicine
at Johns Hopkins University,
and we will now listen to her presentation.
Please go ahead, Dr. Pecker, and welcome.
Help me welcome her.
[applause]
Thank you.
Lydia Pecker: Hey, in Jamaica. I’m from Brooklyn,
which, as many of you know, is a colony of Jamaica,
and I’ve always wanted to eat callaloo in the real place.
So, Samir [phonetic sp]. I hope to join you there.
And it’s so good to see you.
I have so many friends in the audience today.
It’s a pleasure to talk to you
a little bit about fertility preservation and pregnancy
in this exciting year for sickle cell disease.
These are my disclosures, some consultancies,
research funding and work with both
the Sickle Cell Reproductive Health Education Directive
as well as the Medical Advisory Committee for the Foundation
for Women & Girls with Blood Disorders.
So, hopefully, this picture isn’t totally novel to anybody.
We know that we are fortunate to live in an era where children
with sickle cell disease are growing up,
and that this presents a whole set of reproductive
health challenges for our community.
This includes risks for infertility and complications
with fertility preservation, which we’ll talk about today.
It includes high-risk pregnancy that we’ll talk about today.
And of course, what gets sandwiched in
between these two realities
is a very complicated preconception milieu.
Before I get started on the main body of this talk,
I just wanted to take a deep breath
and say, you know, we’re living through this unbelievable year
where suddenly, gene therapy
is an FDA-approved intervention for our patients.
And yet I like to think of gene therapy
in a set of genetic technologies
that are now available for our patients,
all of which either are explicitly reproductive
or have reproductive implications,
and all of which offer lessons to us
as we think about how we are going to ensure access
to gene therapy to our patient community.
We now have in vitro fertilization
with preimplantation genetic testing,
which has been around since 1999,
and about which we have one cohort study of patients
of about 60 patients.
We now have cell-free DNA testing of fetuses
to identify those with sickle cell disease,
and it’s in clinical use at some centers.
Yet the American College of Obstetrics and Gynecology
is not yet completely endorsing the test,
even though it eliminates the need for paternal
testing and amniocentesis, both of which pace --
place significant burdens on pregnant people.
And finally, as we’re all familiar with,
gene therapy at the moment presents a risk for infertility
due to the use of alkylating agents
in the preparative regimen.
And you know, something that has gotten my attention
is that women are overrepresented
in sickle cell clinics, constituting somewhere
between 60 and 70 percent of clinic populations,
but only equally represented in the transplant data,
which means that people may be getting lost
between the clinic and transplant
for reasons that are not fully elucidated
but that perhaps have something to do
with access to fertility preservation.
The other big idea I wanted to present you all or new knowledge
that I wanted to present to you all today
is to just make sure everybody knows
that the Center for Disease Control
and Prevention did release very recently,
updates to the contraceptive recommendations
for individuals with sickle cell disease,
and they put -- they made the contraindication
to estrogen-containing contraception much more firm
than it had previously been in recognition
of the thrombotic risks
associated with sickle cell disease
and the thrombotic risks associated with
the use of estrogen-containing contraception.
Again, that’s a change from the previous set
of recommendations from the CDC.
And with that, I’ll get into the main body of my talk.
So, I’ve been thinking about the ovaries for some years now,
and mechanisms of ovarian injury and sickle cell disease
seem not so distinct from mechanisms of injury
and every other end organ in sickle cell disease.
The ovaries are vulnerable to hemolysis,
anemia, hypoxic-ischemic injury, inflammation,
hypercoagulability, reactive oxygen species,
and the overall hypermetabolic state of this disease.
And that, combined with the fact
that this disease is a disease of accelerated aging,
what we’re seeing is accelerated decline in egg quality --
quantity, sorry,
and I’ll show you a picture of that in a minute.
Many questions about this fact endure,
and among them are,
what are chronic therapies for sickle cell disease
due to the ovaries, as well as what the curative
and transformational therapies do at present?
Whereas what differences or modifications
in our preparative regimens can do to change the risk?
The data so far is limited in terms
of what the effects of hydroxyurea
or chronic transfusions are.
And I’m actually not going to go very deeply into that today,
except to say that people for whom hydroxyurea is indicated,
appear to have some risk;
and people on chronic transfusions,
that risk is not very clear.
We looked at anti-müllerian hormone,
which is a serum marker that I didn’t hear a lot in my --
talked about a lot in my hematology fellowship,
but that may be a marker,
kind of like how we think about creatinine
and other measures of renal function,
or AST and ALT for renal hepatic function,
that we need to start becoming familiar with
as a marker of what’s happening in the ovaries of our patients.
We looked at anti-müllerian hormone levels,
which again is a marker of egg supply,
in the multicenter study of hydroxyurea follow-up cohort.
And this included 98 subjects,
all of whom had hemoglobin SS disease.
What you can see in this graph is, on the y axis,
anti-müllerian hormone levels with a marker
at the measure of 1.1,
which is where diminished ovarian reserve is defined.
Diminished ovarian reserve is a risk factor for infertility
and most importantly, is a risk factor for poorer
outcomes with fertility preservation
and in vitro fertilization. And as we move to an era
where we are harvesting eggs in our patients
before they go to transplant and gene therapy,
this issue of when to harvest in terms of
when the egg supply is optimal, becomes of increasing concern.
I hope what you can see on the x axis
is buckets of age in years,
and the gray bars are the median anti-müllerian hormone values
that we found in our cohort.
Whereas the black bars are the median values
in the assay that we used.
At each measure in the reproductively relevant years,
which I suppose you could debate exactly what that means,
but let’s say before age 46,
I hope you can see that AMH levels in the individuals
with sickle cell tested
are lower than in the standard measure.
And that measure becomes meaningful,
sitting at diminished ovarian reserve
for people between ages 25 and 30,
which is sooner than in the general population.
So, as we’ve thought about this data,
we know that diminished ovarian reserve
and risks for diminished ovarian reserves is an indication
to offer fertility preservation for -- to people.
And yet, we do not yet know exactly,
in people who are on chronic therapies,
when and how to offer these therapies.
But the indications are reasonably clear,
at least for those who are being exposed
to transplant and gene therapy,
anybody exposed to an alkylating agent
who hasn’t completed their --
building their family should be offered fertility preservation.
And then anybody with sickle cell disease
and an indication for hydroxyurea
should at least be having this conversation,
and particularly in those of our patients
who are just thriving --
and we have more of those every day --
and who are going to graduate school
and doing other things to pursue educational goals.
Just like women in medicine who are at increased
risk for infertility, we know that our patients
who are pursuing educational aspirations
are at increased risk for infertility.
One thing I wanted to say about this data
that I didn’t quite say is that at the bottom,
there’s a whole bunch of citations.
And that’s -- I put them all down there,
even though this is my graph, because these findings are --
can no longer be understood
to be an idiosyncrasy of the women
who participated in the follow-up study of the MSH,
all of whom or most of whom were exposed to hydroxyurea
around the world really.
We are getting data on a hemoglobin SS disease
in particular that identifies this same pattern
of accelerated decline in egg supply.
So, we have data from France and from Nigeria
and from the U.K. and even from Atlanta, Georgia,
and it all tells us the same story.
So -- sorry -- to cut back to this idea of,
what do we do with this data?
When are we going to be offering people?
How are we going to be talking about fertility preservation
in our community?
I’m going to talk a little more about this,
but I think it’s a really thoughtful challenge.
I don’t think we have the right answer yet.
But if people are on chronic therapies,
we probably can be waiting until after puberty.
But for people who are particularly anxious and --
probably could be offered sooner.
And one of the reasons for that
is that we have two standard approaches
to fertility preservation now,
and those are ovarian tissue cryopreservation
and egg or embryo cryopreservation.
And I’m going to spend the rest of the talk talking about --
a little bit about what those two things are
because we’re doing it more and more in our patients.
And again, we -- you know, we learn a little bit about
how to manage surgical conditions
in sickle cell disease during fellowship.
But these are relatively new procedures for our patients,
and we need to know a little bit about them to make sure
that we can help accompany people safely through them
and do a little bit of counseling
that hopefully will be meaningful to patients
and their families.
So, ovarian tissue cryopreservation, what is it?
It’s laparoscopic surgery in which you can either remove
an entire ovary or sections of an ovary.
It takes about 60 minutes.
It’s usually done under general anesthesia.
And because in our patients,
the most common indication for this is before transplant,
it’s often done in coordination
with line placement and other things,
so that our patients don’t have to be exposed to two anesthesia.
While this has been a standard of care
in the United States for a few years,
it has been a care standard in France
for a much longer period of time.
And for those reasons,
we’re beginning to see data from France
that we have not yet generated in this country.
It is a fertility preservation option
for both pre-pubescent girls and women who menstruate.
And the hypothesis, at least in offering this to adults,
is that it is less risky and more successful.
But that’s really an untested hypothesis
in terms of pregnancy outcomes.
And even whether ovarian tissue helps --
meaningfully helps over time
to treat premature ovarian insufficiency
with hormone production provided by the ovaries
is not yet totally clear.
And usually, if you have ovarian tissue cryopreserved,
you will ultimately need IVF for pregnancy
if you experience infertility
and wish to use that ovarian tissue to get pregnant.
There’s a risk with reimplantation
of tissue of infarction and graft failure.
And of course, if there are previous exposures to radiation
or sickle cell-related damage to the end organ,
it’s not fixed through these procedures.
So, you know, how do we manage these patients?
Well, we can manage them per our sickle cell routines,
making sure that our patients either have a hemoglobin of 10
or an S fraction less than 30 percent going into anesthesia.
Usually, again, because of the timing of these --
the nature and the timing of these interventions,
exchange is done associated with line placement
and before conditioning for cure.
We can make people sure they’re well hydrated,
first case, all these things we do to protect our patients,
make sure that people are having laparoscopic
abdominal incisions, receive incentive spirometers,
and make sure that individualized pain plans
are available to surgical treating teams
to direct post-operative pain management.
And you know, often, we hope that people will be reimplanted,
post-cure, post-transformational therapy.
And so, the prep for that will be happily nonexistent.
The other standard of care option for --
a bridge too far.
Now, we’ve really gone too far. Sorry, folks.
The other standard or option for preserving fertility
in people who menstruate is ovarian stimulation.
And the purpose of this is to stimulate the ovaries
using hormones to make many mature eggs,
which are then retrieved, harvested,
and frozen or comingled with sperm to make embryos.
And the embryos can be frozen.
This is much more of a process.
It’s a 10-to-14-day process. It’s timed with menses.
It requires many trips to the clinic,
and the harvest is done under light anesthesia
and only takes about 20 minutes. It’s done across the uterus.
So, there’s no abdominal incision,
which is elegant for our patients.
Often these procedures are performed
in outpatient surgery centers, so not in the main hospital.
And of course, that has some implications
for our more medically vulnerable patients.
This, again, is a standard of care for people who menstruate.
You have to be pubescent to get this treatment.
And as I said, AMH predicts egg harvest
and hyperstimulation risk,
and we’ll talk about that in a minute.
This procedure has many sickle cell landmines.
And because I think we are going to continue
to increase use of this procedure in our patients,
I’ve chosen to spend some time
thinking about those landmines in the next few slides.
There are other --
another problem besides the landmines
of going through the procedure is that for those with low AMH,
they may need multiple cycles of stimulation,
which increases the cost, among other things,
to get enough eggs to be considered
a successful fertility preservation outcome.
With egg harvest, as opposed to ovarian tissue harvest,
there’s no potential for resumption of hormonal function
if you lose that as a consequence of the prep regimen.
And again, this does not fix previous exposures of the eggs
to toxic or potentially toxic things
before they were harvested.
So, this is what the ovaries look like
during hyperstimulation.
And you know, a picture is worth a thousand words.
So, first of all, these are pictures
across 14 days of stimulation,
and each one of these ultrasounds
is a visit to the clinic.
So, there’s one side effect of going through this process,
but another is that the ovary is really enlarged
and get quite a lot of dominant follicles,
which you can see on this far right axis.
And we’ve cared for people with a very unique
sensitivity to discomfort and pain.
And so, I think really being able to hold this image
in my mind when I talk to people about
what it’s like to go through ovarian stimulation is helpful.
Because the ovaries are large. They -- people can feel them.
They feel out of place. They feel strange.
And helping people anticipate that,
just as we help people anticipate the discomfort
of an enlarged uterus in pregnancy,
can be really helpful for helping people define
what’s normal with this unusual experience.
Another challenge with ovarian stimulation
is that it is, by design, a hyperestrogenemic state.
This graph just shows you what happens to estradiol levels
across the 10 days of stimulation of the ovaries
for an egg harvest.
You know, and the purpose of that
is to suppress the LH surge.
And then you ultimately trigger the mature eggs
to harvest them to mature.
And that trigger can be associated with a lot of risk.
And so, the VTE risk here is two to three times
higher than in spontaneous pregnancy
and folks without sickle cell disease.
We know our patients with sickle cell disease
who are pregnant have an astronomic risk of the clot.
So, the thrombotic risk here for our patients
is likely not trivial.
After we had a few adverse outcomes at Hopkins
about five or six years ago, we sat down with our REI doctors
and thought together about how we could learn from each other
about how to take excellent care
of our patients going through this.
And this is the protocol that we came up with
and that we’ve been using since we developed it.
And I just wanted to talk you through it.
So, people who are referred to fertility preservation,
we think first about their sickle cell genotype,
whether they have SS or Sβ0 thalassemia versus SC
and Sβ+ thalassemia.
In general, we coordinate a red cell exchange for those
with SS and Sβ0 thalassemia
to target an S fraction less than 30 percent,
and on a case-by-case basis, make the decision
of whether to do that for those with other genotypes.
We consider the need for anticoagulation,
given the thrombotic risks described,
and initiate stimulation.
We meet with our anesthesiology colleagues
and think about the timing of retrieval and availability
of teams to help.
And I actually can’t see the bottom of the slide.
And then we think about --
I just want to make sure I get --
lead you along here [laughs]
-- post-procedural pain control and incentive spirometry,
which the REI teams and anesthesia teams
involved in this care don’t always have awareness of.
And again, they are off site.
So, our sickle cell team can’t just pop in
and make sure these things are happening.
We also, you know, defer to our expert teams
for different dimensions of this.
The pre-procedure assessments of ovarian reserve,
which informs stimulation and predict the stim response,
are really the purview of our expert REI colleagues.
And we talk to them a lot about that before we get started.
These are the places where we’ve identified
real potential pitfalls
in all of this for our patient population.
The first is that we make an active decision
with our patients about whether to start or stop hydroxyurea.
And the reason we make it with our patients
is because there’s not a right answer.
For people who I can stop hydroxyurea in
and give three months of chronic transfusions before doing this,
I do, but there’s not a right answer.
And if a patient doesn’t want to do that, we don’t have to.
This is -- unlike in cancer, this is rarely an emergency.
So, you really do have some time
or should have some time to plan this out.
We engage, as I mentioned,
in care coordination between ourselves, REI,
and anesthesia. We decide together.
Some people empirically use VTE prophylaxis in this setting.
We don’t. We decide with --
on each patient, based on their own risk.
One thing we identified early on
is that our anesthesia colleagues love
giving dexamethasone
as an antiemetic agent after this procedure,
and we know that dexamethasone is associated
with painful crises
and even mortality in this patient population.
And so, we always talk about alternatives to steroids,
except to save life in this setting.
And then finally, everybody’s at some degree of risk
for ovarian hyperstimulation syndrome.
And I have my patients do --
monitor daily weights for that for about 10 to 14 days
after their stim, which is the risk period.
The reason I have them monitor daily weights
is because this is a capillary leak syndrome.
And my hypothesis is that if they are going to
run into trouble with this by having an abdominal ileus
or any other more severe complication,
that I may see a first sign of that in their weight
going up as the capillary leak syndrome is initiated,
and the water retention starts, of this syndrome.
Just a little bit about ovarian hyperstimulation.
So, it’s capillary leak syndrome.
It’s a spectrum disorder.
So, it ranges from mild to critical.
And I hope that if you look at this list of things,
you can see why none of them, not the mild stuff,
and not the critical stuff,
appeals to me in individuals with sickle cell disease.
I don’t really want my patients having mild nausea,
vomiting, diarrhea.
I don’t want them having ascites, abdominal pain,
and urea or any kind of renal injury,
no clots, none of those things. And so,
we are really attentive to this in our patient population,
who, again, are, on average, at lower risk of this
because they have lower AMH on average.
Another thing, you know, all of these patients,
everybody who has an indication --
most, not everybody.
Many people who have indications to go to transplant
and gene therapy have an indication
that is associated with their experience of pain.
And as the late, great James Earl Jones
told us in Field of Dreams,
you know, one of the constants throughout the years
in this country is sickle cell pain,
and we always have to think about
how what we’re doing to our patients
could cause them to have pain.
And so, throughout this process and one of the reasons
that I use red cell exchange up front
is because I’m hyperaware
that a painful crisis during stimulation
or during retrieval could really ruin outcomes
for a very high-stakes and expensive, frankly,
intervention for so many of our patients.
And so, being -- alerting our care teams
about how to manage pain and doing everything we can
to not have to abort a stem cycle
due to a pain crisis is really paramount.
So, some questions we don’t really know the answer to,
should we use a washout period for hydroxyurea?
How many eggs do you need to be enough to -- you know.
What does your insurance package for getting pregnant look like?
What about the outcome?
So, we, you know, we care about pregnancy.
We care about restoration of ovarian hormone function
for those who have ovarian tissue cryopreservation.
And you know, it’s very difficult to compare people
with sickle cell disease to other standard groups
that receive these interventions because our patients have unique
risks and unique exposures and prognostic factors.
When we think about cost, right,
keeping tissue and gametes frozen has an annual cost.
It’s not just the upfront costs of these procedures.
And these costs are not usually covered by insurance.
And then IVF for pregnancy is required
and may not be covered by insurance in the United States,
at least even as we see the march of expanding access
to fertility preservation, at least in some of our states.
We do not see necessarily, coming with that,
an increased access to in vitro fertilization.
So, for people going through transplant,
we have a clear indication -- often, when I give this talk,
I don’t say what I think about this topic.
And so, I finally sort of worked it out,
and I wanted to provide a little anticipatory guidance.
So, over time, I’ve heard a lot from people about, "Okay. Great.
Well, what are we supposed to say
to people about hydroxyurea?"
Because this is a real community concern.
And also, we don’t want to put people off hydroxyurea.
Because as -- and as we’ve just heard today,
it’s an extraordinary therapy for our -- for the disease.
So, these are sort of the four principles
of talking about hydroxyurea and fertility
that I’ve come up with that I use in my own clinic,
and that I hope might be useful to you.
The first is to invite discussion of this topic.
Avoiding it isn’t really helping anybody.
Families are thinking about it. Patients are thinking about it.
And you can gage people’s level of interest.
Some people don’t really -- it’s not their most important thing.
And for other people, it’s a really big deal.
Assisted reproductive technologies, broadly,
are important to our community.
It’s not just fertility preservation and infertility,
but also the potential to have a parent of a child
with sickle cell disease conceive a matched sibling donor
by doing HLA typing on embryos.
It’s the opportunity to use PGT-M for parents
who are interested, who have affected children,
and those are people who are in our sickle cell clinics.
And then it also --
as you start to have these conversations with people,
it helps understand what their individual barriers are to care.
The second thing is this is multi-disciplinary care.
I can’t do this alone.
And so, there’s all kinds of people
that can be your allies in this work,
genetic counselors, adolescent medicine,
GYN, endocrine, MFM, the transplanters,
our psychology services, our advocacy groups.
Everybody’s got to work together on this stuff.
This is -- these are family affairs.
The third thing is, we can claim solid ground.
And I think people -- we can really do this.
You know, first of all, we need to affirm
that sickle cell disease confirms --
confers infertility risks and that those --
the risks factors are multifactorial.
We can’t equivocate about the impact
of hydroxyurea on this disease.
We see that in treated cohorts, that the treated children
just behave totally differently in terms of their hospital use,
their complications than the untreated children.
Everybody deserves a childhood
in which they can play and learn and grow.
And hydroxyurea enables that.
We can tell families that entering adulthood
with the least accumulated morbidity is critical,
especially in places like the United States,
where we lack sufficient adult experts
to care for people with this disease.
We can affirm that many women
with sickle cell become pregnant,
and we can know the definition of infertility.
So, we can screen and monitor people
for when they meet criteria for the diagnosis.
And finally, we can affirm that fertility preservation exists
as a standard of care for those at risk
and work to do what we can to ensure access.
Finally, we can partner with our families to acknowledge
how much uncertainty there is in this space.
We know that there’s dynamic activity.
You know, Dr. Tisdale, I saw at the back of your head.
Dr. Tisdale, hi.
We know that people are working on
making prep regimens that are less gonadotoxic.
We know that novel chronic therapies are coming our way.
We don’t know what 10 years from now
is going to look like for treatment for sickle cell
in the United States and Jamaica.
This is also a dynamic place for healthcare policy
and access to ART.
And finally, it can be a dynamic place for families who --
especially in the United States
where we have a shocking geography
of restricted reproductive health care access,
families may choose to choose jobs, living locations,
or to dedicate their savings in ways that allows them
to make priorities about their life and care.
And this is such a big deal
because it just costs an incredible amount of money.
I did want to let you know that Sickle Cell Reproductive
Health Education Directive,
in partnership with Be The Match --
and thanks to Be The Match --
has issued over 30 grants to preserve fertility
in young people with sickle cell disease
in an attempt to help mimic some of the efforts of cancer groups
and others to help access this fertility preservation care
that is needed for so many of our patients.
And the website for how to apply for those is there.
All right. Well, that concludes my fertility preservation piece.
I’m going to talk a little bit about pregnancies,
starting with the existence of these CDC fact sheets
for patients. They’re in English and Spanish,
and they include preconception care,
prenatal care, and postpartum care
and can help direct care for individuals
with sickle cell disease considering pregnancy.
It’s a difficult time for maternal-fetal medicine
in the United States
and for sickle cell disease as a consequence.
I hope you can see in these maps the distribution
in the upper left column of people with sickle cell disease
and in the lower left column, the distribution of care.
If you can, in your mind’s eye,
overlap that map with the maternity care access.
And this is certainly a shifting terrain
as hospitals in the South continue to close
and restrict access to care.
But you can see why there are parts of this country
where there are many,
many people with sickle cell disease
who may be having trouble
accessing the obstetric care that they need,
just by looking at these maps.
Well, why does this matter?
Because we now have data from California data sets,
from Jamaican data sets,
and from national U.S. data sets,
that over the last 20 to 30 years, there --
the morbidity and mortality of sickle cell disease pregnancy
has not changed.
And I think that we as a community can step up
and start moving the needle on this now,
This is the data that my then-student, Dr. Macy Early --
she’s now a resident at the University of Pennsylvania
in internal medicine
and a future sickle cell doctor of America --
made from the National Inpatient Sample.
And this is -- these are measures
of the severe maternal morbidity index from the CDC,
which are markers of severe obstetric outcomes
that present a risk for death.
Of interest, the SMM index does include vaso-occlusive crisis.
But we didn’t measure it in this study
because it was a comparison study,
and nobody else but people with sickle
should be getting vaso-occlusion crises during pregnancy.
What this graph shows, in the orange and yellow plots
are people with sickle cell disease
who were coded as having Black race, people with --
then the purple and blue plots are people coded with Black race
but without sickle cell disease.
And the line one is people coded as White
without sickle cell disease.
And so, I hope you can see
that the severe maternal morbidity of this disease
and sickle is greater than all these groups.
And, you know, mortality is 26-fold higher than
the general population and 10-fold higher than
Black women in the United States.
We also see concerning outcomes for fetuses and children
born to women with sickle cell disease,
including IUGR, which is a risk factor
for adverse neurodevelopmental outcomes,
fetal demise, and preterm delivery.
In other work that Dr. Early did with me,
she identified
that approximately 30 percent of adverse pregnancy
outcomes for individuals with sickle cell disease
in the United States
may be attributable to disparate treatment
due to race, but that means 70 percent is attributable
to dimensions of this disease,
and I’m going to talk about that next.
Behind this, you can see some of the statistics
on racial disparities in care and also some reporting
on how restricted access to reproductive health care
is affecting the sickle cell disease community
in the South in particular.
So, what do we have to treat sickle cell disease
in pregnancy?
Well, in the United States, we have blood transfusions.
We have prenatal vitamins. We have aspirin.
We have low molecular weight heparin.
And we have antibiotics.
Some of you may be wondering, what about hydroxyurea?
And we just don’t have the data yet to support that.
Whereas we have quite a lot of data
on the use of blood transfusions in the United States,
and we certainly have access to a safe blood supply.
So, I’m going to talk mostly about that today.
The first thing I want to think about
is just why we aren’t using transfusions,
and I assume it’s because we’re afraid of alloimmunization.
So, let’s think about the risk of alloimmunization in pregnant
people with sickle cell disease.
Well, okay, we’re all afraid of delayed
hemolytic transfusion reactions. That is just a terrifying thing
that happens to people with sickle cell.
And yet, we know that there are ways to modify that risk.
We don’t really have great data that supports the idea
that hemolytic disease of the newborn and fetus is that --
is an increased risk in this patient population,
and it’s possible that modulations
in the maternal immune system
actually change the risk of this.
Nevertheless, alloimmunization risks are real.
They’re not trivial for our patient population.
And we need to deploy the highest quality blood
banking approaches we can, to help reduce those risks.
What we see in some cohorts of pregnant people
in which this has been studied,
is that alloimmunization doesn’t really differ
if you put people on prophylactic transfusion
in pregnancy or not.
So, people who are treated with monthly transfusions
throughout their pregnancy,
compared to people who are allowed to --
who are not treated and are only offered transfusions
when they either have a crisis or have severe maternal anemia,
they get alloimmunization at about the same rates.
We also know that about 50 percent of women
with sickle cell disease receive a transfusion in pregnancy
or at least 50 percent.
And so, we’re also balancing the risk
of an unanticipated transfusion,
potentially not at our own center,
where we have experts on care,
versus controlled prophylactic transfusions at our own center,
where we have expert -- access to expert care,
where it’s in a controlled setting,
and where people are not having crises,
which, of course, are an independent risk factor
for alloimmunization.
There’s a lot of talk about the need
for more studies of transfusion
and sickle cell disease pregnancy,
and I think that there’s a lot of interesting questions
that I hope we’ll answer through those.
However, we also have a large meta-analysis from 2015
that shows fairly remarkable results,
and subsequent studies continue to affirm
many of these findings.
In particular, the 2015 blood study by Malinowski et al.,
identified, you know --
and again, you can see across these columns,
the pregnancy complications, the number of studies involved,
the total number of pregnant sickle cell individuals,
and the odds of the outcome.
And so, what they showed is that that overall mortality
was decreased by transfusion.
Vaso-occlusive pain crises were significantly decreased.
Pulmonary complications significantly decreased.
Pulmonary embolize significantly decreased.
Perinatal mortality, neonatal death,
and preterm birth, all decreased.
And yet the authors themselves, who I adore,
did not see fit to say that this data is sufficient enough
to start treating people with SS disease
and Sβ0 thalassemia
with transfusion therapy in pregnancy.
And I just wonder about that, given the state of things.
In the obstetric literature, we’re clear that maternal anemia
is a risk factor for adverse pregnancy outcomes,
and most individuals with sickle cell disease
meet this criterion.
Of course, the risk factor of anemia in general,
in sickle cell disease
is the basis of FDA approval for voxelotor,
and maternal anemia is a recognized risk factor
for many things.
Dr. Early did a second study in the National Inpatient Sample,
and you can see Figure 2 here.
We compared the women with sickle cell disease --
who we theorized to all have maternal anemia
because almost everybody with sickle cell disease
has a hemoglobin less than 10 --
to people who had a nutritional anemia during pregnancy.
And we again looked at the --
at various severe maternal outcomes.
And I hope that you can see that on the one hand,
there are a set of adverse outcomes
in which the risk ratios are similar,
pre-eclampsia, preterm delivery, hypertensive disorders,
C section, and then when you get to some of these
really more profoundly terrible outcomes,
and also the thromboembolic pathophysiology
of sickle cell disease
really starts to come out on the far right side
at the top of this graph.
So, this was a bit of a thought experiment.
But, you know, obviously,
transfusions treat maternal anemia.
It’s a risk factor for autism and other things in children.
There has been a randomized control trial
of prophylactic transfusions for sickle cell disease.
It was completed by Dr. Koshy and many others,
in the late ‘80s. And I was impressed not long ago
to read this letter to the editor
in response to that publication.
Just to summarize briefly that publication for you,
the randomized controlled trial of prophylactic transfusions
for sickle showed significant reductions in pain
and maternal complications of sickle cell disease,
but it did not reduce poor perinatal outcomes.
And so, the study was deemed sort of indeterminate
in terms of how we should use transfusion therapy
and pregnancy for women with sickle cell disease.
And yet transfusion expert Morrison and transfusion --
and obstetrician Morrison from the University of Mississippi,
wrote a letter in response to this publication,
and I think that they --
their objections to the conclusions are notable.
They wrote, you know, "This paper doesn’t reflect
our experience over the past nine years."
And again, this is in the ‘80s. "Over the past nine years,
we’ve delivered 69 pregnant people with sickle cell anemia,
at the University of Mississippi --"
in that southern part of that map I showed you.
All have received prophylactic transfusions,
and there have been 68 live births and one abortion.
The authors conclude that the omission of prophylactic
transfusions during pregnancy does no harm to a mother
with sickle cell anemia or to her baby.
But we think that conclusion far overreaches the data.
And I worry that many of the conclusions
that we continue to draw about studies of transfusion
and sickle cell pregnancy continue to overreach that data.
It’s also interesting, you know, as we think about
how people’s minds change across their careers.
Perhaps mine will change someday too.
One of these Morrisons was somebody who, in just two --
in the 10 to 15 years before he wrote this,
had been writing that people with sickle cell disease
should never become pregnant at all.
And so, we see how opinions and treatments
really can inform the kind of clinical care that we provide
and the kinds of expectations we have for our patients.
You know, one of the things that really impresses me
about the randomized control trial of transfusions
and the meta-analysis is that they all show
that transfusions in sickle pregnancy reduces pain.
And I wonder why reducing pain is an inadequate endpoint
for pregnant people with sickle cell disease.
We know that pain occurs in 50 to 80 percent
of sickle cell pregnancies, and we know that reducing pain
is a completely standard endpoint
for most of our trials. Right?
Hydroxyurea, L-glutamine, Crizanlizumab, and gene therapy,
all of these things we do to prevent pain,
and yet we are not universally offering transfusion
to a vulnerable patient population
where we’ve made no progress
in improving outcomes in many decades,
even though they have a clear indication for pain prevention.
Downstream challenges of people with pain
and sickle cell disease pregnancy
are not horribly different than everybody else.
It’s just that you also have a fetus
that’s exposed to these things.
So, we have toxic stress, not just to the patient,
but also to the fetus. We have opioid exposure,
not just to the patient, but to the fetus.
And then we have infection, clots, as needed, transfusion,
and other things downstream of that.
All of these things are in those severe maternal morbidity
indexes as being fantastically increased in people
with sickle cell disease and pregnancy.
And if we can keep people out of the hospital,
that may really be part of the puzzle.
So, I hope we can apply this clinical logic
and end some of our inertia.
The American Society of Hematology
identifies transfusion as a low-risk
intervention in pregnancy -- in sickle pregnancy
and potentially profoundly beneficial.
We don’t even know what it would look like
if we started giving people transfusions
in the preconception period and really help to optimize
placental development from the get-go.
And we don’t really have great data
on what it looks like for people who get treatment for nine --
a full nine months of therapy.
Most of the trials start transfusion
somewhere in the second trimester of pregnancy.
There are calls in the literature
for randomized control of chronic transfusions,
which suggests that our community thinks,
or some of us think,
there’s equipoise for a randomized controlled trial.
I think that’s an interesting idea.
And so, if that’s true, then first of all,
we can do transfusion offerings
for our pregnant patients at the present
with a shared decision-making model,
acknowledging that that’s -- that we think there’s equipoise.
But the second thing is that I think we need
to have a really rigorous debate
about what the primary endpoints of that trial for the --
should be, whether pain is an adequate endpoint
for pregnant people with sickle cell disease
and that should be enough to change management,
or whether we should be thinking about perinatal outcomes
and maternal outcomes that would define who to treat.
Angela Rankine-Mullings: Sorry. Dr. Pecker.
Lydia Pecker: This is the Who? When? How?
slide, and I’m not going into that now.
Angela Rankine-Mullings: Out of time.
40: 03 And
I’ll conclude by saying, you know, we just --
we have to move the needle on survival
for adults with this disease. And so, every little bit counts.
I think incorporating patient priorities like fertility
and providing high-quality maternal mental health care
is one of the ways we’re going to start
moving the needle in the next decade.
And I’m really hopeful for all of the work
that you do to move the needle as well.
Thanks so much.
Angela Rankine-Mullings: Thank you, Dr. Pecker.
We actually ran out of time. I see no questions in the chat.
We have -- probably we can have just one question,
please, quick. Thank you.
Male Speaker: Hi.
I had -- it was a fascinating talk, and I was just --
you mentioned something concerning anemia and autism.
And I’m wondering, in sickle cell patients,
do you see a higher rate of autism,
and if you can actually reduce the autism
by doing transfusions during the pregnancy?
Lydia Pecker: To my knowledge --
thanks for that great question --
to my knowledge,
we have done the only study looking at that question.
And that study was in the Boston Birth Cohort,
where we did a propensity match score of children
born to women with sickle cell disease,
and we compared them to race and ethnicity match controls.
In that study, there were differences
in neurodevelopmental outcomes between children born
to women with sickle cell disease
and those in the general population.
It’s important, though, that not just maternal anemia
is a neurodevelopmental risk factor --
yeah, there is a terrible echo. I’m sorry.
It’s a little distracting to speak.
It’s important to know that it’s not just maternal anemia
that’s a risk factor for adverse neurodevelopmental
outcomes in children
born to women with sickle cell disease.
Opioid exposure is a risk factor
for adverse neurodevelopmental outcomes.
Having a parent with a chronic disease
is also a risk factor
for adverse neurodevelopmental outcomes.
Being born with low birth weight,
small for gestational age, and preterm,
these are all neurodevelopmental risk factors,
and there are indications that transfusion therapy
could help address many of these things.
Male Speaker: Thank you so much.
Angela Rankine-Mullings: Thank you, Dr. Pecker.
Thank you for a wonderful presentation,
[applause]
And now, we will go on to our second speaker,
Dr. Thomas d’Humières,
who is a cardiologist and physiologist
working at the Henri Mondor Teaching Hospital.
Thank you so much. Let’s welcome him.
[applause]
Thomas d’Humières: Perfectly said.
Angela Rankine-Mullings: I said it. Thank you.
Thomas d’Humières: Very good. Okay.
So, I just have to figure this out.
Okay. Oh, the other one. Okay.
Nice. Okay. It’s a good thing. Okay. Hi, everyone.
Thank you for the invitation once again.
I’m very happy to talk about a subject
that has been a bit forgotten
in the field of sickle cell disease,
which is cardiovascular abnormalities.
And I’ve been working on this topic for six years now.
And so, I had a lot to say. So, I had to choose.
So, I will be more than happy to talk more about this later,
because I can -- for hours actually.
No, the other one.
[laughter]
So, everybody said it.
The SCD population is living longer,
which is really a good thing. But we are seeing --
we are facing more and more cardiovascular disease,
which is now the first cause of mortality
in the adult population.
So, we have to understand it. We have to face it.
And we have to somehow try to treat it.
I’m not going back to all the pathophysiology
of sickle cell disease
because you’re better than I am in this field.
But it is true that every patient is unique
and is actually in a spectrum of very high hemolysis
to very low hemolysis,
and the complications are very, very different.
And we know from epidemiological studies
that the more hemolytic they are,
the more cardiovascular disease they have.
So, the exact pathophysiology between is yet to be understood
but mostly, probably because of the heme release,
the chronic vascular disease, free hemoglobin release,
NO scavenging, and everything linked
to hemolytic complication.
So, every -- all the vascular complications
are tied to this hemolytic phenotype.
And this is something that I wanted to start with.
Sickle cell population don’t have normal echocardiography
according to a non-SCD population
normality distribution.
And this is something that really has to be understood.
Because I’ve seen a lot of conclusions of echocardiography
saying dilated cardiomyopathy. It’s not cardiomyopathy.
If this is adapted, if I’m doing some echocardiography
in all elite athletes who are doing more
than 20 hours of sports per week,
they all have dilated cardiomyopathy.
If I’m saying this, their career will end.
So, we have to properly address what we are saying.
So, they -- we are not in the same frame of thinking.
So, we have to rethink.
What is the normal value among the SCD population?
And we know that there is an adaptation that is normal.
Because they are -- they have strong anemia,
strong cardiac output since they were born.
At some point, it shifted towards pathology.
And this is the tricky part.
It’s when can we say that we have cardiomyopathy?
And this is very difficult actually.
Because we all know that all these patients
have cardiac output.
It’s normal because there is anemia.
They have low systemic arterial pressure.
It was too -- not strong enough.
I was hearing a lot of my voice, so more voice for me.
[laughter]
There is tachycardia. It’s actually normal
because there’s a lack of oxygen delivery.
And they all have dilated -- more or less, dilated heart.
All cavities are often dilated, and it’s not a problem, per se.
Then we go through problems when there is a remodeling
of left ventricle by fibrosis development.
The left ventricle becomes stiffer.
The vascular resistance is beginning to rise,
and the coronary microcirculation is not adapted
to face this -- yeah, these changes.
And how can we put the difference
between adaptation and pathology?
This is something very difficult.
So, of course, all of you know, the most --
yeah, the most known complication of --
cardiovascular complication of sickle cell disease,
pulmonary hypertension, 20 to 30 percent of mortality.
It is a real prognostic factor for sickle cell disease.
But pulmonary hypertension is not a disease.
It’s a consequence, just a pressure consequence.
It’s just means that there is high pressure.
Actually, I’m doing this right? Yeah.
There is high pressure here,
just in front of the right ventricle.
Okay. Once we said that, we said, actually, nothing.
Where does it come from? That’s the actual question.
Is it because there are several embolic thrombotic problems
repeating,
cutting some vascular -- pulmonary vascular bed?
Maybe. Is it because there is a pulmonary vascular disease
with increased resistance,
such as we can see in scleroderma?
Or is there a systemic inflammatory disease?
Or is it because the left heart is sick,
and so this is post-capillary hypertension?
So, this is really important to understand that it’s --
these are three different diseases.
And when we look at the literature,
there are three major publications
that explored with right heart catheterization,
sickle cell disease patient.
They all have about the same conclusion.
We -- they observed about 10 percent
of true pulmonary hypertension in sickle cell disease,
just knowing that, at the time,
the definition was 25 millimeters of mercury
to define the hypertension. And now, it’s 20.
So, if we look back to all these studies,
maybe we underdiagnosed some patients.
But what was most disturbing is half was precapillary --
classified as precapillary, so pulmonary vascular disease;
half was classified as postcapillary,
so left heart disease.
And when we think about the disease pathophysiology,
the systemic disease pathophysiology,
it is a bit puzzling to think that half of the patient
will have only vascular disease in the lung,
and the other part only systemic vascular disease
but not the lung.
So, this is not very, yeah, convincing for me.
So, just a quick example -- and I’m going --
not going into detail
because this is actually what we see on a daily basis.
These are the results from a patient here
of a right heart catheterization.
I will explain a bit.
But you have the cardiac output, 10 liters per minute.
It is high. You have the pulmonary pressure, 29.
This is high.
You have the left pressure -- the left heart pressure, 12.
Okay. The vascular -- pulmonary vascular resistance,
1.9 Wood units, okay.
And volemia, right atrial pressure.
And if you look at the most recent guidelines,
2022, well, okay, there is hypertension
because it’s above 20.
But it’s not from the left heart disease because it’s below 50.
It’s not from vascular lung disease because it’s below 2.
So, what is it actually? And this is -- for a long time,
it has been called high cardiac output hypertension,
which is nonsense.
And actually, you really have to put,
once again, the specificity of this population in this context.
All this classification was validated
on very broad spectrum of patients,
not sickle cell patients.
If you have 1.9 Wood units of vascular resistance
with 7.2 grams of hemoglobin, what would it be with 12?
It would be a lot higher because they are --
there is anemia and high cardiac output.
So, vascular resistance is low, naturally low.
So, 1.9 is relatively very high.
So, this is something that is really not normal.
And then -- it’s a mechanism you have to train,
but you see that the pressure in the left cavities
is not that far from the limit.
But the patient is, like, very dehydrated.
So, what happens if we give him, like 2050 cc of saline?
You will see that you will have a linear augmentation
of right atrial pressure
and exponential augmentation of left pressure.
And so, you have actually, this non-classified patient
is actually a typical example of mixed pre-
and post-capillary patient and is very severe, actually,
but it’s just -- it doesn’t fit in any framework.
This one. So, we have a good, non-invasive assessment
for pulmonary pressure. Because, as you can see,
it leads to major prognostic impacts.
The famous tricuspid regurgitation velocity.
So, it’s quite an easy echocardiography parameter
to assess as you can see on the image.
You just take the max velocity of a leak.
Just to know, for the record,
20 to 25 patients have no leak, or we underestimated.
So, this is something that has to be accounted for.
And we know that above 2.9 meter per second,
there is a high probability of true pulmonary hypertension.
And this is a criterion that is most commonly used
to assess cardiac outcome or inclusion/exclusion criteria
in clinical trial or safety. This is the only parameter.
And I’m not saying that it is a bad one,
because it is actually a very good one,
but my point is it might be a late one.
So, if you are with me, you’re seeing that a lot
is coming from left heart failure actually.
There is a lot of left heart failure.
Because when we say
post-capillary pulmonary hypertension,
we are actually saying left heart failure.
There’s exactly the same thing.
So, in cardiology, it’s always quite simple.
Why is there left heart failure?
Is it systolic, a contraction function problem?
No. In sickle cell disease, it’s really, really marginal.
So, is it a feeling problem, a stiffness problem? Yes.
Fifteen to 20 percent of diastolic dysfunction
has been reported in sickle cell patients
with a strong association with mortality.
But once again, we had this discussion with Vandana,
who worked a lot and brought a lot to this field,
and we agree on the point
that we accept that diastolic dysfunction
is responsible for this heart failure.
But all the studies applied the criteria
and the classification validated in non-SCD population.
So, what are we really measuring here?
It’s -- yeah, it’s quite limited actually.
So, we all agree that diastolic dysfunction
that we cannot assess is associated with problems,
but we should go further.
So, when we see diastolic dysfunction,
stiffness increases. Why?
Is it iron overload, as it has been suggested
as the reason for a while?
No. All MRI studies are quite unanimous,
and actually, I have --
I haven’t any patients with iron overload.
But they always found some fibrotic component
with some microcirculatory involvement.
But with MRI, this is something to be nuanced.
This is the -- an interesting study from Blood from 2018
that showed that sickle cell patient
versus a control patient had an extracellular volume in MRI,
which is the volume between cells,
basically fibrosis or edema,
that was very increased in sickle cell disease
and that the T1,
which is more likely fibrosis than edema, was also higher.
And interestingly, they linked this extracellular volume
to both diastolic function measurement on echocardiography
and cardiac biomarkers, NT-proBNP.
The correlation is really not perfect,
but this is -- the story makes sense, actually.
So, this is good.
So, we have this -- yeah,
this understanding that chronic hemolysis is linked
to endothelial dysfunction, microcirculation ischemia,
vascular resistance elevation;
all of this leading to left ventricular
remodeling with fibrosis and diastolic dysfunction,
leading ultimately to pulmonary hypertension,
post-capillary pulmonary hypertension.
And this is a unique phenotype in heart disease
of heart failure with a high cardiac output,
with a preserved left ejection fraction in a young population.
This is something you will only find in sickle cell patients.
So, if diastolic function, impairment seem central,
diastolic function must be understood.
I’m just looking at the time.
So, there is a toolbox that I just wanted to give you
to just better understand diastolic cardiomyopathy marker
and evolution using echocardiography.
Very simply, but we always use the same four index.
The first one is a very old one, not fancy at all,
but the best one, in my opinion,
is something we call E prime wave.
It’s just the velocity with which the mitral annulus
is moving during diastole.
If it’s fast, it’s good. If it’s slow, it’s stiff.
Kind of straightforward thinking,
but it’s actually kind of good.
And then if there is a diastolic dysfunction,
so an increase in stiffness,
this can lead to an increase in pressure behind,
in the left atrium. So, we will see here --
yeah, we will see a more dilated left atrium
because of the increase in pressure.
And ultimately, this will lead to an increase
in pulmonary pressure with the TRV.
And this is a one-way disease, not the other way.
So, this is very important to understand.
Because what if we can be --
we can stratify the risks sooner than later actually?
That’s my point.
And you can see -- just to show I’m not lying,
but this is the European guidelines to evaluate
diastolic function in the normal,
non-sickle population.
And they are using the E prime, the TR velocity,
the LA volume, with cutoffs, very defined cutoffs.
So, the first thing I wanted to try
is I had the chance to analyze big data
set of sickle cell patients and [unintelligible]
adult sickle cell patients,
and very importantly, very non-severe,
without any organ damage, at steady state.
And the idea was to just -- each dot here is a patient,
and each vector is an echocardiography feature,
just to try to see, how can we reorganize among these patients?
And what’s interesting in that three clusters we saw,
we could find four, five, six.
It’s not that -- the question is not here.
The interesting point is that the more remodeled
hypertrophied, the more -- the less the prime was.
So, the more remodeled the heart was,
and depending on the age, the worse the survival was,
most from cardiological complication.
And when we look at those patients,
they had more hemolytic anemia.
So, we actually find the pathophysiology,
but backwards, starting from echocardiography.
So, that’s actually reassuring.
But what is most important, in my opinion,
is that when you see all that I’ve been telling you about --
and we’re not going to spend time on those numbers,
but if you try to classify this patient
according to the usual classifications,
they are all normal in terms of compliance.
They’re all normal in terms of feeling pressure.
And they are all abnormal in terms of left atrial volume.
So, it is not adapted at all. That’s my point.
You cannot apply what’s on the left on the screen
to the right that the best patients have --
still criteria of diastolic dysfunction.
So, this is not possible.
Okay. So -- okay. I have to be very quick.
The idea was to early define diastolic cardiomyopathy
before the problem because there is no definition
because we have to stratify the risk before the problems,
even in the pediatric population, before PH onset,
that we can maybe reinforce treatment or include them
in dedicated clinical trial.
So, I’m going to go quick on this one.
We analyzed this huge cohort of patients
and matched this cohort to another one,
aged matched with the most factors
in terms of confounding factors, matched to a big,
big data sets of normal echocardiography patients.
And what we can see is that -- you see in red here
that even young sickle cell patients,
20 years old, they have lower left ventricular compliance
than controls even young.
And this is actually very parallel with --
it’s always lower through life, like early aging, actually.
And when you check the left atrial volume,
it’s quite flat in the normal population.
But in the sickle cell population,
you can see an exponential rise. At 60 years old,
they usually have a huge, huge, huge left atrial.
So, I have to go faster.
But I will be more than happy to talk about all this data later.
Because I have some very interesting messages
I want to share before the end.
When we do the multivariate analysis
on a subgroup of young SCA patients
where age does not impact stiffness --
this is quite a confounding factors --
only one criteria pops out,
and it’s good because it’s left atrial compliance.
If a young patient -- the mean age was 26 years old.
If a young patient quite stable without severe organ damage --
once again, this is a selected population --
has a value of compliance below 11, he reached 12 --
20 percent of mortality in 10 years.
So, this is really interesting
because these are very stable patients.
And if we go through time, three years after,
the patient with diastolic dysfunction,
with brackets once again,
they are starting to show functional impairment
on six-minute walking tests.
They are going to show a trend to a higher TRV
because disease is evolving. Left atrial volume is pumping,
pressure rising -- there is a process --
and the glomerular filtration rate is going down.
So, there is consistency in all this data.
Though, this is just a summary that we can, I think,
identify patients at risk before pulmonary hypertension
by exploring left ventricular compliance at younger age,
more frequently.
In five minutes --
when I arrived in 2018 in Henri Mondor,
I started the DREPACOEUR registry cohort of care.
It’s a multi-disciplinary evaluation of all patients,
sickle cell patients,
that were suspected of having heart problems.
It was very wide inclusion criteria,
basically all that can make you think that there’s a problem.
So, the idea was to -- for me to see a lot of patients
and to try to understand the patterns.
And they all had, in a day hospital,
a very systematic examination with clinical exam,
EKG, biology sample, echocardiography,
24-hour Holter EKG, six-minute working test.
If we suspected pulmonary hypertension,
they went to the referral center for dedicated exploration,
and they all had cardiac MRI and CT coronary angiogram
for the reason I will explain after.
We now have more -- in the day hospital,
there are more than 350 SCD patients followed.
Most of them are SS.
And as we said before, 12 percent are SC.
And this is something that we are -- the work is ongoing.
After describing all the SS complication,
the SC is actually ongoing
because, as you said, this is a problem.
And the first problematic for me,
at the forefront, there is, in this population,
10 to 15 percent of sudden deaths that we can’t explain.
And in cardiology or in intensive care,
a sudden death is not very -- there’s not a thousand cause.
It’s a stroke or ventricular arrhythmia
or pulmonary embolism.
Must be one of the three. There is no other explanation.
We know that this patient have a lot of stroke,
53 percent in silent,
infarct below 30, 4 percent severe stroke below 40.
But regarding ventricular arrhythmia
or other arrhythmia, we don’t know.
But yet, pathophysiology tells us
that they are the best candidate to develop
both ventricular arrhythmia and atrial arrhythmia.
Ventricular arrhythmia can lead to sudden death.
Atrial arrhythmia can lead to atrial fibrillation,
one of the first risk of stroke in the population,
just after systemic hypertension.
They have all that is needed.
It’s basically an experimental model for rhythmic disorder.
They have the fibrosis, the atrial enlargement,
the -- some triggers, such as inflammation,
hypoxemia, electrolytic disorder.
They have everything needed to develop
ventricular or atrial fibrillation.
So, first, the first description we did
on the first 100 patients, it was more like an alert.
Last year, was -- you see 100 SCA patient,
40 years old, so it’s not a very young cohort.
We did all the exams I talked to you about before,
and we diagnosed 22 percent of ventricular arrhythmia,
non-symptomatic ventricular arrhythmia,
on 24-hour EKG monitoring.
In every disease, it has been linked to sudden deaths,
not in sickle cell disease.
So, we can just assume, but it’s not proven.
And interestingly, it concerns more male gender
with an odds ratio of 4.3,
which is actually exactly the same in other cardiomyopathy.
Men are more exposed to ventricular arrhythmia.
And a feature on echocardiography is strain,
which I have no time to explain,
but I will be happy to explain later.
But there is a measurement that, if it is bad, can --
yeah, you can do an Holter EKG based on this measurement
with a good predictive value.
And just to finish fast, atrial arrhythmia,
same story, different -- very different kind of patients,
but 26 percent of atrial arrhythmia
in this patient, 26 percent.
This is a huge, huge, huge amount.
And like in the general population,
age was independently associated
with a number of premature atrial complex per day.
This is a logarith [sic] scale.
So, from here, this is more than
10,000 premature atrial complex per day.
So, it’s basically atrial fibrillation,
left atrial volume.
And very interestingly, we have the luck
to have very good expertise in the stroke field.
When looking at the patient with a history of stroke
without underlying vasculopathy, there was an odds ratio of 6.6.
So, this changes the way we took care of patients in our center,
the local guidelines. And now, we do actually this,
which was just published in Blood Advances.
It’s when to do arrhythmic evaluation in adult patients
and in what presentation.
If it’s just without any symptoms, you do systematic EKG.
And if you get older or with a very large left atrial volume,
then you are going for 24-hour monitoring.
And then I have to stop. Okay.
And same thing with if you had a stroke
without underlying vasculopathy,
we go very easily to prolonged more than 24 hours,
but 14 days monitoring with excellent results.
I can tell you about this later. They don’t have coronaropathy.
And I will end with this.
Even this new population aging with kidney failure,
with systemic hypertension, they don’t have --
still don’t have any coronary artery disease.
So, I won’t talk a lot about this,
but I just raise one question that, for me, is very important.
What happens when we cure them,
when we restore normal or high lipidemia,
and we level down the bilirubin protective role
on the systemic vasculopathy that is already existing?
This just -- this is just a question.
I don’t have the answer.
But they might be prone to a very high cardiovascular risk
knowing that we are restoring all that is needed to develop
some atherosclerosis they didn’t have.
So, this is, for me, a point of attention, very important.
And I’m out.
So, this is, yeah, a very difficult,
unique presentation of heart failure.
You have to have dedicated cardiologists
or people interested in this disease
to have a good evaluation.
There is a high prevalence, very high,
of ventricular and atrial arrhythmia
with a potential implication in both sudden deaths and stroke.
So, we have to be careful. Thank you.
[applause]
Angela Rankine-Mullings: Thank you.
Thomas d’Humières: [unintelligible]
Angela Rankine-Mullings: Thank you so much.
Thank you, Dr. d’Humières.
[applause]
We can only have one question because we are behind.
You’ll take one question, the first hand.
I’ll encourage everyone to catch him at lunch.
John Tisdale: Thank you for a really great presentation.
I’m always wondering,
when we think about heart disease and sickle cell disease,
we’re often attributing it to hemolysis
and NO scavenging and the like.
And hemolysis also reduces hemoglobin.
So, I’m just wondering to what extent the hemoglobin itself,
the anemia itself, is contributing.
Because in thalassemia intermedia back in the day,
you know, there was this finding that
when you leave hemoglobins chronically low,
patients develop heart failure and pulmonary hypertension.
And in this disease, we leave hemoglobins chronically low.
Thomas d’Humières: Yeah.
John Tisdale: So, I’m just wondering
to what extent the anemia --
not the hemolysis and all the downstream complications
that we know about,
but just the anemia itself -- has contributed?
Thomas d’Humières: Yeah. This is a good question.
Anemia itself will contribute to the remodeling, of course,
because there is a need to increase the cardiac output
and to increase the left ventricular volume each bit.
But there is a very good, interesting paper
with preclinical model of mice.
One is a Townes model, if I’m remembering good.
One is just an anemic model of mice
with the same level from the -- from birth,
and they are following heart remodeling.
And the association of hemolysis behind
is crucial in the development of remodeling like fibrosis
and microvascular impairment.
That is not observed in the chronic anemia situation.
Actually, we have a lot of patients with chronic anemia.
We never see that kind of pattern
we have with sickle cell disease.
For me -- yeah, it’s just by doing the echocardiography,
I can tell you that, no, he’s not --
he doesn’t have sickle cell.
It was a mistake. He’s just ASR. It was a mistake.
So, there is a really good pattern,
and I think this is the conjunction of both.
Angela Rankine-Mullings: Thank you.
Thank you so much.
[applause]
Our third speaker is Dr. Lori-Ann Fisher.
And we invite her to come to the podium.
Dr. Fisher is a nephrologist
at the University of the West Indies
and will share with us on renal disease.
Let us welcome her.
[applause]
Lori-Ann Fisher: Okay. So -- okay.
So, I’ve been warned that I must be within the time.
So, I’m going to check this out. Hold on. Okay. Cool.
So, thank you very much to the organizers
for allowing me to present or inviting me to present.
And I just wanted to start off with a clinical case
because, you know, first, I’m a clinician.
So -- and a lot of my questions
often come from being on service.
So just last month, I was on service.
I’m on service again.
A 60-year-old gentleman came into the hospital.
He’s referred from the renal clinic
with hyperkalemia and anemia.
It was noticed on his blood test.
We don’t do chronic transfusions here,
so people will have a baseline hemoglobin,
and his baseline hemoglobin is about 6.7.
He has sickle cardiomyopathy.
I’m so sorry to the last presenter.
Yeah, that’s a bad term [laughs].
But he has CKD, and he’s followed by the renal clinic.
He has a baseline creatinine of about 130 to 147.
That’s about 1.4 to 1.6, 1.7 for the Americans amongst us.
And he has kidney disease stage 3a A3.
Nephrologists like to make things complicated.
So, essentially, his GFR is about 45,
and he has more than 300 milligrams of alminuria [sic].
So, he has severe alminuria, right?
He’s on medication. So, he’s on Resonium.
And now -- and he’s on Resonium because he gave a history of,
you know, prior hyperkalemia, which -- and enalapril.
He’s on allopurinol.
MIRCERA, which is long-acting erythropoietin,
200 micrograms once monthly, folic acid, and Lasix.
So, he had been having shortness of breath
when riding his bicycle. He was having some light --
he didn’t have any lightheadedness
or symptoms of heart failure,
but he had some fatigue and weakness.
No cough, fever, chills, or any respiratory symptoms, no pain.
His exam was just noted for like pallor.
His abdomen was non -- was benign.
He didn’t have hepatomegaly. He had some edema.
His chest was equal. There’s no crackles.
But his hemoglobin was 4.1, [laughs]
and his platelets, 152. He was hyperkalemia, 6.3.
And his creatinine was above his baseline.
It was 171, so he had AKI, and his bilis were elevated.
I’m sorry, the -- I didn’t put the units there.
But these are within his baseline, though,
when I looked through all his prior labs.
And this is what happened. So, he came into the hospital.
Oh, boy, this thing is really confusing.
So, he got two units of red cells,
because that’s what we could get,
and he came back up to hemoglobin of 6.
His potassium dropped. His bicarb came up,
and his creatinine came back down to his baseline.
So, that kind of highlights a lot of kind of issues
that we face in a lot of patients
that we tend to see in Jamaica,
which is like the super small dot right here.
I don’t know. All right. I think that’s in the region there.
Yeah.
And we have -- as we know,
we have one of the highest rates of sickle cell disease
in the world, second to West Africa.
And this is data from Professor Knight-Madden.
I actually just used her data.
You know, 0.7 percent have sickle cell disease,
about 15 percent have either S or C trait.
And, you know, we’ve gotten much better in the region,
as we know, and many people have said this,
at, you know, the infectious complications
that people are living much longer in this data
from the sickle cell cohort.
And what we found is that, you know, chronic kidney disease
is one of the leading causes of death --
oh, boy, yeah, chronic kidney disease is right there --
as patients with sickle cell disease get older, right?
So, everybody knows the pathophy.
I feel like this is high school
compared to people in the audience.
But we know that in areas
[laughs], you know, in sickle cell disease,
you know, there’s low -- when there’s low oxygen tension,
you get polymerization of the sickle cell moiety
that leads to macrovascular damage,
cell adhesion, vasoconstriction,
and the resultant vascular injury.
When you think of sickle cell nephropathy, again,
it’s a very basic kind of pathogenesis.
You think of like viscosity or vaso-occlusive phenomena.
And if you remember from your physiology,
your renal physiology,
the medulla is a very low oxygen tension space, right?
And so, recurrent sickling can cause interstitial damage.
As a nephrologist, the favorite part of the tubule
is the distal convoluted tubule.
Yes, nephrologists have a favorite part of their tubule.
[laughter]
So, the distal nephron gets affected in kidney --
in sickle nephropathy.
So, you actually have a problem with ammonium secretion,
and essentially that leads to a failure of acidification.
So, they’re prone to metabolic acidosis and hyperkalemia
because if you can’t excrete potassium,
you can’t get rid of -- can’t excrete hydrogen ions,
you can’t get rid of potassium as well.
They also -- my second favorite part of the tubule
is also affected, which is the proximal convoluted tubule.
So, you get an increase in phosphorus reabsorption
and uric acid reabsorption and also increased or impairment
in clearance of creatinine. And so, you get this --
also this artifactual increase in creatinine clearance.
The other kind of mediated effect is hemolysis
and hyperperfusion,
reperfusion injury that leads to endothelial dysfunction
and hyperfiltration, which is such well --
which is well described in our patients,
which ultimately leads to sclerosis, alminuria,
and, you know, changes --
and, you know, over time, progressive nephron loss.
It’s actually quite interesting,
because the hyperfiltration mechanism is actually similar
to diabetic kidney disease. And that’s really important
when I talk about kind of therapeutics later.
Ultimately, you know, they’re at risk for two things,
acute kidney injury and chronic kidney disease.
So, in kids, one of the early signs of kidney disease
or at least one early effects of kidney
is actually nocturnal enuresis,
and that’s because of a failure of concentration of urine,
and that’s because of interstitial and tubular damage.
Also, you know, infection risk,
all these other things lead to AKI.
In people who do not have sickle cell disease,
AKI increases risk of chronic kidney disease.
So, there’s kind of this bidirectional relationship
between acute kidney injury and chronic kidney disease.
This is really great work from --
I think this is Jeff Lebensburger in UAB.
And essentially, we -- what we know is
that hyperfiltration predates alminuria, right?
So, people who hyperfilter are more likely
to develop alminuria over time.
And this is some work with people in the audience,
including Monika, that showed that, you know,
a lot of patient people have alminuria.
You can have transient alminuria
without it being a true kidney disease.
That’s why the definition of kidney disease
is persistent alminuria for more than three months.
What we found is, like, you know,
a cutoff point of 100 initial baseline
alminuria predicts persistent albuminuria, right?
And those people with persistent alminuria meaning --
and this study was two values of greater
than 30 milligrams per gram in a two-year period.
Those people were more likely to have GFR decline, right?
So persistent alminuria bad.
We know that sickle cell nephropathy
leading to kidney disease is really, really common.
Gets more common as we get older.
And it’s higher in sickle SS disease
and sickle ß0 thalassemia,
less common in HBS -- sickle SC but does occur.
We used to think sickle cell trait was benign,
but it doesn’t. It’s not very benign.
There’s U.S. data that shows that sickle cell trait
is associated with chronic kidney disease.
And in our data from the Jamaica Health and Lifestyle Survey,
sickle cell trait was associated with a twofold
increased risk of reduced GFR.
This is an old slide because we don’t really
call it microalbuminuria and macroalbuminuria.
It’s called moderate and severe alminuria.
So, macro -- microalminuria is 30 to 300,
macro is above 300.
Gray is SC and HbSS, so much -- you know, high rates of --
in this cohort, high rates of alminuria in people,
which SC -- SS up to 40 percent, and it increases with age.
So, presenting some data from our population,
you know, this is from -- data from Monika Asnani
and Prof. Reid, CKD and above, in 99 people with --
Jamaicans with sickle cell disease,
and this is HSS,
about two-thirds of them had alminuria.
Commonly, you know,
hyperfiltration occurred in about a quarter of patients.
And what was really important is that they actually measured GFR
and did creatinine and cystatin testing.
And, you know, compared to measured GFR,
you know, creatinine-based estimates
of GFR performed very poorly, right?
So, you actually -- we actually know that creatinine
was a very insensitive marker of,
which the audience tends to know, renal dysfunction,
and actually only started rising after measured GFR fell.
So, as I said before,
sickle cell trait really is not benign,
and it’s associated with kidney disease amongst Black people.
And, you know, whether or not it interacts with equal one
[phonetic sp] is unclear. Some data says no.
Some data says yes.
But certainly, sickle cell disease --
sickle cell trait is associated with chronic kidney disease
and alminuria in African Americans
and also in Brazil.
Kidney function declines faster in people
with sickle cell disease.
So, this is some data which was published about three years ago.
Comparing the second line here is --
oops, this thing confuses me. I’m sorry.
You know, GFR slopes or GFR
decline compared to age AA controls.
And really and truly compared to the reference group,
you know, GFR declined in the order of kind of 2
to 3 mils per minute per year
in sickle cell SS versus AS disease.
Going back to our patient, remember,
he’s very hyperkalemic and had metabolic acidosis.
And this is some really great work from --
I think this is Santosh Saraf that looked at,
you know, multicenter cross-sectional study.
And what they found was that compared to controls,
you had higher rates of hyperkalemia metabolic acidosis
in what they termed the severe SCDs genotype.
So that’s SS and S beta-thal-not .
And it occurred at higher GFR.
So, you’re looking at a GFR here of --
oopsie -- like 85 to 91, about 21 percent of them
had acidosis and 13 percent had hyperkalemia.
And, you know, a pretty sore point for me
as a nephrologist is,
how do I manage these people or patients
with sickle cell disease who have CKD.
How do I manage their anemia?
And, you know, there’s not a lot of data on this.
The -- we know that they have really high and --
especially in our country,
where we don’t have a lot of blood,
and we don’t have a lot of --
we don’t have transfusion programs.
What dose of ESA agents should we be using?
And, you know, this is some preliminary --
this is actually a letter to the editor
looking at kind of EPO responses or hemoglobin responses
to hemoglobin agents with or without hydroxyurea.
And they actually found increasing hemoglobin responses.
The concern that had been raised in prior papers from the ‘90s
was that, you know, ESA agents may increase risk of veno
[sic]-occlusive crisis may increase risk of DVTs and PEs.
Didn’t really quite find that in their data.
Didn’t have increased risk of veno-occlusive crisis.
They had one or two VTE events,
but not statistically kind of significant.
Please know that this is a really small sample size,
so kind of hard to kind of do associations,
but certainly an area that needs further study
and especially because we have such high rates
of kind of EPO resistance in our patients,
especially with advanced kidney disease with sickle cell.
We know that creatinine is not a very good biomarker
for kidney disease in general.
It’s even worse in sickle cell disease.
So, this is a paper from, again, Monika and Marvin.
And they kind of looked at, you know, crack --
the different -- the performance of different equations,
including the CKD-EPI equation compared to measured GFR.
And, you know, the bias of --
especially even the new CKD-EPI equation
was pretty, pretty bad, about 45 mils per minute.
So, recently, in the nephrology world,
there is a move towards removing race from equations.
So, you’ll notice that most times in --
or in the newer reporting of GFR,
there’s race out of the equation.
And this is some newer CKD cystatin-based
race-free equation.
This is the European version, which is the EKC version.
And, you know, I always use MDCalc.
So, you’ll see like four different equations.
But newer recommendation is to exclude race.
And we actually, myself and Monika,
are actually looking at how these newer equations
compare to measured GFR.
And, you know, what we found was that the European equation,
EKFC equation, the P30, which just means, you know,
how the percentage of persons with the GFR,
how close they are to 30 percent of the measured GFR
or within 30 percent of the measured GFR.
I mean, all these equations perform pretty poorly
when you compare them to,
you know, people without sickle cell disease.
So, you know, the best correlation
was actually the EKFC equation,
which is a European-based equation
that was about 67 percent versus the new equation,
which is CKD-EPI, 57 percent.
The cystatin C-based equation
actually did not perform as well,
50 percent compared to the old equation,
which was like 27 percent when you included Black race.
So well, we’re working on that publication.
I promise, Monika [laughs].
All right.
So, you know, hydroxyurea has been talked about many times.
And I’m running out of time, so I’m so sorry.
You know, it does reduce --
may reduce hyperfiltration in children.
This is information from the -- data from the BABY HUG trial.
And so, you know, they found indirect markers
of improved kidney function.
And certainly, this is a study from out --
from a UC [sic] Chapel Hill, I think.
You know, they looked at patients with hydroxyurea use.
And they found that, you know,
alminuria certainly, in their cohort,
was less in patients with -- treated with hydroxyurea.
And they were less likely to develop alminuria.
And I think, based on the conversation I had
with someone in Brazil, yeah, it seems kind of [laughs]
-- yeah, it seems to be kind of congruent with their findings.
The case for the ACE.
As a nephrologist, I love ACE inhibitors.
They’re the best. And certainly, captopril, enalapril,
and other agents have been used
with variable kind of, you know, benefits in alminuria.
There’s not a lot of data on, like, long-term effects, like,
long-term use over time
and reduction of progression of kidney disease,
but certainly a very good data in sickle --
in non-sickle cell disease, right?
Other agents to consider
because nephrology in the last five years has kind of advanced.
It’s really exciting to be a nephrologist now and [laughs]
-- because we have no -- other than ACE inhibitors,
we have really new agents, right?
So, this is a trial looking at -- again,
from Santosh Saraf and his colleagues --
looking at preliminary data for voxelotor,
and they actually found a reduction in alminuria.
But more recently, we have newer agents,
so GLP-1 agonists. For the non-informed,
these are agents that we use in diabetic kidney disease
and now actually expanded across many different applications.
SGLT-2 inhibitors, which is sodium glucose transport
receptor inhibitors.
They have been used in proteinuric kidney disease.
And, you know, the -- this essentially reduce alminuria
by essentially reducing hyperfiltration.
It makes me wonder that, you know,
this may potentially be beneficial,
given the pathogenesis of sickle cell disease.
The only problem with these agents,
potentially, is because --
especially with the GLP-1 agonist and SGLT-2 inhibitors,
is that they tend to cause dehydration.
SGLT-2 is because they cause osmotic diuresis,
and GLP-1 agonist as well.
So, you know, the concern clearly would be kind of
increased
sickling and vaso-occlusive crises in these patients.
So, this was an experience by, again, Santosh Saraf
and his group in Illinois.
And they actually looked at off-label
use of SGLT-2 inhibitors.
They actually had a reduction in proteinuria,
but they had more, you know,
slightly increased rates of vaso-occlusive events.
So, I mean, I think that would be a caveat to that,
but certainly, you know, promising.
End-stage renal disease, in terms of data on that,
so, certainly most of the data
is from the U.S. with their NHANES
[phonetic sp]. About 0.1 of --
percent of the U.S.-based end-stage renal population
has sickle-related kidney disease.
Mean age was younger, so 40 years.
SCN patients were less likely to relive --
receive renal transplantation.
And, you know, renal transplants have occurred in patients
with sickle cell disease.
There’s a nice series of about 105 patients
who underwent renal transplantation.
They’re less likely --
their graph of survival was less, though,
compared to the general population.
And, you know, as we kind of understand
sickle cell nephropathy, patients were independently
associated with risk of mortality.
I kind of shared this slide because I think it was pretty.
But I thought it was really cool [laughs].
So, essentially, you know, we should be screening patients.
And I think the sickle cell unit has been really good
at sending the patients to us in nephrology with --
especially if it was patients with persistent alminuria.
And we should be screening pretty early.
We should be repeating the test.
Because, you know, the problem with alminuria
is that many other things can cause it.
If you have a urinary tract infection,
if you just finished exercising, if you’re acutely ill,
these things can increase.
So, what’s really important is, you know,
serial checking and persistence.
And certainly, please send the patients to us.
I’m really happy managing our sickle cell patients.
And I think, you know, we continue to do --
continue checking.
I mean, early ACE initiation, hydroxyurea,
and a better argument, I should say,
for hydroxyurea initiation as well.
I’m going to shift gears, and I’m going to talk about AKI.
You know, so as an -- as another hat,
which is my intensivist hat,
you know, we see AKI a lot in ICU,
and it’s associated with mortality.
This is a series from Batte --
Anthony Batte and his colleagues in Uganda.
They found a high rate of AKI, 70 percent of children
and 10 percent of adults.
You know, of 185 people admitted with acute SCD pain, 60 --
33 percent of them, a third of them,
actually had AKI on admission,
and another quarter developed AKI.
And we kind of did a preliminary analysis.
Myself and Monika presented this last year at ASN.
And what we found was, amongst our patients,
144 persons admitted to -- with sickle cell disease.
Mean age was 27, 62 female.
Most of them were HbSS disease. A third were children.
We had a rate of about 20 percent had AKI.
Most of them were KDIGO stage 1.
And what we found is, like, you know,
blood transfusion was associated with AKI
in adults, but not children.
Bearing in mind, our numbers are small.
We actually are going to present the --
we’re actually in the process of analyzing the larger sample,
which is about 500 participants.
And those results are not quite ready yet.
Yes, I’m sorry, Monika [laughs].
So, again, this is something
we kind of looked at in our patients.
We looked at a case series of our people
that were admitted with AKI in COVID in sickle cell disease.
Especially with COVID admissions,
over half of them had AKI,
was associated with a long length of stay.
It was important as most of our patients were not vaccinated,
and most of them were not in hydroxyurea.
But certainly, blood transfusion again was associated,
as well as a decrease from baseline
was associated with AKI. And I think that’s it.
And CKD frequently complicates or occurs
in sickle cell disease, as we all knew.
Creatinine measures are really,
really poor biomarkers for kidney function.
Consider using the EKFC equation,
which is available online, and, you know,
it highlights the need for biomarkers in kidney disease,
especially in sickle cell disease.
We know that hydroxyurea and ACEs may reduce progression,
but we may need to look at,
like, newer disease-modifying drugs,
so SGLT-2 inhibitors, MRAs. More recently,
endothelial-1 receptor antagonists.
So that would be kind of something that’s interesting.
It’s kind of changed the shape of IgA nephropathy.
But I think we need new therapeutic targets, right?
So, kind of understanding the targets and pathways
in sickle nephropathy.
AKI occurs frequently,
and we need to kind of have longitudinal studies
looking at the impact of AKI events in sickle cell disease.
I’m really proud of myself
because I finished in one minute.
[laughter]
[applause] So, thank you, guys.
Angela Rankine-Mullings: Thank you so much, Dr. Fisher.
And we’ll just take two questions [laughs].
Male Speaker: Yeah. Great talk.
I -- I’m just curious if you thought about the risk
of renal medulla carcinoma in sickle cell patients
and how we might be able to modulate that,
maybe with some of these therapies
or even with fetal hemoglobin induction.
Lori-Ann Fisher: Right.
So, yeah, that’s a really good question.
And I haven’t found -- I actually looked around,
looking at data on this,
and I haven’t really found anything.
And I suspect, because, you know,
the renal medulla carcinoma is,
you know, repeated ischemic events.
If we can reduce that progression,
even understanding more of the endothelial dysfunction
that happens in sickle nephropathy,
we could actually modulate that.
And I think that’s a course for future studies on this.
Manu Platt: Yes. Hi. This was really cool.
Lot to learn, and I’m interested in the sickle nephropathy
and endothelial part.
But one thing we’ve been talking about here
are large arteries and their issues with sickle cell.
What do you all see with the renal artery
with sickle cell complications?
Lori-Ann Fisher: Oh, that’s a really good question.
And I think the problem with that
is that we don’t look at it, right?
So, I mean -- and if -- we talk about non-sickle cell disease,
even diabetic kidney disease, it’s microvascular,
but also macrovascular changes which happen.
And that’s pretty well documented.
But we don’t really look very well at,
like, what happens with large blood vessels.
We know that, you know, there may not be much --
there’s not much accelerated atherosclerosis
or any changes in blood flow, but certainly, you know, again,
another area to kind of look into
because we haven’t really --
we seem to -- as nephrologists, we’re alminuric.
We like alminuria, but we don’t look
at other big kinds of things
that may influence renal function.
Angela Rankine-Mullings: Thank you so much.
[applause]
Our fourth and final speaker is Dr. France Pirenne,
and she is from the University Paris Est Créteil, France.
She will speak to us on alloimmunization
and hyperhemolysis. Help me welcome her.
[applause]
France Pirenne: It’s this one? This? Okay.
Angela Rankine-Mullings: Yeah.
France Pirenne: Okay.
Thank you very much for the invitation
to speak about this topic.
And back to the French accent also [laughs]. Does it work?
Angela Rankine-Mullings: [affirmative]
The other one. The other.
France Pirenne: Oh. Okay.
So, the first description of all the characteristic features
of the sickle hemolytic transfusion reaction syndrome
dates from 1997. And after the transfusion,
the patient developed vaso-occlusive symptoms
with reticulopenia
generally that worsen the hemolytic anemia.
And generally, in the very severe case,
there is the post-transfusion hemoglobin is below.
It doesn’t work.
Angela Rankine-Mullings: No. It needs to be --
France Pirenne: Oh, okay. I have to [laughs]
-- so the post-transfusion hemoglobin
is below the pre-transfusion hemoglobin level.
It is the reason why we speak about hyperhemolysis.
So, the hyperhemolysis, the most severe form,
is because of the hemolysis of donor red blood cell,
but also with the destruction of the own patient red blood cell.
It’s called bystander hemolysis,
and it is increased the low level of hemoglobin
by this reticulopenia.
So, a new transfusion can exacerbate the hemolysis.
And when we performed the immunohematological workup,
we found alloantibodies but also autoantibodies.
And in many case, which is quite enigmatic,
no detectable antibodies.
There could be a gradual improvement in some cases,
and it’s frequently recurrent situation.
So, the known risk factor for this syndrome
has been described in many theory,
case theory of this accident.
Generally, the main risk is when patients are transfused
for an acute or punctual
[phonetic sp]
indication and when they have history of alloimmunization,
history of this transfusion reaction,
and generally, they have been transfused
with a few units in the past. And infection has been shown
also as an independent risk factor
for the post-transfusion hemolysis.
So, classically, the trigger of a post-transfusion hemolysis
is the --
is because of the reappearance of evanescent antibodies
through reexposition of -- to the antigen.
So, alloimmunization has really a pivotal role in this reaction.
And the rate of alloimmunization
is particularly high in sickle cell transfusion,
first, because of difference between --
in blood group between donors and the patient.
And when donor -- when patient --
Black patients are in a European environment,
there is different for the common antigen.
Frequently, the patient is negative for big C,
big E, JKB, Duffy,
which we spoke about Duffy before, big S.
There is also a characteristic.
There is many what we call partial antigen
in the RH blood groups. So, a partial antigen is defined
by the absence of some immunogenic epitopes.
Then when the patient is exposed to the complete molecule,
it can produce antibody against the missing immunogenic epitope,
which explains the production of anti-RH in patient
despite RH matching and in various high incidence,
for example, of partial D in Black individuals.
There are also specific rare blood types.
A rare blood type is defined
by the absence of expression of high-frequency antigen.
When a patient carry a rare blood type,
when you receive common blood,
it’s always exposed to the high-frequency antigen
and can produce the antibodies leading, generally,
to transfusion deadlock.
And the last characteristic
is what we call low-frequency antigen.
So, individuals of African ancestry
have many low-frequency antigen expressed.
We say low frequency in reference
to the European population.
But it’s not low in this population.
Then the mismatch can be very frequent
if a patient receives blood from a Black donor.
But the problem is that the antibodies are not detectable
at the common screening test because the red blood cells
that are used do not express this antigen.
So, the second very important factor for a higher rate
of alloimmunization is inflammation.
It has been known for a long time in the murine model.
But inflammation is a risk factor for alloimmunization.
And it has been shown also in patients
that red blood cell alloimmunization is influenced
by the recipient inflammatory status
at time of transfusion in sickle cell disease patient.
So, the rate of alloimmunization is quite -- it’s very high.
It’s between -- depending on the study,
depending on the transfusion protocol
in the different country,
it’s between 30 and 50 percent of patients
who are allo immunized.
In our last survey in France, among 6,000 patients,
27 percent of the patient were immunized.
So, not all patients get immunized
when exposed to foreign antigen.
We can say that there is a high and low responder,
and the characterization of these two population
would allow to apply preventive measure to high responder only,
such as to extend the matching to RH/K.
It’s done for everybody, but also to Duffy,
JK, and MNS, the other immunogenic group,
or also to provide additional immunosuppressive therapy.
However, on a routine basis,
there is no easy way to differentiate,
at first opportunity, a patient who is high or low responder.
There have been many study
on the immunogenetic background of the patient,
but these results are very interesting.
It cannot be used on a routine basis.
So, the only way we have is we know
that an immunized patient is a high responder.
It will produce, again, more antibodies.
And also, we could show on a very big cohort
that after transfusion of 20 RH/K match red blood cell,
when the patient did not get immunized
against the other blood group system,
it could be considered as low responders
and not be longer get immunized.
So, alloimmunization is very important
in the trigger of this reaction.
However, antibodies are not always detectable.
In many cases, there is no antibodies.
And also, very important, the severity of the reaction
is not correlated to the type of antibody
and also to the presence of antibodies.
And it was shown recently that extended phenotyping
prevention to Duffy, JK, and MNS
does not always prevent against this reaction.
So, there is [laughs] an enigmatic mechanism.
We try to speak about it a little.
So, no antibody -- or no detectable antibody
or no antibody at all.
It’s likely also that sometimes it’s not the good time
for the screening test, so it has to be repeated.
Also, it could be that there is a low concentration
under the screening test sensitivity.
Flow cytometry could be used, for example,
to find the antibodies.
And also, these -- there are these antibodies
I spoke about against low-frequency antigen.
And for that, we have to use a specific red blood cell
carrying the antigen to find these antibodies.
However, many cases are described
with no antibody at all, despite repeated workup.
And we know that rituximab do not prevent always DHTR
in sickle cell disease.
So, it can be also an indirect proof of situation
with no antibodies. Then what is it?
So, it is likely that DHTR with hyperhemolysis,
the most severe case of DHTR, is like a two-hit phenomenon.
You know, the first hit is the background of the patient
that we are going to speak about with heme,
activation of complement, and many other things.
And the second hit is the antibodies,
even at very low concentration,
or maybe something else that we do not know about yet.
So, it’s important to understand the destruction pathway
and the potentiating mechanism to get preventive measure.
But we don’t know --
there is many gap in our understanding, unfortunately.
So, the more -- the most important way
to destroy the red blood cell is the complement.
The complement has a very important role.
And when red blood cells are sensitized with the antibody,
it is the classical pathway, classically, that is activated.
And there is two ways for the destruction of red blood cells.
First, if complement is activated to C3b,
the complex are destroyed by the macrophages
in the spleen or in the liver.
And the second way is when complement is activated
to the membrane attack complex,
it is an intravascular hemolysis,
and it’s generally the more severe situation.
So, in sickle cell disease, there is a heme circulating.
And it has been shown that heme can recruit the macrophage
in the spleen, hence seeing the possibility
for the sensitized red blood cell to be destroyed.
So, it is one potentiating mechanism.
And it has been shown also that
the circulating free hemoglobin S
can induce monocyte activation.
So, in everybody,
and also in patients with sickle cell disease,
there is a permanent low-level activation
of the alternate pathway. And it has been shown that heme,
which is produced by the intravascular hemolysis,
can interfere with complement factor, the protector --
the protecting factor against the activation,
and also intravascular hemolysis
activates complement via cell-free heme
and also heme-loaded microvesicles.
So, there is an increase in potentiating of this pathway.
It’s likely that there is increased potentiation
of this pathway in --
of intravascular hemolysis in sickle cell patients.
So, this is just a case, a reporting case,
showing that an increase of a BB molecule with sign --
which signed the activation of the alternate pathway
in a case of hyperhemolysis.
So, it could be that there are other potentiating mechanisms.
For example, it’s like --
we studied the effect of the sickle cell plasma
on stored red blood cells, those red blood cells
that we are going to transfuse to the patient.
And we show that when we take plasma from acute patient,
this plasma induce increased
senescence of stored red blood cell
as compared to steady-state patient and also to control.
So, we want to know which component
of the plasma of acute patient is responsible for this effect.
In fact, we do not know yet [laughs].
Maybe heme. What else?
So, we wanted to know if there was something related
to the proinflammatory disease.
So, we do -- we did the same experiment
with the plasma of sepsis patient
with non-sickle cell disease.
And in that experiment, we did not see the same thing.
Only the age of red blood cells was correlated
with an accelerated senescence in vitro.
So, it’s not something linked to the inflammatory situation.
Another potentiating mechanism.
So, you can see, it’s a lot of question.
I don’t -- I do not have a response.
It’s maybe G6PD deficiency. So, it is very frequent
to have G6PD deficiency in Black individual.
And it was shown that G6PD deficiency red blood cell unit
were associated with decreased post-transfusion red blood cell
survival in children with sickle cell disease.
That was a study in patient transfused chronically.
We do not have data correlated to hyperhemolysis
or increase of hyperhemolysis
when we transfuse patient with G6PD deficiency unit.
But it is -- we know that the blood quality for transfusion
is not as good when the red blood cell --
when the donor has G6PD deficiency.
And in a cohort of Black donors,
we could see that 14 percent of the unit had G6PD deficiency,
which is -- which was expected looking to the --
over a study in over the country.
So now, there is --
I said that there was also the destruction
of the own patient red blood cell.
We call that bystander hemolysis.
So, it is the destruction of a patient --
the destruction of patient red blood cells represents,
finally, collateral damage in a conflict
that does not concern them in the first place.
So, when the donor red blood cells are destroyed,
there is a big release of free hemoglobin
A and free heme, and the natural defense against free hemoglobin
A and free heme are overwhelmed.
And there are also a huge amount of circulating C5b-9,
the end-activated factors of the complement.
Then the autologous red blood cells are also destroyed.
We know that.
And they release free hemoglobin S and free heme also.
But -- so what is the mechanism for this destruction?
So, it is known that there is a sensitivity of sickle cell,
red blood cell,
to complement attack with the potentialization
of the alternate pathway by circulating free heme.
And also, it has been shown that some molecules
at the surface of the red blood cell --
of dense red blood cell of sickle patient,
they have a decreased expression of protection,
such as CD35, CD55, and CD59.
So, it could be also the production of autoantibodies
when there is alloimmunization,
frequently, patients that produce autoantibodies,
that can participate through this destruction
of the autologous red blood cell.
And it’s not destruction,
but no more production, the reticulopenia.
And it could be the effect. It could be a necrosis --
a bone marrow necrosis through circulating activation --
circulating activated complement molecule,
as shown in this -- in a case report.
So -- and there is also a vicious circle of inflammation
with the release of this hemoglobin S
and this heme from the autologous red blood cells.
So, patients can die from this syndrome.
And the reason of death is generally organ damage.
So, with the release of hemoglobin
A, hemoglobin S, and heme in the blood flow,
it has an impact on the NO biodisponibility.
It has an impact on the --
it increase the damage of the endothelial cells
and the little pieces of membrane
that are released from the hemolytic red blood cell.
They induce, which [unintelligible] --
they induce a proinflammatory phenotype
of the endothelial cell.
Altogether, it is the reason why we have vaso-occlusive crisis,
but also kidney failure to the first organ,
which is fail -- which failed,
and also multiorgan damage at the end.
So now, how to prevent alloimmunization and
hyperhemolysis with what we know?
So, we have to know the history of the patient
to do recommendations. So, when a patient is transfused
for an acute or punctual situation,
if he has history of immunization
and history of DHTR,
we provide RH-matched red blood cell,
like for all sickle patient,
but we extend the matching to Duffy, JK, and MNS.
And when they have this very severe history
of hyperhemolysis,
generally, we discuss the additional --
an additional immunosuppressive therapy such as rituximab.
However, to apply this recommendation,
we have to know the history of the patient,
and we have also to prevent the risk of reexposure
of an evanescent alloantibodies with a very good file
with the history of the patient.
So now, how to treat this hyperhemolysis
when it’s very severe with what we know?
So, the goal of the treatment is to provide supportive care,
also stimulation of erythropoiesis,
especially for those with reticulopenia,
with erythropoietin mainly.
And we have to act on the destruction mechanism.
So, it can be the macrophage activity.
So, some -- generally, on the first basis,
we can give to the patient intravascular immunoglobulin.
But it doesn’t work very quickly,
and it can be also contraindicated
in sickle patient. And also, we can act.
It’s what we do in the very severe case
now on the complement cascade activation with eculizumab.
It’s important if we can do it
to eliminate the toxic component.
So, some case reports show you the use of plasmapheresis.
But to use plasmapheresis, we need to have a high --
good hematocrit.
Some study with hemopexin, haptoglobin are ongoing.
So, the anti-inflammatory action is very good.
So, you know, I know clinicians
do not want to use corticosteroids,
so there is a risk balance. But in many -- in few,
so not many, but some case report,
they use the tocilizumab as an anti-inflammatory action.
And after that, if we have to retranfuse the patient
because he has a very low hemoglobin level,
in all the case reports.
Each has its own, I would say, recipe.
Some use transfusion plus rituximab plus eculizumab
plus corticosteroids.
So, there is no consensus on all these treatments.
And it’s not real-based science with many.
It’s -- there is no really good studies that say,
"Oh, you have to do this" or "you have to do that."
So, for two years now, in our country
and at the national level,
we have organized multi-consulting meetings.
And so, we have clinician. We have transfusion specialist.
And so, we discuss the transfusion protocol
for patients who are at high risk
to develop post-transfusion hemolysis.
So, we always -- we discuss the indication,
but generally it’s maintained.
So, we discuss the transfusion protocol.
We discuss additional therapy and also we give advice
for very close post-transfusion monitoring
to be able to detect very quickly
if a patient developed a new --
despite all this record, all the prevention,
if the patient developed again a post-transfusion hemolysis
to be able to act very quickly and to treat if it’s severe.
So, to finish my last slide, how to advance our understanding
of the pathophysiology of DHTR and hyperhemolysis
in sickle cell disease.
So now, we are on the process to organize a registry
for all the case in France of DHTR.
Just to give you a number,
we have about 30,000 patients in France.
Every year, we have about 5,000 patients who are transfused.
And last year, we had 45 declared cases --
and I think it’s underappreciated --
45 declared cases of DHTR.
So, it’s going to be very interesting
to collect all the data of --
clinical and biological data of the patient
and also to collect a sample to be able to do more studies,
such as, for example, the exploration of a complement
and to revert all the subunit,
submolecule of the activation, some --
to do some complement genetic in patient also,
to explore what we have in the plasma of patient,
an example, to do proteomic in this plasma of patient
who developed this very severe hyperhemolysis,
and also to do very sensitive technique
to really know if really we do not have antibodies
using flow cytometry
and also looking to the different
characteristic of the antibodies.
And what about IgA? Nobody look at IgA.
In fact, we should look at IgA
because they are in autoimmune hemolytic anemia,
very severe case with IgA that give Coombs negative.
So, it’s -- why not [laughs]? And also, murine studies,
because there is no murine studies
on this specific problem.
So, I’m done. And I would like to thank my --
all the people of my research teams
in Henri Mondor Hospital and all the clinicians.
And we all work together to try to improve
transfusion for this patient --
safety of transfusion for this patient.
Thank you for your attention.
[applause]
Angela Rankine-Mullings: Thank you.
Thank you so much, Dr. Pirenne. We will take a few questions.
We are very late into lunch. So --
[laughter]
Marilyn Telen: I don’t know.
So, well -- so I think so much valuable data on the syndrome
has come out of France. And this was a wonderful talk.
I wonder what you think, though, about the frequency
with which we can’t find antibodies to explain
what appears to be hyperhemolysis
in which I think, I agree, I think is hyperhemolysis.
I’ve spent a lot of time telling people
that not finding an antibody
doesn’t mean it isn’t hyperhemolysis.
I mean, I guess by biases,
IgA is still a pretty rare reason why we can’t find it.
And I wonder whether you think that there’s just,
you know, phenomenal clearance of the antibody
because it’s very avid and it clears the red cells.
There’s no antibody excess.
You know, are there particular antigens
that are just sometimes hard to detect?
The antibodies too, Kidd is one which,
at least by the literature,
they say it is hard to detect sometimes.
So, you know, is it titer? Is it specificity?
Just wonder what you think.
France Pirenne: Yes.
We had a prospective study a long time ago.
And we follow -- yes, because it can be --
it can disappear with the red blood cell
if it’s bound to the red blood cell, the antibody.
But we follow with screening test
and sensitize screening test after one month, two months,
because generally it can reappear,
and we didn’t find anything. And also, in many --
we are not the only ones to say that we do not find antibodies.
So, there are also this antibody against low-frequency antigen.
Now, we try to look for them.
Swee Lay Thein: Yeah.
France Pirenne: But sometimes we have one like that,
but there is really a case where there is nothing.
So --
Swee Lay Thein: Yeah.
Marilyn Telen: So, the cooperative study
of sickle cell disease
showed very nicely that antibodies disappear
quite frequently.
France Pirenne: Yes.
Swee Lay Thein: France, that was really very good.
Thank you so much. I have two comments to make.
One is that I think we --
it’s very important to clinicians who are not aware --
France Pirenne: Yeah.
Swee Lay Thein: -- of DHTR that when a patient comes in --
France Pirenne: Yeah.
Swee Lay Thein: -- with acute pain or crisis,
first question is, when did you receive a transfusion?
Did you receive one recently?
France Pirenne: Yes.
Swee Lay Thein: Because that could trigger
a mimic SL acute pain.
France Pirenne: Yeah.
Swee Lay Thein: That’s one thing.
Secondly, during VOC, they should always measure LDH.
France Pirenne: Yes.
Swee Lay Thein: And always do a HPLC --
France Pirenne: Yes.
Swee Lay Thein: -- especially when they transfuse.
Because when you talk about DHTR, we see hemolysis.
We should see a parallel drop --
France Pirenne: Yes.
Swee Lay Thein: -- of the transfused hemoglobin A
and the hemoglobin S.
That’s -- I think this should be made clear
to the trainees and clinicians, so they’re aware of this.
And I often get so upset that they don’t do LDH, you know.
France Pirenne: Yes, yes.
And like that, we have a basic --
Swee Lay Thein: Yeah. France Pirenne: --
and if it’s increased, something happened.
Swee Lay Thein: Yeah.
France Pirenne: But you’re right.
I mean, I didn’t think about all that.
Swee Lay Thein: And then when the LDH is very high, 3-,
4,000 -- France Pirenne: Yeah, yeah.
Swee Lay Thein: -- then it’s time to give eculizumab.
France Pirenne: Yes.
Swee Lay Thein: That has a role in that.
France Pirenne: Yes.
Swee Lay Thein: The second thing is, in fact,
you and John actually did a very nice study
that was published maybe a year or two years ago.
And we’re working with him. And he actually found a locus.
I think it’s on -- I can’t remember the chromosome,
but it’s upstream of an immune response gene.
And there are people with that variant and then people without.
And these are kind of more common
in people of African descent or Black people.
And this may be account partly for the reason
why alloantibodies occur more commonly during,
you know, acute -- when they’re transfused,
during acute pain, when inflammation is high --
France Pirenne: Yes.
Swee Lay Thein: -- and also, why in Black people.
It’s worth looking at your patient cohort.
France Pirenne: Yes, yes, yes, yes.
You should give me the paper in that.
[laughter]
Male Speaker: Should I go, or should you go?
Female Speaker: No.
Male Speaker: All right.
Well, some of what I wanted to say has been,
in a sense, addressed slightly by Swee Lay.
I just wanted to ask you a few things, though.
So, in your high responders versus your non-high responders,
if your hypothesis is correct,
that is probably driven to some extent by heme
or hemoglobin S perhaps, then we would expect at baseline
that there should be a difference in those levels
between both groups. Go ahead.
France Pirenne: No.
What I say about hemoglobin S and heme --
I said that it potentiate the hemolysis,
in fact, when it occur.
Male Speaker: Right.
France Pirenne: But I didn’t speak about alloimmunization
versus the circulation of free heme
and free hemoglobin S.
There is only one study from Karina Yazdanbakhsh,
from the New York Blood Center. She showed that heme can --
it’s an immunomodulator for alloimmunization,
but it’s quite complicated the way it works.
In fact, we could think that it’s increased, but not always.
So, it’s -- yeah. So --
Male Speaker: Right. All right.
So, my follow-up question is that comes from your side,
in terms of your algorithm for screening individuals
to prevent hyperhemolysis
as part of your treatment options moving forward.
And so, in the absence of the --
in the observations, for example,
that the extended matching for the extended heme --
RBCs antigen, they don’t necessarily prevent
or identify individual with any degree of specificity
who are likely to develop the hyperhemolysis.
From a family medicine perspective,
then we would say then perhaps one needs to comment
on the cost effectiveness of actually doing that,
vis-à-vis just depending on the history.
France Pirenne: Yeah.
But we do not do that to many, many patients, you know.
We do that -- we extend -- once a patient, for example,
I ask to produce anti-JKB,
which is quite frequent in our cohort,
we know that is going to continue to produce antibody.
For specific patients, we try to extend the matching,
you know, especially if they are patients who are --
not transfused a lot.
But for the chronic patient who are transfused,
and everything is going okay, if I want antibody,
we just take into account the antibody,
and we do not extend.
It’s really when they are transfused
for an acute indication that we do that.
We try to do that. But yes, in many case,
maybe in 50 percent of the case --
because we did it quite often --
a score in 50 percent of the case,
we will not develop -- we can --
they would have been okay with regular protocol.
But we don’t know who are these 50 percent
who would have a good follow up.
Swee Lay Thein: You want to go next?
I have another comment to make. You want to go next?
[laughter]
Female Speaker: Okay. Yes.
Well, I think this is a general comment.
You’re obviously interested in this topic.
And when Swee Lay talked about the need to do LDH and HPLC,
I said that’s where we practice.
The patient will not be able to --
France Pirenne: No. Female Speaker: -- do this test.
So, I’m just wondering if we are missing an opportunity,
especially with the presence of disease registries now
and trying to follow our patients prospectively,
if this is not something that we should look
at more closely in areas of high burden,
you know, by working together maybe.
France Pirenne: Yeah.
Female Speaker: Thank you.
France Pirenne: So, you know the previous talk about
having kidney failure in patient transfused, it’s been --
it’s likely because they got a reaction
to transfusion, you know. So, it’s --
Swee Lay Thein: Exactly.
France Pirenne: Yeah.
Swee Lay Thein: I can tell you, it’s a very scary time
when you manage somebody with DHTR,
and hemoglobin fall to 2 -- France Pirenne: Yeah, yeah.
Swee Lay Thein: -- and the clinicians
want to transfuse,
and I said, "Only if dying, okay?"
France Pirenne: Yes.
Swee Lay Thein: "Because you’re going to make problems worse."
France Pirenne: Yes.
Swee Lay Thein: One thing I like to ask you, France.
I manage patients with DHTR too, except the LDH is not so high.
It’s extravascular. I can see the spleen.
France Pirenne: Yeah.
Swee Lay Thein: No, the liver, not the spleen.
France Pirenne: Yeah.
Swee Lay Thein: The liver going right down to the pelvic area.
France Pirenne: Yes.
Swee Lay Thein: So, it’s almost all the blood that we transfuse
has gone to the liver.
Can you differentiate why some patients have this extravascular
and some more intravascular?
France Pirenne: No. I don’t have a response.
And really, it’s something that --
I think that with this registry, you know,
with every clinical staff and everything --
Swee Lay Thein: Yeah.
France Pirenne: -- maybe we will understand --
we can do cohorts. We can divide patient with this
and that and maybe understand better what happened.
Because right now, it’s like [laughs] --
Swee Lay Thein: Yeah.
France Pirenne: Yes.
And it’s only case report in literature and also --
Swee Lay Thein: Yeah, yeah.
France Pirenne: -- it’s difficult to --
there is no history of the patient,
so we don’t know exactly what -- yeah.
Angela Rankine-Mullings: Thank you.
France Pirenne: Sorry [laughs].
Angela Rankine-Mullings: Thank you very much.
France Pirenne: Yes. Thank you.
Angela Rankine-Mullings: Okay. Okay. Sorry.
John Tisdale: Go ahead.
Angela Rankine-Mullings: Well, I was about to end this session
because it’s our lunch. John Tisdale: Yes. Sure.
Angela Rankine-Mullings: Okay. Thank you so much.
So, we thank all our speakers.
[applause]
Thank you for participating. Our return time is 1:40 p.m.
John Tisdale: So, while you’re getting settled in
with finishing up your lunch,
we’re going to go ahead and get started.
Our first speaker is Wynona Coles.
Nona currently serves as a senior technical lab manager
for both the cellular molecular therapeutics
and the molecular and clinical therapeutics
branches within the NHLBI.
And she has been actually screening individuals
with sickle cell disease for research protocols
for decades now. And she’s going to talk to us
about the five most frequently asked questions.
Nona?
[applause]
Wynona Coles: All right. Good afternoon.
Female Speaker: Good afternoon.
Wynona Coles: Thank you for that, John.
Thank you for the skiff organizers for inviting me
to speak this afternoon.
So far, everything has been very lovely.
I’ve enjoyed wonderful conversations,
meeting new faces.
I’ve enjoyed carpool karaoke with Manu.
[laughter]
I’ve seen some old faces. Not that their faces are old,
but it’s been a while since I’ve seen them.
[laughter]
So, it’s been lovely to see all of you.
So, thank you again.
So, I’d like to share my experiences and observations
as the transplant referral coordinator for NHLBI cellular
molecular therapeutics branch at the NIH on John Tisdale’s
and Courtney Fitzhugh’s clinical teams
and present the common questions we receive
from patients who are considering transplant
as a curative option for their sickle cell disease.
We receive referrals from many sources,
some from other physicians
who are aware of the transplant clinical trials at NIH.
Online searches have led to the largest referral source,
with some patients emailing directly to me
or to Dr. Tisdale
or contacting our office of patient recruitment
using the clinicaltrial.gov website.
We’ve also received referrals from Swee Lay’s
natural history of sickle cell disease screening study.
And now, after 20 years and over 100 transplants,
a large number of referrals are coming by word of mouth.
Patients and their family members are openly sharing
their transplant experiences in their communities,
support groups, and on social media.
Roughly, a quarter of our transplanted patients
are actually international and, again,
have found out about our clinical trials online
or through word of mouth.
So, the first question asked is sometimes
actually from the transplant team to the patient.
How much do you know about what a transplant is?
Even with information widely available on the internet,
I still think it’s hard to visualize how this is done.
Is there surgery? Will I be awake? Will it hurt?
What is the difference between a bone marrow transplant
and a stem cell transplant?
Our team of staff clinicians, advanced practitioners,
and research nurses do a great job
of providing this pivotal education
and making it easier to understand.
So, bone marrow transplant, stem cell transplant,
hematopoietic stem cell transplant, the adage,
a rose by any other name is still a rose, applies here,
and these are used interchangeably.
Specific to sickle cell disease,
a bone marrow transplant is a procedure
that can cure sickle cell disease
by replacing abnormal bone marrow stem cells
with healthy ones from a donor.
We oftentimes meet a prospective patient virtually first,
and using graphics are helpful in educating patients
on how the bone marrow works as a factory
producing all the blood stem cells for the body.
I like how Dr. Mathew Hsieh
sometimes describes it as cracking open a chicken bone
and what’s inside [laughs], the part that we enjoy the most.
We also let the patient know how in sickle cell disease,
the red cells are abnormal,
containing defective sickle hemoglobin,
which distorts the shape of the red cells,
blocking blood flow,
and causing many of the complications of their disease.
Usually, our virtual meeting will not have --
will not only have just the patient present
but also their potential donor, if applicable.
So, we explain the process of collecting
the donor’s peripheral stem cells via apheresis,
or in the case of gene therapy,
the collection of their own stem cells using the same procedure.
After all the basics are discussed,
the next slide is what makes me eligible for a transplant.
Next question, sorry.
I try to be sensitive to those who seek participation
in a clinical trial,
not to dismiss how they perceive their illness.
Patients may ask, "How sick do I have to be for a transplant?
Why am I not eligible?
Why do I have to wait until my disease worsens?"
I explained that in clinical trials,
we evaluate whether the potential benefits
outweigh the potential risks in determining eligibility.
Transplant is not without significant risk,
and therefore determining disease severity is essential.
So, I start by reviewing lots of medical records,
trying to determine disease severity
and if standard treatments were maximized
before advancing to an experimental therapy.
Mild disease would indicate that current medical treatment
is working by showing little to no organ damage,
infrequent hospitalizations,
and that the patient is able to achieve their life goals,
going to school, working,
participating in activities that they enjoy.
Skip over the moderate and jump to the severe disease,
which on the other hand
is indicated by debilitating complications such as stroke,
frequent hospitalizations, or ER visits.
Records would show permanent or progressive organ damage,
sometimes multiple organs requiring intensive management.
Reviewing past medical history and lab results can show us
if standard treatments are effective.
And the moderate is kind of somewhere in between.
This next slide shows the hematologic changes
with consistent use of available standard treatments.
The first block shows common lab values if untreated.
The next block shows the lab changes
by introducing hydroxyurea,
which was approved in March of 1998
for treating sickle cell disease
and its corresponding lab changes.
If there’s a good response, there can be as much as a 20
to 30 percent displacement of hemoglobin S,
leading to reduced pain and hospitalizations.
L-glutamine was approved in 2017 to reduce acute pain,
including chronic pain,
potentially leading to reduced hospitalizations
but no real hematologic changes.
In 2019, both crizanlizumab and later voxelotor
were approved similarly to reduce pain.
However, some five years later,
their efficacy is still questionable.
You can see -- you can also see that there is little
to no hematological changes for crizanlizumab,
but voxelotor may provide a bump to total hemoglobin.
So, nearly 30 years later, even with newly approved drugs,
we still have not found a pharmacological treatment
as effective as hydroxyurea.
So, when someone reaches out asking about transplant,
is it -- it is recommended that they have been treated
with some standard sickle therapy,
preferably hydroxyurea, for a minimum of six months
before thinking about a clinical trial.
But what are the options
for those who are intolerant to hydroxyurea
or do not have access to it or other treatments,
or even for those who did respond initially
but now have reached a plateau
in response to their disease symptoms?
Is the best next option now transplant?
Understanding the patient’s transplant goal
is also important to make sure
that expectations are reasonable.
Some organs may have irreversible damage
from complications such as stroke.
Transplant will not restore joints destroyed by AVN.
Borderline kidney function may actually worsen with transplant.
And so, transplant education
is essential to provide realistic outcomes.
Right now, we don’t know if transplant
is the best option for everyone.
Long-term studies are needed to decide
what provides the best outcomes.
After disease severity has been identified
and expectations discussed, the next question is,
what type of transplant is best.
Curative options for sickle cell disease
can be divided into donor versus non-donor
or allogeneic versus autologous transplant.
Decades after the first allogeneic
bone marrow transplant in sickle cell disease
confirmed that indeed a cure is possible.
Researchers have been refining the treatment
to make it safer and more effective and more accessible.
Clinical trials have shown
that even patients with severe diseases
can tolerate milder conditioning regimens
with successful outcomes.
Therefore, the challenge therein lies
in finding a suitable donor.
Data has shown that successful outcomes
are critically tied to donor selection.
Currently, having a full HLA match related donor
is the best choice,
but there is only a 25 percent chance
that a sibling who shares the same parents
may be a full HLA or tissue match.
That percentage increases to 50 percent
for haplo-related donors,
where a healthy sibling who was not a full match,
a parent, or a relative can help to enlarge the donor pool.
Donors with sickle cell --
with sickle traits are not excluded
and are equally successful as donors without.
But donor selection goes beyond
just donor-recipient histocompatibility.
Other factors such as donor age, size, gender, viral status,
and ABO compatibility also play a role in transplant outcomes.
Gene therapy, on the other hand,
eliminates the need for a donor altogether.
The patient’s stem cells are genetically modified
in several different ways
to cure them of sickle cell disease.
Gene addition involves adding one or more copies
of the normal beta-globin gene like bluebird bio’s LYFGENIA,
which was recently FDA approved in the U.S.
for treatment of severe disease.
Gene edit transplant changes the existing gene
to alter production of fetal hemoglobin.
CRISPR Therapeutics’ CASGEVY reactivates gamma globin
to increase fetal hemoglobin, which is not sickle,
thereby curing the patient by reducing or eliminated --
eliminating sickle complications.
Lastly, gene correction is the next level in gene therapies,
which works by actually correcting the sickle mutation.
Once we know what type of transplant a patient
is eligible for,
we explain the procedures involved to prepare
and go through transplant. For the allotransplants,
the stem cells are collected from the donor.
Meanwhile, for the patient,
they start to undergo their pre-transplant testing,
like dental exams, pulmonary function tests,
bone marrow biopsies, social work, et cetera,
and possibly auto collection for backup from the recipient
is occurring simultaneously.
This may take up to about two to three months to accomplish.
After all the pre-transplant tests
and procedures are done,
the patient is admitted to the hospital for transplant.
Month-long admission includes preparing the recipient
in the first half of the hospitalization,
excuse me,
by using non-myeloablative conditioning regimens
that make space in the marrow --
that’s so by using chemo or radiation --
reduces or lowers the immune system,
either, again, by chemoradiation and antibody therapies,
and then medications to prevent graft versus host disease,
such as sirolimus or post- transplant cyclophosphamide.
Infusion of donor stem cells is typically one day,
and the remainder of the hospital stay
is waiting for the donor cells to engraft.
After discharge, patients return to clinic for frequent
monitoring for transplant-related complications
such as viral reactivation, GVHD monitoring,
and to adjust transplant medications.
After about 100 days after transplant,
the patient is typically stable enough to return home.
For the auto transplant, the hydroxyurea is actually
stopped in advance of their auto collection,
and the patient is started on red cell
exchanges for about two months.
Same thing, part of the preparation is going under --
undergoing all the pre-transplant testings
that I mentioned before.
After the auto collection, this time,
instead of banking it, the cells are actually sent off
to manufacturing for genetic modification.
And this may require more than one collection
to reach adequate cell dosing.
When the patient is admitted for their month-long stay,
the recipient now receives full myeloablative conditioning
to make enough space in the marrow
to give the genetically modified stem cells advantage to engraft.
In the future, the hope is that this can be achieved
using antibody therapy
and avoid the toxicity associated with chemo.
These modified stem cells make --
then make healthy red cells.
And similar to allotransplant, once discharged,
the patients are followed closely as an outpatient
for any post-transplant complications for up to 90 days.
Next question we may receive
is what are the possible side effects?
This slide can be divided into those side effects
that may be considered par for the course,
such as nausea, vomiting, hair loss.
So, those are the ones that we anticipate will likely happen.
Then on the other side are the ones that we try to avoid,
such as graft versus host disease,
the secondary malignancies, transplant failure,
infertility, seizures, and tragically, even death.
These risks are higher or lower
depending on the degree of conditioning.
So, this slide shows the difference
between our partial or mini bone marrow transplant
versus the full transplant.
You can see the differences in the success rates,
what can happen with blood counts, infections,
the incidences of graft versus host disease,
and other complications such as thyroid disease.
Fourth common question is how successful
is the transplant?
The answer may be influenced by factors such as age of recipient
at the time of transplant, organ injury, donor selection,
and conditioning regimen used.
But overall, the success rate is favorable.
90 to 95 percent for a matched sibling donor transplant,
80 to 90 percent success rate for haplo,
and then 80 to 90 percent of gene therapy
will have some kind of effect,
like increased in the modified gene hemoglobin T87Q
or increased fetal hemoglobin,
depending on type of gene therapy.
Overall, the younger the patient and the younger the donor
seem to be the best combination for good transplant outcomes.
Last question is what is the recovery process like?
I touched on this a little bit before,
but the post-transplant clinical trial
is essentially the same for most transplant
with frequent monitoring
for both allo and auto transplants,
and that goes up to about 100 days after transplant.
They may have a repeat of pre-transplant testing,
like we might repeat the echo [laughs],
the pulmonary function testing.
I’m telling you; it comes back to bite you right at the time.
[laughter]
Bone marrow transplants, bone marrow biopsies,
not only for clinical purposes now, but for --
especially as it relates to clinical research trial
where we’re evaluating the long-term effects
of transplant on organ function over time.
There is more intensive follow up required for gene therapies,
with the U.S. FDA mandating at least 15 years
of follow up post-transplant.
Medications, for some patients,
they may leave on more medications
than they actually came in with,
so that requires [laughs] a lot of education,
especially about their immunosuppressive medications,
antivirals, antibacterials.
So, some of these meds may stay on
until the patient is revaccinated,
if needed for the allotransplant.
One of the previous slides again
talked about thyroid dysfunction.
So, there may be some meds that have to be added
that they hadn’t expected, like high blood pressure
or a number of other health issues
as it relates to the transplant.
Education on the importance of post-transplant medication
adherence is necessary.
I always emphasize how failing to take post-transplant meds
as prescribed can attribute to even losing the graft.
To go through this whole thing only to lose it for a reason,
such as not taking your medications, would be tragic.
And in fact, Dr. Courtney Fitzhugh
considers a patient’s medication compliance before transplants.
It’s a good gauge to see
if they will be compliant post transplants.
She doesn’t play that.
So similar to my slide that showed key hematologic
changes to the standard sickle cell treatment --
treatments, this slide now shows
the hematological changes on hydroxyurea,
red cell exchange, and then the final three boxes
based on auto versus allotransplant.
So, my final thoughts as a transplant referral coordinator.
My goal is to provide as much education as I can
so that patients can make an informed decision
to review not only the potential benefits
but also to discuss the potential risks.
Dr. Mathew Hsieh often says that during these talks
that it’s our job to kind of be the bad guy,
the Debbie Downer, and emphasize the risks,
because this is not a decision to be made lightly.
Matt provides other options for consideration,
even when the option may not even be transplant.
Lastly, making sure that patients have realistic
expectations and understand
that the goal is to move the needle towards overall
improved quality of life.
So, I’d like to thank you all for your time
and to the clinical teams
that I’m blessed to work with every day.
A special thank you to John for inviting me and for --
to Swee Lay for inviting me as well.
I’d like to thank Matt Hsieh for helping with the slides.
I’ve actually called him my Matt GPT instead of ChatGPT.
[laughter]
And again, just to John for supporting me
over these many, many, many years. Thank you.
[applause]
John Tisdale: I see the hands up already.
So, let’s start with Haydar and then Jane.
Haydar Frangoul: That’s great.
You did a great job explaining the story here.
So, what is your experience when you talk to patients
about a gene therapy versus an allo?
In allo, you can go to within a month.
While gene therapy, it’s a year before they get the product.
Although, on the back end, they recover much faster
because it’s an autologous graft.
What’s your experience in that
when patients are making decisions
between gene therapy and allogeneic transplant?
Wynona Coles: I mean, I think the way we’re headed
is going to be gene therapy. And I think for patients,
they also are kind of leaning in that direction
because they don’t want to have to involve a family member.
A lot of them are concerned,
"What’s going to happen to my donor
who’s decided to do this procedure?"
So, I think gene therapy is definitely the future.
And even the time thing
isn’t really that big of a difference for them.
I think they’re just more concerned about,
"Well, if I don’t have to involve my brother, sister,
my mom, dad, or whatever, I prefer that route, actually.
If this can just all be on me is what I would prefer."
Jane Little: Nona, that was really great.
Thank you so much.
You know, I looked at your slides,
which are -- some of which are great.
There was you or Matt. Doesn’t matter [laughs].
But, you know, not every center is going to have a Nona.
Like you’re not that common, I hate to tell you.
[laughter]
And I do believe that the personal discussions
are the most,
you know, important part of that counseling.
Are there any web-based tools that you found help you for --
you know, to help get people up to speed?
Wynona Coles: I wish there were [laughs],
because I do have a large backlog of patients
just to get back in touch with them.
No, I don’t. I don’t know of any.
I’m not aware of any. I’m happy to consider that for sure.
I think people now -- their phone is their friend,
is their tool. That’s what they use.
We’re starting to -- support groups are also great,
just talking to other people in the community.
YouTube podcast is just where a lot of people
are finding their information.
Now, as far as getting plugged into being able to enroll
into a clinical trial,
I think that part is still backed up.
So, you know, if we get referrals from mouth to mouth
or from a physician through our office of patient recruitment,
but it’s still a backlog, so we’re just waiting.
I guess I’ve heard other people say, you know, thankfully,
this isn’t a decision that has to be made overnight,
so that we do have a little bit of luxury of time
for you to consider the benefits and the risks of moving forward.
But yeah, Jane, I wish there was something like that,
but not that I’m aware of.
Jane Little: Thank you.
John Tisdale: Other questions?
Manu Platt: Thank you. It’s an easy one, Nona.
How does this conversation change if it’s a child,
and at what age do you explain it to the child
or just the parents? How do you make those decisions?
Wynona Coles: Yeah.
So, you know, obviously, it’s going to be the parents
that are reaching out to us for this.
But working with Matt and Emily Limerick,
Mary Lacy Grecco, Liz Harvey, they’re just phenomenal
with speaking even to the younger patient population.
They really do explain it in terms that they understand.
Obviously, when it comes to clinical trials,
we have assent from these pediatric patients.
We have assent informed documents
that it’s broken down into that level of understanding.
Also, at the NIH, we have a psychosocial --
social work department that’s responsible
for the pediatric donors,
making sure that they clearly understand their role too.
I think it’s pivotal for them to understand
that if they do this for their sibling
who has sickle cell disease and the transplant doesn’t work,
what kind of guilt does that put on that young child.
So, they have several counseling sessions
with the psychosocial group at NIH, which is key.
And then it’s just constant education
as much as we can for the younger kids.
We have a great pediatric department as well.
So, I think it’s just constantly having
that conversation with them.
Male Speaker: Yeah.
I was wondering if you could speak more
to the international referrals you get
and how you deal with that kind of more complicated issue
of an international patient.
Wynona Coles: Yeah.
International patients are great [laughs].
It’s always fun trying to figure out visas
and how they’re going to get here.
So, while we do it, and in fact,
we’re doing more and more international patients,
it just takes more in terms of logistics.
It’s really difficult to receive medical records that --
to help establish the eligibility criteria.
So, you know, we’re constantly being monitored to make sure
that all the patients are appropriately enrolled.
And when we have to review, you know,
handwritten paper documents that may have been, you know --
it’s just really difficult [laughs]
to get some of these documents.
And a lot of centers don’t even keep long-term documentation,
so that also makes it difficult.
I think what’s great from our point of view
is that we kind of just give international patients
benefit the doubt, right?
Because we understand that there’s all these challenges
to keeping medical records
and getting those medical records to you.
And so, we offer, at the NIH, for --
if you can get to NIH, then I think after that,
everything is pretty much covered.
So, of course, the transplant is covered.
Medications are covered.
In some instances, housing is covered.
Everything is covered.
So, it’s nice. So, it’s just getting here.
And then also the commitment of making sure that you can return,
because again, we’re collecting information and data.
And then we again assist with visa extensions
as long as you’re needed to be there.
So, we do have a good system all kind of set up
for the international referrals.
It’s just that we still need a lot of --
we still have a lot of physical barriers,
such as getting them here and then when they return.
So sometimes we have to make sure
that you can receive post-transplant medications.
Does your country take FedEx packages?
Do you have a physician that’s going to be able to feel
comfortable taking care of you, post-transplant,
in case there’s any long-term complications?
So those are things we have to check for.
John Tisdale: All right.
Wynona Coles: All right.
John Tisdale: Thank you so much, Nona.
Wynona Coles: Thank you.
[applause]
John Tisdale: Okay. So, our next talk
is a recorded talk from Julie Kanter,
who’s the director of the adult sickle cell clinic
at the University of Alabama at Birmingham.
So, if you can queue that up.
Julie Kanter: Hi. Thank you so much to the --
these are my --
hi.
Thank you so much to the organizers
for having me here with you today.
And I’m so sorry that I cannot be there in Jamaica
with you in person. My name is Dr. Julie Kanter.
I’m the director of our adult sickle cell disease program
at the University of Alabama in Birmingham.
And today, I’m going to talk about
how we measure the therapeutic efficacy of genetic therapies
for sickle cell disease.
Hi. Thank you so much to the -- these are my disclosures.
So, I hope at the end of this time,
you will have a better understanding
of why we’re using gene therapy for sickle cell disease,
though I think you’ve heard quite a lot about that already.
You will also have an increased understanding of the current
two genetic therapies that have been approved
by the FDA for sickle cell disease
and a few that are on their way down the pipeline.
And then, of course, our focus. We’re going to talk about
how we’re going to measure the therapeutic efficacy.
So, why sickle cell disease?
Well, I know this audience understands
the devastating complications of sickle cell disease.
It affects every organ, as every organ relies on blood.
And the downstream effect of pain
due to vaso-occlusion and tissue damage is truly horrendous,
and we need a better therapy to improve our outcomes.
But specifically, why sickle cell disease?
Because it is actually a genetic abnormality, as you all know.
And the idea is, if we could fix that genetic abnormality,
perhaps we can change or alter all of these downstream effects.
So, when we think about the current treatment
strategies for sickle cell disease --
and I do want to credit my colleague,
John Tisdale, for this fantastic slide --
we think about the many different drug treatments
that are both available now and coming down the pipeline.
We think about the importance of transplant
and allogeneic transplant specifically,
which is curative for sickle cell disease.
We also think about blood transfusions
and how impactful they have been on the care of individuals
with sickle cell disease.
And then the future of in-vivo gene therapies,
as well as our current gene therapies, gene addition,
and gene editing that have been approved.
So, what are the goals of treatment
with these genetic therapies in sickle cell disease?
Well, as everyone knows, and as I mentioned,
this is a genetic disorder.
So, in theory, our goal is to actually fix the gene
that causes sickle cell disease.
At current, none of our therapies actually do that.
However, they use different methods to reduce red blood cell
sickling by adding healthy hemoglobin.
This will help improve oxygen delivery,
eliminate or reduce hemolysis,
decrease adhesion within the blood vessels,
which, of course, should prevent vaso-occlusion,
reduce or eliminate blood vessel injury,
and prevent the organ damage
that is caused by all of those mechanisms I listed.
There are other goals of treatment as well.
These are related to function.
We want to improve or resolve fatigue,
pain, decrease the organ damage that causes so much discomfort,
improve energy due to improving anemia,
and then, of course, be able to improve attention, memory,
and focus and so many other functions
that are lost during complications of sickle cell.
So, let’s spend just a minute reviewing the current gene
therapies with a focus on the recent FDA approvals.
Lovo-cel is a one-time ex-vivo lentiviral vector gene therapy.
It introduces a beta-globin gene
modified for the production of hemoglobin
A, specifically with the mutation T87Q
that makes it a little more anti-sickling.
But very important, this does not remove or change
any of the existing genes.
So, we’d love the ideal goal of gene therapy
to actually fix the hemoglobin S mutation.
But this doesn’t do that,
and instead it adds a new gene that makes hemoglobin A.
These are the articles discussing lovo-cel gene therapy
that I’m going to reference today.
Then we have exa-cel, an ex-vivo gene editing therapy
that first uses electroporation and then uses CRISPR-Cas9,
which targets the BCL11A erythroid-specific enhancer.
By doing this, it can reactivate
hemoglobin F or fetal hemoglobin.
But again, we are not actually
targeting the hemoglobin S mutation,
instead reactivating fetal hemoglobin,
hopefully to overcome the amount of sickle hemoglobin
and lead to better outcomes.
How does it work?
Well, specifically, the role of BCL11A
is in globin gene expression,
and you can see here that it’s on chromosome 2.
And so, what happens normally is this complex results
in turning off fetal hemoglobin so that as adults grow older,
of course, we don’t have fetal hemoglobin.
Instead, by editing a BCL11A,
we’re able to actually turn that fetal hemoglobin back on
to produce healthy fetal hemoglobin.
I’m going to be referencing this paper today.
So, let’s compare these trials,
specifically looking at their points of efficacy.
I know you’ve already heard quite a lot about these studies,
so I’m not going to review this in detail.
Just here, showing the demographics
and patient characteristics side by side,
pointing out the genotype of individuals
who are included in the trial, the genotype for alpha-globin,
which we now know may change the outcomes of the trial,
as well as the number of individuals
who had adjudicated vaso-occlusive events,
serious vaso-occlusive events,
their total hemoglobin, and their stroke history.
Importantly, only individuals in the lovo-cel trial
had a history of prior overt stroke.
Now, I want to talk more about the results.
First, focusing on biology.
Here, we’re seeing the results from the lovo-cel studies
that I showed earlier. And I want to specifically note
that we’re looking at biologic outcomes
with the goal being that blue bar or blue hemoglobin.
Again, total hemoglobin is the y axis,
and the x axis is months from therapy.
And blue is our goal,
our therapeutic hemoglobin A T87Q.
And what you can see here is a substantial
almost 50 percent of the total hemoglobin
is now hemoglobin T87Q.
We also know, when we think about biology,
the importance of hemolysis or cell breakdown.
And here we show
that the reticulocytes in the upper graph,
indirect bilirubin in your lower left corner,
and lactate dehydrogenase in the right corner
are all remarkably improved
and, in many cases, normalized after this treatment.
Now, let’s change over to exa-cel.
Again, we’re talking about total hemoglobin here,
as well as the percentage of fetal hemoglobin,
which is the therapeutic goal, and F cells.
F cells means the number of red cells or percentage,
in this case, of red cells that contain that fetal hemoglobin.
The top graph is looking at total hemoglobin
and how much of that hemoglobin
is actually due to the fetal hemoglobin,
average around 40 percent. And you can also see
an almost pancellular expression of F cells.
Similarly, we saw significant improvement in hemolysis.
Here, you can see reduction in LDH in that top graph.
And on the bottom, you can see other improvements in hemolysis.
Now, as I talked about earlier,
we don’t want to just see biologic improvements
with these therapies.
We really want to understand how they affect individual function.
Now, I know I’m not showing anything new here,
as just about everyone has seen this slide in some way.
On the y axis is each individual person,
on the x axis, represented by little dots,
are the numbers of VOEs or vaso-occlusive events.
And as you can see on the left,
prior to receiving lovo-cel, there were quite a lot of dots.
And on the right, there are very few.
And in fact, 88.2 percent of people
had complete resolution of all VOEs.
Here, though, we’re really talking about pain
and pain events,
and we all know that these can be incredibly difficult
to measure and remain very subjective.
For this trial, like other trials,
vaso-occlusive events required a visit to a healthcare facility
and were basically defined by pain
that did not have any other cause.
And so, we certainly recognize
that there could be better biologic endpoints.
But this is truly a functional endpoint in terms
of how much pain did people have after the therapy
that required a visit to a healthcare facility.
Whether it was truly a vaso-occlusive event
versus other pain can be very difficult to differentiate.
We do know that adolescent patients enrolled in this study
had even better improvement
with 100 percent of resolution of VOEs.
Similar here, we’re looking at the severe VOEs.
Again, lots of red dots on the left,
very few red dots on the right.
And we see that lovo-cel again reduced
significantly the number of severe
VOEs, so that 94 percent of individuals
had a complete resolution of all severe VOEs.
There were very few people that did have
some hospitalizations after treatment.
And as you can see on the bottom right above my head,
that even in these very few people,
they had a significant reduction
in the number of hospitalizations,
as well as a huge reduction in hospital days,
from a median of 15.75 to a median of 2.
Now, we’re talking about patient-reported outcomes.
And we really chose the three here,
pain interference, fatigue, and pain intensity,
as some that we felt were the most important
to individuals with sickle cell disease.
And we’re showing here the significant improvements
that you can see displayed on this graph,
noted as early as six months after therapy
and sustained for up to 36 and really 48 months.
We saw clinically meaningful improvements in pain intensity,
pain interference, and fatigue in 57, 64,
and 64 percent of patients, respectively.
Now, some individuals didn’t have a lot
of pain interference or fatigue, and so we couldn’t reduce beyond
where they were already at a good level.
Again, these are functional outcomes
that are also really important to assess.
Now we’re switching over to exa-cel,
where we see a very similar
and very clinically meaningful benefit.
In the same type of swimmers’ plot,
the y axis is the number of individuals,
the x axis is the number of dots
representing vaso-occlusive crises.
Again, you can see a lot of dots on the left
and a lot less on the right.
And we can see that, as we saw previously,
some individuals do continue to have pain events
after this therapy.
Again, these events are defined by having pain
with no other discernible cause and, of course,
recognizing that pain can be very difficult to differentiate.
They saw consistent efficacy
and clinically meaningful benefit
from exa-cel in both adolescents and adults.
Adults on the top portion of the graph here,
and the bottom portion, adolescents.
Again, very few blue dots post-treatment
really showing us significant improvement.
We also saw significant improvement in patient
reported outcomes.
Now, these outcomes are displayed differently
than the ones I showed you before,
and there are slightly different outcomes.
And this is from the recent New England
Journal paper that showed improvements,
specifically looking at the EuroQol visual analog scale
as well as the numeric rating system
and showing the minimally
clinically important differences.
Let’s briefly compare the results of these two trials.
Again, we’re really talking here about the therapeutic efficacy,
and that’s what I want to compare here.
So, you can see, similarly,
the primary outcome for both trials
was the number of vaso-occlusive events.
For lovo-cel, we saw an 88 percent
complete resolution of VOEs from month 6 to 18.
And if we measure it the same way
that exa-cel measured it, that would have been 93 percent.
That’s because the measurement was a fixed point
starting at 6 months to 18 months.
Exa-cel saw 96 percent achieve
at least 12 months without a VOC.
And in this case, that was a sliding 12 months
of any 12 months in which it was consecutively without a VOC.
Secondary outcomes, we see that 94 percent of patients
had a complete resolution of severe VOEs.
In the lower cell group and in the exa-cel group,
that number was 100 percent for at least
those consecutive 12 months again.
Now, one thing that we’re going to call attention to
is the difference in duration.
At the time these were approved, we saw a median duration
for lovo-cel of 35.5 months and exa-cel of 22.4 months.
Globin response, or the biologic response, again,
is really thinking about the total hemoglobin
and the percent of that hemoglobin
that comes from the therapeutic gene therapy that’s intended.
And the way this was defined for lovo-cel,
86.8 percent of individuals achieved globin response
with that very complicated definition.
And on the right, you can see that 100 percent
achieved a globin response
with a less complicated definition of fetal hemoglobin
greater than 20 percent with a pancellular distribution.
Again, just calling attention here,
the definitions for resolution of vaso-occlusive crises
were slightly different.
So, when you’re comparing efficacy,
recognize that they are slightly different
in the way they’re defined
and the time that they’re defined over.
And similarly, there’s a pretty significant difference
in median duration at the time these therapies were improved.
So, what about other gene therapies
that are ongoing in sickle cell disease?
Well, the three most far along therapies
are the RUBY or Editas therapy. It’s a gene editing therapy.
Instead of aiming at BCL11A, it’s a CRISPR-Cas12 deletion
at the gamma globin hemoglobin F promotor.
We know the GRASP therapy is the BMT-CTN 2001.
It uses a viral vector, that same lentiviral vector,
to insert a small hairpin RNA that does affect BCL11A
to reactivate fetal hemoglobin.
And the BEAM-101 or BEACON therapy
is a base editing therapy,
so no longer a double-stranded DNA break.
This is actually targeting a promoter
that is also preventing an edit of a repressor,
so it prevents the turning off of the gamma globin gene.
In all three of these,
we’re looking to assess the total hemoglobin
and the percent fetal hemoglobin,
as well as vaso-occlusive crises and patient-reported outcomes.
So, the real question, though, is how are we going to define
the therapeutic efficacy of these treatments?
So, when we think about efficacy,
we need to start with biology.
As we discussed earlier, none of the current gene
therapies are actually targeting the mutation
that leads to hemoglobin S.
Instead, they are producing different hemoglobin
that will help prevent the hemoglobin polymerization
that leads to all the downstream complications.
So, all individuals receiving these therapies
will continue to make sickle hemoglobin,
but they need to make enough hemoglobin ATV-7Q
or fetal hemoglobin,
to prevent that polymerization and sickling.
Not only should they prevent the polymerization,
they also really have to prevent hemolysis.
They have to completely resolve hemolysis
to prevent ongoing endothelial damage
and to prevent the loss of nitric oxide
in the vessel system.
And they have to act like a red cell that is healthy.
And one measure of that is somebody with sickle cell trait.
That’s because in sickle cell trait,
all of the red cells actually contain hemoglobin
A and S, and we know that
unless they’re under significant hypoxic conditions,
those cells act normally.
They don’t hemolyze or break down,
and they’re squishy and not adhesive.
So, we want to make sure that the individuals
who get these therapies end up with rheology
at least equivalent to sickle cell trait.
And those would be biologic definitions of efficacy.
And if you could meet all of them,
you could even suggest a biologic cure.
But again, we also need to think about
those functional definitions of efficacy.
So, one difficulty, as I mentioned,
is that we are measuring pain. And as everyone knows,
not all pain is caused by vaso-occlusive crises,
even individuals with sickle cell disease.
And as individuals age and have different types
of bone and muscular damage or just get older,
they will experience more pain.
And we need to understand what pain
is actually caused by sickle cell disease
versus other pain that we can all have.
I was speaking recently to a patient of mine
who’s 23, beautiful, wonderful young man, and I --
he was explaining his pain to me.
And what he was explaining is that his pain
is really severe after he’s been working.
And he works in a factory, lifting things.
And at the end of the day, he notes that he’s got
a lot of pain in his shoulders, and he’s very sore.
And he said, "Well, of course, it’s my sickle cell pain.
What other pain could there be?"
And I tried to explain that there are lots of other pains.
Because he clearly had musculoskeletal pain
because he was lifting very heavy packages.
So, we really need to start to figure out a better way
to differentiate pain versus vaso-occlusive-induced pain.
We need to make sure we keep acute pain crisis
in our title of these episodes.
Because it is a crisis. Because pain is a crisis.
But perhaps we need to look at other definitions
to differentiate acute pain crisis
and acute vaso-occlusive crises to really help us understand
this functional definition of efficacy.
What about fatigue?
So, I’m sure none of you in the audience are ever fatigued,
even if you don’t have sickle cell disease, right?
Well, of course, this can be really challenging.
How do we know what fatigue is from life and adulting,
and what fatigue is from sickle cell disease?
And how are we going to differentiate
that as time goes on?
I have another individual that I take care of,
who’s a wonderful woman who, after receiving gene therapy,
actually began working as a teacher’s aide
for a first-grade class.
She’d never had a full-time job before.
And she was exhausted at the end of the day
and wanted to know why her fatigue hadn’t improved.
Remember, before she got this gene therapy,
she hadn’t worked at all.
So, this was all very new to her.
So, again, how do we measure fatigue
when it may not be the same before and after?
And what about quality of life?
How do we make sure that what we’re measuring
are changes in quality of life due to sickle cell disease
and not due to other things that can happen in our lives?
We know that fixing sickle cell disease is just one part,
and it may not fix everything.
So, how can we measure these differences
when we’re really thinking
about functional definitions of efficacy?
John Tisdale: Are you working on the volume back there?
Because we’re not hearing.
Yes. We can’t hear anything still.
Okay. It’s over. Well, sorry about that.
I think we’re going to have to move on in the interest of time,
but we lost the last bit of audio.
Hopefully, you were able to read the slides
for Julie’s final comments.
So, we’re going to move now back to a live presentation.
Dr. Melanie Fields is going to talk to us
about cerebral hemodynamics. She’s a pediatric hematologist
and tenured professor at the Department of Pediatrics
and Neurology at Washington University in St Louis.
So, I hand it over to you, Melanie.
Melanie Fields: So, Julie is a tough act to follow,
even when she freezes.
[laughter]
There we go. Okay.
So, thank you to everyone. Thanks for the invitation.
This is an incredible crowd to get to meet with
and speak in front of. I’m going to focus on the brain,
which I can talk about for a very long time.
So, we’ll try to do this in 20 minutes.
Except that’s not it. Yeah. These are my disclosures.
I’m going to give an overview first
of what I mean when I say cerebral hemodynamics
and start with where the field started.
And then as this field has grown,
some controversies have developed,
conflicting data, and I want to dive briefly into that.
And then lastly, end with how we can potentially use
these biomarkers to assess treatment efficacy.
So, as everyone in this room knows,
the neurologic comorbidities of sickle cell disease
are significant,
from overt stroke, vasculopathy, silent stroke,
and cognitive complications.
The pathophysiology of these comorbidities
really remains unclear.
Current guidelines, at least in the U.S.,
recommend that a screening MRI
be obtained when a child becomes school age,
so between the ages of five to seven.
And that MRI is really for structural purposes.
Because if there are silent infarcts,
if there’s vasculopathy,
that might mean that we would recommend a change
in primary disease modification.
However, once that infarction has occurred,
once that vasculopathy has occurred,
I would say we really missed the boat.
And can we use technology to define and prevent this,
instead of just then having to move forward
with secondary prevention?
So, we’re going to talk about that.
So, when you put someone in an MRI scanner,
you can take a lot of pictures.
Clinically, we really take almost all structural pictures.
However, with the scanner,
you can look at the function of the brain.
You can look at white matter microstructure.
And then you can look at these measures
of cerebral blood flow and oxygen extraction,
which is what we’re going to focus on today.
And then really exciting data is coming out of Emory,
Dr. Erin Buckley’s lab,
where she’s using this bedside tool, DCNIRS
[sic], to obtain similar measurements regionally.
So, we’ll also briefly touch on her data.
So, when I say cerebral hemodynamics,
I think we have to start with the fact
the brain consumes 20 percent of the oxygen supply
to meet what we call the cerebral rate
of oxygen utilization, or CMRO2.
We calculate CMRO2
by multiplying arterial oxygen content by cerebral blood flow,
or the rate of arterial blood delivery to the brain,
and then by oxygen extraction fraction,
which is the percentage of oxygen
removed from the blood into the brain tissue.
So, old -- very old, PET imaging data in the setting
of carotid stenosis arterial ischemic stroke,
has shown us that there are multiple phases
of hemodynamic compromise in the setting of arterial stroke.
So, when you have stenosis or an occlusion,
you have decreased focal perfusion pressure.
However, even with that stenosis or that occlusion,
cerebral blood flow regionally remains stable
due to autoregulation or dilatation
of the surrounding blood vessels.
So, cerebral blood flow stays steady.
CMRO2 stays normal.
However, if that stenosis or occlusion persists,
all the surrounding blood vessels are vasodilated.
You will eventually see a decline in cerebral blood flow.
The brain can then further compensate
from pulling more blood from --
more oxygen from the limited blood
that is available to the tissue,
and that’s this increase in oxygen extraction fraction,
again, to maintain the CMRO2.
When both of these compensatory mechanisms max out,
though, that’s when you see a drop in CMRO2,
and that’s when brain tissue dies.
So, what does this mean for sickle cell disease?
So, a minority of patients do have stenosis;
the majority don’t, though.
However, they are all severely anemic
with a decrease in arterial oxygen content.
So, this field really took off
when there’s a desire to understand,
how does the brain compensate for that decrease
in arterial oxygen content,
when it comes to these metrics of blood flow
and oxygen extraction?
So -- and there was a delay in this
because we don’t like to use PET imaging and research
because it involves radiation.
So, MRI had to come far enough along that
we could look at these measures without radiation exposure.
And so, to start off,
a study out of my lab looked at these metrics in children
and then a study out of Vanderbilt
looked at these metrics in adults.
And we found that there was a significant increase,
about a 1.5-fold increase,
in cerebral blood flow in both children and adults.
And then when we looked at oxygen extraction fraction --
and this this data is globally --
we found a similar increase in oxygen extraction fraction.
And in these two figures,
you’re looking at arterial oxygen content on your x axis
and then these metrics of blood flow on your left,
oxygen extraction on your right. The more anemic the participant,
the higher the cerebral blood flow,
the higher the oxygen extraction.
But how do these metrics relate to the clinical outcomes
that we care about?
So, this is some data published by Dr. Andrea Ford at WashU,
and she had a great opportunity.
She took all the brain MRIs from the SIT trial.
She outlined where those silent infarcts occurred
and created a heat map.
And so, she also had imaging data to help us define
the regions of the brain with the lowest cerebral blood flow.
And so, in the bottom figure, what you see in red
is the region of the brain where blood flow is the lowest.
Overlaid on top of that, in blue,
is that heat map where silent strokes
are most likely to occur. And then in purple,
you see that these regions really nicely overlap.
The figure up top is looking at infarct density in the brain
and what you see -- on the x axis.
And then on the y axis, you see cerebral blood flow.
And you see that the region of the brain
with the greatest infarct density
has a significantly lower cerebral blood
flow compared to the region with the lowest infarct density.
So, what this would suggest is, is that where this --
where blood flow drops,
that’s where these infarcts occur.
And then when we think about oxygen extraction --
so, this was a different study out of my lab,
but we took a cohort of kids with sickle cell disease
and a cohort of kids unaffected.
And we averaged their oxygen extraction mass.
We then made a ratio metric map,
meaning that in each voxel of the brain,
you had a ratio of that average sickle cell oxygen extraction
to the average control oxygen extraction,
and then thresholded it.
And then the top figure you see in blue,
the three regions of the brain, where there’s a 60, 70,
and 80 percent increase in oxygen extraction
in that average sickle cell map
compared to that average control map.
So, this is the region
where oxygen extraction is the highest.
In an independent cohort of kids,
we again created an embark density heat map,
just shown in red. And when you overlay the region
with increased oxygen extraction,
you see that they again, nicely colocalized.
So, together, these two studies suggest
that where blood flow nadirs
and oxygen extraction is the highest,
that’s the region of the brain that’s vulnerable to infarction.
And this potentially gives us insight
into why these infarctions may be occurring.
And then this is data out of Vanderbilt,
and this is a really nice study, where they were correlating
these imaging biomarkers with cognitive measures.
And so, through multivariate modeling,
where they’re controlling for age,
household income, presence of stroke,
they found that blood flow was inversely related
to working memory and inhibitory control.
And oxygen extraction was inversely
related to processing speed.
And then when they removed the patients that had infarcts,
they found similar relationships between blood flow and memory
and oxygen extraction and processing speed.
So, again, this was the start of the field to understand
how the brain is compensating
in the setting of sickle cell disease.
As the field has grown, there’s been conflicting data.
There’s been a lot of progress, and there’s some controversies.
And so, I want to talk about why those controversies exist
and how we’re kind of learning to better understand that data.
So, the first thing to understand is that
when we talk about oxygen extraction fraction,
there are two different MR sequences
that can be used to obtain this measure.
So, there’s what we call a TRUST sequence.
And with the TRUST sequence, there’s a single measurement
of the MR T2 signal in the superior sagittal sinus.
That measurement of the T2 signal,
they then use calibration models to convert that measurement
to a measurement of venous oxygen saturation,
from which you can
then calculate the oxygen extraction fraction.
However, that’s a single measurement that’s applied
globally to the entire brain.
In contrast, you can also use an arterial spin --
sorry, an ASE or asymmetric spin echo sequence,
which is a tissue-based measurement
of oxygen extraction fraction.
And so, this measurement is based on the variation
in the MR field
caused by deoxyhemoglobin in the microvasculature.
So, then you’re getting a measurement
of oxygen extraction fraction within each voxel of the brain.
So, if you’re seeing regional data,
not just global measurements,
that data was obtained with an ASE sequence.
So, the reason why I’m explaining this to you
is because a couple of years later, this was published.
So, on your left, you see some great data out of LA
using a TRUST sequence,
showing that in kids with sickle cell disease,
that whole brain oxygen extraction
is significantly lower than healthy controls.
And then a year later, our lab published data
showing that in kids with sickle cell disease,
whole brain oxygen extraction was significantly elevated
compared to healthy controls and children
who are anemic for other reasons.
So, you don’t have to be a scientist
to see the data is moving in the exact opposite direction.
So, why is this?
So, like I said, with the TRUST sequence,
you get an MR measurement that then --
is then calibrated or converted
to this venous oxygen saturation.
And that -- those calibration models --
there are different ones.
The original one was this bovine model.
It was based off of experiments done with bovine blood.
And the criticism of that model is that they --
the samples weren’t anemic, right?
And so, then you’re applying that
to a very anemic population.
And then the Bush model came,
and that used hemoglobin S containing blood and was anemic.
But they didn’t control for the hemoglobin level,
and then the Li model and then the Li-Bush model.
And this data that I’m showing here
comes from a paper from Dr. Eboni Lance
at Kennedy Krieger, looking at TRUST data obtained
and the relationship with hemoglobin
using these four different models.
And you can see that with the original bovine model,
the more anemic the patient, the higher the OEF,
and then an opposite relationship
with the other three models.
And then this, very recently, was published out of WashU.
And so, this was a cohort of adults who were scanned
and had OEF measurements using both sequences.
And on the x axis, you see the ASE OEF measurement.
On the y axis, you see the TRUST measurement
with three different models,
and you see a significant correlation
between ASE OEF and TRUST OEF when the Li model is used,
but we lose significance with the Bush and Li-Bush model.
So, why?
So, I’m [laughs] -- this is really complicated,
and I have 20 minutes.
So, I’m not going to go through the data
from these three papers cited here,
but these three papers are trying to get at why.
So, maybe not one is right, and one is wrong.
Maybe these are two different sequences,
two very different techniques,
and they’re each telling us something.
And the TRUST sequence, again, it’s that single measurement
in the superior sagittal sinus.
It’s a flow-weighted measurement from -- you know,
it’s a vein that’s draining huge territories of the brain.
And so, there’s something called cerebral capillary shunting.
And these three papers are using MRI
to try to quantify cerebral capillary shunting
and explain how, with a TRUST sequence,
you could see, actually a lower oxygen extraction fraction.
So, just conceptually,
the concept is that in a healthy brain,
you have an artery supplying blood to the brain.
The blood then travels through the capillary.
The capillaries, at a normal transit time, offloads oxygen
and then goes to the draining vein.
In compensated anemia,
that supplying artery vasodilates.
The blood travels a little faster,
offloads its oxygen, though normally,
and you again have a normal oxygen extraction fraction.
However, when anemia is uncompensated,
you have further vasodilation. The blood is moving even faster,
and it’s unable to properly offload the oxygen.
And then in that vein,
you have a lower oxygen extraction fraction.
And some really fancy imaging in humans is being used
to try to demonstrate this in sickle cell disease.
So, I think -- and I’ve read all of this literature.
So, my takeaway is -- my job depends on it.
[laughter]
My takeaway is that regardless of the sequence
that’s used or the calibration model,
the majority of literature would suggest that sickle cell disease
impacts the cerebral hemodynamics of the brain.
And that possibly, we don’t have to say one’s right or wrong,
but we could learn different things about the physiology
from the different sequences.
And I just hope that we don’t throw this away
because it’s a little confusing and then not potentially use it
as a biomarker to help our patients.
Okay. That’s my hill.
Now, I’m going to tell you about how these biomarkers thus far
have been used to understand
the different treatments that are available.
And this has been hit upon at least 10 times
in the past two days, so I’m not going to review it.
But just the timeline, at least in the United States,
of different treatments that are available to our patients.
And I’m going to start with chronic transfusion therapy
because it’s really the cornerstone for our patients
with sickle cell disease, and that’s what we fall back on.
So, on the left is a figure from a paper out of WashU using MRI,
the ASE sequence, to look at cerebral blood flow
and oxygen extraction
immediately before and immediately
after a transfusion in a cohort of 21 children.
And what we found is that there was a significant reduction
in cerebral blood flow and oxygen extraction
after a single transfusion, while CMRO2 remains stable.
Then more recently, the group out of Emory,
using a diffuse optical spectroscopy --
which is that bedside tool with the sensor
on the brain measuring light frequencies and wavelengths.
And I’m not a physicist,
but it’s a really cool technology.
And they get regional measurements of cerebral blood
flow and oxygen extraction with this tool.
And they found similar results,
showing that cerebral blood flow decreased,
oxygen extraction decreased,
and CMRO2 didn’t change with a single transfusion.
And so, this gives you some insight
into why chronic transfusion therapy
is neuroprotective in this population.
So, contrasting that figure on the left out of WashU
with the figure on the right out of Vanderbilt,
and they did a very similar study,
but they included adults in their study.
And so, on the bottom is their pediatric data
showing similar results,
that cerebral blood flow and oxygen extraction,
each significantly went down with transfusion.
But in adults, they found that cerebral blood flow
didn’t change,
and oxygen extraction was significantly reduced.
And so, I think here is our first hint, right,
that our therapies don’t impact adults necessarily,
in the same way that they impact children with sickle cell.
So, this is a paper out of my lab.
This was a cross-sectional study in children and adults
with sickle cell disease, 87 patients, a cohort of 23
not on primary disease modification --
not because we didn’t try -- a cohort on hydroxyurea only,
and a cohort that’s chronically transfused.
And on the left side of each brain,
you see the average oxygen extraction map.
On the right side of each brain, you see a generic brain atlas,
but overlaid on that in teal and white,
are the regions of the brain
with increased oxygen extraction.
And there was a significant reduction in the volume of brain
with elevated oxygen extraction
as a potential biomarker of metabolic stress
in the people with sickle cell disease
receiving treatment with hydroxyurea
compared to those not receiving disease modification.
However, the volume of threshold of brain
was significantly higher than the cohort
that was receiving chronic transfusion therapy.
So, you know, it’s probably not equivalent, but it definitely --
I think this suggests and further supports
the mounting evidence
that hydroxyurea is neuroprotective
in the setting of sickle cell disease.
And then voxelotor, which we’ve talked about --
and I think there have been discussions in the past day
or so about concerns about the drug’s ability
to appropriately offload oxygen in vulnerable organs.
So, this paper was published this year, again, out of Emory,
in a very small cohort, eight children,
using that bed site tool to look at regional cerebral blood
flow and oxygen extraction.
And they found reduction in both of these biomarkers,
four weeks after initiating voxelotor,
and that persisted out to 12 weeks.
So, I think we’re starting to see physiologic data
about the impact of this drug.
Okay. Last but not least, transplant.
We have no gene therapy data. So, transplant.
So, this is a paper published by Dr. Monica Hulbert,
who’s now in Boston, and she looked at this data --
these measurements, before and after transplant in children.
So, these were 10 children that underwent curative
stem cell transplant.
So, in orange, you see pre-, post-transfusion data.
In like teal green, you see pre-, post-transplant data.
And then you see data from healthy controls in blue.
And what you see is that after curative transplant --
this is about a year out from transplant --
you see a significant reduction in cerebral blood
flow on the left and oxygen extraction on the right.
You also see that it’s reduced, not only from pre-transplant,
but reduced from pre- and post-transfusion.
And you see that there’s no longer a difference
when compared to the healthy controls.
And this was a pediatric-only study.
In adults, this is data out of Vanderbilt
using a TRUST sequence.
And their calibration curve, I believe,
was hemoglobin F-based.
So, you have healthy controls in red.
And then you have pre-,
post-transplant in blue and green.
And you see a reduction in cerebral blood flow,
post-transplant, without a change in oxygen extraction.
When they further dove into their OEF data,
they found that in the adults
who started with a higher oxygen extraction,
they had a greater decrease, post-transplant.
However, if they were starting
with a more normal oxygen extraction,
they didn’t see that decrease.
And then this is data very recently published
out of the Netherlands using a TRUST sequence,
a different calibration curve,
so the data is moving in the opposite direction.
However, again, you have your healthy controls for comparison.
And what they see is a --
they see a decrease in cerebral blood flow
and an increase in oxygen extraction towards,
again, the healthy controls,
so a normalization of hemodynamic metrics,
post-transplant.
Again, this is about a year out from transplant.
So, hopefully, I can convince you guys
that advanced neuroimaging
has provided us with some insight
into the impact of sickle cell disease on the brain.
And today, I really focused
on these cerebral hemodynamic measures.
There’s much more that MRI can offer us, again,
looking at function and structure.
But learning more can help us
then possibly link these biomarkers
with the clinical outcomes that we care about.
And then can we use these tools to assess for risk prediction
but also to assess treatment efficacy?
Because trials looking for stroke take a very long time,
and that damage has then already occurred.
And those brain cells cannot be saved.
So, can we use technology to look in a different way?
Okay. Thanks.
[applause]
John Tisdale: Trying to sneak off before the questions.
[laughter]
Swee Lay is already up, so --
Swee Lay Thein: Melanie, that was really wonderful.
I’ve got two questions.
One is, when you talk about pre-, post-transplant, pre/post,
you have discussed a lot about, in the patient, variability.
It is comparing it with the patient.
And the change that you give,
is the change from baseline and the average?
Or is it taken across --
you see what I’m saying -- the baseline?
Melanie Fields: It’s a pre/post. It’s the same patient before --
Swee Lay Thein: Right.
So, there’s a huge difference in that.
Because let’s say you, pre and post,
then I should take your change from your baseline.
Mine changed from baseline, and we average the baseline.
We average the change. Is that what you did?
Melanie Fields: Yeah.
And I think in some studies, they show you --
well, I didn’t show it to you, but in like -- for instance,
I just published a paper using connectivity,
and I showed that measure for each person, pre and post.
So, you can see the delta.
Swee Lay Thein: Yes. This one took in the delta --
average of the delta, the change.
Melanie Fields: [affirmative]
Swee Lay Thein: Sorry, John. Can I ask another question?
John Tisdale: Yeah.
Swee Lay Thein: The second is, when you talk about --
[laughter] John Tisdale: [unintelligible]
Melanie Fields: I think you’re the boss.
Swee Lay Thein: Okay.
You talk about decompensated anemia.
So, this could -- maybe could explain why, you know, like,
say, when someone with sickle cell disease
who is a decent hemoglobin, not like, say, 8,
and then maybe has a crisis or a parvovirus
and they dropped. Then it’s not compensated.
And is this associated with a high incidence
of cerebral infarc?
Melanie Fields: Yeah.
So, there was a really great paper published
about 2010-ish in Blood, where they did acute
imaging in the setting of acute anemia in sickle cell disease
and in patients who are anemic for other reasons,
and showed these acute ischemic events
using a different sequence. So, I’m going to go with yes.
And with the recent parvovirus surge, you know,
we have patients come in with neurologic symptoms
as their hemoglobin drop, so exactly.
I think -- but I do think that there’s also chronic damage
from this persistent anemia. So, I think it’s both.
John Tisdale: Okay.
I’m going to jump in with a quick question.
And then we have one more question.
And then we’ll move on. And that is,
I’m always struck -- and I always ask this question
by about this time in the meeting --
I’m always struck by how much better the patients
that are getting transfusions look by every measure,
by kidney function, by heart function, by brain imaging.
I mean, the difference was pretty stark, I thought.
So, are we not transfusing enough in this disease?
Melanie Fields: I like how I got the loaded question.
[laughter]
I think each hematologist has their --
I mean, there’s the concrete, like, you have to transfuse
for X, Y and Z, right?
TCD is, all of you have to do it.
And then there’s the middle ground.
And I think then the way that I practice
is that that’s a very serious conversation with each family
about the benefits and the risks.
And then we go through every risk,
and it’s probably 50/50, where we land.
But I don’t think we have -- I don’t think we can --
it is an art, right? I don’t think we can practice,
but we can only transfuse for X, Y and Z.
So -- but I agree; they feel better.
John Tisdale: Okay, last question.
Male Speaker: I need to add to this --
great presentation, by the way. Love it.
So, how much do you think this is all hemoglobin?
You mean -- I’m going to add to what has been said thus far --
you mean,
because transplant corrects the hemoglobin the most,
so they are having a hemoglobin of 13 or 14?
While voxelotor might increase you by one gram.
Correct? And their baseline is lower.
So, how much of this is truly all based on hemoglobin?
Melanie Fields: Yeah.
So, I don’t think that it’s all hemoglobin.
I think that hemolysis --
the endothelial activation, plays a role.
I think the metabolic demands differ.
And there’s old data, I think, from Jamaica --
don’t quote me on that -- looking in the periphery.
So, I don’t think it’s just the anemia.
And every time I have presented this over the many years,
a hematologist asks me
if it’s just a really expensive test for CBC?
And I don’t think it’s -- and which is why
I did that study with kids with sickle cell disease,
kids who are anemic, for other reasons,
and healthy controls, because -- I didn’t show it.
It’s only 20 minutes.
But in that data set, the kids who are anemic
for other reasons were equally anemic.
So, their hemoglobin were sitting at 7 and 8,
and their oxygen extraction was significantly lower
than the kids with sickle cell disease.
So, I mean, that’s not -- it’s a cross-sectional study,
but I think it supports the idea
that it’s more than just the anemia.
John Tisdale: All right. Great. Thank you, Melanie.
[applause]
All right.
So, to finish up this session, we have Dr. Parker Ruhl,
who’s my colleague and my neighbor in D.C.,
who’s going to talk to us about cardiopulmonary function
in sickle cell disease.
She’s an associate research physician in the Physiology Unit
of the Laboratory of Malaria and Vector Research at NIAID
and in the Pulmonary Branch of NHLBI.
So, welcome Parker.
You can bring us to the end of this session.
Parker Ruhl: Thank you.
[applause]
Thank you, everyone.
So, I wear many hats, as many people in this room do,
but certainly pulmonary function in sickle cell disease
is something that’s close to my heart.
And today, I will talk about lung function
after non-myeloablative hematopoietic
cell transplant for patients with sickle cell disease
from a cohort that’s all from the NIH Clinical Center.
Getting used to the -- oh, the other.
Oh, the big green button. All right.
So, I will start off with a background
in sickle cell lung disease.
I will do a little primer on pulmonary function
testing and spirometry for the non-pulmonologists in the room.
And then I will go through our own data on PFTs
after transplant and then talk about some next plan steps.
And I’d love to hear everybody else’s ideas and input.
So, starting off, we know that sickle cell disease
is a multi-organ disease.
We’ve discussed the contributions of that,
the polymerization of hemoglobin S,
hemolytic anemia, vaso-occlusive events.
I think if we think back to medical school
and our training, I remember the phrase,
if you know syphilis, then you know medicine.
If you know HIV, you know medicine.
And I think it’s really important to consider
sickle cell disease as truly a multi-organ disease.
So, in the pulmonary arena alone,
we have acute chest syndrome. We have pulmonary hypertension.
We have sleep-disordered breathing, nocturnal hypoxemia.
And today, I’ll be focusing on lower airways disease
and pulmonary function.
So, when we think about lung health and sickle cell disease,
it’s really important to consider
that it’s a cycle that lung health
has a significant impact on sickle cell disease
due to the oxygenation of our bloodstream.
So, when we think about otherwise more typical ailments
that impact the lung --
pneumonia, asthma, lower airways disease,
sleep-disordered breathing,
recurrent hypoxemia, pulmonary hypertension, pulmonary
and venous thromboembolism --
that can cause damage to the lung
but then also interact with ongoing issues
that are more specific to sickle cell disease,
so the V/Q mismatch that you might get from atelectasis,
among the other issues that we have, vaso-occlusive events,
fat emboli syndrome, infarction pain, inflammation,
and how that cycle then can continue.
It can damage the lung further,
which can then impact overall sickle cell disease.
And then, you know, we’ve had a lot of,
I think, really healthy discussions about
what is a high-income, middle-, low-income country.
I actually majored in Economics,
so I really value that Jennifer brought that in.
But we do know that in otherwise
using the term low-resource settings
or places where there’s other particularly infectious insults,
that there are other things that are impacting lung health.
And we know that the predictions
are the 85 percent of expected births
will be occurring in Sub-Saharan Africa,
where under-five child mortality due to pneumonia
in all children remains very high.
Tuberculosis, other infections like malaria, tobacco,
vaping, air pollution that’s indoor, outdoor,
all of those things can additionally impact lung health.
I have a couple of pulmonary colleagues in the U.S.
that are starting to look at wildfires
and how that might impact sickle cell disease.
So, there’s a lot that can be factored in.
So, when we think about pulmonary complications
of sickle cell across the lifespan,
we know that they’re one of the more common,
if not most common,
depending on different study population studies
that you look at, morbidity and mortality factors
in sickle cell. And pulmonary complications
can affect nearly every lung cell type and structure
as patients age.
And this is all happening in racial and ethnic groups
that are profoundly impacted
by the social determinants of health and commonly,
with poor access to health care. Again, as we’ve discussed,
even in countries with lots of resources,
those resources are maldistributed.
So, these are all factors leading to health disparities
and our limited understanding of pulmonary complications.
You know, I think all of the subspecialists in this room,
the nephrologist, the cardiologist, neurologist,
everybody, we’re all kind of talking about
how there’s a lot of low-hanging fruit.
There’s so much that we can research in sickle cell
because a lot has not been
appropriately funded to investigate.
So, a group of pulmonologists and myself,
both Liz Klings and Robyn Cohen at BU
and Christy Sadreameli at Hopkins,
got together a diverse group of specialists
through the American Thoracic Society.
And in 2019, we published a workshop report.
And we were really proud
of how diverse our interest holders were.
So, we had 18 pulmonologists, 12 hematologists,
two emergency medicine physicians with pediatric
and adult represented throughout that group.
We had hematologists from Mali.
We had Dr. Jennifer Knight-Madden from Jamaica,
from the U.K., Dr. Thein -- you know, Dr.
Thein gets to pick where she says she’s from right now.
[laughter]
But we also had Ann Greenough, Jo Howard.
So, it was a really representative group.
And also, importantly, we had a sickle cell disease advocate.
So, we had a patient by the name of Debbie Bennett,
who has passed away,
but she was really proud to be a part of this.
And I’ve had some discussions with people here
in the room that having a patient advocate,
literally, the seat at the table,
it changes the tenor of the discussions.
We all know that,
and I think it’s really valuable and important.
We’ve had -- at the American Thoracic Society,
we’ve had a number of panel discussions,
where we would have invited a sickle cell patient to come,
and we get standing room only crowds.
So, it’s really important to bring that patient in.
And so, through this process, we did a systematic literature
review with our librarian at the NIH,
and we had our expert panel discussions.
Because there’s not a high-enough level of evidence
to really write guidelines for pulmonary care.
But we were able to document
that there’s inconsistent or low quality of evidence
and study design, nonuniform classifications
of things like acute chest syndrome.
So, I don’t have enough time to talk about that today,
but don’t get me started. We all know that
it’s a very general definition of acute chest.
And then inconsistent strategies for interpreting
pulmonary function testing, which I’ll go into more detail.
There’s a lack of longitudinal data.
I know that Dr. Little is very eager
to have consistent registries.
I’ll talk a little bit about CF later,
but obviously, that’s one group that’s benefited from having
a very consistent registry program.
And then importantly, as Dr. Fisher alluded to earlier,
there’s important factors about race adjustment.
So, there’s a lack of ethnically diverse normative data
for PFT reference equations.
What that means is that the global long initiative values
that we use,
there’s 59,000 healthy patients that are included in those.
And there’s 4,500 that have African ancestry,
and they happen to all be African American.
But then in addition to that,
there’s been an incorrect use of race as an adjustment factor
when it does not have a biological basis.
So, I think the pulmonary community
is a bit behind the nephrologist community, for example,
but that has come out in the last year or two
to actually reevaluate our guidelines.
And that’s moving through pulmonary function testing labs.
We have made that change at the NIH.
So, now, I’ll go through a little primer on spirometry.
So, I know these curves can be a little bit daunting,
but the important thing to know is
that if you look at the y axis,
we have the volume exhaled, and then we have the time.
So, the FEV1 is one of the most important outcomes
in pulmonary medicine
because it’s been shown to be associated with mortality
in a number of different populations, COPD, CF,
also now, in sickle cell disease.
So, the FEV1, you can see at that one second,
that gray dotted line.
The FVC, or forced vital capacity,
is a demonstration of restrictive lung disease,
which we can see by scarring to the lung tissue,
which can happen in sickle cell disease.
And so, with that yellow line, you can see that the plateau,
the FVC, is lower when you have restrictive disease.
And then obstructive diseases, so that’s more your asthma,
COPD, when you have inflamed bronchi.
People with sickle cell disease can also have obstruction,
and I’ll discuss that more.
In children, it’s a more common finding.
But -- so, that’s when you have
the ratio of FEV1 to FVC is lower.
And so, that you’ll see in the blue line there.
And so, going back to this idea of having race-neutral
equations,
so here, a group at UPenn looked at about 2500 Black patients.
And what they did was they reinterpreted --
so, using the pink as the new interpretation,
they identified that with race-neutral equations,
a significant chunk moved from having a normal assessment
to having restrictive disease. And so, those were people
that were being underdiagnosed previously,
purely because someone had added a variable to a formula
that didn’t necessarily have a biological basis.
And so, here’s another example in a multi-center cohort
that was analyzed through Mayo,
that found that both FEV1 and FVC --
so, those are both different markers that look at --
you know, together, they can look at obstruction;
apart, they can be a sign of restriction.
So, looking at the old equations on the left, the GLI-2012,
and then the GLI Global, those values were lower,
meaning they were more likely to be identified
as having restrictive disease. They both do come down.
So, it looks like that may not have impacted
the diagnosis of obstructive disease as much.
So, looking at current guidelines, NHLBI and ASH
have both actually come out against screening
PFTs in asymptomatic patients.
And I think that’s the most important thing to remember,
is that dyspnea, as classified by the New York
Heart Association, Class 2, is very common.
And we all know that it’s a little bit of a gestalt
for your patient. Is this a new dyspnea?
Is this something that they’ve always had?
But no matter what, I feel, and many folks agree,
that PFTs are essential in evaluating patients
that that have dyspnea,
so that we don’t assume it’s only the anemia.
I know it’s fun to hear the hematologist argue
about how much the anemia matters,
but you know, it’s there. But let’s think about, you know,
do they have something else going on?
And then in terms of the reduced FEV1,
so I mentioned that this has been associated
with mortality in sickle cell. So, Kassim and colleagues
had looked at the cooperative study of sickle cell.
So, you know, this is a little bit
before the widely accepted hydroxyurea era.
But they found that 6 percent decrease
in FEV1-percent predicted was associated
with an 11 percent higher hazard of death,
and that the mean decline of FEV1
was 47 milliliters per year,
which is twice the general population.
One small study that I saw
that came out a bit during the pandemic,
was a group looked at getting lung CTs before transplant
and comparing that
to whether or not patients had PFT abnormalities.
They were trying to pick through,
do we really need to get PFTs before a transplant?
And I thought it was really interesting.
Now, this is in pediatrics.
But they found that CTs were normal in 58 percent of children
that did have PFT abnormalities.
So, that, again, just to underscore,
I think it’s really important to get this baseline testing,
particularly before transplant.
But you know, I think it’s important
if there’s any possible lung issues.
So, this is one study looking at PFT abnormalities
in sickle cell,
I think, is representative of the of the population.
So, this is a study looking at 146 patients with SS or S-ßthal.
And this had 39 percent of pediatric patients
had abnormalities,
with the most common being obstructive, at 18 percent,
with the risk factors being increasing age,
family/patient history of asthma or wheezing,
and increased hemolysis.
And then looking at adults, in adults,
there is a higher amount of abnormal pulmonary function
testing that’s identified.
This is, again, from the cooperative study,
so a bit older.
There’s a couple of different studies
that show relatively similar percentages of these.
But it is important to notice
that the restrictive at the bottom
is the most common finding in adults.
So, here’s a representative normal chest CT.
You see a lot of black air, those well-aerated alveoli.
And then so, on the right,
we have chest CT from a sickle cell patient
that had a number of severe acute chest episodes.
And so, they have what we call honeycombing fibrosis.
So, not all sickle cell patients have this dramatic of a CT scan,
but it’s representative to show the degree of fibrosis
that you can get. You can also have restrictions.
So, when you do blow and do your pulmonary function testing,
you can have restriction from impaired muscle function,
muscle ischemia, from rib pain,
bone infarcts that can all play out
into what is lung restriction.
In terms of looking at diffusion capacity,
there are several potential mechanisms,
so anemia, reduced lung volumes,
or reduced alveolar gas exchange area,
the fibrosis that we’ve talked about,
and then you could also have reduced
pulmonary vascular perfusion. I’m looking for a cardiologist.
Maybe he’s behind the pole, but --
so, all of these factors play a role together.
Oh, and then just otherwise, real quickly.
So, this is a cross-sectional graph
showing DLCO levels across age.
So, just showing that with age, the DLCO can decrease
and why it’s important to do studies in both pediatrics
and adults for everything that we’re looking at.
Because there will be differences.
So, this study was a neat little snapshot
done at Vanderbilt University by Hodges and Shaina Willen,
that looked at the rate of annual decline in FEV1 in adults
that were living with sickle cell disease
and cystic fibrosis.
And so, if you look at this, the blue line is sickle cell.
And so, the median FEV1 at the starting age of 20
from this cohort, was 3.
And for cystic fibrosis, it was a little bit lower at 2.7.
But already you’re seeing, okay,
wow, sickle cell disease and cystic fibrosis,
they’re already somewhat similarly impaired.
But then in their statistical analysis,
there’s not a statistical difference
in the rate of decline.
And this is, you know, a pretty clear graph to see.
So, this is striking.
This is now before the era of the cocktail
ivacaftor therapies in cystic fibrosis.
But I think, if anything,
it’s really important to have these data
to see what was happening without some of these therapies,
to compare these two illnesses.
So, when we consider other existing evidence
for post-transplant pulmonary function
testing outcomes, it’s difficult to extrapolate
from the effects of transplant in malignant disease
to a chronic, lifelong disease with vascular impairments.
The prior reports in sickle cell
for post-transplant pulmonary function
are often of myeloablative transplant protocols
or retrospective analyses.
There -- a couple of larger studies with pediatrics
showed in one with 174, a stable FEV1.
In 350, there were about 2 percent
that had abnormal FEV1 at four years.
But these studies were not prospective,
and they did not have baseline data to compare to.
And so, the important gap in literature
is prospectively collected, multi-center data,
particularly in adults.
So, I’ll now walk you through -- or in a moment.
First, we’ve got to talk about the heart.
I’ll walk you through our single center data.
So, looking at cardiac outcomes after a transplant,
as our colleague earlier alluded to,
volume overload in sickle cell
anemia can contribute to cardiac remodeling.
I don’t think I used the word cardiomyopathy.
So, I think I’m safe.
But Vandana Sachdev and others at the NIH
looked at the NIH cohort and then also in conjunction
with similar transplant protocols
that were done at the University of Illinois, Chicago,
and Riyadh, Saudi Arabia.
And what they found was that two years after transplant,
there was an improvement in the cardiac size,
mass, an improvement in diastolic function,
an improvement in the tricuspid regurgitant velocity.
And so, that’s a really important finding,
that in the -- once the high blood flow state was resolved,
that many cardiac changes reversed.
So, now, looking at our data in pulmonary function
after transplant.
So, our hypothesis was that patients after transplant
would have stable lung function.
And so, that we really hypothesized
and kind of were eager to demonstrate
that the transplant wouldn’t hurt their lungs.
This has been shown in non-myeloablative transplants
outside of sickle cell. But we really need to not assume
that that’s going to be the case in sickle cell
and look at it clearly.
So, our primary outcome measure was FEV1-percent predicted.
And so, we looked at spirometry. We also did lung volumes.
So, we have body plethysmography or nitrogen
washout in all of our patients. This is one of the luxuries
of being at America’s research hospitals
is that we can get a number of these different studies.
We looked at DLCO.
And then we also performed six-minute walk distance
testing, a sub-maximal exercise test.
And so, looking at our flow diagram,
we had 112 people living with sickle cell
that underwent transplant. 97 had baseline PFT data.
So, that’s the analysis that we did.
Year 1, we had 91 patients, 72 at Year 2, and 55 at Year 3.
So, you see there is some drop off.
By that Year 3, half of those patients had lost a follow up.
And this is -- we had to exclude them
if they didn’t have the pulmonary function data
at the beginning.
But either lost a follow up, or some of them were censored.
Because when we pulled the data,
they hadn’t yet had that observation.
In terms of preconditioning, they all uniformly had
Alemtuzumab, total body irradiation, and sirolimus.
And half received pentostatin and cyclophosphamide.
So, looking at our cohort characteristics --
so, these are just descriptive statistics --
we can see that the median age in the group is 31.8.
41 percent are female. In terms of the hemoglobin --
I know you guys would ask about that.
[laughter]
So, the baseline was 8.8. And then the median in Year 3 --
and it’s pretty stable throughout -- was 12.5.
So, we know that the transplant in this population
increased the hemoglobin.
I will discuss; this includes 22 patients
who experienced graft failure.
We made the decision to include those within these data
because patients who might experience graft failure
will also want to know what their pulmonary outcomes are.
We didn’t want to just exclude them from the beginning.
So, 87 percent are hemoglobin SS.
And as we had hypothesized --
now, these are just the descriptive data.
I’ll go through some more detailed analyses.
The FEV1 and FEV1-percent predicted
were really rock solid,
almost surprisingly solid. So, that is encouraging.
And as Nona went through, this is really something --
and I’ve been able to do this.
You can talk to your patients about it.
You can say, you know, that we have data that show
that your lungs won’t be hurt by this."
And I think just saying that alone --
whether or not we can say there’s improvement
in some patients is a different story,
but I think that’s an important thing that you can communicate.
How we breathe is important.
That’s what we think in the pulmonary world.
And then there’s also not a change
in the sign of obstruction with FEV1 over FVC.
So, looking at DLCO --
so, this is unadjusted for hemoglobin.
As we might expect, because the hemoglobin went up,
the DLCO does improve and stays consistent out to Year 3.
We did also look at it, adjusted for hemoglobin.
And I would say this took me down
a whole rabbit hole of understanding --
oftentimes, when we all rely on something,
and you go back, and there’s one paper from 1983
that enrolled 20 patients that had anemia.
And that’s how they devised
the DLCO hemoglobin adjustment formulas.
And I spoke with a number of world-level experts
in physiology to really be certain about that.
So, I felt really unconfident about adjusting for hemoglobin,
particularly once people come out of that anemic range.
But you can see, we looked at it a couple different ways.
And overall, it remains stable.
In terms of looking at the six-minute walk distance,
there is an improvement from 490 at baseline median
to 520 at Year 3.
And I’ll go through the minimal clinically important difference
for that in a little bit.
So, this is just a snapshot of baseline comorbidities.
This is a national and international referral network.
And so, there’s a relatively high severity of illness
coming in.
So, one-third of patients have had ACS
requiring ICU or ventilator support.
10 percent had right heart cath-defined PH.
About one in five had thrombosis.
So, these are our models, really looking
at the longitudinal PFT change from baseline by year
using generalized estimating equations.
And this gets to one of the questions
that Dr. Thein had earlier
about looking at inter-individual variation
versus the variation of the cohort.
So, here, we do have inter-individual evaluations.
And so, what we can see, if you jump to the Year 3 column,
so for FEV1-percent predicted and FVC,
there’s very little change.
So, that’s as compared back to the baseline measurement.
So, if anything, it, you know --
our hypothesis bore out that there was not change.
And then looking at the DLCO,
there was a statistically significant increase.
But it’s not quite what we would consider
a clinically important difference.
So, we would want to see a 10 percent change.
When people are reading your pulmonary function testing,
and they say there’s a significant change.
It’s really that they’ve seen a 10 percent change.
That, again, is not based on very robust data,
but that’s kind of where the pulmonary community has settled.
So, overall, there was a slight improvement in DLCO
but not a clinically significant change.
But then looking at the six-minute walk test,
there was a -- both clinically significant
and statistically significant improvement,
with an increase in 26 meters from the baseline.
There was additional lost data
in the six-minute walk testing patients
compared to the pulmonary function testing data.
So, it’s possible that we missed some people
who weren’t able to do the six-minute walk.
But I think this is still very represented --
representational of the people who were able to do that.
So, this colorful plot, it’s called an alluvial plot,
and it was very fun to make. But this is able to show us
the ventilatory patterns in each year
and who moves in and out of the different groups.
So, if we start at the top, in the pink, that’s normal.
The yellow is obstructive. Green is restrictive.
The blue is mixed.
Purple is nonspecific, which is a little bit --
people you can’t quite put in any bucket.
And then the pink are the missing data.
And so, I think what’s most important to see about this
is that the relative proportions stay similar.
So, once you get rid of that missing data over time, overall,
the proportions of the categories
that people are in remain stable over follow up.
And most importantly, no patients were diagnosed
with pulmonary GVHD or other moderate GVHD in this study.
And only two patients went from having
had normal pulmonary function
testing at the beginning to ending with obstructive disease.
So, that’s very reassuring in a transplant setting.
So, in summary, FEV1 and pulmonary function
remained stable three years after transplant.
There’s a clinically meaningful improvement
in six-minute walk distance from baseline,
a slight improvement in DLCO
in the setting of increased hemoglobin,
ventilatory patterns remained stable,
and no patients developed pulmonary GVHD.
So, is it possible that we can break the cycle
of sickle cell disease
by using curative and transformative therapy?
So, I’m coming along with the language.
I think there’s a lot that that we can do
and communicate to our patients
by describing some of these patient-relevant outcomes.
It means a lot to tell people about the six-minute
walk distance. I know that might not --
that might seem very wonky for some of you,
but if you kind of explain it
and the fact that they can walk further,
that’s something that really can -- that sink in.
So, our paper was just recently published
in the Annals of American Thoracic Society.
So, one thing I was excited about
is that now more pulmonologists are seeing this as well.
And we’re looking ahead to evaluate the association
of the six-minute walk distance
testing with health-related quality of life.
One thing I kind of mentioned
was the minimal clinically important difference.
So, that really should be studied
in different populations.
So, within the cardiopulmonary community,
ranges about 20 to 30. And so, I think that’s one thing
that has not yet been done in sickle cell.
So, I think, really setting a minimal clinically important
difference would be important. And then, of course,
looking at multicenter and longitudinal studies.
So, COALESCE is an effort to continue this study
across multiple sites.
And we will, at the NIH, also be able to dive
in a little bit more closely into deep phenotyping,
looking at long MRI
and working closely with colleagues in Africa as well.
And I know I’m out of time, so just going to jump ahead.
I just want to show these shining faces
at the American Thoracic Society,
who are all excited to learn about sickle cell disease
and want to bring in best practices
into their own clinics.
So, with that, I’ll thank you for your attention,
and happy to take questions if there’s time.
[applause]
John Tisdale: Any questions? I can start with one.
Parker Ruhl: Okay. Yes.
John Tisdale: Another question that I always ask.
So, when looking at the effects
of an intervention on some physiology,
it always seems to me that one step further to go
is not just look at the whole population that some failed,
but to only look at the population where it worked,
so that -- Parker Ruhl: Yes.
John Tisdale: -- so that you’re understanding
whether making the hemoglobin go to normal
and have all that hemoglobin be hemoglobin A or AS
is valuable for this measure of that.
So, it makes me wonder, did you look at DLCO
in only those where it was successful and compare?
Parker Ruhl: Yes.
So, we did also look at the group
excluding patients that had graft failure.
And for both the DLCO and the six-minute walk distance,
the measures were a bit higher.
So, they weren’t dramatically different
but several points higher for the DLCO.
So, for example, that went from 3 to, I think it was 5.9.
And then for the six-minute walk distance,
it went from 25.9 to 33.
So, I think higher but also not dramatically higher
to really change your interpretation of those data.
Yes.
Swee Lay Thein: Parker, that was great.
You’ve seen this in some of your patients,
and you also see, you know,
other patients with pulmonary function abnormalities.
Supposing I give you the PFTs,
and you can ask for blood, everything.
Look at the pattern.
I won’t tell you what disease the patient has.
Parker Ruhl: Yeah.
Swee Lay Thein: Is there a typical signature from the PFT,
so you can say,
"I think this patient has sickle cell disease"?
Parker Ruhl: So, I don’t think I could do that,
like our cardiologist suggested that he could earlier.
Now, there would be a pattern that would be consistent,
but I think there’d be enough other patients
that might also have that pattern
that I wouldn’t be able to see that,
you know, there’s a signature for sickle cell.
But for example, you know,
if I’m allowed to look at the hemoglobin,
there would be a --
you know, if you’re ordering DLCO, please make sure
that there’s been CBC done within the last week.
But then also, I think one thing that I could say
that you would see, is you might see a DLCO --
an isolated low DLCO or a DLCO that’s lower out of proportion
to a mild restriction.
So, I think that’s something that can be fairly common
in what we see with that sort of gestalt
that you’re asking about.
Female Speaker Parker, great -- sorry.
Go ahead.
Male Speaker: Please.
Female Speaker: Great presentation.
I want to say --
you said that pulmonary function didn’t improve,
but I want to say, natural history
of pulmonary function has declined.
Parker Ruhl: Yes.
Female Speaker: So, if you can prevent decline,
that is improvement. So, just --
Parker Ruhl: Yes. No, that’s completely fair.
And so, I think part of this is once
we’re looking at a three-year window,
anytime we’re looking at a long-term data point,
and we’re trying to annualize it,
it can be a little tricky to say,
"How meaningful is it to look at these three years
versus the next three years?"
So, you know, you can look at these annualized declines
of 49 ccs per year versus 25 in the general population.
That was also another deep dive I did,
is looking at the general data on what is an annual decline.
There’s not data on the expected annual decline
in Black patients or in Black --
or in patients with African ancestry, for example.
But in the general population, it’s also just a very --
it’s kind of so general
as to not be terribly meaningful about year to year.
So, I think this is where looking at coalesce,
multicenter, and truly longitudinal data --
I think, as everyone here has talked about,
really looking at five- and 10-year data
is going to say a lot more about that point.
But I agree with you, with age --
and I have some other slides I didn’t include for time
about just aging in the lung
as kind of one of the additional insults.
But basically, you’re going to see expected ages.
The beauty of these percent predicted equations
is that it does account for a lot of that.
But I agree. I think this is --
should be seen as a success, that it remains stable.
John Tisdale: Mark.
Mark Walters: That was that was really wonderful.
I got nervous because I was afraid
that you were going to show a different conclusion
about lung function [unintelligible].
Parker Ruhl: [laughs] I didn’t.
Mark Walters: Because children we observed
in a much smaller cohort in a real-world setting,
that we came to the same conclusion.
But we don’t have the luxury of John
and Matt Hsieh’s incredible work
where they don’t get graft versus host disease
after allogeneic transplantation.
And myeloablation with busulfan
is generally a part of our world in children
and in gene therapy too.
So, what would be your predictions
about the overlay of those two potential toxicities?
Parker Ruhl: Yeah. That’s a great question.
We should look at those data. I think it’s going to be --
yeah, it’ll be a different situation
than the non-myeloablative.
And I think that’s, again, where looking at those --
you know, everyone’s talked about how doing it younger --
with a younger donor is a benefit.
So, I think as we consider the aging lung,
I think you’re going to see even more differences
in the impact in, for example, 20 decile, 30 decile.
If you were doing gene therapy in a 40 decile,
I think that’s where you’re going to see
increasing risk, for sure.
So, be very interesting to look at that. Please. Yes.
Male Speaker: What’s the difference
with the graft failure cohort? Is there a difference?
Parker Ruhl: So, the graft failure cohort,
they did not worsen.
So, their pulmonary function test did not worsen.
But, for example, the DLCO did not increase as much.
So, I think -- the reassuring thing to me there is
that if you go through the transplant
and you do experience graft failure,
that, you know, there might be other things that happen.
For example, there were three deaths in this cohort,
but they weren’t related directly to the transplant.
But just that, overall, you don’t come out of having
had the transplant with -- even if you have graft failure
with additional injury to the lung. Thank you.
[applause]
John Tisdale: Okay. Thank you.
We’re going to take a 10-minute break
and be back at 3:40 p.m.,
which is actually an eight-minute break.
Swee Lay Thein: Okay.
It’s my pleasure to continue the session
from the early session about outcome of curative therapies
in sickle cell disease,
but this time it is to talk about mutation of variant
screening to try to improve the outcome.
And the first speaker that we have is Dr. Lachelle Weeks.
And it’s really a pleasure that she could come in person.
Because we’ve been working with her,
and she’s been looking at CH markers
in patients with sickle cell disease.
So, Lachelle is a physician scientist
at the Dana-Farber Cancer Institute
in the Department of Medical Oncology
and an assistant professor of medicine
at Harvard Medical School.
And she’s probably the only person in the world
who does the clinic on clonal hematopoiesis.
[laughter]
[applause]
Lachelle Weeks: I thank you so much
for that introduction, Swee Lay.
And I -- there are a couple of different CHIP clinics
around the world.
And so, today, I’m hoping to tell this audience,
which doesn’t think about clonal hematopoiesis
and blood cancers as often as I do,
to sort of orient you to the idea of clonal hematopoiesis
as a complication, potentially, of cellular therapies,
and then talk about what we do in our CHIP clinic
for patients who are diagnosed with CH.
So, these are my disclosures. None, relevant to this talk.
So, cancer early detection and interception
is something that we think about a lot in our CHIP clinic.
And really, the framework that we use for this
is that there are three requirements
for any sort of effective screening program.
You have to have the ability
to detect an asymptomatic pre-cancer state,
like a colon polyp or a skin mole.
You have to be able to identify a population
that’s at risk for developing malignancy.
And one must have an intervention that
is likely to block progression and improve survival.
Because that’s what the sort of public health
relevance all boils down to.
And so, we think about this
in the context of clonal hematopoiesis,
which is a precursor of blood cancers
such as myelodysplastic syndrome
or MDS and acute myeloid leukemia or AML.
There are currently no approved screening programs
for blood cancers,
and our CHIP clinic is a hybrid clinical and research endeavor.
And we’re working to develop a screening program for MDS
and AML,
which are deadly cancers that affect older adults.
So, what is clonal hematopoiesis?
We know that as we age and as our cells divide,
we acquire or accumulate genetic alterations or mutations.
These are inevitable. They’re ubiquitous.
And clonal hematopoiesis really is describing
those somatic events in our blood cells.
So, it’s the age-related expansion
of a genetically related population of blood
stem cells or progenitor cells,
that’s detected as contributing more than its fair share
to the development of blood cells,
so red blood cells, white blood cells, and platelets.
In 2014, Ben Ebert and Sid Jaiswal
described clonal hematopoiesis as a precursor of blood cancers,
showing that, one, clonal hematopoiesis
was increasing with age,
and that, two, clonal hematopoiesis
existed in this continuum
from the movement from normal hematopoiesis
to the development of clonal hematopoietic
blood cancer like MDS or AML.
There are many different subtypes,
and I’ll bore you with all of these data sort of later.
But subtypes of clonal hematopoiesis
that we talk about the most have to do with somatic mutations,
so mutations in leukemia driver genes.
So, these are genes that we think of as causing leukemia,
found in individuals who don’t actually have leukemia,
who are otherwise healthy.
And we have now in the World Health Organization,
CHIP and CCUSS,
which are two subtypes of clonal hematopoiesis
that have been formally defined in the WHO
fifth edition of blood cancer classification.
There are other subtypes of clonal hematopoiesis,
so basically, other ways that you could have a single,
genetically related population of cells, but we --
predominantly, when we’re talking about CH,
we’re talking about the acquired mutations in leukemia genes.
So, like I said, these are precursors of blood cancers,
and they’re also quite common,
so about 15 percent of the population over the age of 65
and about 30 percent of the population by age 80.
With our standard clinical next-generation sequencing,
we can detect these precursors of blood cancers,
of MDS and AML.
So, again, these are people who don’t actually have leukemia.
They don’t actually have blood cancer.
They have the precursor.
So, they have the presence of the mutation in the absence
of any of the clinical characteristics of a cancer.
The rate of transformation from the precursor state
to the blood cancer is about 0.5 to 1 percent per year.
And one of the questions that we asked very early on was,
how do we actually determine which people in the U.S.
or around the world,
who we identify this precursor in,
should we actually be following in our CHIP clinics,
should we actually be worried about as being high risk
for developing a blood cancer?
In 2023, we developed a risk stratification system with that
in mind to estimate the risk of transformation from CH
to blood cancer.
And this risk stratification system is available online.
It’s called the clonal hematopoiesis risk score.
And it basically incorporates eight different factors
that you would have with a person
who you knew had clonal hematopoiesis;
whether or not they have low blood counts,
whether or not they have more than one mutation,
what those mutations are, how big the clone size is,
so what the allelic fraction is,
and then whether or not their red blood cell indices,
the MCV and RDW, are perturbed, and their age.
And using this risk stratification score,
we can tell if a person is high risk, intermediate risk,
or low risk for progression to a blood cancer.
So, in a general population setting,
individuals who are high risk for progression
have over 50 percent risk of transformation to blood cancer,
and individuals who are low risk have a less than 1% chance.
This is just showing what I just said.
So, individuals who are low risk have a threefold increase
in their risk of developing blood cancer
compared to individuals without any mutations.
Individuals who are high risk
have a 348-fold increase in their risk.
And this model we developed using a U.K.-based cohort,
so the UK Biobank, which is a cohort of healthy individuals.
And the model performed very well in the UK Biobank,
and we validated it using clinical data from Dana-Farber.
One of the challenges that we have with the CHRS
is that we did develop it in a very healthy population --
because those are --
that’s where our large clinical genomic databases
are sort of focused --
and in specific contexts such as sickle cell disease,
such as individuals who are undergoing cellular therapies
or receiving chemotherapy for other indications,
or people who happen to be in both categories,
such as sickle cell disease patients
undergoing cellular therapies, this sort of risk stratification
doesn’t really take those patients into account.
So, a lot of the work that I’ll talk about in a second
is really focused on understanding,
one, what’s the prevalence of clonal hematopoiesis
in a population of individuals with sickle cell disease?
And can we take the data that we’re starting to generate
and develop risk stratification systems
that are specific to this population?
So, now, in our clinic, we do a risk-informed management
of individuals with CH.
So, people who are high risk for transformation
are people we’re following pretty often.
We’re doing repeat next-generation sequencing.
These are our patients that we’re referring
for clinical trial participation,
and we’re -- these are patients with whom we’re doing more
than one bone marrow biopsy.
Individuals who are low risk, however,
typically are returned back to their primary care doctor
or whoever their primary provider is.
And they have their annual blood counts with that person
and only come back if there’s some sort of clinical change
that’s indicative of progression.
So, we have the ability to detect
an asymptomatic precursor state, which is CH.
We can identify populations at risk,
with the caveat that it’s not specific
to highly specified situations
such as chemotherapy or individuals
with chronic illnesses using the CHRS.
But we don’t yet have an intervention
that is available to block progression from CH
to blood cancer and improve survival.
And many therapeutic intervention studies for CH
are in their early stages,
and it would be lovely to think about cancer prevention
in this way for individuals who have sickle cell disease
and think about how we might include this population
in some of these early observational
as well as interventional studies.
So, thinking about sickle cell disease and clonal hematopoiesis
together, how are these two things related?
What’s the underlying biology?
Can we actually identify individuals
who are at risk for developing MDS
and AML as patients with sickle cell disease?
And can we prevent it from happening really
is the sort of crux of the issue.
This idea sort of came about for me and for my colleagues
in thinking about the lentiviral gene
therapy studies and their pause during the clinical trials
because of the development of MDS and AML and CCUS,
a precursor of MDS and AML,
in several patients who are on these trials.
And this really raised the question whether or not
this was a side effect of the gene therapy itself,
was a consequence of an increased risk of MDS
and AML in the context of sickle cell disease.
So, what was really causing this?
And so, there are two real hypothesis that are --
hypotheses that are floating around this issue
that are pretty viable. One is that the MDS and AML
that we’re seeing in sickle cell disease,
particularly in patients who are undergoing gene therapy,
is perhaps therapy related.
So, we know from individuals who are undergoing autologous stem
cell transplantation for myeloma or lymphoma,
that there’s about a 15 percent cumulative
risk of therapy-related myeloid malignancy in that setting.
There’s also donor-derived MDS and AML
that arises in individuals
who receive allogeneic stem cell transplantation,
if their donor happens to have CH.
And we know as well that these premalignant lesions
could be present years preceding the diagnosis of CH.
And so -- and that the selection pressures of chemotherapy,
of requiring a cell to undergo engraftment,
could potentially select for clones
that are better at proliferation or are better at self-renewal.
The second hypothesis,
which I find a bit more biologically interesting,
is that perhaps there’s something intrinsic
to the sickle cell disease environment.
So, perhaps in the context of chronic hemolysis,
there’s this erythropoietic stress --
and we heard a little bit about hematopoietic aging earlier.
Perhaps there’s some degree of bone marrow stress
from high output erythropoiesis,
the inflammation that’s associated with hemolysis,
that might increase the likelihood
that you develop somatic alterations in the first place,
or you develop clonal hematopoiesis
in the first place.
And this, in turn, leads to an increased risk
of developing hematologic malignancy in patients
with sickle cell disease.
Now, if this hypothesis is true, then one would expect
that irrespective of cellular therapy,
there would be an increased rate
or increased incidence of blood cancers
in a population of patients with sickle cell disease.
And looking through the epidemiologic data,
this is actually indeed the case.
So, this is data from Ted Wun out of California,
and he basically showed that individuals
with sickle cell disease in California
registries had an increased risk of leukemias
and particularly, myeloid leukemias,
relative to individuals without sickle cell disease.
We looked through the literature and noted
that there were a number of case reports
about blood cancers in sickle cell disease patients,
and a lot of these blood cancers
that were reported had pretty high-risk features,
including multiple genetic abnormalities,
including multiple chromosomal abnormalities,
mutation in a gene called TP53,
which confers resistance to a lot of the therapies
we like to use to treat MDS And AML.
And so, these were really high-risk scenarios.
And we wanted to know,
is this sort of just the cases that people are reporting
because they happen to be particularly bad?
Or is this sort of a universal experience
of a patient with sickle cell disease?
Do they all have this sort of high-risk phenotype?
And so, Miriam Osei, who’s in my lab,
looked through our database,
and we pulled together some patients from Duke,
courtesy of Marilyn,
who’s here, as well as MD Anderson, from Guillermo.
And what we noted first was that, fortunately,
the incidence of myeloid neoplasia
in sickle cell disease is not very high.
And so, we were only really able to find about 12 cases
from these three databases of individuals
who had myeloid malignancies, so MDS, AML, or Ph-MPNs,
in a diagnosis of sickle cell disease.
The other thing that we noted
was that there were a couple of features
that were characteristic of this population that stood out.
One is that the age of diagnosis was much lower
than one would expect for these blood cancers
that typically occur in adults
in their sixth and seventh decade.
So, the median age of diagnosis for AML,
for instance, was around 35.
The median age of diagnosis altogether was around 50.
And then the other thing that we noted
was that there was an increased rate of complex karyotype
as well as TP53 mutations in this population.
And again, these -- having these genetic features
confer a sort of resistance to the kinds of therapies
that we have available to treat MDS and AML.
And so, you know, this was associated then
with a pretty poor survival,
particularly for the MDS and AML populations,
with a median overall survival of around 11 months
for these folks.
So, thinking about and wrapping up this idea
of myeloid malignancy and sickle cell disease,
there’s an earlier age at diagnosis.
So, we’re looking at the third to fifth decade
instead of the sixth to seventh decade.
There’s a high mortality when folks are diagnosed
with MDS and AML
and they happen to have sickle cell disease.
And there are high-risk features associated with the diagnosis
of at least MDS and AML in sickle cell disease.
And so, then we ask the question,
should patients with sickle cell disease or thalassemia
who are being considered for curative therapies
be screened in some way for clonal hematopoiesis?
If this outcome is so bad, should we be making sure
that we’re at least detecting individuals who have
low-level clonal hematopoiesis involving TP53?
And the answer here is that we still kind of don’t know,
and we’re gathering the data.
We know that in data that has been published
using whole exome and whole genome studies
looking at clonal hematopoiesis
prevalence in sickle cell disease
have actually yielded conflicting results.
And so, in a whole exome situation,
clonal hematopoiesis
was more prevalent in sickle cell disease.
And in a whole genome analysis,
the report was exactly the opposite,
that clonal hematopoiesis was not more prevalent
in sickle cell disease.
And so, what we’re doing right now,
under the leadership of Coleman Lindsley at Dana-Farber,
is doing what we’re calling sickle cell disease
clonal hematopoiesis prevalence study,
a very simple study that has just two objectives.
One is to define the frequency and gene distribution
of clonal hematopoiesis in sickle cell disease
and to do this definitively using a large cohort
of individuals with sickle cell disease.
And then secondly, to determine what the incidence
and longitudinal progression of CH
is in patients who have undergone cellular therapy.
So, we’re currently --
have sequenced about 5,000 individuals
and have some very early data,
and hopefully we’ll have some data to present at ASH as well.
And this sequencing that we’re using
is targeted duplex error-corrected sequencing.
And the difference here,
for those who don’t think about sequencing all the time,
is that your standard next-generation sequencing
that you use in hematology clinics
to kind of screen for MDS have a limit of detection
of around a VAF of 1 to 2 percent generally.
And in this case, we can get down to point 0.001 percent
using our custom panel and our technique.
And so, we are able to detect much smaller clones
of clonal hematopoiesis
than are typically connected -- detected clinically.
So, in our very early data so far -- and again,
this is data from about 5,000 patients
that have been sequenced
and just sort of summarized descriptively here --
clonal hematopoiesis tends to have what we are seeing
as a distinct age and gene distribution
in sickle cell disease.
And just to sort of point your eyes
to a couple of the bars here, on the red graph,
we have the percentage of individuals
with clonal hematopoiesis in red.
And then in gray is the individual’s percentage
in that age group,
which are negative for clonal hematopoiesis.
And you see that there is red in the zero-
to 17-year-old group. And if you look at the same bar,
the corresponding bar for the blue graph,
there was no one in that group who had clonal hematopoiesis.
So, we’re seeing clonal hematopoiesis
detected at much younger ages
in the sickle cell disease population.
And the other thing that we’re seeing
is that the gene distribution is a little bit different.
So, there are a couple of different genes --
genotypes of clonal hematopoiesis
that we typically see.
One is mutations in these epigenetic regulators,
and that’s mostly associated with age.
And so, individuals who are 50, 60,
tend to have mutations in DNMT3A,
which is involved in methylation,
and TET2, another epigenetic gene
that’s involved in methylation, versus individuals
who are receiving chemotherapy or cytotoxic radiation
tend to have mutations in TP53 or PPM1D.
And these are genes that are involved
in the DNA damage response and repair pathway.
And so, what we’re seeing in the sickle cell disease population
is that, yes, we are seeing
the sort of age-related clonal hematopoiesis,
but we’re also seeing in young --
individuals who are young in age,
and most of these individuals did not have any sort of gene
therapy or cellular therapy or chemotherapy exposure.
We’re seeing that they’re having the development
of clonal hematopoiesis
involving TP53 and ppm1d at these younger ages.
And so, altogether, what this is saying
is that it appears that something different
is happening in the bone marrow of individuals
with sickle cell disease,
that clonal hematopoiesis is occurring at a younger age,
and is more likely to be associated
with these DNA damage repair and response pathway genes.
So, in summary, there’s an increased incidence
of myeloid neoplasia in sickle cell disease.
However, the absolute risk of this remains very low.
We see MDs, CMML, and AML
being associated with high-risk features,
particularly high-risk molecular features
such as TP53 mutations, complex cytogenetic abnormalities,
and this results in poor survival for this population.
CH has a distinct age and gene distribution
in sickle cell disease.
And again, we are seeing CH at a younger age in individuals
with sickle cell disease,
and individuals are more likely to have
these DNA damage response/repair pathway mutations,
even in the absence of cytotoxic chemotherapy exposure.
Screening and prevention of high-risk genotypes of --
for high-risk genotypes of MDS and AML,
could one day save lives.
And that’s sort of the whole premise of having a clinic
and a research lab that’s focused on development
of a screening program for CH.
And really the populations that I’m most concerned about
are these populations that develop
these types of myeloid malignancy,
MDS and AML, that we are unable to really treat,
where the -- that tend to be invariably, sort of fatal.
However, in the absence of proven
therapeutic intervention strategies,
wholesale screening for CH
currently has pretty limited benefit.
Because the question then is, what do you do with the results?
And further study evaluating how the presence
of CH influences cellular therapy outcomes
is going to be really necessary for us
to determine what benefit screening has
in this very specific context. And with that, I’d like to say
thank you to Miriam and my group,
who did the myeloid malignancy work,
and then to all of our collaborators in the Sickle Cell
Disease-CH Collaborative Group and the NHLBI,
who is funding that study. And I’ll take any questions.
[applause]
Swee Lay Thein: That was fabulous.
You know, I will say one thing
before anybody has any questions.
I’ve heard this word premature aging.
This is probably the third or the fourth time.
And this is what I say, sickle cell disease,
there’s inflammation occurring in this.
We heard about premature aging in the bone marrow,
when the doctor presenting --
I forget the name, excuse me -- on hydroxyurea.
So, it worries me a little bit, like, say,
you know, when they --
I’m not really the bad girl for hydroxyurea. Okay?
What I’m saying is, if you push the dose too hard
and, you know, and they get mild suppressive,
and then we are probably accelerating
this premature aging. And those [unintelligible]
clones will appear earlier. So, anyway, I rest my case.
[laughter]
John Tisdale: To be continued. Right?
Lachelle Weeks: To that point,
we are currently working with Russell Ware
to gather the blood specimens from individuals
who are on many of his hydroxyurea clinical studies.
And we’re hopeful that with those longitudinal samples,
we’ll be able to tell if the dose increase associates
with emergence or expansion of clonal hematopoiesis.
That will be really interesting.
It is notable, however, that at least in our populations
and our cohorts that are coming from outside of the U.S.,
many of those individuals actually don’t --
are not on hydroxyurea.
And so, a number of our younger individuals
don’t have any hydroxyurea exposure
but still have that DNA damage repair and response pathway, CH,
which is completely curious to me.
And, you know, hopefully we’ll get some information
about that in the next couple of years.
John Tisdale: So, I’m going to have a question
and ask you to speculate.
Lachelle Weeks: Okay.
John Tisdale: So, the question is that,
given that, you know, P53 mutations
are seen more frequently as a CH event
in sickle cell disease at a young age,
and the malignancies that have been seen
at least post-allogeneic bone marrow transplantation
have included TP53 mutations that, in retrospect,
were found before the transplant.
Is that one mutation that we could at least say
we should be screening for until you finish your analysis?
And then the second question that I’m going to ask you
to speculate on is,
you know, since this is, you know, proliferation,
and maybe there’s hyperproliferation,
and is causing this that,
you know, are these transplants --
because we’re seeing it across transplants, right?
Gene therapy, allogeneic transplants,
match sibling, haplo, what have you.
Is it because of this, you know, hyper, sort of, reconstitution,
that if we do find this P53 mutation beforehand,
we might give those cells an upper hand
in this whittled down hematopoietic stem cell number,
and should we again be going earlier?
Lachelle Weeks: Yeah. You know, to the point of screening,
I think identification or screening --
starting to screen for at least TP53 now does make some sense.
You know, I think you would have to have a conversation
about what the risks and benefits are of proceeding
with any sort of cellular therapy,
all things considered, with the individual in front of you,
the patient in front of you.
We do actually have patients, for instance,
who are diagnosed with ovarian cancer,
who are found to have CH and have a TP53 mutation.
It’s not the same since scenario but similar flavors.
And the question always comes up,
what do we do with that information?
And how do we sort of counsel our patients
as to what chemo therapies are safe versus not safe?
And we always say that you have to treat the sort of beast
that’s in front of you, you know.
And so, you want to make sure that you’re doing
whatever is best for the patient’s primary issue
and not trying to avoid something
that could potentially be beneficial in the now
because of a statistical risk later.
But that that whole calculus might completely change the more
that we learn about TP53 mutations.
Swee Lay Thein: Francine, I’m sorry.
Time’s up.
Francine Baker: Really? Well, that’s okay.
Because you and Dr. Tisdale asked my question [laughs].
Swee Lay Thein: All right, quick one then. Quick one.
Francine Baker: Okay. So, I was going to --
quick comment though. I really do think that,
just given your talk and your presentation,
jumping on Dr. Little’s soapbox here,
this is really why we need to have a global registry
to have all this data and all this information.
Because I’m pretty sure -- okay, I am speculating now --
that there might be more to the story than what we’ve --
what you’ve shared today. Thank you.
Lachelle Weeks: Absolutely.
Swee Lay Thein: And as to what we’re going to do for now,
I think it’s very important to collect the dots
and then you can join them later.
Okay? It’s very important.
Lachelle Weeks: Absolutely.
Swee Lay Thein: So, we should do that.
Okay. So -- okay [laughs].
[applause]
I also like to say that I do tell all my patients
that you have to start with hydroxyurea.
Okay? It’s not because I don’t give them hydroxyurea.
Anyway, it’s my pleasure to introduce our next speaker,
who is John Pierciey,
and he’s going to talk about screening for alpha thalassemia
in gene therapy. Okay. Thank you so much.
Oh, John is currently the vice president of bluebird bio.
[applause]
John Pierciey: All right. Thank you, everybody.
So, you know, my name --
as Swee Lay said, my name is John Pierciey,
and I’m currently the head of Research at bluebird.
And we’ve had some wonderful talks talking about,
you know, some exciting data from gene therapy.
And I’ve been tasked with talking
about a particular situation
where the data may not be as we expected it to,
in particular, the impact of alpha-globin gene deletions
on gene therapy outcomes in sickle.
First, disclosures.
I am an employee and shareholder of bluebird bio.
So, first couple of slides are about,
just a background to make sure we’re all on the same page.
We know gamma-globin well,
but the other major genetic modifier
of sickle cell disease severity
are variants that regulate alpha-globin protein levels.
And when we talk about alpha-globin gene deletions,
the most common in individuals of Sub-Saharan African descent
is the 3.7 kb rightward deletion,
which actually deletes a part of α1
and α2 to create a single hybrid gene.
In sickle patients, it’s estimated
that about 30 to 35 percent have a single deletion,
and about 3 to 5 percent have two-gene deletions.
And this figure will become more relevant later.
And this is not in sickle cell disease,
but this is the alpha/beta-globin mRNA ratios.
And unsurprisingly,
with an increasing number of gene deletions,
you have a decrease in that alpha/beta ratio.
There we go.
When it comes to the impact of alpha-globin gene deletions
on biologic and clinical outcomes,
I want to cover a paper on the left.
But before I do that, I want to talk about the color scheme.
So, I kept the color scheme
consistent through the rest of the presentation
to keep it manageable and digestible.
And red are patients with no alpha-globin gene deletions.
Blue is single alpha-globin gene deletion.
And that yellow gold color -- can we see? Yeah, we can see it.
Good -- is two alpha-globin gene deletions.
And so, you know,
with an increasing number of gene deletions,
we have a corresponding increase in hemoglobin,
hematocrit, and RBC count,
but we also have a corresponding decrease in MCHC, MCV and MCH.
And I definitely do want to point out
the significant reduction in the two-gene
deletion patients, in MCV and MCH.
As it relates to clinical complications
of alpha-thalassemia,
there was a nice meta-analysis published last year
by the group at St. Jude.
And what we know, right, the co-inheritance
of alpha-globin gene deletions confers protection
against cerebral vascular disease,
which is stroke on the bottom there in gold,
also silent cerebral infarcts,
vasculopathy, and also, prefer --
you know, confers some protection against priapism
and renal complications, et cetera.
There is some, you know, mixture in the data here,
but several studies have shown some increases
in the frequency of VOCs,
particularly in two-gene deletion patients.
This is thought to be due to the fact
that although in these patients,
the red blood cells are more deformable,
they’re more adhesive.
And so, that increased aggregation,
coupled with the higher hematocrits,
the proposed mechanism for that.
Regardless of the protective effects though,
the figure on the right is from the same paper on the left,
where the authors didn’t see any difference in admissions
or inpatient days per year.
Now, the focus of this talk is on gene therapy,
but I did want to do a single slide for hydroxyurea.
Now, as you all know way better than me,
you know there is some conflicting data here.
But I think what it all sort of aligns around is that in --
with alpha-globin genotypes --
sorry, alpha-globin gene deletions,
there is not as a significant of increase in total hemoglobin,
but that is thought to be due to the fact
that they have higher baseline total hemoglobins.
And so, in terms of a comparison of two papers,
and the main point I want to make,
I have the Darbari 2014 paper on the left.
Please don’t criticize [laughs].
And on the right is the same paper,
the Brewin 2022 paper on the previous slide.
And what I want to point out the discrepancy of
is the Brewin paper
did highlight in the alpha-thal group --
so, combining the single and two-gene deletion patients --
that there was a reduction in the increase in MCV and MCH.
While the Darbari paper didn’t see a difference
between the no deletions
and the one and two-gene deletion group.
I think the main point I want to make is in the bullets below,
is that in the Darbari paper,
only 7.7 percent of patients had two-gene deletions.
And in the Brewin paper,
18 percent had two-gene deletions.
And so, I think the theme from my talk
throughout this entire --
you know, next few minutes is going to be that
by combining the single and two-gene deletion patients,
we may be masking some of the effect
in the two-gene deletions.
Now, onto gene therapy.
Now, the great thing here is that Dr. Frangoul, Dr. Tisdale,
and Dr. Kanter did all the heavy lifting for me.
So, I’m going to shave time off and not really go through this.
I’ll make a couple of points though.
So, these are the three protocols
where data specifically on alpha-globin genotype
are available, and I’m going to talk about
some of the outcomes on the following slides.
So, lovo-cel, Lyfgenia, which is gene edition,
which was covered --
I do want to reiterate the point that Dr. Kanter made.
There -- we are inserting a functioning copy of beta-globin,
but we do not impact the gene expression of βS.
We reduce intracellular βS protein --
which I’ll cover later -- but not mRNA levels.
And then as Dr. Frangoul gave a nice overview
of these BCL11A approaches, right,
reduce the transcription of βS while they up-regulate
the transcription of fetal hemoglobin.
Onto the data.
So, on the left, we have some demographic information
from lovo-cel data as of, I believe, February of 2023.
And ultimately, right, we see about 30 percent of patients
have a single alpha-globin gene deletion,
and 2 or 5 percent have two alpha-globin gene deletions.
I wrote the 3.7 kb at the bottom here
because every single alpha-globin gene deletion
identified was the 3.7 kb deletion.
Now, if we look at total hemoglobin in the middle,
you know, if you look at the no deletion
and the single deletion, you’re like,
"Oh, actually, maybe the single deletion
looks a little bit lower."
But when you dive into the details,
in the no deletion group, only 25 percent are female.
And in the single deletion group, 64 percent are female.
Additionally, right, as we know from hydroxyurea --
we’ve published on this --
you know, as your therapeutic protein goes up,
your total hemoglobin is going to go up.
And you can see on the right, all gene therapy protocols
currently have a pretty decent range
in the therapeutic protein.
So, when you actually attempt to control for sex
as well as the amount of therapeutic protein,
we don’t actually see a significant difference
between total hemoglobin. Numbers are small.
We’re still looking at it but thus far, no difference.
As it relates to the shmiR data, now, Dr Frangoul did give us
a nice overview of the 2021 New England Journal paper.
The authors did provide a nice update at ASH of 2022,
where they gave us patient-specific
level information, including a single patient
with two alpha-globin gene deletions, Patient 11.
For ease in digesting the data, we’ve graphed it down below.
So, on the bottom left, you have total hemoglobin.
And on the bottom right, we have HbF levels.
And similarly -- actually, I am just --
I completely realized that I forgot to talk
about the two-gene deletion patients.
Wow. I was just in the zone. Sorry about that.
So, yeah, two-gene deletion patients, right,
so the pediatric patient in gold and the adult patient in gray.
And so, ultimately, they had lower total hemoglobins.
The adult patient was not transfusion dependent
before coming on study
and became transfusion dependent, post-lovo-cel.
And I’m going to talk about that a bit more.
And then additionally, the pediatric patient,
you know, the hemoglobin was between 8.8 and 10,
between six months and 24 months, post-transplant.
The other thing I will comment on
is that both participants had erythroid-specific dysplasia
in their marrow, post-lovo-cel.
And I’m going to go into that into a lot more.
Wow, I bungled that. Geez.
All right.
So, now, we’re going to go back to total hemoglobin levels
for the shmiR protocol.
And so, although there was a pretty decent increase
in total hemoglobin in the two-deletion patient,
the total hemoglobin was lower at 8.8
compared to the no deletion in single deletion patients
with similar levels of HbF.
I will comment on that single gray dot
and the no deletion who did have a lower total hemoglobin.
But you can also see in the right figure,
they had a lower percent F because they had
a lower peripheral blood vector copy number.
Last but not least, we have the exa-cel or Casgevy data.
And I do want to thank the authors
for including this supplemental table
in the most recent New England Journal article,
where they did break out data between no deletions
and that they combined single and two-gene deletions.
Looking at the demographics on the top,
34 percent had a single deletion.
And similarly, there was two patients, or 5 percent,
that had two alpha-globin gene deletions.
Unfortunately for me, in the purposes of this talk,
they combined the two, single deletion and two deletion.
So, we can’t make any more conclusions,
except that the -- what the authors made
that there was no difference between the two groups.
But we don’t know, right, whether or not this --
the two-deletion patients were on the low end.
Did they have low F, high F?
So, unfortunately, we can’t, you know,
distinguish anything more from this particular data set.
In the interest of time,
I’m not going to go through the full slide here.
But for -- as an interim summary,
before we dive deep into some of the lovo-cel data,
out of the 89 patients that I just summarized
on the previous three slides,
where alpha-globin genotype is available,
33.7 percent had a single deletion,
and 5.6 percent had two deletions,
which aligns with the accepted prevalence,
which I think is really cool when we consider the fact
that these gene therapy protocols
have pretty stringent inclusion criteria
as we think about disease severity
in these different genotypes.
The last two.
The next bullet, right, from what we can see so far,
is total hemoglobin is generally not different
between the no deletions and the single deletion patients.
And then, you know, sometimes we can mask differences
or not be able to determine differences
between the single and two-deletion
by combining them. The rest of it --
I’ll skip to my last slide. Because I do want to make sure
that we get into the lovo-cel data.
And so, as we think about the impact
of alpha-globin gene deletions,
what has our experience with lovo-cel taught us?
Before I really get into our data,
I do just want to do a quick,
high-level overview of the literature.
You know, over the past, you know, 40 years now,
there have been sporadic reports -- and the data is evolving --
that ineffective erythropoiesis occurs
in baseline sickle cell disease.
And I’ll sort of summarize all of these papers to say
that we know that the bone marrow is hypoxic.
Developing erythroblasts can sickle.
And there was a nice paper by Sara El Hoss and colleagues,
recently showing that cell death occurs between the polychromatic
and orthochromatic erythroblast stages.
So, what do we see in our data?
So, well, we’ve been collecting baseline
bone marrows at screening
and sometimes prior to transplant,
and we’ve been having them centrally red.
And so, here in the bars on the bottom left,
at the top, we have a healthy reference
from a recent paper in 2020 with, like, 200 --
with 240 healthy marrows.
And then below that, each bar is an individual participant
coming onto our study.
You can see on the left, it’s broken up by genotype,
and you can see the cumulative proportions
of the different erythroblast types.
If we put all the data together and the figure on the right,
you can see that there doesn’t appear to be a difference
between the single deletion and the no deletion.
Numbers are small.
We’re continuing to gather this data.
And you know, there’s a --
and compared to the healthy volunteers,
there was a lower polychromatic erythroblast population.
And because this is proportion, there was a corresponding
increase in the other populations.
I’ll also point out on the bottom left,
the adult participant with two gene deletions.
We did have a baseline bone marrow available.
And you can see the quite significant orthochromatic
erythroblast population.
But I think the most important finding,
at least for me, on this slide,
is the fact that we do see low-level stress erythropoiesis
in the bone marrow of sickle patients at baseline.
And we had five patients with dysplasia
with a median of 5 percent and a max of 10 percent,
with some of those dyspoietic findings
being nuclear karyorrhexis, multinucleation,
you know, cytoplasmic asynchrony,
and basophilic stippling.
And you know, if you talk to any hematopathologist
with experience, here, they’ll go, "Yeah. Duh."
Right? You know, these are --
these dyspoietic findings are quite common in sickle cell.
Unfortunately, most of these data are largely unpublished.
And that has been challenging, specifically for us,
because distinguishing dyserythropoiesis
from myelodysplastic syndrome
can be quite challenging. And as we have --
actually, I think the previous presentation
mentioned it as we presented -- and is also on our label,
the pediatric participant with two-gene deletions
was diagnosed with MDS in January of 2023,
30 months, post-lovo-cel.
This was done by a local tumor board, based on the anemia,
the erythroid-restricted dysplasia,
as well as clonality identified by karyotype.
And ultimately, what I wanted to do on this slide
was talk about the diagnostic and clinical features of MDS
on the left and compare both the pediatric
and the adult participant on the right.
As it relates to clinical symptoms,
the pediatric participant is doing well.
They are transfusion independent.
They have not had any VOEs, post-transplant.
The treating physician as well as the family
are actively monitoring
and are currently not pursuing treatment for MDS.
However, as I mentioned,
the adult participant is transfusion dependent
and does continue to experience chronic pain.
As it relates to blood counts, there are no other cytopenias
aside from the anemias discussed.
The pediatric participant, since diagnosis,
has had a stable hemoglobin greater than 10.
It’s actually been slowly going up,
and it’s been hovering between 11 and 12 for the past year.
As it relates to the dysplasia that I mentioned,
in the marrow, the dyspoietic findings
are similar to the previous slide.
It is bi- and tri-nucleation.
It is basophilic stippling, et cetera.
And I’ll show you some pictures in a couple of slides.
We’ve had all available bone marrows
reviewed by two independent pathologists,
and they have both concluded that these findings
are consistent with stress erythropoiesis.
As it relates to clonality,
the adult participant has had no clonal process identified,
whether or not by insertion site analysis,
looking for a vector clone,
or by karyotype or any other measure.
And the pediatric participant did have two clones
identified at their Month 30,
but there was significant discrepancy in the frequency
between the local and the central labs.
And when there was a subsequent bone marrow at month --
the Month 36 assessment, we did bilateral bone marrows.
And there was essentially -- only one iliac crest
showed one of the clones at a frequency of 1.4 percent.
And then as we look for, you know,
driver mutations consistent with MDS,
there have been no mutations identified by,
you know, next-generation sequencing
or multiple other assays.
And there have been no aneuploidy
identified by karyotype.
I will comment that the adult participant
did have trisomy 8 identified by FISH
in a single bone marrow aspirate,
six months post-transplant.
However, six weeks later, when we came back
and did another bone marrow aspirate,
the trisomy was not found, and it was never seen again.
They did originally have an MDS diagnosis
at that original trisomy 8 finding.
But that diagnosis was changed a few weeks later.
As it relates to the pediatric participant,
the FISH has been all over the place.
We’ve seen low-level aneuploidy, specifically trisomies,
which has been significant discrepancy
between the local lab and central lab.
In one particular assessment,
I think every single chromosome tested on the --
by the local lab had trisomies,
and the central lab had no trisomies.
So, there’s definitely been
a significant amount of discrepancy there.
So, if we put all of the data together,
the data do look consistent with dyserythropoiesis,
likely due to the globin chain imbalance
from two-gene deletions
and exacerbated from gene addition therapy.
The challenge though is, how do you definitively prove
that this is dyserythropoiesis from globin chain imbalance
and not MDS?
So, in the last couple of data slides,
I’d like to show some things
that the research and clinical teams have been doing.
And so -- and how --
I don’t know how I’m doing on time,
but I’m going to try to rush.
So, we have been getting blood and bone marrow samples
at the lab at bluebird, and we have been enriching CD71
reticulocytes out of peripheral blood
and erythroblasts out of the bone marrow.
And one of the things that we did
in the figure on the left here
is look at the proportion of T87Q mRNA of total beta mRNA
and comparing that to the proportion
of transduced erythroid colonies.
And this is a shockingly straight line.
And you know, I like this
because it tells us a little bit about cell biology.
If we look in the literature for globin chain imbalance,
when the cell tries to deal with that stress,
it shuts down translation.
But because an erythroblast needs so much hemoglobin,
it does not down-regulate transcription.
And I think that’s what we’re seeing here.
You can see in the top right, the two-gene deletion patients
have very high transduction efficiency.
So, even in the context when you have only
two alpha-globin gene deletions
and a high number of vector copies
or a high number of beta-globin mRNA,
we’re not seeing the transcription
deviate from that line.
Then when we look at the alpha/beta mRNA ratios,
we’ve got the reference range that I showed you
on that first slide in blue in the back,
but we don’t actually see the alpha/beta ratio
in the peripheral blood be outside of the reference ranges.
And the lovo-cel data is in black here.
When we look at the protein ratios, however,
both in the peripheral blood and the bone marrow,
we don’t see a statistically significant difference
in the protein ratio between the no deletion
and the single deletion, which makes sense.
We’re not really seeing a difference in hemoglobin
or any other outcome.
But we are starting to see a drop in the protein ratio.
Now, in the interest of time and space,
I didn’t show the bone marrow alpha/beta ratio.
But I did want to specifically point
out the average ratio of the adult participant
that was 0.29, which comparing that to,
you know, the ratios of HbH disease, which are 0.2.
But remember, this is Gene addition therapy,
meaning that there is a distribution of vector
copy number or vector copies.
And so, this particular participant
had a peripheral blood vector copy number of almost 5.
And so, when you think about that 0.29 average,
half of the cells are going to have
an alpha/beta ratio below that.
And when we think about the very high vector copy numbers,
we’re probably getting very, very low alpha/beta ratios.
Become even more apparent here --
and this is my last data slide.
The other thing that we started to do was to pick individual
BFU-e colonies grown from the blood
and bone marrow of some patients with no alpha-globin single
and two alpha-globin gene deletions, post-gene therapy.
And you know, I like picking BFU-es
because BFU-es are clonal,
meaning all cells will have the same VCN.
And so, we can pick a BFU-e,
and we can measure the vector copy number,
and we can separate the protein by globin chains.
And that’s what we have here.
On the y axis, we have the proportion of globin fractions.
On the x axis, we have the different VCNs.
And in white, you have the T87Q. In blue, you have the HBS.
And because this is in vitro culture of colonies,
it does up-regulate fetal hemoglobin expression.
But it’s actually pretty cool that it’s here.
Because we can think about affinities for alpha-globin.
And so, if we look, I grouped the no deletion
and single deletion together, largely due to space,
but also because the results looked so similar.
And we can see just how different
the two alpha-globin gene deletion data looks.
And when I look at these, I think one of the big things
that really stands out to me is that,
one, I like to say that HBS is the biggest loser, right?
When we think about the affinity for alpha-globin
and how the T87Q, the βS,
and the HbF are going to compete,
it does look here
that the βS is ultimately not pairing for alpha.
The other thing that we can get out of this too
is that it does look like the protein levels
with two-gene deletions are significantly different,
which is really throwing off the ratios that we’re seeing here.
The other thing I’ll comment,
which I mentioned on the previous slide,
is the adult participant that has the high VCN.
Over 50 percent of their colonies measured here
had that VCN a 4-plus,
so that all the way on the right there,
I mean, we have almost undetectable amounts of βS.
So, the question becomes, we can’t speak to the amount
of translation, right, the competition between,
you know, mRNAs at the ribosome, but what it does look like here
is that when alpha-globin is limiting,
βS is not pairing to alpha-globin.
And so, therefore, you know,
is that accumulating in the cytoplasm,
and what does that stability of that protein do?
Well, what do we know about how the cell deals with this?
This is a nice review from Mitch Weiss
and Eugene Khandros from 2010.
So, we know that irreversibly folded proteins
will be ubiquitin tagged and sent to the proteasome.
But when they accumulate too much,
chaperone proteins will get them
together into an aggresome in an attempt to deal with that.
And if the proteasome can’t deal with it,
then autophagy kicks in.
And so, we’ll end in the context of, sorry, denatured hemoglobin.
In this context, we call them Heinz bodies.
So, you know, are we seeing these aggresomes
in these bone marrows?
So, here are some pictures that I’ve cropped out
of some of the bone marrow images,
the pediatric participant on the top, adult in the middle,
and some baseline beta thalassemia marrows
from our 207 study.
And you can see these eosinophilic cytoplasmic
inclusions that look quite similar to the inclusions
that you do see in the thal patients.
Now, I will say -- and I’m running out of time –
but we had a very difficult time
actually proving these are globin chains.
Some of the techniques just aren’t really around anymore.
No one’s doing it.
And some of the logistics associated with doing this
with fresh have been quite difficult.
But I’ve had some great conversations
with all of you for some ideas.
So, I’m going to wrap up and say that, you know, ultimately,
in the context of two alpha-globin gene deletions,
regardless of the gene therapy approach,
there will always be a thalassemic phenotype.
And so, you know, even if you’re not,
even if you are reducing ßS, you are still likely going
to have some level of globin chain imbalance.
And so, ultimately, you know,
we should continue to characterize
what those outcomes are going to look like.
And so, I’m just going to kind of skip through the conclusions
a little bit. Right, with the lovo-cel data,
we did see some unexpected results
in the two patients treated in the lovo-cel studies.
And because of this, you know,
patients with alpha-thalassemia trait
are included in the limitation of use section
on the Lyfgenia label.
But I do expect that all gene addition approaches
are likely to exacerbate globin chain
imbalance in two-gene deletion patients.
And as we saw in the shmiR trial,
the single two-gene deletion patient
did have lower hemoglobin.
And unfortunately, at this time, we can’t actually figure out
how the two patients did in the exa-cel study.
But, right, the purpose of this session,
I would propose that all patients
that are undergoing gene therapy do get alpha-globin genotypes.
I would also kindly request that all -- you know,
until we have a registry, all future manuscripts
publish the two-gene deletion data separately,
even if it’s in the supplement.
Because I would love to get invited back in maybe five years
and I can talk about the results.
[laughter]
So, with that, I want to thank the study sites.
I want to thank the patients, their families,
the bluebird research team,
and especially Melissa Kinney, who made all the figures,
because I am not that good at PowerPoint and GraphPad.
All right. Any questions [laughs].
[applause]
Swee Lay Thein: John, this is great.
I mean, you can --
sometimes you can get very severe myelodysplasia.
I remember looking at a patient
coming in with a hemoglobin of like 4,
and she turned out to be very iron deficient
and turned out to have [unintelligible].
And when we treated her,
the bone marrow became completely normal.
We thought initially, it was MDS.
Second point, John -- comment I’d like to make is,
can I suggest something very simple?
I mean, you may laugh. Okay?
When you have gene therapy,
they all undergo myeloablation, right, or some form or other.
And even -- if you already have two-gene deletion,
then you’re wiping out the beta component
as well as the alpha component.
But you’re only replacing the beta subcomponent, right?
And so, the chain imbalance gets worse.
So, it’s like a hemoglobin H disease.
And have you tried staining the peripheral blood
with brilliant cresyl blue --
John Pierciey: Yeah.
-- to see whether they have H bodies?
John Pierciey: Yeah.
So, yeah, the question was around whether --
oh, did I just break it? I think maybe I did --
about finding HbH bodies in the peripheral blood.
So, that was done, and we didn’t see any HbH,
maybe a couple of percent.
And that was ultimately why we started
looking at peripheral blood.
But then we shifted our focus to investigating the marrow.
Because if we weren’t seeing HbH in the peripheral blood,
is that because these cells
weren’t making it out of the marrow?
Or that second to last slide, you know, are --
is the globin chain imbalance
because we’re getting that accumulated ßS in the cytoplasm,
and it’s just aggregating or denaturing faster
than it can form? We don’t have the answer,
but those are some of the things we’re trying to figure out.
But the answer is, no, we didn’t see any broad amount of HbH
in the periphery. No.
Jane Little: This is Jane Little.
I just had -- I’m just a little curious.
Julie Cantor is looking at trait,
and she’s seen a -- to me, a surprising number of patients
who had alpha chain triplicates or more.
It was not a small number. I think was more than 5 percent.
And when I think about it, I’m a little surprised
that this isn’t coming up in any of these gene therapy.
There was one triplication in your --
John Pierciey: Yeah.
There were triplication in the exa-cel study.
We did -- our lovo-cel studies have not seen any triplication.
Jane Little: Because I wonder if it might not be enriched.
Because it will make the disease worse,
I have always thought, more hemolytic.
Right, Swee Lay?
John Pierciey: Right. I mean, that’s --
Swee Lay Thein: There was one.
It was a little bit higher than your two-gene deletion,
the triplicated one, in your slides. I saw it.
John Pierciey: So, there was --
so, the only triplicate was in the exa-cel study.
And I actually thought that the triplicate
was excluded from that supplemental analysis.
But I mean, to your point, right, the reason why, right,
we -- you know, the --
it’s thought that there is a higher RBC count
in patients with alpha-globin gene deletions
is because the MCHC is lower, right?
And when your concentration of hemoglobin in the cell
is lower, you’re going to have less sickling.
So, to your, comment, right, with triplication,
if there’s more alpha globin, does that mean that
you’ll actually get more intracellular ßS?
I mean, maybe. Unless, of course, right,
you’re just not having enough translation of beta globin
to actually compensate for that.
But we didn’t see any triplication in lovo-cel.
Yeah.
Swee Lay Thein: Your numbers are so small.
You’re only one. John Pierciey: Yes.
Swee Lay Thein: And it was actually higher
than the two genomes, you know.
It was equivalent to the one single gene.
I think you cannot base it on one case of [unintelligible].
John Pierciey: Yeah.
Male Speaker: Great talk, John.
I -- as, you know, somebody who thinks
about global biology a lot, I agree with you.
This looks like these were the voices from an induced
thalassemia versus anything MDS related.
So, I just want to say that as well.
I think that -- I just wonder
if you looked at zeta-globin expression at all,
just in terms of compensatory aspects.
I mean, it’d be very small.
We don’t really have great inducers
or any, you know, knowledge of how to switch this.
But I’m just curious if you’ve seen increases in that
or compensation in anyway.
John Pierciey: Yeah. You know, by HPLC,
whether or not it’s delta-globin, gamma-globin,
et cetera, no.
The -- all the globin chains remained pretty consistent.
Now, the globin -- looking at the globin chain
in the adult participants is hard.
They were on transfusions.
But if you look at the pediatric participant,
yeah, the, you know, T87Q, ßS, all very consistent.
And all the other globin chains were quite low.
Male Speaker: I’d just be interested in looking at HbZ
in RNA-seq as well.
Because even with 3.7 kb deletion,
you still have that region
that’s present in the alpha-globin locus.
John Pierciey: Did my team hear that
about looking at the RNA-seq data?
Male Speaker: That’s true. Yeah, that’s true.
John Pierciey: Yeah.
No, good suggestion. We can look.
Because we did -- at the same time
that we did the enrichment of the erythroblast
for looking at protein ratios
and other things, we have done RNA-seq.
And we’re still analyzing the data,
trying to see if we can get anything else out of that.
Male Speaker: Yeah.
John Pierciey: Okay? Thank you.
Swee Lay Thein: I think that was excellent though.
Excellent.
[applause]
Jennifer is dying to get here.
I just want to read a message here.
It says, "From Lisa Wisdom to the meeting group,
kudos to the organization --
organizing team and all the presenters.
This has been an excellent seminar, has instilled hope,
even as it’s raised more questions for future efforts.
Keep up the great work. Thank you to all of you."
[applause]
Jennifer Knight-Madden: Okay.
Thank you for making it to the final session.
And we have some interesting discussions ahead.
So, I’m going to go ahead and invite Dr. Mark Walters to come.
He’s going -- Dr. Walters is the Jordan Family director
of the Blood and Marrow Transplantation Program at UCSF
Benioff Children’s Hospital and professor and chief,
Hematology Division in the Department of Pediatrics
at the University of California,
San Francisco School of Medicine.
And he’ll be talking about curative therapies.
Dr. Walters.
[applause]
Mark Walters: Thanks, Jennifer.
And thank you, Monika, John, and Swee Lay
for giving me this topic at the end of the meeting.
[laughter]
So, I surmise that I would be in this situation.
And so, I thought, why don’t I show something that’s so old,
I’m hoping most of you will have forgotten about it,
and it’ll look new again? So, I’ll start there.
[laughter]
And then I’ll share some data
that have been submitted for publication
but not published yet.
And I’m going to focus on bone marrow transplantation.
The disclosures I have, the conflicts,
have nothing to do with what I’m about to present.
So, we started this over 30 years ago, 1991.
Keith Sullivan and I led an international
multi-center collaborative investigation,
27 transplant centers, and we completed enrollment
almost 25 years ago.
So, 59 children with severe sickle cell disease
received HLA-identical bone marrow transplants.
And these were the results.
They -- I’m sure they look very similar.
Overall survival, event-free survival,
has shown 3 percent rejected their grafts.
So, you know, 20-some years ago, this looked really pretty good,
so 85 percent of event-free survival.
But there are two problems.
Patients were dying of the conditioning regimen
or graft versus host disease
or something related to transplant too often.
And too often, the sickle cell disease was coming back.
So, all of the current iterations really come back
to what do we do to mitigate those two risk factors?
And so, today, I think
HLA-identical sibling bone marrow transplantation
is still a standard
because it has very good event-free survival,
particularly in children less than 12 years of age.
And we understand pretty well the late effects
of myeloablation with busulfan in that population.
And the risk of graft rejection in graft versus host disease
have largely been manageable. So, the question though is,
because very few of our patients have --
are young and have a sibling donor,
what about HLA-haplo-identical transplantation?
What about unrelated donor transplantation
from well-matched donor, donor?
And then you already know the answer to the last one.
So, let’s -- I thought I would share
then some fairly contemporary bone marrow transplant
trials like this first one,
all multi-center, NIH-supported --
and let me tell you,
these are really hard to do properly, and --
but we learn a lot from them and --
but often, the information is not spectacular
because it takes so darn long to finish the studies.
But anyway, let’s go through it
because I think they’re instructive.
So, the first one is -- goes under the acronym STRIDE2.
Lakshmanan Krishnamurthi at Yale led the study with me.
And Mary Eapen, Donna Neuberg,
and Keith Sullivan were key leaders.
This has been submitted to Blood Advances,
where it’s under review.
So, this was a bone marrow transplant trial
that compared transplantation to best available therapy.
And to be eligible,
patients had to be adolescents or young adults
with severe sickle cell disease, as defined here.
And this is a fairly familiar list of indications
of severe disease that we followed.
And the idea though was to perform a biologic assignment,
which was our best attempt
at doing a randomization comparison.
So, if a person had a well-matched donor,
either a sibling or unrelated donor,
they were assigned to a donor arm.
And for the majority who lacked a donor,
they were assigned to the new donor arm.
And at the time of biological assignment,
that’s when we began to track for endpoints.
And the primary endpoint
was just to compare overall survival.
And what we reasoned was that two years after a transplant,
survival would be worse after a transplant
than best available therapy.
But because most of the mortality
after an allotransplant occurs in those first two years,
their survival should be static at that point,
while it would continue to accrue on the no donor arm.
And the idea was that over 10 years,
we would begin to show a benefit
in terms of survival after transplant.
But for us to be able to make that comparison,
we actually need not 40,
but 60 in the donor arm and 140 in the new donor.
So, it was a myeloablative regimen that was in 2015.
The standard approach, busulfan, fludarabine, rapid-ATG,
and then tacrolimus,
methotrexate for GVHD prophylaxis.
And the consort diagram indicates problems.
So, we didn’t enroll 200.
We only enrolled 142 largely because of the pandemic.
And of that group, 138 were eligible;
28 were assigned to the donor arm
and 95 to the no donor arm.
And because we didn’t meet the accrual goals, this --
the study was suspended before it was completed
because of the accrual challenges.
We lack power to compare overall survival.
So, Donna Neuberg insisted that I emphasize
that this is a descriptive comparison.
This is not -- didn’t have statistical power.
So, please keep that in mind.
But I think the results are interesting.
So, the two-year overall survival
indicated by the red curve on the donor arm
was 89 percent and 93 percent on the no donor arm.
So, I thought the mortality in adults --
in adolescents getting best available therapy
was quite eye opening, over a two-year period.
And you can imagine that if that overall survival
after a transplant is stable, that would -- it would,
over a much shorter period of time than six to eight years,
probably in the next several years,
show benefit in terms of survival of transplant.
But, of course, I’m not allowed to say that
because Donna would slap my wrist.
[laughter]
But it’s more complicated because the current way
that we look at event-free survival is --
particularly in sickle cell disease, is this is --
to do graft versus host disease-free
event-free survival.
And that declined all the way to 38 percent.
So, that’s sobering.
So, graft versus host disease was a significant problem,
both acute and chronic GVHD,
and particularly after unrelated donor transplantation.
So, that’s the green curve where acute
GVHD approached 50 percent in both acute and chronic GVHD.
So, why didn’t that cause significant
transplant-related mortality?
I think it’s because our treatment of graft
versus host disease has gotten quite a bit better.
We have a broader armamentarium of drugs.
And it comes. It’s treated.
And generally, it goes away these days.
So, that’s my interpretation of why
this didn’t impact overall mortality.
So, what about the secondary endpoint comparison?
So, this is -- you’ve been accustomed
to looking at these now.
John showed Alexis Leonard’s data
after his allogeneic transplantation cohort.
You’ve seen all of the swim lane plots --
swimmer plots after gene therapy.
Well, so, this is what happened in this study.
And so, the point of comparison
is at the time of biological randomization.
And the donor arm is on the top panel
and the no donor best available care in the bottom panel.
And in some cases, there was a long delay between randomization
and actually getting the transplant.
So, it’s the period of time in dark blue
that’s the pain rate --
pain event rate after transplantation.
And there was a significant improvement
in vaso-occlusive pain.
These are contemporary prospective populations
that we studied in the study.
So, that’s, I think, an important finding.
It’s not surprising, but this is the first time
that someone showed this in an intent-to-treat way.
The other important finding was that these domains,
in particular fatigue and participation in social roles,
got better after a transplant. So, fatigue went down.
Participation in social roles got better.
We’re comparing red after a transplant,
to blue, no donor standard of care.
And then pain interference also got significantly better
following the PROMIS 57 PRO domains.
Although in the others, there was no significant difference.
And again, I think some of these,
like physical function and depression, anxiety,
were probably affected by the high rate of chronic GVHD.
So, that’s an important difference between gene therapy,
where those things got better, and this type of transplant.
So, that’s a summary of the of the STRIDE2 data.
I’m going to go now to the BMT CTN haploidentical
bone marrow transplant study.
This has been submitted and is under review
in the New England Journal of Medicine Evidence.
And the leader of this study --
well, the co-chairs are shown here.
Adetola Kassim led the adult study,
and this was sponsored by NHLBI.
So, there are two strata for this study, children and adults.
The adults followed the same eligibility criteria
that we used in the previous study.
And in children, it initially focused on stroke,
either silent or avert,
and then was later expanded once safety was observed
in the early patients to include recurrent pain,
life-threatening acute chest, and priapism.
So, the data are mature and have been analyzed
in the adult stratum.
The pediatric stratum will be available
at the end of this calendar year.
So, we’ll be able to see more about that at next meeting.
So, here’s the regimen that was utilized.
It follows the Johns Hopkins
post-transplantation cyclophosphamide,
and it aimed to improve
on the initial Johns Hopkins experience,
which had a 43 percent incidence of graft rejection
with return of sickle cell disease
by augmenting with thiotepa
that’s administered on day minus seven.
Otherwise, it’s identical to the Javier Bollon
[phonetic sp]
study that was published previously.
And then post-transplantation Cy
to accomplish in vivo T-cell depletion
for post-grafting immunosuppression
and then sirolimus and MMF
to augment engraftment of the donor cells.
So, the event-free survival in the adult cohort
is shown here, quite good, 88 percent at two years.
And while there were graft failures,
ended up at a total of 7.1 percent,
so a decline, after adding thiotepa
to the conditioning regimen, from 43 percent to 7 percent.
So, I think that was this principal improvement
that was shown in this study.
Graft versus host disease though was still a problem,
both acute and chronic.
And so, Grade 3, 5 percent acute GVHD
and quite severe, moderate,
or severe chronic GVHD is 7 percent.
So, the overall cumulative incidence rate was 22.4 percent.
So, still HLA-haploidentical half-matched donors,
very good event for survival,
but still problems with graft versus host disease.
Again,
after post-transplantation cyclophosphamide, it happens.
You can treat it, and it tends to get better.
So, here we are. Should we pursue genome therapy
or an HLA-haploidentical transplant?
Both will have a readily available donor,
but in one instance, no -- graft versus host disease,
no graft rejection while, on the other hand,
still risks of GVHD and graft rejection.
One relies on ex-vivo manufacturing,
high-dose busulfan with perhaps a risk of myeloid leukemia.
Reduced intensity conditioning regimen
probably causes fewer toxicities in the short term.
It’s less expensive.
But both will still be inaccessible to some patients,
maybe to most patients.
So -- and here are what we’ve been listening to
for the last two days. Here’s what they cost.
So, let’s face it;
this is not going to have the impact that we dreamed about.
So, this is a steppingstone,
and we’re going to make improvements.
But I thought it would finish
with these provocative conclusions
that Jane and Marilyn will shoot me down for.
[laughter]
So, risks associated with chemotherapy
and radiation conditioning,
graft versus host disease graft rejection
have tempered enthusiasm for allogeneic transplantation
in this era of gene therapy.
But I would argue that the data, at least in adults,
argues that HLA-haploidentical transplantation
is an alternative,
particularly in young adults with sickle cell disease,
and should have broad accessibility, theoretically.
So -- but still my prediction --
and this is just my prediction --
it’s very likely that improvements
in the safety/efficacy of genomic modification therapies,
autologous cells will supplant allogeneic transplant.
But in the immediate future,
I think disease-modifying therapy options
will continue to dominate care and sickle cell disease.
But curative therapy should eventually be transformative.
So, I leave you with, I think, what John shared,
what others have shared,
is that that where we are now is a steppingstone,
and we will continue to make improvements.
So, we should invest in them and encourage our families
to participate in the clinical trials
as we get better and better At this.
So, thanks very much for your attention.
[applause]
Jennifer Knight-Madden: [unintelligible]
Mark Walters: Okay.
Jennifer Knight-Madden: Okay.
Thank you very much, Dr. Walters.
We’re going to have questions at the end of the session.
So, we’re now going to move to our illustrious tag team.
First, we’ll have Dr. Marilyn Telen,
who’s a Wellcome Clinical Distinguished Professor
of Medicine at Duke University School of Medicine.
And after her will be Dr. Jane
Little, who’s a professor of Medicine at UNC Chapel Hill.
I don’t know how these two get together.
You know, they -- with the two different blues.
But Dr. Telen is definitely from the better blue.
Oh, okay. I’m a Duke alum, okay?
Okay. All right, right. And so, Dr. Jane Little
is a professor of Medicine at UNC Chapel Hill
and directs the adult sickle cell disease program there.
And they’re both going to talk
about more disease-modifying small molecules.
[applause]
Marilyn Telen: Thank you.
I’m trying to make sure I know how to advance the slides.
Jennifer Knight-Madden: It’s the other one.
Marilyn Telen: It’s this one?
Jennifer Knight-Madden: Yeah.
Marilyn Telen: Okay. Oh, if I were tall,
I could actually see what the slide says.
[laughter]
Well, as we heard Mark Walter’s comment,
we need to still think about modifying --
disease-modifying therapies.
And the reason is that curative therapies,
such as we’ve heard a lot about yesterday and today,
will not reach most of the patients
with sickle cell disease in the world who are alive today.
And so, it behooves us to provide
those patients with alternative
therapies to improve both survival and quality of life.
So, there’s no question that hemoglobin S
and the sickle red cell --
sickle, not sick old, necessarily --
is the root of the problem. Hemoglobin S is not stable.
It polymerizes with deoxygenation.
It causes sickling. It causes hemolysis.
But if you actually start listing what’s wrong
with sickle red cells, it goes beyond there,
and there is a lot wrong with sickle red cells.
I think Swee Lay talked about it a little.
We’ve heard other things about it.
And I probably don’t have, in my 10 minutes,
the time to actually go through all of this.
But if you read through it, you can see that every place
you look in the red cell of a sickle red cell
has something wrong with it, the membrane,
distribution of things like phosphatidylserine,
metabolic components,
the deformability and rheology of the cells.
They’re much younger than normal red cells,
and they have abnormal adhesive properties,
interesting but abnormal signaling properties,
and deficient expression of antioxidant compounds.
And so, while the red cell
is the center of sickle cell disease
and causes anemia and vaso-occlusion
and then chronic tissue damage and organ damage,
the Pathways leading to these are multiple and complex.
And this is one incomplete illustration of things
that are going on in sickle cell disease.
And while, as you see this, the red cell
is in the center of it, the arrows go all over,
and they involve adhesive interactions.
They involve inflammatory effects.
They involve activation of coagulation,
free hemoglobin, and oxidative damage,
endothelial dysfunction, and it goes on and on.
And I’ll spend about -- and the blue here
is some of the possible ways we can intervene
with this vicious cycle of effects
of having hemoglobin S in the red cell.
But while there are a lot of targets,
or therapeutic targets, in sickle cell disease,
the critical issue is, what -- which ones are most important?
Which ones will have most effect on the patient’s well-being,
the patient’s survival?
And in the old days, Durham was the center
for making cigarettes. And at one point, the supervisor
of the cigarette-making factory retired.
And a few months later,
the head of the company called him up and said,
"You’ve got to come and help us.
The cigarette-making machine stopped working,
and we can’t figure out how to fix it."
And the guy said, "Well, if you give me $500,
I’ll come and fix it for you."
So, that was a lot of money at the time,
but they said okay because their factory was stopped.
And the guy came in, walked around the machine,
gave it a good kick, it started working.
And the guy said, "Why should I pay you $500.
All you did was kick the machine."
And the guy, the retired supervisor, said,
"But I knew where to kick it."
[laughter]
So, it’s the same thing here. It may take multi-agent therapy.
That’s my particular bias.
But there are a lot of things going on.
And if we just aim at one,
we may not accomplish what we’re trying to accomplish.
So, we do have three relatively new FDA approved medications
that you haven’t heard much about.
Voxelotor increased hemoglobin levels in its trials.
It decreased sickled red cell levels,
increased oxygen affinity,
didn’t have any notable effect on vaso-occlusive events.
L-glutamine decreased hospitalization for VOC,
decreased number of hospital days,
decreased acute chest syndrome. Crizanlizumab reduced VOC,
although the European agency in charge of drug approval
has decided maybe not enough to make it worth it.
And so, that’s where we stand now,
but there’s a lot in the pipeline.
So, some of these things target adhesion.
Crizanlizumab is the one that’s in -- on the market.
Rivipansel was tested in a phase 3 study.
Those two drugs are anti-selectin agents,
crizanlizumab directed against P-selectin,
rivipansel against E-selectin --
rivipansel did a great job in mice -- and then inclacumab,
which is currently in phase 3 study,
is simply -- it’s similar to crizanlizumab,
but it has a three-month half-life,
instead of requiring doses every four weeks.
And the other way of approaching adhesion
is that you can inhibit the signaling pathways
and the metabolic pathways inside the cell,
which actually increase activation
of the adhesion receptors that there --
exist on the outside of the red cell,
of which there are a number.
And I’m not going to get into that.
Because then it’ll be a long talk.
So, crizanlizumab is a humanized monoclonal antibody
that binds to P-selectin. And inclacumab, as I said,
is simply engineered to have a longer lifespan.
And the value of crizanlizumab, I think,
depends on who you talk to.
Although there’s some evidence now
also that it may help with priapism,
which is a very interesting -- actually interesting idea,
but I don’t have time for it.
So, in any case, even if it does reduce vaso-occlusion,
all the other things listed here,
so far, there’s no evidence.
And I don’t think there’s much coming
that it has much effect on any of the other things
that we know goes wrong in sickle cell disease.
Other potential anti-adhesive medications include things
like beta-adrenergic receptor inhibitors like propranolol,
which reduce the activation
of several of the adhesion molecules,
including the laminin receptor and the integrin receptor
on red cells. Again, it works in mice.
It works with the surrogate endpoint in people,
but it’s never gone through a real clinical trial.
Inhibition of MEK and ERK --
and there’s MEK inhibitors on the market in oncology --
also inhibit activation of these same adhesion receptors.
That’s never been tried in sickle cell disease.
Although we tried to get some companies interested.
Prevention of oxidative stress has been shown
by Dr. Zennadi’s group
to reduce red cell adhesion to the endothelium.
And then rivipansel, which failed its primary
endpoint of shortening acute VOC,
nonetheless looked like it
was probably at least somewhat effective if it was given early.
But at least in the United States,
our standard practice is to tell patients to stay home
and take pain medicine until they can’t manage their pain,
and only then to come to the hospital.
And if we were to use a drug like rivipansel
or even retest it,
we would probably have to change that practice.
Okay.
So, another source of problems is oxidative damage.
And we’ve heard a few things about oxidative damage,
especially to the membrane and membrane components,
but also possibly to submembrane and cytoskeletal components.
And we know that one way that hemoglobin F may be helpful
is because it actually reduces oxidative damage.
So, L-glutamine or Endari was FDA-approved
to reduce VOC frequency in sickle cell disease.
L-glutamine has antioxidant activity.
Although initial studies did not try very hard
to demonstrate how the drug worked, only that it worked.
But a recent study has had some really interesting results,
showing that, on the one hand,
it actually worsens cell dehydration.
It increases blood viscosity.
So, there are at least some, probably, cation transport
processes that are not made better.
But anyway, it does decrease point of sickling
and reduce reactive oxygen species.
Voxelotor, osivelotor, which is now undergoing trial,
decreases sickling. And I’m going to skip this.
And we heard a lot about PKR activators,
which have probably, as Dr. Thein said,
multiple effects on the red cells that could be helpful.
So, since I’m told my time is up,
I’m actually going to go -- to skip all this.
But in any case, as the old saying goes,
many roads lead to Rome.
Other drugs out there include anti-inflammatory drugs,
down-modulation of free hemoglobin,
like with hemopexin,
upregulation of hemoglobin F, either by gene therapy,
but even potentially and certainly
by a number of pharmacologic agents, anti-sickling compounds,
and other hemoglobin modifiers that we’ve probably yet to see.
Nonetheless, the health of millions of patients
living with sickle cell disease today
depend upon the success of both developing
and delivering targeted
and probably multi-agent therapeutic approaches
to the sequelae of having red cells
with predominantly hemoglobin S.
And I’m going to turn it over to Dr. Little.
[applause]
Jane Little: Yeah. It’s really fun to follow
right after Marilyn and Mark. That’s okay.
So, I’m also glad we ended up in Rome, in Marilyn’s talk,
because that’s kind of where I’m going to -- thank you.
I knew there was a lot of trouble with this.
I mean, sickle cell is quite amazing because it is really --
started when a gene sort of talked to an endemic infection,
9,000 years ago, right?
Like the sickle gene mutated.
And then it spread across Sub-Saharan Africa.
Because it saved millions and millions of people’s lives.
And now, I feel like it’s time for the globe
to talk back to sickle cell.
And I’ll go through that very briefly.
The Blue Devil is in the details, as you know.
[laughter]
And I’m just going to sort of summarize
a little bit about the newborn screening
that we’ve learned yesterday,
which was lovely, access to medications,
adherence to medications,
and assessing impact of medications.
I can follow it [laughs].
So, you know, you can’t give new therapies
these wonderful things we’ve heard about,
if we don’t know where the patients are.
So, you need resources for that.
Access to medications is also a struggle.
Adherence to medications is a struggle
in human beings everywhere.
And I think, finally, learning from high-prevalence sites
will be a benefit to all of us.
And then assessing the impact of medications,
I don’t know if you guys have heard of registries,
but I thought I might just mention a few things at the end.
[laughter]
So, you know, targeted therapies are not valuable
if the target is hidden.
And so, again, you heard some of this.
And in the U.S., it is 100 percent,
but it’s state by state. And I asked Mary Hulihan
if we knew how many babies are born every year
in the U.S. with sickle cell disease.
And she said, "You know, it’s like --
this is the most resourced country in the world,
and we still do not know how many babies actually are born
in the U.S. every year with sickle cell disease."
In Jamaica, you have 100 percent newborn screening,
which is lovely. I know COVID took its toll,
but you’re recovering beautifully.
And in Sub-Saharan Africa, as you heard,
it’s starting out strong, but it’s very patchy.
CONSA was described, the ASH effort,
Ghana, Uganda, and Tanzania.
This was very interesting to me.
You know, the gross domestic product in the U.S.,
where we have 100 percent newborn screening,
is $26 trillion.
The Mexican GDP is -- sorry, Mexican --
Jamaican GDP is about 20 billion.
And in Sub-Saharan Africa, the whole country, it’s --
Female Speaker: The whole country?
Jane Little: Yes. Thank you.
The whole Sub-Saharan, I meant -- yes, thank you --
the whole series of countries. It’s 2 trillion.
But you can see the ones where they have
the most newborn screening are the more wealthy countries.
So, Ghana is 76 billion. Uganda is 50 billion.
Tanzania is almost 80 billion.
So, even though it has cumulatively --
a median of 16 billion and cumulatively, 2 trillion,
there are places like Malawi
where it’s, you know, way, way down.
And those places do not have newborn screening.
So, I think the places where they have resources, as usual,
we’re starting to get newborn screening.
And as you know, without newborn screening,
we won’t have that beautiful uptick in survival.
You’ve heard this as well.
It’s always amazing to me to realize
that there are half a million babies
born every year with sickle cell disease.
Mary Hulihan estimated that 1600 babies per year
are born with sickle cell disease in the U.S.,
and the prevalence overall is about point 0.035 percent.
In Jamaica, as you’ve heard those lovely talks yesterday,
it’s 0.67, with about 180 to 200, is what I understood.
And in Sub-Saharan Africa, the countries -- continent --
it’s greater than 290,000 babies per year.
So, it’s estimated that there are 7 to 8 million people
around the world living with sickle cell disease.
And again, that’s probably very distorted
by our lack of newborn screening
and all the deaths that happen in kids.
So, I think if we did newborn screening
and figured out how to get care to those children,
this number would expand.
In the U.S., it’s 0.1x106 living in the U.S.
with sickle cell disease is estimated,
or 1.3 percent of the global burden,
Just as -- I was just trying to understand the numbers.
Because you keep hearing about PEPFAR
and how great it has been using high-prevalence sites
to inform low-prevalence sites. It’s estimated, in 2023,
there are about 40 million people
living with HIV in Sub-Saharan Africa --
sorry, in the world, and most of them are in Africa.
And again, 1.2 million are living in the U.S. with HIV.
So, that’s about 3 percent of the global burden.
So, it’s actually not as different as I thought.
I was sort of surprised.
So, I started with Jamaica. It seemed only right.
And when you think about learning
from high-prevalence settings
and how that really teaches us all.
There was a nice study from Lesley King
about giving IM penicillin and how it was much more --
they might have much less sepsis in the children
who got the monthly injectable.
And then there are all the cohort studies
that have taught us so much over the decades about --
I just pulled a few out, just to sort of show you,
and of course, the obligatory picture.
But it really is important that they really tracked people
in a very deep and consistent way across many decades.
And people have learned a ton.
In HIV, the -- they’ve learned things
like giving HIV medications more effectively,
so oral versus monthly prep.
Turns out, people don’t like to take pills every day.
And so, they had 43 percent plasma levels in daily oral
and 36 new infections.
A monthly injection, 93% coverage for infections.
So, again, you know, they learned
this over three years in 3,000 patients in Malawi.
There’s a consortium that did this.
This is the kind of study, when Mark talked about his study
that took 5 million years to accrue,
you know, if you’re in a high-density setting,
you can answer a lot of really simple, important questions
that we’ve been asking for decades.
And it’ll really inform care across the world,
including in the U.S.
Because we won’t be able to do gene therapy
on everybody for a decade at least, and transplant likewise.
And then they did this study on --
using one day of IV liposomal
Amphotericin with seven days of an oral antifungal,
and it was equivalent.
And so, it saved them a lot of time, a lot of money,
and this went into the U.S. -- to the worldwide guidelines.
So, again, we can learn a lot from places
where there are people who have the disease.
And I think that’s like pregnancy, you know, like,
that’s something where you can learn a ton
from places where there’s a lot of pregnancy.
And we’re just not sharing that kind of data.
Okay. I’m sorry. One of my colleagues said,
"You know when -- you know that thing, like,
where everyone rolls their eyes when Jane says, GRNDaD?’"
I thought, what?
[laughter]
No, I didn’t know that thing.
But apparently, I might be obsessed,
and I’m sorry about that.
But it was actually because of this conference
about five years ago.
They also asked me to do this debate thing,
which I don’t really understand.
But I was looking at all the registries and was like,
CF has had a 50-year registry,
hemophilia has had a 60-year registry.
They’ve really informed and improved care
and made it consistent. They had quality feedback.
And the sickle cell experience has been really unfortunate.
The CSCCD was so valuable,
but it died in the sort of late ‘80s.
But it -- sort of its offspring
are all those things like penicillin prophylaxis,
hydrea, partly, the STOP study.
They all grew out of problems that were identified in CSCCD.
And then we have these little --
like walk fast, rush, not little,
but they’ve never been consistent or comprehensive.
And I think there are two efforts now.
The one I know best is GRNDaD.
And we started that in 2010, I think, ‘13.
And this is PI driven. ASH has a more EHR driven one.
I can just tell you about GRNDaD, which is --
it’s a prospective, longitudinal registry.
We now have about 4,000 people in it.
And we’re really starting to learn things
about how we’re taking care of people
with sickle cell disease in the U.S.
that are helping us take better care.
Because you learn from yourself.
Because it’s amazing how, when you don’t actually look at data,
you don’t actually know what you’re doing.
And you think, "Oh, I’m doing so well." And then --
[laughter]
-- and then you suddenly see, "Oh, I didn’t know at Hopkins,
they did it better."
I mean, it’s -- I’m a little embarrassed, actually,
at how powerful that was.
So, these are the three registry efforts
that we’re undertaking now.
COUSIN was one we did with the U.K.,
where we just looked at symptom burden in the two populations.
And they were quite similar, which was surprising.
GRNDaD is now -- has more than 4,000 people,
and it’s really been kept alive by Sophie Lanzkron
and Julie Kanter, to whom I give full credit.
And GRNDMA is a very small, SPARCO-aligned effort
that we’re undertaking in Malawi,
where they’re facing the same thing
we all faced in the U.S., 30 years ago.
They have this whole cohort of children who are coming up,
and they’re right at the gate.
And there’s no one on the adult side to catch them.
And so, we’ve started to collect data on those adults,
so that we can hopefully take better care of them.
So, I really hope, as gene therapy becomes really --
and bone marrow transplant,
they all become part of our landscape,
that we’re able to have one or two registries
that can talk to each other,
so that we can understand the impact.
We don’t even know this about hydrea. It’s shocking.
Like we don’t really have 30 years of data
telling us its impact. So, I think we can do better.
PepNear -- [laughter]
-- you know, sometimes late at night --
and my computer broke. So, I couldn’t modify.
But I don’t think PEPFAR is the answer.
But I think investing more in resource-limited settings
will really help us all everywhere,
to take better care of people with sickle cell disease.
I think registries need to be comprehensive
and compatible with the local environment,
and we really need to get on top of it with gene therapy,
so that we’re being comprehensive about,
is there clonal hematopoiesis? Is there an alpha gene?
How are we reporting the outcome,
so that we’re really consistent? We know what we’re doing.
I think hydroxyurea, you know, we need to get it to people.
Like these other treatments are terrific, but we haven’t even --
like, there was -- Jamaica is 10 to 20 percent.
I’m embarrassed to admit that we looked
at the Medicaid data in North Carolina.
Across the whole state, it’s 25 percent.
So, it’s not even like -- we haven’t solved that problem.
And I think local interests in the U.S. absolutely synergize
with local interests in international sites,
and we need to be more collaborative
and support each other. Thanks.
[applause]
Jennifer Knight-Madden: I’m afraid
to touch this, but let’s try.
Okay. So, you know, one of the highlights
for me of any conference that we do
is actually to hear some feedback from the patients
about their lived experiences.
And today, we have two wonderful people to share with us.
We have Miss Morette Wright, who’s the co-founder
of the Sickle Cell Support Foundation of Jamaica
and a sickle cell patient at the University of the West Indies.
She’s going to speak with us first.
And then she’ll be followed by Mr. Patrick Onwuemene,
who’s a patient of Professor
Thein’s at NIH Clinical Center, Bethesda, Maryland.
And we’re going to hear from them.
And then we’re going to have a short panel discussion,
where I’ll invite the other speakers for this session
to also join us at the front,
so that we can have a discussion back and forth amongst them
and us as a wider audience. So, Miss Wright.
[applause]
Morette Wright: Good afternoon, everyone.
Okay. As you heard, I’m Morette Wright.
And it’s my honor to be here
as a sickle cell patient, representing.
So, I would say I have been living
and generally thriving with sickle cell disease.
I’ve long passed the average survival age.
So, you know, I’m thankful for that.
As a young girl, I was told I would not be employed
because of my condition.
But fast forward over two decades,
I have built a successful career in human resources
and have been recruiting top talent
for one of Jamaica’s leading companies.
[applause]
And I say this is possible because of my faith,
my resilience, a supportive family,
and access to medical care and treatment.
So, I’ll start my presentation today
with a simple yet profound Japanese proverb,
and it says, "Pain is inevitable.
Suffering is optional."
This perfectly captures the reality of living
with sickle cell disease.
So, pain is a constant companion for most of us.
This lifelong condition doesn’t take a break.
How we manage the pain and suffering
that it can bring depends primarily on the support,
the treatment, and choices available to us.
So, as someone living with sickle cell,
I understand the daily struggles, the physical pain,
and the emotional weight that this disease brings.
Yes, at times, we say life, hard, and it is.
I also know the importance of resilience, of hope,
and the need for treatments that can transform our experiences.
So, where are we headed in the treatment
of sickle cell in Jamaica?
So, much have been shared about the current state
of treating sickle cell disease in Jamaica.
You’ve heard about the strides
in the options available for pain management,
the comprehensive care that is available,
and I must pause to commend
the excellent work of the sickle cell unit.
And I want to acknowledge the team,
the past and the present team. So, yes, let’s acknowledge them.
[applause]
And we also heard about the National Sickle Cell Program
and the strides that have been made in Jamaica.
But with that, we still have some hurdles.
So, there’s not equitable access for all patients.
Because it depends on, you know,
one’s social and economic status.
And so, the burden of the cost of healthcare
is still prevalent. There’s also the inconsistent --
yes, treatment in the public sector is accessible,
but it is inconsistent.
The quality of care, at times, is not equitable.
So, there is the long wait, the inadequate pain management,
the inadequately trained health care workers,
and stigmatization.
But with that said, where are we headed?
What does the future hold for us here in Jamaica?
And we’ve heard -- I mean, this has been
a really rich content, rich session two days.
And, you know, it just reinforces where we want,
what we want in terms of treatment.
And I’ll start with, yes, we need a cure.
But hope is on the horizon with the advent of gene therapy.
We heard all about that.
So, we hope to see this soon in Jamaica.
Right, Prof?
So, rather than just treating the symptoms,
the possibility of life without pain is on the horizon.
We also need more access to the new medications
and the treatment approaches.
So, in addition to the curative therapies,
we hope to benefit from these new medications
that we have been hearing that’s changing the landscape
for persons living with sickle cell disease.
So, we are -- we’ve made some progress with hydroxyurea,
but yes, there are those other drugs
that are designed to reduce the frequency of the painful crisis
and help to improve our overall quality of life.
And in fact, next week, Wednesday,
during our annual lecture,
Professor Asnani will be speaking
about the innovative approaches and emerging therapies
in management of sickle cell disease.
So, she’s going to give us, Jamaican patients,
a little more hope.
So, we are also expecting better pain management options.
So, managing pain remains a key focus of treatment
in Jamaica and all around.
However, there’s a shift in how we approach it,
from non-opioid pain relief to more holistic methods.
So, we want to look at cognitive behavioral
therapy, mindfulness, acupuncture,
whatever else we can do to support.
It might not necessarily remove the pain,
but it helps the patient to better manage the process.
We’re on a path with policy changes, advocacy,
strengthening the healthcare system.
With the inclusion of sickle cell disease
in the Ministry of Health and Wellness strategic plan,
there have been some significant advancement
in treating persons living with sickle cell disease in Jamaica.
And our desire is to have a system
where no patient is left behind, and no one has to suffer.
So, as I started, you know, pain is inevitable.
Suffering is optional. Pain may still exist,
but with the medical advances, with the policy changes,
and with the -- with comprehensive care,
suffering does not have to define our lives.
So, let’s continue this work, research, care, advocacy,
policy, so that future generations will know a world
where sickle cell disease no longer brings suffering
but instead brings resilience, hope,
and a life filled with possibilities.
Thank you.
[applause]
Did I go down or stay here?
Jennifer Knight-Madden: You can stay here.
Okay.
[applause]
Patrick Omwuemene: Good evening, everyone.
My name is Patrick Omwuemene, one of Dr. Thein’s patients.
I am going to be talking more on the personal side,
my side of the story, when it comes to sickle cell.
My experience as a child -- I guess I would fall
under the threshold of the mild sickle cell,
according to the presentation Wynona Coles made.
And as a child, I really didn’t experience sickle cell,
like many other children did,
because I didn’t have much crisis.
I grew up with a lot of boys on my streets,
four very athletic brothers, very athletic neighbors,
and as a matter of fact,
one of them had a father as a coach.
So, he encouraged us in whatever sports we played.
It’ll shock you that I didn’t just play with them.
I played in the ring with them.
So, a lot of people cringe when they hear,
"You played in the ring," you know.
But that was life growing up.
So, my very first crisis came at about the age of 7, 8.
I believe my mom was testing me.
She told me to -- it was raining.
It was a cold day.
I had never experienced crisis at this point.
And she asked me to go get something
from the neighborhood grocery store,
which was just a couple of streets away.
So, without the thought of grabbing an umbrella
or a raincoat, I just dashed into the rain.
And in a few minutes, I was back,
ran as fast as I could.
Getting home, I began to feel this very funny pain
emanating from my back. And before I knew it --
I mean, it just crawled from my back
through the left side of my chest.
And before I knew it, I was engulfed in pain.
Pain felt like glass -- broken glass,
just crawling very slowly,
making its way from my back to the chest,
to everywhere else, and then the joints.
So, everybody was perplexed. Everybody was confused.
Because they had never seen me that way before.
All of a sudden, my mom is getting ointment,
trying to massage me.
My cousin eventually grabbed me some water.
I drank that.
And eventually, after a few hours, I felt better.
So, after that, they began watching me closely,
for fear that -- it shouldn’t happen again.
And before you knew it, I was back to my old self,
just running the streets
with the rest of the boys, playing soccer.
Of course, this was during the summer break.
So, we had the time of our lives, you know [laughs].
We had the time of our lives.
And I just can’t tell you how much fun that was.
And I really, after that point,
did not experience any more crisis.
My crisis basically was to myself,
in the sense that I was accident prone.
[laughter]
Yeah. It was me and my younger brother,
and I was the one getting the injuries.
He was just only -- he was just having fun with me.
That’s all, just -- and I --
it got to the point that they almost amputated my arm.
That’s how dangerous I was to myself.
But that wasn’t my fault.
Because that was a whole different freak accident.
I wasn’t being dangerous or anything to myself.
And then they made up a name for my brother and me.
They called us destructive elements
because of how bad we were, ruined the house,
when there was the one home, you know,
destroyed all the electronics and everything,
just everything [laughs]. So, growing up in my --
growing up into my teenage years, everybody found out,
yeah, there was something peculiar with me.
Because I wasn’t growing as fast as the rest of the kids.
So, I had stunted growth.
No pain, just -- no crisis, just stunted growth.
Still played, walked from school,
home and back, you know.
So, I wasn’t challenged physically.
On certain occasions though, during my teenage years,
I will -- I would get some crisis,
and they’ll say, "Okay, that sickle cell is back,
and we need to pay a close eye on him."
And eventually overcome it.
But, again, that experience of the sharp pain
that go through the vein was very scary.
You know, it was not just scary
because you see the concern in the faces of your loved ones,
it affects you too, you know.
It affects you emotionally that everybody’s --
that joy that’s there has disappeared
just because you are being worried about.
So, I felt some kind of way -- I felt very guilty for that.
And not only that, I also felt --
I felt strong mentally after the whole thing had come and gone.
It was like, you know, arrows in the night that pierces you,
and in the daytime, you finally overcome that --
whatever battle you were going through the night.
And you be made stronger.
So, in that sense, mentally, I got stronger, you know.
Fast forward to when I came to this country.
I got here when I was in the 11th grade.
Now, when I got here,
it looked like I was still in elementary school.
I had that stature.
And then my parents took me to a doctor
who diagnosed me and said, "Okay."
He gave me ion shots, and -- oh, God [laughs].
She’s telling me one minute.
I have 10 more minutes left in me.
But make it quick.
I had a growth spurt of two --
for about two years after I had seen this doctor.
And come to my mid-20s --
I mean, I went to school, went to work.
It really didn’t affect me until I got to my mid-20s.
I got to my mid-20s,
and I started feeling the effects of sickle cell again.
And I thank God --
I don’t know if you guys know about the Affordable Care Act.
Obamacare, they call it back home.
And that was a godsend.
Because sickle cell made me
broke over and over and over again
before that Obamacare or Affordable Care Act came.
Because year after year,
I was spending a weekend in the hospital.
That’s easily 15 to $20,000 out of my pocket.
Okay. And I’ll round up real quick.
Fast forward to when I came to the NIH,
I was evaluated and got into Dr. Thein’s program.
Ever since I started taking mitapivat,
I have not had one sick day in my life,
one crisis in my life.
[applause]
So, I thank God for NIH. I thank God for the team,
Dr. Thein’s team, and Wynona, who was the very first person
I met when I walked through NIH. I wish I had more time.
But she’s driving me off stage. It’s not my fault. Thank you.
[applause]
Morette Wright: Don’t go.
Patrick Omwuemene: Okay.
Jennifer Knight-Madden: Okay.
I’m going to ask the speakers earlier this session
to just join us back on the platform.
So, Dr. Walters, Dr. Little, and Dr. Telen.
And as they come, we’re going to turn the panel
discussion around a little bit.
Because what we’re actually going to do
is that we’re going to ask our patient representatives
to lead off with the questions, and they have the freedom
to ask anybody in the room or their fellow panelists,
anything that might have come to them
that they might be wondering and would like answered
before they go home. All right. Any questions?
Morette Wright: Well --
Jennifer Knight-Madden: There’s a mic there,
or you can use this one.
Morette Wright: Okay. Thanks for that opportunity, Prof.
This section of the presentation on the complications,
okay, right, the cardiac disease by Dr. Thomas.
Renal disease became heavy --
that section really, really became heavy for me.
Having the burden of living with sickle cell disease
and then there are these added complications
that we might experience
and know we have to live with that, it had me thinking.
Are there any strategies? Are there any techniques?
How can you guide people living with sickle cell disease
so that we can mitigate some of these other complications?
That’s what was on my mind during that segment.
So, you know, it’s more preventative strategy.
Because here, you’re teaching or sharing
with the healthcare workers how to treat us.
But even before you get there, how can you help us?
That’s where my thought is.
Jennifer Knight-Madden: Okay. That sounds like a question
for a jack-of-all-trades, adult clinician.
Or yes, if you want to come, please go.
Female Speaker: Nice shorts.
Thomas d’Humières: Yeah. I changed my --
[laughter]
Sorry about that. I’m in Jamaica.
This is actually a very good question.
Because I talk about how we can provide some help
to diagnose rhythm issues.
But before this -- and I didn’t have time to talk about this.
But for me, this is -- there is a very, very deep question
about physical exercise and metabolic disorders.
These are the two main things.
And we are very into physical exercise again.
Because for a long time,
no exercise for sickle cell patients.
And then we are seeing now, more and more data about, yeah,
it should be -- yeah, you could do it but be careful.
But without any real frame.
So, we are currently doing an ongoing trial, randomized,
with, really, how are we going to implement into life,
into real life, the start of a good physical exercise
that we know is beneficial for the quality of life,
the occurring of a vaso-occlusive crisis,
and the -- even the quality of the muscle
when we look at it in the microscopic way.
And the second part is metabolic way.
For a long time, my patient asked me,
"Do I have to pay attention to what I eat, to what --"
I was like, there’s so much for them.
I won’t bother telling them to pay attention to the diet
because there is so much --
and actually, I’m going to -- coming back to this statement,
because I think metabolic disorder
is amplifying the disease.
So, I think that in terms of prevention,
there is an access to diet and healthy condition
also to prevent the complication.
This is speculative, but I truly think --
[applause]
Marilyn Telen: Can I -- I would just add, you know,
when we heard about heart disease,
lung disease, kidney disease,
one of the points that kept on being made is,
right now, we’re picking these things up for the most part,
when they’re there already, not before they’re there.
And I think the registries, like Dr. Little talked about,
my own effort,
which is looking at what non-hemoglobin genetic variation
affects outcomes like kidney disease --
and we’ve developed a risk score that can predict the progression
of decreasing kidney function.
That needs to be tested prospectively still,
but these are the things that help us figure out,
you know, who needs what treatment,
so we prevent things like renal failure
or bad lung disease or bad heart disease.
And we really need to put a lot more effort into learning that,
so that when people like you ask the question,
how are you going to keep me from getting kidney disease
that I don’t have now, we have an answer for you.
Either we can test you, and you’re low risk.
Or, well, you are high risk by these standards,
and this is what we could do.
Or at least, this is the study that we’re doing with people
who are at high risk to find out what the best thing to do is.
Jane Little: I was just going to say,
I think this is a little bit like cancer used to be,
where they would do -- you know, do anything to save your life.
And then they realized there were side effects
of the treatments
that they could change that would make things better.
So, I think your question is really going to go back
to the pediatricians, who, for a long time,
have just been trying to get kids through the keyhole.
And now, I think they’re trying to refine what they’re doing,
so that the kids have better --
you know, I’m sure that people are working on exercise,
working on diet.
Because the kids are going to be the answer, right?
Like, if they’re healthier,
it’s going to make the stuff that Mark does easier.
It’s going to make -- if they don’t have a transformative
or curative therapy, easier. I mean, I think it’s --
the kids are going to really change that, I think.
Patrick Omwuemene: Okay. For someone such as me
dealing with a mild form of sickle cell --
I mean, I didn’t think it was mild form with all the pain
[unintelligible] even, until I was told,
well, I’m not sick enough to get onto the genome generic program.
But I found out recently that self-care
is supposed to be one of the -- foremost things to do,
not just talking about it, hearing about it, watching TV,
sitting down, and getting the information
and without doing anything with it.
Eating whole foods, vegetables, blending your own smoothie,
not eating anything like what they offer in fast food
and all that.
I have practiced that for years, and it’s kept me healthy.
And then this summer -- now,
this is the part you guys are going to cringe at --
this summer, I found out, well, I’m exercising,
but my body is not recovering fast enough.
So, I -- what do athletes do
to get their body to recover fast enough?
They soak themselves in ice. So, I did that this past winter.
Yeah, I know. That’s the reaction I was expecting.
But [laughs] yes, I did that all winter,
and it helped me a great deal. No, I won’t recommend --
[laughter]
I won’t recommend you send your patients going down this route.
This is just me. So, I ate properly. I exercised.
I watched my exercise. I didn’t overdo it.
I took cold -- you know, cold baths.
And during this winter,
I began to learn how to swim in cold water.
So, again, this is not something you --
Mark Walters: Don’t do this outside the NIH.
[laughter]
Patrick Omwuemene: But for people with mild sickle cell --
and Dr. Thein did not -- please, do not point at her.
She did not know anything about this before I began doing it.
I did not tell I was going to do it [laughs].
But then again, I’m just trying to say self-care is paramount
if you’re going to, you know,
think of preserving your kidney and liver or other organs,
at least for people dealing with the mild form of sickle cell,
and drinking a lot of water,
listening to your doctor too, unlike me.
Jennifer Knight-Madden: Patrick, do you have any questions
for any of our panelists?
Patrick Omwuemene: So, my question
was for Dr. Allan Doctor, but he doesn’t seem to be --
Jennifer Knight-Madden: [unintelligible]
Patrick Omwuemene: Okay.
So, I guess, yeah, that was my only question really.
He said something that sparked my interest,
when he talked about eNOS
and the nitric oxide and how they react.
And that was my question was going to be.
Is it something that -- is eNOS something
that could be artificially generated,
to be introduced to the body,
so that it helps the nitric oxide in your body,
and therefore the oxygen level increase
and all that, for you to function --
for your cells to function much better?
I got a brief answer from him.
I was bringing up this question for the benefit of everybody.
He said, they are still walking on it.
It’s still being worked on.
But the best way to go about it right now is through exercise.
Because it does that too.
Jennifer Knight-Madden: Thank you very much.
So, you can see that our patients have listened
and have very good questions that really interrogate
what we’ve been saying over the last two years -- two days.
Okay. I’m going to now throw the floor open.
If there are any questions in the room,
either to our patients or to any of our other panelists,
we could take those now.
Female Speaker: Comment on your question
about what can we do? So, I’m a pediatrician,
and I agree with Dr. Little that we have to do good job
with our patients when they are young.
And I want to tell you we have a clinic at my institution
where we are working on providing whole-person care
to our patients.
So, we are focusing on sickle cell,
all the disease-modifying therapies,
and other things,
but also looking at how can we help with the pain?
So, using non-pharmacologic measures,
like acupuncture, mindfulness, nutrition, very important,
also physical therapy,
and what are the things people --
kids can do, like at young age, exercise, stretching,
and things like that?
So, those are some of the things we are doing
and including psychology and psychiatry.
Because many times, you know, depression,
anxiety, these are very -- they are risk factors for pain.
So, we work as a multidisciplinary clinic,
and starting at the young age of eight,
when patients can understand why these things are important,
and hopefully we can improve the outcome.
We also have access to education specialists.
So, patients, you know, they don’t miss school.
Because our goal is for them to have --
be successful like you and be employed
and financially independent.
So, we are working at, you know --
so, I think pediatrics is the key.
We need to do all these things at a young age. Thank you.
[applause]
Jennifer Knight-Madden: One more question.
Swee Lay Thein: I should also add that, you know,
we are all here together.
I say that to you repeatedly. We work together.
On your part, the patient, as you say, practice self-care.
As you know, I keep saying that all the time
when I see you in the clinic.
You know, it’s not [unintelligible] limitation,
even for us without sickle cell disease.
We exercise. We make sure we eat properly.
And then the other thing is,
if you want to bring more treatments on the market,
is for the patients to be more research aware
and to participate when you can. Because if you don’t,
we will not be able to bring more medicines into the market.
Jennifer Knight-Madden: Okay. Thank you. Any more questions?
Okay, Dr. Obi.
Obiageli Nnodu: Yes. Thank you very much.
I’ve had an exciting time at this meeting.
And I was just wondering, especially when Jane was talking
about the import of the disease registry
that has been established in high-budget countries,
I don’t know if there is any interest in exploring
the usefulness of that registry.
Because we in -- sickle in Africa,
we have over 34,000 patients registered now in that registry.
Jennifer Knight-Madden: That’s the one I was telling you.
Obiageli Nnodu: But I haven’t seen anyone
take an interest in it, apart from me [laughs].
So, I’m just wondering how we are going to collectively --
because [unintelligible]
was saying that we should work together.
Jane Little: Yeah.
Obiageli Nnodu: And I believe that working together;
it’s working together globally.
Jane Little: Yes, I agree.
I absolutely agree with that. And I think --
I remember when GRNDaD was born, it was at a meeting
where these different people from different leadership things
kept saying a registry is coming.
I thought, you know, I can’t wait that long, you know.
And so, I think there is some role in --
as individual investigators and people with some power,
to start investigating registries where you are,
and we have -- I came to Jamaica day early
because we’re sort of talking about
whether we can try to develop some sheets
that are appropriate for low-
and middle-income countries that might be shareable.
So, we might have a committee that we’re going to form.
I have a really good partner in Malawi,
and she’s very interested in doing that.
So, I don’t know if that’s going to be the best thing,
but I think it’s worth a try.
Because I think, you know, like WhatsApp, like I didn’t --
when I was in clinic here on Tuesday,
they were using WhatsApp to reach out to patients.
And that would never have occurred to me.
So, I think there are --
you can’t base it on internet in the clinic.
Because I think it’s unstable in a lot of places.
But you can certainly store it there,
and you can probably communicate through phones
in ways that I don’t understand.
So, I think if we do try to work together --
and if you’re interested, let me know.
Because I don’t know if our efforts going to work,
but we’re going to try to make some common elements
that are SPARCO-compatible, GRNDaD-compatible,
so we can learn together over the next decade,
Jennifer Knight-Madden: The two registries actually are
fairly close.
Because we’ve looked at the ontology, both of them.
Because, you know, in terms of us starting a registry here,
clearly we have links in different places.
And they actually overlap quite a bit.
And I think it would be a great PhD project
for the appropriate person to actually try to come up
with a way to really bridge those properly,
so that, you know, people who come on board afterwards
would actually be speaking to both registries.
Jane Little: Yeah. I think that’s going to be the key.
Jennifer Knight-Madden: Yeah.
Jane Little: Because I’m trying to be too top down about it,
but make sure that the elements can speak to each other.
And what we did in GRNDaD is that we try to update it
once a year with international partners, so no one --
so, we’re not mutating too far.
You want them to change consistently.
But I think the needs of the low-
and middle-income countries are different,
and I don’t think GRNDaD will be purely applicable.
So, I think there are changes that we need to make.
But I think it’s really important.
Jennifer Knight-Madden: So, definitely something
coming out of this meeting
is a meeting of the mind so that -- going forward.
Patrick Omwuemene: One last question.
I want to ask if any of the researchers here
or any researcher you know, is doing something about --
somebody spoke about insomnia yesterday,
and I’m greatly affected by insomnia.
And the reason I’m greatly affected by insomnia
is because of priapism. I wake up every two hours,
and sometimes I can’t go back to sleep.
Sometimes I have to drink water, do some exercise,
just to get some relief. So, open question.
Monika Haack: This is one topic where [unintelligible].
So, I think we talked about diet and exercise.
And I think sleep is another big issue
that I think can be used as a preventive measure,
so -- to really strengthen.
Because sleep is really involved in so many different diseases.
And for example, it can increase inflammation,
which is a big issue also in sickle cell.
It increases pain. Pain processing can be changed.
And it can also not be easily changed.
So, it’s not like, oh, I get better in sleep.
So, I think this preventive measures of really making sure
not to get any sleep disorders, I think is very important.
And there’s very -- a lot of things out there.
There’s wearable out there. There’s diaries, questionnaires,
where we really can target sleep early on, and then do measures.
But then once insomnia is there, right,
what you just described of waking up frequently at night,
I think that would then really-- needs follow up to really see,
what are the causes of that insomnia?
Is that related -- is there a specific cause?
Or is that -- what kind of the --
what are the reasons for that?
To really then go -- that was what?
Female Speaker: So, he has a cause for it.
Monika Haack: Oh, yes. Yeah. Exactly.
So, that would be then important to really figure out
what that is and what can be done.
And it also can be --
I mean, there’s also a lot of medications
that we are aware of.
They have sleep disturbing effects.
So, I think that’s also important to take
into consideration.
Jennifer Knight-Madden: Thank you.
Okay. We’re going to give Morette the last question.
And then I’ll end -- we’ll wrap up the panel.
Morette Wright: Right. Just a quick question, you know,
following up on Patrick’s lead.
Is there anyone here who has been treating avascular necrosis
outside of hip replacement?
If you have been, I’d really love to hear your approach
to helping your patient manage AVN.
Jennifer Knight-Madden: Okay. Nobody is -- okay.
So, I’d like you to join with me
with thanking the panel for their --
[applause]
Okay. And that brings the end of this session.
So, I’m going to invite Swee Lay back on.
Swee Lay Thein: I thought you heard enough from me already.
Well, the people listening on Zoom,
and I hope you all agree with me
that this has been a really fantastic conference.
It has rejuvenated me.
And I am so pleased to meet so many new faces too.
And I hope we can start collaborating on many things.
What this conference brought is it raised many questions,
but we’re slowly trying to answer them.
And I’m so pleased also to see
how far curative therapies have come.
But we’re going to improve on the pharmacology approaches,
so that you won’t have so many patients
for your curative therapies [laughs].
And I love to see you all next year at the NIH.
Thank you, all.
[applause]
Oh, yes. Because I forget, I have to give a great,
great thanks to Nancy, Tiffany, Marivi [phonetic sp],
and [inaudible].
[applause]
They have been fabulous. I couldn’t --
we couldn’t have a better team, I tell you.
This is done in their part time, you know.
It’s not their profession.
[applause]