SO GOOD MORNING AND WELCOME TO
THE 2024 ANNUAL SICKLE CELL
DISEASE RESEARCH MEETING.
I'M JULIE PANEPINTO, DIRECTOR OF
THE BLOOD DIVISION AT THE
NATIONAL HEART, LUNG AND BLOOD
INSTITUTE HERE AT THE NIH.
I'M EXCITED TO KICK OFF THIS
THREE-DAY MEETING AND WANT TO
RECOGNIZE THE BEHIND THE SCENES
WORK THAT.THIS TAKES A LOT OF PS
YOU MIGHT IMAGINE.
SO I THANK THEM FOR THEIR
EFFORTS.
SO THE NEXT FEW DAYS, WE'LL HEAR
RESEARCH PRESENTED THAT FOCUSES
ON KEY THINGS SHAPING THE
LANDSCAPE OF SICKLE CELL
DISEASE.
TODAY WE'RE STARTING WITH A
SYMPOSIUM ON CELL AND GENE
THERAPIES AND OTHER THERAPEUTICS
FOR SICKLE CELL DISEASE, WE'LL
EXPLORE LATEST DEVELOPMENTS AND
ALSO LEARNING HOW THESE
THERAPIES IMPACT QUALITY OF LIFE
AND PATIENT OUTCOMES.
TOMORROW WE WILL EXAMINE AND
HEAR ABOUT RESEARCH HAPPENING
GLOBALLY IN SICKLE CELL DISEASE,
SPECIFICALLY INDIA, AFRICA AND
BRAZIL.
WE'LL ALSO HEAR PRESENTATIONS
THAT INCLUDE GENOMICS, PUBLIC
HEALTH, AND CLINICAL DATA
RESOURCES TO UNDERSTAND OUTCOMES
IN SICKLE CELL DISEASE,
HIGHLIGHTING THE IMPORTANCE OF
DATA-DRIVEN APPROACHES AND
ENHANCING PATIENT CARE.
ON THE LAST AND THIRD DAY OF THE
WORKSHOP, WE WILL EXPLORE TOPICS
THAT INCLUDE SICKLE CELL DISEASE
PAIN MANAGEMENT, WOMEN'S HEALTH
IN SICKLE CELL DISEASE, AND
EMERGING DISEASE MODIFYING
THERAPIES.
WE WILL ALSO DISCUSS THE ROLE OF
RESEARCH COLLABORATIVES AND
ALLIANCE -- NATIONAL ALLY ANSES
IN ADVANCING SICKLE CELL DISEASE
CARE AND TREATMENT.
SO I HOPE THE MEETING HELPS
FOSTER COLLABORATION AND
ADVANCES OUR SCIENTIFIC
DISCOVERIES IN SICKLE CELL
DISEASE AS WE WORK TO IMPROVE
THE LIVES OF THOSE LIVING WITH
SICKLE CELL DISEASE.
SO THANK YOU ALL FOR JOINING US
AND I'LL TURN THIS OVER TO
DR. QASBA.
>> THANK YOU, JULIE, AND GOOD
MORNING AGAIN TO EVERYBODY, AND
WELCOME TO OUR 2024 MEETING.
SO BEFORE I INTRODUCE OUR FIRST
SYMPOSIUM TO GET STARTED ON, I
JUST HAVE SOME MINOR LOGISTICS
THAT YOU MAY OR MAY NOT BE
AWARE.
IN TERMS OF THE CAFETERIA, THE
NATCHER CAFETERIA IS CLOSED ON
MONDAYS, BUT IT WILL BE OPEN
TUESDAY AND WEDNESDAY.
SO FOR FOLKS WHO HAVE ORDERED
THEIR FOOD AND ALL THAT STUFF
WITH THE CONTRACTS PEOPLE, YOU
CAN COLLECT THAT AT THE TIME OF
LUNCH.
AND EVERYBODY ELSE IS FAMILIAR
WITH THE RESTROOMS ON YOUR RIGHT
AND LEFT, ET CETERA.
AND I WOULD URGE ALL THE
SPEAKERS TO PLEASE STAY ON TIME.
WE HAVE A VERY ASTUTE TIMEKEEPER
HERE, AND WE'LL HOPEFULLY KEEP
YOU ON TIME.
AND OTHER THAN THAT, I REALLY
DON'T HAVE MUCH TO SAY, AGAIN,
WELCOME AGAIN TO THIS WONDERFUL
MEETING.
AND JULIE HAS ALREADY SUMMARIZED
THE DIFFERENT AREAS THAT WE'LL
BE TALKING ABOUT.
SO WITHOUT ANY FURTHER DELAYS, I
THINK I'LL GET STARTED.
AND WELCOME THE CO-CHAIRS,
DR. LAKSHMANAN KRISHNAMURTI AND
BETH STENGER FOR GETTING STARTED
WITH THE SYMPOSIUM 1, WHICH IS
UPDATES ON GENE AND CELL THERAPY
AND OTHER THERAPEUTICS FOR
SICKLE CELL DISEASE.
KRISH, DR. STENGER?
>> GOOD MORNING.
WELCOME TO THE KICKOFF SESSION.
[SPEAKER NOT ON MIC]
>> THIS WOULD WORK A LOT BETTER
IF THE MIC WAS ON.
SO IT'S MY PLEASURE TO INTRODUCE
MYCO-CHAIR, DR. BETH STENGER.
DR. STENGER, TAKE IT AWAY.
>> I THINK WE HAVE SOME SLIDES.
SO OUR SESSION IS ENTITLED
HEMATOPOIETIC CELL
TRANSPLANTATION, AND WE WILL
BE -- IF YOU CAN GO TO THE NEXT
SLIDE, WE'LL BE -- HAVE EIGHT
SPEAKERS IN OUR SESSION WHO WILL
BE PRESENTING DATA FROM
PUBLICATIONS FROM THIS PAST
YEAR, AND EACH SPEAKER WILL HAVE
ABOUT 10 MINUTES FOR
PRESENTATION AND QUESTIONS AND
HOPEFULLY WE CAN STAY ON
SCHEDULE.
JUST TO NOTE, THE ORDER OF
SPEAKERS LISTED ON THIS SLIDE IS
DIFFERENT THAN WHAT IS IN THE
PROGRAM NOTES AND I'LL PUT THAT
IN THE CHAT FOR FOLKS WHO ARE
ONLINE AS WELL AND PLEASE DO PUT
QUESTIONS IN THE CHAT.
WE'LL BE MONITORING THOSE AND
CAN READ THEM ALOUD FOR THE
AUDIENCE AS WELL.
SO WITH THAT, I'LL TURN OVER TO
DR. KRISH TO INTRODUCE OUR FIRST
SPEAKER.
>> IT QUITE LOVELY THAT WE'RE
STARTING TO THE NOD WITH THE
USUAL OUTCOMES OF TRANSPLANT THE
WAY WE'RE USED TO, BUT ABOUT
SOMETHING THAT'S REALLY
IMPORTANT THAT HAPPENS AFTER
TRANSPLANT.
AND WHAT WE CAN DO ABOUT IT
BEFORE TRANSPLANT.
THIS IS THE WHOLE FERTILITY
QUESTION AND FERTILITY
PRESERVATION.
SO TO START OFF OUR CONVERSATION
TODAY, DR. TAMARA
DIESCH-FURLANETTO FROM THE
UNIVERSITY CHILDREN'S HOSPITAL
IN BASEL, SWITZERLAND WILL BE
TALKING TO US ABOUT
CRYOPRESERVATION OF OVARIAN
TISSUE IN SICKLE CELL PATIENTS
PRIOR TO STEM CELL
TRANSPLANTATION, SAFETY,
FOLLOW-UP AND OUTCOMES OF
OVARIAN TISSUE TRANSPLANTATION.
AND THIS IS A RECORDED
PRESENTATION, AND DR. TAMARA
SAID SHE WILL BE ON.
WELCOME, DR. TAMARA.
>> GOOD MORNING.
FIRST OF ALL, I WANT TO THANK
THE ORGANIZER FOR GIVING ME THE
OPPORTUNITY TO PRESENT OUR
STUDY.
ON BEHALF OF ALL OF US, I WILL
PRESENT OUR STUDY ON
CRYOPRESERVATION OF OVARIAN
TISSUE IN SICKLE CELL PATIENTS
PRIOR TO STEM CELL
TRANSPLANTATION.
SAFETY, FOLLOW-UP AND OUTCOMES
OF OVARIAN TISSUE
TRANSPLANTATIONS.
I HAVE NOTHING TO DISCLOSE.
AS YOU KNOW, STEM CELL
TRANSPLANTATION IS A CURATIVE
OPTION FOR PATIENTS WITH SICKLE
CELL DISEASE.
THE ADVANTAGE IS A VERY GOOD
OVERALL SURVIVAL OF ABOUT 98%,
ESPECIALLY IN MATCHED SIBLING
DONOR.
THE DISADVANTAGE IS THAT AFTER
ABLATIVE CONDITIONING REGIMEN,
MOST OF THE PATIENTS HAVE A
PREMATURE OVARIAN INSUFFICIENCY,
AND PREGNANCY RATE IS REALLY
LOW, ABOUT 2%.
SO FERTILITY PRESERVATION IS A
MAJOR ISSUE IN SICKLE CELL
DISEASE CARE.
WHICH OPTIONS CONCERNING
FERTILITY PRESERVATION CAN BE
OFFERED?
ONE, WE HAVE ALL --
CRYOPRESERVATION, AND ON THE
OTHER HAND OVARIAN TISSUE
CRYOPRESERVATION.
-- CRYOPRESERVATION CAN BE
PERFORMED IN POST PUBERTAL
PATIENTS.
THEY NEED HORMONAL STIMULATION
OF ABOUT 12 DAYS, AND THE OOCYTE
WILL BE EXTRACTED BY VAGINAL
ACCESS.
OVARIAN STIMULATION HAS MANY
RISKS, SUCH AS THROMBOGENIC
INDUCED VASO-OCCLUSIVE CRISIS.
THE FIRST CASE OF OOCYTE
CRYOPRESERVATION WAS REPORTED IN
2012 BY DOVEY.
THE PATIENTS RECEIVED A MINIMAL
STIMULATION PROTOCOL, THROMBOSIS
PROPHYLAXIS AND INTRAVENOUS
HYPERHYDRATION.
WHEN WE LOOK TO THE LITERATURE,
SO WE SEE THAT THE MAJORITY OF
THE PATIENTS HAD AN ACUTE PAIN
CRISIS AND THE NEEDED SUPPORTIVE
CARE, SUCH AS INTRAVENOUS
HYDRATION, BLOOD EXCHANGE, OR
HOSPITALIZATION ON ICU.
WHAT WE ALSO SEE IS THAT THE
OOCYTE YIELD FOR PATIENTS WITH
SICKLE CELL DISEASE COMPARED TO
NORMAL POPULATION IS SUBOPTIMAL.
UNTIL NOW, FEW CASES OF EMBRYO
CRYOPRESERVATION HAVE BEEN
REPORTED, AND WE HAVE NO REPORTS
ON THE USE OF THE OOCYTES UNTIL
NOW.
OVARIAN TISSUE CRYOPRESERVATION
CAN BE APPLIED IN PRE AND POST
PUBERTAL PATIENTS.
ONE OVER VEE WI OVARY WILL BE RD
COMPLETELY SO WE HAVE ONE
IMMATURE OOCYTE AND IT WILL BE
CAPTURED IN SMALL SECTIONS,
SO-CALLED FRAGMENTS, WHICH WILL
BE CRYOPRESERVED.
IT'S POSSIBLE TO COMBINE IT WITH
OTHER SURGICAL PROCEDURES.
AND AFTER YOU CAN PERFORM
OVARIAN TISSUE TRANSPLANTATION.
SO IN OUR STUDY, WE INCLUDED 75
GIRLS AND WOMEN WITH SICKLE CELL
DISEASE.
ALL HAD AN INDICATION FOR STEM
CELL TRANSPLANTATION.
THEY HAD CEREBRAL VASCULOPATHY
OR RECURRENT VASO-OCCLUSIVE
CRISIS DESPITE HYDROXYYOU'RE YA
TREATMENT.
OVARIAN TISSUE CRYOPRESERVATION
WAS PERFORMED BETWEEN APRIL 1998
AND DECEMBER 2018, PRIOR TO STEM
CELL TRANSPLANTATION.
ALL PATIENTS RECEIVED A BLOOD
EXCHANGE BEFORE OVARIAN TISSUE
CRYOPRESERVATION TO ACHIEVE A
HBS LEVEL BELOW 30%.
HERE YOU CAN SEE PATIENTS'
CHARACTERISTICS.
MEDIAN AGE AT TIME POINT OF
OVARIAN TISSUE CRYOPRESERVATION
WAS 9.6 AND MEDIAN TIME BETWEEN
OVARIAN TISSUE CRYOPRESERVATION
AND STEM CELL TRANSPLANTATION
WAS EIGHT MONTHS.
AT FOLLOW-UP THE MEDIAN AGE WAS
9.3 YEARS.
FROM THE 75 PATIENTS, 56 OF THEM
WERE PRE-PUBERTAL.
ALL HAD A -- OWE BLAITIVE
CONDITIONING REGIMEN.
ONE RECEIVED OVARIAN TISSUE
TRANSPLANTATION TO INDUCE
PUBERTY.
AT LAST FOLLOW-UP, WE HAD
RECORDS FROM 49 PATIENTS.
96% OF THEM HAD A PRIMARY
OVARIAN INSUFFICIENCY.
FROM THE 75 PATIENTS, 19 WERE
POST PUBERTAL.
TWO -- RELATED TO TRANSPLANT
MORTALITY AND TWO WERE LOST
DAWRNG FOLLOW-U --
DURING FOLLOW-UP.
SO 15 OF THEM, SO ALL OF THEM
HAD A PRIMARY OVARIAN
INSUFFICIENCY AFTER STEM CELL
TRANSPLANTATION.
FOUR OF THEM HAD OVARIAN TISSUE
TRANSPLANTATION TO RESTORE
FERTILITY.
HERE YOU CAN SEE THE PATIENTS'
CHARACTERISTICS OF PATIENTS WHO
UNDERWENT OVARIAN TISSUE
TRANSPLANTATION.
PATIENT 5 IS THE PREPUBERTAL
PATIENT WHO HAD OVARIAN TISSUE
TRANSPLANTATION TO INDUCE
PUBERTY, AND PATIENT 1 TO 4 WERE
POST PUBERTAL.
ALL HAD THEIR RECOVERY OF
OVARIAN FUNCTION.
PATIENT 4 CAME FOR THE FIRST
TIME NINE MONTHS AFTER STEM CELL
TRANSPLANTATION, AND THE
EXAMINATION REVEALED THAT SHE
WAS PREGNANT.
SHE BORNE A HEALTHY CHILD.
MEDIAN TIME BETWEEN OVARIAN
TISSUE TRANSPLANTATION AND
OVARIAN FUNCTION RECOVERY WAS
4 TO 6 MONTHS.
NO SEVERE COMPLICATIONS WERE
REPORTED.
SO IN CONCLUSION, WE CAN SAY
OVARIAN TISSUE CRYOPRESERVATION
CAN BE PROPOSED INDEPENDENTLY OF
THE AGE FOR PRE AND POST
PUBERTAL UNDER THE AGE OF 35
YEARS.
IT'S SAFE.
NO MAJOR COMPLICATION WERE
REPORTED, IMPORTANT TO PERFORM
BLOOD EXCHANGE BEFORE OVARIAN
TISSUE CRYOPRESERVATION, AND
OVARIAN TISSUE TRANSPLANTATION
IS AN OPTION TO RESTORE OVARIAN
FUNCTION AND FERTILITY.
I WANT TO THANK ALL PATIENTS AND
THEIR FAMILIES FOR THEIR
PARTICIPATION AND YOU FOR YOUR
ATTENTION.
THANK YOU VERY MUCH.
[APPLAUSE]
>> THANK YOU.
THAT WAS A WONDERFUL
PRESENTATION.
THANK YOU, DR. TAMARA.
QUESTIONS FROM THE AUDIENCE?
FOR
DR. TAMARA?
I'D LIKE TO START OFF IF I MAY,
SO ONLY A SMALL MINORITY OF THE
PATIENTS WHO HAD OVARIAN TISSUE
CRYOPRESERVATION ACTUALLY WENT
FORWARD WITH TRANSPLANTING THE
TISSUE.
COULD YOU TALK A LITTLE BIT
ABOUT SOME OF THE REASONS WHY?
>> YES, THANK YOU.
I HAVE JUST A PROBLEM WITH MY
CAMERA.
SO MOST OF THEM DIDN'T REACH THE
AGE TO THINK ABOUT THEIR OWN
CHILD.
THAT'S WHY IT WAS NOT USED
OVARIAN TISSUE TRANSPLANTATION
IN THESE PATIENTS.
I THINK IN FIVE TO 10 YEARS, WE
WILL HAVE MORE DETAILS, MORE
INFORMATION.
AND MORE PATIENTS COMING BACK TO
ASKING THEIR TISSUE.
>> SO IN EUROPE, COST MIGHT NOT
HAVE BEEN A CONSIDERATION?
>> WELL, IN FRANCE, IT'S COVERED
BY HEALTH INSURANCE.
IN SWITZERLAND, IT'S COVERED IN
POST PUBERTAL PATIENTS.
IN PREPREU PREPUBERTAL IT'S STN
AS EXPERIMENTATION.
>> OTHER QUESTIONS FOR
DR. TAMARA?
>> WE HAVE A QUESTION HERE ON
THE EFFECT OF HYDROXYUREA.
"I MISSED THE EFFECT OF
HYDROXYUREA."
>> SO IN THIS STUDY, WE JUST
LOOKED TO SAFETY FOLLOW-UP AND
OUTCOME OF OVARIAN TISSUE
TRANSPLANTATION, BUT WE JUST
PUBLISHED A PUBLICATION ON THE
IMPACT OF HYDROXYUREA ON OVARIAN
RESERVE AND WE DIDN'T SEE A
SIGNIFICANT ALTERATION OF
OVARIAN RESERVE IN PATIENTS
UNDER HYDROXYUREA TREATMENT
COMPARED TO THOSE WITHOUT HIGH
HYDROXYUREA.
>> WE HAVE ANOTHER EXCELLENT
QUESTION ABOUT THE RELATIVE
COMPLICATIONS OF -- IN SICKLE
CELL DISEASE VERSUS OTHER
PATIENTS IN TERMS OF THE
PROCEDURES FOR OVARIAN
CRYOPRESERVATION OR STEM CELL --
OR COLLECTION OF OOCYTES.
>> WELL, THE INCIDENCE OF
HYPERSTIMULATION SYNDROME IS
HIGHER IN PATIENTS WITH SICKLE
CELL DISEASE COMPARED TO NORMAL
POPULATION, AND AS I SHOWED THE
OOCYTE YIELD IS LOWER IN
PATIENTS WITH SICKLE CELL
DISEASE COMPARED TO NORMAL
POPULATION.
IT'S JUST IMPORTANT THAT THEY
KNOW IT.
>> EXCELLENT.
SO TO PREVENT HYPERSTIMULATION
SYNDROME, DID YOU DO HYDRATION,
DID YOU DO ANTI-COAGULATION?
CAN YOU EDUCATE US --
>> YES, EXACTLY.
SO PATIENTS -- AS YOU SAW BY
DOVEY AND ALL, WE PROPOSED
THROMBOSIS PROPHYLAXIS, WE
MAKE -- HYDRATION.
IT'S IMPORTANT.
AND YOU NEED A LOWER DOSE FOR
HORMONAL STIMULATION.
>> THANK YOU.
PLEASE GIVE IT UP FOR DR. TAMARA
DIESCH-FURLANETTO.
THANK YOU VERY MUCH.
[APPLAUSE]
>> THANK YOU.
>> SO WE'LL MOVE TO OUR NEXT
SPEAKER, DR. KISS T CHRISTINA PS
FROM VIENNA, AUSTRIA, LOOKING AT
CONDITIONING BEFORE ALLOGENEIC
TRANSPLANT FROM MATCH SIBLING
DONORS IN PEDIATRIC PATIENTS
WITH SICKLE CELL DISEASE.
>> THANK YOU SO MUCH.
IT IS WONDERFUL TO PARTICIPATE
IN THIS GREAT WORKSHOP.
I WANT TO HIGHLIGHT AND COMPARE
TWO VERY POPULAR CONDITIONING
REGIMEN HERE YOU SEE MY
DISCLOSURES.
BECAUSE AS WE LEARNED OVER THE
YEARS, WE HAVE DEMONSTRATED AND
LEARNED THAT MYELOABLATIVE
CONDITIONING REGIMEN BEFORE
ALLOGENIC STEM CELL
TRANSPLANTATION PERHAPS IS MORE
USEFUL THAN IN NON-MYELOABLATIVE
CONDITIONING, ESPECIALLY IN
PATIENTS WHO ARE --
PRETRANSFUSED.
BECAUSE IF WE DESTROY OR
ERADICATE PATIENTS' BONE MARROW,
WE HAVE AN ELIMINATION OF THE
DEFECTIVE RED BLOOD CELL.
IT IS AN OLD HISTORY THAT WE
PERHAPS NEED SPACE FOR THE DONOR
STEM CELLS.
AND WE ALSO HAVE SHOWN THAT
ENGRAFTING OCCURS EARLIER AND
BETTER IF WE HAVE EMPTY BONE
MARROW IN THE PATIENT.
OF COURSE WE HAVE TO SUPPRESS
THE IMMUNE SYSTEM TO PREVENT
REJECTION, AND ALSO AUTOIMMUNE
PHENOMENON, AND OF COURSE WE
WANT TO ENABLE A QUICK
HEMATOPOIETIC RECONSTITUTION AND
ENGRAFTMENT OF THE TRANSPLANTED
NOT ONLY MARROW BUT ALSO OF
THE -- OF ALL CELLS.
SO IN THE PAST THE CLASSICAL
CONDITIONING REGIMEN BEFORE AN
ALLOGENIC STEM CELL
TRANSPLANTATION USUALLY
CONSISTED OF A COMBINATION OF
BUSULFAN AND CYCLOPHOSPHAMIDE.
BUSULFAN IS AN ALKYLATING AGENT,
HAVING -- AS BACKBONE TOGETHER
WITH -- WITHBUTANE, HIGHLY TOXIY
FOR STEM CELL BUT OTHER BONE
MARROW AND BLOOD CELLS.
CYCLOPHOSPHAMIDE IS ALSO AN DNA
REPLICATION AGENT, LEADING TO
ALKYLATION OF THE CELLS.
AND IN THE LAST LET'S SAY 10 TO
15 YEARS, LESS TOXIC WITH LESS
ACUTE AND CHRONIC LATE EFFECTS
TURNED OUT TO BE VERY EFFICIENT
THAT IS A COMBINATION OF
BUSULFAN AND FLUDARABINE.
NOW WE HAVE A THIRD PLAYER WHICH
IS CALLED THE LITTLE SISTER OF
BUSULFAN.
IT IS TR IOS ULFAN, IT IS ALSO
OF COURSE AN ALKYLATER AND IT
HAS SIMILAR FUNCTION AS BUSULFAN
BUT IS MORE STABLE IN ACTION AND
IS NOT SO MUCH INTERACTING ALSO
WITH OTHER DRUGS.
AND THIOTEPA IS BASED ON A BIG
PHOSPHOROUS ATOM WHICH ALSO
LEADS TO DESTRUCTION OF BONE
MARROW CELLS AND STEM CELLS BUT
IS ALSO PENETRATING THE BRAIN,
WHICH MIGHT BE A POSSIBILITY
ESPECIALLY MALIGNANT DISEASES TO
AUGMENT THE CYTOTOXICS EFFICACY
OF THOSE DRUGS.
SOME WORDS ABOUT
THE DONOR ISSUE.
THE GOLD STANDARD SO FAR AND
PERHAPS IT MIGHT CHANGE IN
FUTURE, IS A HEMATOPOIETIC
TRANSPLANTATION FROM MATCHED
SIBLING DONORS, AND HERE YOU CAN
SEE THE OUTCOME OF PATIENTS WHO
WERE TRANSPLANTED BETWEEN
'86 AND 2013, WHERE WE HAD A
5-YEAR EVENT -- OF 70%.
AND OF COURSE STEM CELL SOURCE
MATTERS.
WE HAD BETTER RESULTS WITH
PERIPHERAL -- WITH CORD BLOOD
FROM SIBLING DONORS AND BONE
MARROW COMPARED TO -- STEM
CELLS.
WHY?
BECAUSE THIS RESULTS IN A HIGHER
INCIDENCE OF ACUTE AND CHRONIC
GRAFT-VERSUS-HOST DISEASE.
AND THE SECOND IMPORTANT
OBSERVATION OF THIS WORK IS THE
OVERALL SURVIVAL ACCORDING TO
AGE, WHERE WE CAN SEE IT IS
BETTER TO TRANSPLANT PATIENTS
BEFORE THE AGE OF 16, I WOULD
SAY BEFORE PUBERTY, BECAUSE HERE
WE HAVE LESS SEVERE TOXICITY, WE
HAVE LESS SEVERE GRAFT VERSUS
HOST DISEASE, AND PERHAPS WE
MIGHT ALSO, AS WE HEARD BEFORE,
SAVED FERTILITY IN SOME
PATIENTS.
THE OTHER PROBLEM, OF COURSE, IS
THAT MATCHED SIBLING DONORS ARE
ONLY AVAILABLE IN 20% OF
PATIENTS, AND IN EUROPE IT'S NOW
A PROSPECTIVE STUDY UNDERWAY
WHERE WE COMPARE MATCHED SIBLING
DONOR TRANSPLANTATION WITH
ALTERNATIVE TRANSPLANTATION FROM
HAPLOIDENTICAL DONOR.
AS I HAD SAID BEFORE, AGE
MATTERS, BECAUSE WE HAVE
INCREASED TREATMENT-RELATED
MOTILITY DUE TO MORE INFECTIOUS
COMPLICATIONS IN OLDER PATIENTS,
AND IMMUNIZATION GRAFT
REJECTION, ENCEPHALOPATHY
SYNDROME AND OTHER CEREBRAL
VASCULAR COMPLICATIONS, THE IRON
OVERLOAD INCREASES OVER TIME
DESPITE CHELATION THERAPY.
WE HAVE MORE RISK FOR
VENOOCCLUSIVE DISEASE,
ESPECIALLY IN PATIENTS WHO HAVE
PRE-EXISTING LIVER
COMPLICATIONS, AND ALSO
NEPHROPATHY AND OTHER SICKLE
CELL DISEASE-RELATED
COMPLICATIONS INCREASE OVER
TIME.
SO FOR US, THE BEST AGE TO BE
TRANSPLANTED IS, LET'S SAY,
BETWEEN 3 YEARS AND 13 YEARS.
WE NOW HAVE INVESTIGATED ON A
EUROPEAN LEVEL THE INFLUENCE OF
BUSULFAN FLUDARABINE OR
TREOSULFAN-FLUDARABINE BASED
CONDITIONING IN TRANS PLANTED
PATIENTS BETWEEN 2010 AND 2020
BELOW THE AGE OF 18 YEARS WHO
HAD THE FIRST AALLO TRANSPLANT
WITH A MATCHED SIBLING DONOR AND
UNDERWENT A MYELOCONDITIONING
REGIMEN WITH EITHER BUY SUL FAN
OR TREOSULFAN.
WE HAVE PUBLISHED THIS INCLUDING
A COMMENTARY.
THE PATIENT CHARACTERISTICS WERE
COMPARABLE WITH HAVING LITTLE
DIFFERENCE IN THE YEAR OF
TRANSPLANT WITH HAVING YOUNG
PATIENTS IN THE TREO GROUP AND
WITH HAVING MORE FEMALE PATIENTS
IN THE TREO GROUP AND WE HAD
MORE FEMALE TO MALE PATIENT
TRANSPLANTS ALSO IN THE TREO
GROUP.
ONE INTERESTING SITUATION WAS
THAT IN THE TREOSULFAN GROUP,
MORE PATIENTS RECEIVED --
COMPARED TO THE BUSULFAN GROUP,
MATURITY WAS PERFORMED IN
EUROPEAN COUNTRIES AND THE
BUSULFAN FLUDARABINE GROUP HAD
CONTRIBUTION FROM EUROPEAN
COUNTRIES.
ENGRAFTMENT, OF COURSE, IS
IMPORTANT.
WE HAD TWO YEARS INCIDENCE OF
SECONDARY GRAFT FAILURE
COMPARABLE IN TWO GROUPS.
THE INCIDENCE OF SECOND
TRANSPLANT, THE NECESSITY OF
SECOND TRANSPLANT WAS LOW IN
BOTH GROUPS.
AND IN THE BU-FLU GROUP, WE HAD
VERY FEW PATIENTS WHO DIED AFTER
THE FIRST TRANSPLANTATION, ONLY
ONE DUE TO AN INFECTION
ASSOCIATED MULTIORGAN FAILURE
AND WE HAD SOME PATIENTS WITH
EARLY AND SOME PATIENTS WITH
LATE GRAFT FAILURE.
ALL IN ALL, THE ENGRAFTMENT WAS
GOOD IN BOTH GROUPS.
HERE ARE THE OUTCOME DETAILS.
AS YOU CAN SEE HERE, ONLY VERY
FEW SIGNIFICANT DIFFERENCES.
FOR INSTANCE, THE OVERALL
INCIDENCE OF GRAFT-VERSUS-HOST
DISEASE WHICH WAS A LITTLE BIT
INCREASED IN THE TREO GROUP BUT
EXTENSIVE CHRONIC
GRAFT-VERSUS-HOST DISEASE WAS
NOT SO DIFFERENT AS COMPARED TO
OTHER FACTORS.
HERE YOU SEE THE OVERALL
SURVIVAL WHAT IS REALLY
EXCELLENT.
IN BOTH MYELOABLATIVE
CONDITIONING REGIMEN AND ALSO
THE INCIDENCE OF SECOND
TRANSPLANTS WAS QUITE LOW.
HERE YOU HAVE AN OVERVIEW WITH A
COMPARISON OF THE TWO DIFFERENT
CONDITIONING REGIMENS.
AS YOU CAN SEE THE TWO YEARS
OVERALL SURVIVAL IS MORE THAN
99% IN BOTH GROUPS, WITH A VERY
LOW INCIDENCE OF SEVERE
GRAFT-VERSUS-HOST DISEASE AND
ALSO OF CHRONIC
GRAFT-VERSUS-HOST DISEASE, AND
THE INCIDENCE OF LATE SECONDARY
GRAFT FAILURES IS BELOW 10%.
SO WHAT WE CONCLUDE IN THIS
PAPER IS THAT BOTH CONDITIONING
REGIMENS ENDED IN EXCELLENT
OVERALL SURVIVAL WITH LOW RATES
OF ACUTE AND CHRONIC
GRAFT-VERSUS-HOST DISEASE AND
GRAFT FAILURE.
SO WHAT CAN WE LEARN FROM THAT?
UNFORTUNATELY WE HAVE NOT ENOUGH
DETAILS ON THE INCIDENCE OF
SEVERE AND CHRONIC
GRAFT-VERSUS-HOST DISEASE IN
COMPARISON WITH THE
PRE-TREATPRE-TREATMENT OF GVHD S
QUITE INTERESTING BECAUSE IT
MIGHT HAVE ADDITIONAL SIDE
EFFECTS ON ENGRAFTMENT,
LYMPHOCYTE FUNCTION AND
POSSIBILITIES TO GET AS QUICK AS
POSSIBLE THE GRAFT IN.
HOWEVER, IN EUROPE, I CAN SAY
THAT THE FAVORABLE OVERALL
SURVIVAL, A GOOD
GRAFT-VERSUS-HOST DISEASE
PROFILE IS IN THE TREO-FLU
GROUP, IN MOST CASES THIOTEPA IS
EXCELLENT AND LED TO THE USE OF
THIS TRIPLE MYELOABLATIVE
CONDITIONING REGIMEN, AND WE
WILL BE HAPPY TO INVESTIGATE
PROSPECTIVELY THE LONG TERM
GRAFT FUNCTION, THE TOXICITY
PROFILE OF COURSE INCLUDING
FERTILITY QUESTIONS AND ALSO
GROWTH RETARDATION AND PERHAPS
SECONDARY MALIGNANCIES IF THEY
OCCUR IN ANY CASE.
IT'S NOW TIME TO SAY THANK YOU.
OF COURSE MY COLLEAGUES AND MY
CO-AUTHOR AND THE STATISTICIAN
OF THE EBMT, THE PARTICIPATING
CENTERS, AND PATIENTS AND
FAMILIES.
THANK YOU.
>> THANK YOU, DR. PETERS.
FOR THE SAKE OF TIME, WE'RE
GOING TO ASK THAT QUESTIONS BE
POSTED IN THE CHAT.
AND DR. PETERS, IF YOU CAN
RESPOND TO THEM THEN.
SO THAT WE CAN KEEP MOVING
THROUGH OUR TIGHT SCHEDULE.
>> THANK YOU.
CONTINUING ON THE THEME OF POST
TRANSPLANT SEQUELAE IS THE
IMPORTANT QUESTION OF WHAT
HAPPENS TO PAIN AFTER
TRANSPLANTATION FOR SICKLE CELL
DISEASE.
TO SPEAK TO US ABOUT INCIDENCE
AND RISK FACTORS FOR VOC AFTER
TRANSPLANTATION, PLEASE WELCOME
DR. VINEETHA NALLAGA TLA.
SHE STARTED HER INTERNSHIP ABOUT
TWO WEEKS AGO SO THANK YOU FOR
TAKING TIME OUT FROM YOUR
ROTATION TO BE WITH US.
>> THANK YOU FOR THAT, AND THANK
YOU FOR THIS OPPORTUNITY TODAY.
SO I AM HERE TO SPEAK ON OUR
PAPER ON THE INCIDENCE AND RISK
FACTORS OF PAIN CRISIS AFTER
HEMATOPOIETIC CELL TRANSPLANT
FOR SICKLE CELL DISEASE.
RECURRENT VOC OR PAIN CRIES SEES
HAVE EMERGED AS A PRIMARY REASON
FOR PATIENTS UNDERGOING ECT FOR
SICKLE CELL DISEASE.
SEVERAL REPORT A DECREASE IN THE
HEALTHCARE USE FOR PAIN CRISES
AS WELL AS A DECREASE IN THE USE
OF OPIOIDS AFTER A SUCCESSFUL
TRANSPLANT.
HOWEVER, SICKLE CELL DISEASE
PATIENTS MAY CONTINUE TO SUFFER
FROM OTHER CHRONIC PAIN
SYNDROMES AS WELL.
AS THUS ELIMINATION OF PAIN
CRISES AFTER TRANSPLANT IS A
CRUCIAL PATIENT-CENTERED OUTCOME
AND HELPS BETTER UNDERSTAND THE
NATURAL HISTORY OF OTHER CHRONIC
PAIN SYNDROMES AS WELL.
WITH THAT, THE AIM OF OUR STUDY
WAS TO DETERMINE THE INCIDENCE
AND PREDICTIVE FACTORS OF
RECURRENT PAIN CRISIS AFTER HCT
IN SICKLE CELL DISEASE.
AS WAS A RETROSPECTIVE
REGISTRY-BASED STUDY OF PATIENTS
UNDERGOING HCT FOR SICKLE CELL
DISEASE BETWEEN 1991 TO 2021, IN
THE UNITED STATES WITH DATA
SUBMITTED TO THE REGISTRY, THE
DE-IDENTIFIED DATASET WAS
OBTAINED THROUGH THE NHLBI BAY
BIOLINCC HOSTED ON THE URL
CURESICKLECELL.RTI.ORG.
DATA WAS COLLECTED AT 3, 6, 12
AND 24 MONTHS AFTER HCT AND
EVERY TWO YEARS UNTIL DEATH,
LOSS TO FOLLOW-UP.
PATIENTS WERE ASSIGNED TO EITHER
THE TED TRACK OR COMPREHENSIVE
OR CRF TRACK WHICH COLLECTED
DETAILED DISEASE, OR
TREATMENT-RELATED DATA.
FORM 2030, WHICH IS THE SICKLE
CELL DISEASE PREINFUSION FORM, A
TYPE OF CRF TRACK FORM, ASKED
QUESTIONS ON WHETHER
VASO-OCCLUSIVE PAIN REQUIRING
HOSPITALIZATION OCCURRED WITHIN
THE TWO YEARS PRIOR TO THE
TRANSPLANT, AS WELL AS SPECIFIES
THE FREQUENCIES.
FORM 2130, WHICH IS THE SICKLE
CELL DISEASE POST HCT FOLLOW-UP
FORM, ASKED QUESTIONS ON THE
OCCURRENCE OF VASO-OCCLUSIVE
PAIN POST TRANSPLANT AND THE
FREQUENCY.
A VASO-OCCLUSIVE EPISODE WAS
DEFINED AS ANY PAIN WHICH WAS
REQUIRING HOSPITALIZATION OR
TREATMENT, THAT IS IN THE
EMERGENCY ROOM, A DAY HOSPITAL
OR INPATIENT ADMISSION.
THERE WAS NO CAPTURE OF ANY
PATIENT-REPORTED VASO-OCCLUSIVE
CRISES OUTSIDE THE HOSPITAL
SETTING, NOR WAS THERE DATA
REGARDING THE TREATMENT OR THE
TIME POINT OF OCCURRENCE OF
THESE EPISODES POST TRANSPLANT.
THE DATA COLLECTED WAS ANALYZED
BY UNIVARIABLE AND MULTIVARIABLE
LOGISTIC REGRESSION MODELS USING
BACKWARD SELECTION PROCEDURES.
TWO MODELS WERE DEVELOPED, ONE
FOCUSING ON ONLY THE
PRETRANSPLANT FACTORS, AND THE
SECOND INCLUDING ALSO THE POST
TRANSPLANT FACTORS.
A PREDICTIVE NORMALGRAM WAS
CREATED TO VISUALLY EXAMINE THE
RELATIONSHIP BETWEEN THE VARIOUS
FACTORS AND THE OCCURRENCE OF
PAIN CRISIS.
OUT OF THE TOTAL 1,718 PATIENTS
WHO UNDERWENT TRANSPLANT BETWEEN
1991 TO 2021, 1453 PATIENTS
UNDERWENT TRANS PLAIN FROM 2008
TO 2021 WITH 763 ASSIGNED TO THE
CRF TRACK WITH DATA REPORTED ON
THE OCCURRENCE OF VASO-OCCLUSIVE
CRISIS AS A YES OR A NO.
THE REMAINDER OF THE PATIENTS
HAD NO DATA AVAILABLE OR HAD A
VALUE OF UNKNOWN.
OUT OF THE TOTAL 763 PATIENT, 66
PATIENTS HAD PAIN CRISIS POST
TRANSPLANT, OF WHICH 41 HAD
GRAFT FAILURE AND 25 HAD STABLE
ENGRAFTMENT.
IN OUR FIRST MODEL, WHICH
INCLUDED ONLY THE PREHCT
FACTORS, STATISTICALLY
SIGNIFICANT PREDICTORS FOR THE
OCCURRENCE OF VOC POST
TRANSPLANT WERE INCREASING AGE
AT HCT, PAIN CRISIS TWO YEARS
PRIOR TO HCT AND A KPS SCORE AT
LESS THAN 90.
IN THE SECOND MODEL WHICH
INCLUDED EVEN THE POST HCT
FACTORS AND INCREASING AGE, A
HISTORY OF PAIN CRISIS TWO YEARS
PRETRANSPLANT, A KPS OF LESS
THAN 90 AND GRAFT FAILURE TURNED
OUT TO BE SIGNIFICANT.
THIS IS THE FIRST NORMALGRAM
THAT WE HAD WHICH PREDICTED THE
PREHCT RISK OF VOC POST
TRANSPLANT.
SO IF WE TAKE A TEST PATIENT WHO
IS 10 YEARS OLD WITH A WEIGHT OF
25 KILOGRAMS WITH A HEMOGLOBIN
OF 7 AND A KPS SCORE OF LESS
THAN 90, WHO'S UNDERGOING A
MISMATCHED RELATED BONE MARROW
TRANSPLANT WITH A
NON-MYELOABLATIVE CONDITIONING
REGIMEN AND A HISTORY OF
VASO-OCCLUSIVE CRISIS IN THE TWO
YEARS PRETRANSPLANT WOULD HAVE A
TOTAL SCORE OF 230, WHICH WOULD
TRANSLATE TO AN APPROXIMATE POST
TRANSPLANT VOC RISK OF 15%.
IF THE SAME PATIENT WERE TO HAVE
GRAFT FAILURE POST TRANSPLANT,
HIS SCORE IN THE POST HCT
PREDICTIVE RISK NOMOGRAM WOULD
INCREASE TO A 259, WHICH WOULD
TRANSLATE TO A RISK OF 34%.
WE ACKNOWLEDGE THE LIMITATIONS
OF A REGISTRY-BASED STUDY IN THE
SENSE THAT THE ACCURACY OF THE
DATA DEPENDS ON THE COMPLETENESS
AND COLLECTION AND SUBMISSION
DATA LACKED GRANULAR DETAILS OF
CLINICALLY RELEVANT INFORMATION.
THERE WAS NO DATA AVAILABLE ON
THE PARTICULAR TIME POINT AFTER
HCT THAT THE PAPER CRISIS
OCCURRED, NOR WAS THERE ANY
CAPTURE OF PAIN CRISIS OUTSIDE
OF THE HOSPITAL SETTING.
FURTHER THERE WERE NO DETAILS ON
ANY NON-VASO-OCCLUSIVE PAIN
EPISODES OR CHRONIC PAIN.
FURTHER WE COULD NOT CROSS
VALIDATE THE MODEL'S PERFORMANCE
DUE TO THE SMALL NUMBER OF HCT
PROCEDURES PERFORMED IN PATIENTS
WITH SICKLE CELL DISEASE.
IN CONCLUSION, OUR STUDY FOUND
THE RECURRENCE OF PAIN CRISIS
POST TRANSPLANT IN SICKLE CELL
DISEASE TO BE 8-POI 8.65% WHICHS
CORRELATED WITH THE AGE AT
TRANSPLANT WITH THE PREHCT
HEMOGLOBIN DONOR AND GRAFT TYPE
CONDITIONING INTENSITY, PRIOR
HISTORY OF PAIN CRISIS, AND THE
OCCURRENCE OF GRAFT FAILURE.
THERE IS A NEED FOR A MORE
DETAILED CAPTURE OF THE
FREQUENCY, TIMING, TREATMENT OF
THESE EPISODES AND COLLECTION OF
OTHER PATIENT-REPORTED OUTCOMES.
THESE DATA CAN HELP US TO
UNDERSTAND, PREVENT, AND REDUCE
THE IMPACT OF HCT ON THE BURDEN
OF THE ACUTE AND CHRONIC SICKLE
CELL DISEASE-RELATED PAIN.
THANK YOU.
[APPLAUSE]
>> THANK YOU.
I'M SURE THERE WILL BE SOME
INTERESTING QUESTIONS.
PLEASE WALK UP TO THE MIC.
>> COURTNEY FROM NIH.
GREAT TALK.
I JUST WANT TO KNOW HOW YOU USED
THESE FINDINGS TO EDUCATE
PATIENTS BEFORE THE TRANSPLANT.
HOW TO TALK TO THEM ABOUT THE
RISK ESPECIALLY WHEN YOU'RE
TRYING TO TELL THEM ABOUT THE
RISK OF PAIN AFTER THE
SUCCESSFUL TRANSPLANT.
>> WE HAVE NOT YET USED THE
FINDINGS OF THE NOMOGRAM TO KIND
OF EDUCATE THE PATIENTS, BUT
DEFINITELY SOMETHING WE LOOK
FORWARD TO DOING IT.
>> THAT WAS AN EXCELLENT
QUESTION, IF I MAY ADD, SO A
NOMOGRAM WOULD GIVE YOU A
GENERAL IDEA, AND I THINK THE
GENERAL IDEA IS THAT OLDER
PATIENTS AND PATIENTS WHO HAVE
HAD A LOT OF VOCs MAY BE AT
HIGHER RISK, AND PEOPLE WANT TO
KNOW ACTUALLY WHAT THEIR OUT
COME IS GOING TO BE.
SO USING DATA LIKE THIS, YOU
COULD MAKE A GENERAL PREDICTION
THAT YOU HAVE SOME INCREASED
CHANCE OF HAVING PERSISTENT
PAIN.
BUT AS YOU KNOW FROM YOUR WORK
AND ALEXIS LEONARD'S WORK, THAT
WITH MULTIDISCIPLINARY
INTERVENTIONS, MOST OF THE
PATIENTS EVENTUALLY BECOME
PAIN-FREE.
AGAIN, THIS INFORMATION WOULD
HAVE TO BE PROVIDED IN THAT
CONTEXT.
I HOPE THAT ANSWERS YOUR
QUESTION.
THANK YOU.
WE HAVE OTHER QUESTIONS.
WAS THERE ANY WAY TO LOOK AT THE
TIMING OF VOCs POST
TRANSPLANT?
DID THEY MOSTLY OCCUR SHORTLY
AFTER TRANSPLANT OR TWO TO FIVE
YEARS OR GREATER THAN FIVE
YEARS?
>> SO THE DATASET THAT WE HAD
DID NOT TELL US THE TIMING,
WHETHER IT WAS IN THE SHORT
TERM, LESS THAN ONE YEAR, ONE TO
TWO YEARS, TWO TO FIVE YEARS, SO
THAT'S A LIMITATION THAT WE
ACKNOWLEDGE.
>> DR. HORWITZ.
>> YOU ACTUALLY COULD ESTIMATE
IT BY LOOKING AT THE DATE OF THE
REPORTS, BECAUSE THE QUESTION
IS, WAS THERE VOD SINCE THE LAST
REPORT.
SO IF YOU HAD THE DATE OF THE
REPORTS AND THEY'RE GENERALLY
REQUIRED EVERY YEAR AFTER A
CERTAIN POINT, YOU COULD GET A
ROUGH IDEA OF WHETHER IT'S EARLY
OR LATE.
SO YOU MIGHT WANT TO LOOK AT THE
DATASET FOR THAT PARTICULAR
VARIABLE.
>> WE WILL, THANK YOU.
>> THIS IS A WONDERFUL -- WHO
BETTER TO ANSWER THAT QUESTION
THAN DR. HORWITZ HERSELF.
SO THE FORMS ARE ABSOLUTELY
TIMED, RIGHT?
THIS WAS A PUBLICLY AVAILABLE
DATASET THROUGH THE BIOLINCC, SO
WE'D ACTUALLY GO BACK TO THE
NON-MALIGNANT HEME COMMITTEE AND
SAY WE OUGHT TO TAKE A DEEPER
DIVE LOOKING AT THIS.
SO THANK YOU VERY MUCH.
WE HAVE MORE QUESTIONS.
>> I ALSO WANT TO POINT OUT
THAT -- [INAUDIBLE]
>> YES, THE -- THREE-POINT --
ALSO COLLECTS INFORMATION ON THE
CHRONIC PAIN PRETRANSPLANT, SO
WE'RE REALLY LOOKING FORWARD TO
THAT.
>> SO MYCO-CH MY CO-CHAIR IS SAP
IT UP.
THANK YOU, DR. NALLAGATLA.
>> WE'LL MOVE TO OUR NEXT
SPEAKER, DR. ALEXIS LE IN ORDER.
NOW AT ST. JUDE'S CHILDREN'S
RESEARCH HOSPITAL WILL BE
PRESENTING ON IN VIVO
MEASUREMENT OF RBC SURVIVAL IN
PATIENTS WITH SICKLE CELL
DISEASE BEFORE AND AFTER
TRANSPLANT.
>> GOOD MORNING.
THANK YOU ALL FOR HAVING ME
TODAY.
AND I APOLOGIZE FOR NOT BEING
THERE IN PERSON.
I AM THRILLED TO TALK ABOUT THIS
WORK THAT I DID WHEN I WAS A
MEMBER OF THE TISDALE LAB, WHERE
WE LOOK AT MEASURING DIRECTLY
RED CELL SURVIVAL BEFORE AND
AFTER TRANSPLANT.
THESE ARE MY DISCLOSURES.
THANK YOU.
SO AS THIS AUDIENCE IS WELL
FAMILIAR, THE IDEA BEHIND A
CURATIVE STRATEGY IS TO RESTORE
RED CELL FUNCTION EITHER BY
REPLACING THE SICKLE RBCs WITH
THAT OF A DONOR OR IN THE CASE
OF GENE THERAPY, INCREASING
ANTISICKLING GLOBIN ENOUGH TO
CORRECT THE ANEMIA AND PROLONG
THE RED CELL SURVIVAL.
AND WE'VE KNOWN FOR A LONG TIME
THAT STABLE MIXED CHIMERISM IS
SUFFICIENT TO REVERSE THE
PHENOTYPE BASED SOLELY OF THE
NATURAL SURVIVAL ADVANTAGE AND
ENRICHMENT OF THE DONOR RED
CELLS.
SO WHEN YOU LOOK AT THE
RELATIONSHIP BETWEEN THE
CHIMERISM THAT YOU SEE IN THE
PERIPHERAL BLOOD, YOU SEE A TWO
TO FIVE FOLD ENRICHMENT OF THE
DONOR RED CELLS IN PATIENTS WITH
MIXED CHIMERISM.
THERE'S NEARLY FULL REPLACEMENT
IN THE PERIPHERAL BLOOD BY THESE
DONOR DERIVED MATURE RED CELLS
EVEN IN THE SETTING OF MIXED
CHIMERISM, WHICH EXPLAINS THE
CLINICAL AND FUNCTIONAL
IMPROVEMENTS, BUT AS THIS FIGURE
SHOWS, IT'S NOT ALWAYS 100%.
SO WE KNOW FROM DR. FITZHUGH'S
PUBLICATION ABOUT THE 20%
THRESHOLD THAT IN THEORY, A
PATIENT WHO HAS A SHORTER SICKLE
RED CELL LIFESPAN MAY TOLERATE A
LOWER DONOR MYELOID CHIMERISM TO
ACHIEVE EQUIVALENT FRACTION OF
DONOR RED BLOOD CELLS IN THE
PERIPHERAL BLOOD.
SO WE ASKED OURSELVES INSTEAD OF
USING AN EQUATION, COULD WE
ACTUALLY DIRECTLY MEASURE THE
RED CELL SURVIVAL, AND COULD WE
THEN USE VARIOUS FACTORS THAT
ARE MEASURABLE TO PREDICT A
PATIENT'S LIFESPAN AND,
THEREFORE, THEIR DONOR MYELOID
CHIMERISM.
CAN YOU MEASURE THIS EITHER BY
POPULATION STEADY WHERE YOU'RE
MEASURING A POPULATION OF RED
CELLS, NEW AND OLD, OR A COHORT
STUDY WHERE YOU'RE MEASURING ALL
RED CELLS AT THE SAME AGE.
AND THIS HAS BEEN DONE IN MANY
DIFFERENT DISORDERS.
BUT IT ACTUALLY HAS BEEN DONE IN
PATIENTS WITH SS DISEASE WITH
VARIOUS DIFFERENT METHODS, AND
YOU SEE A -- HEALTHY TRAIT.
AND YOU CAN SEE THESE FRACTIONAL
SURVIVAL CURVES COMPARED TO THE
NORMAL CONTROL.
SO THIS IS OUR STUDY.
YOU CAN SEE THE INCLUSION AND
EXCLUSION CRITERIA.
MEASURING THE RED CELL SURVIVAL
IN PATIENTS BEFORE AND AFTER
TRANSPLANT.
SO ANY ADULT WITH ANY GENOTYPE
OF SICKLE CELL DISEASE -- SORRY,
THERE'S AN ECHO -- WHO HAS
NORMAL RENAL FUNCTION BECAUSE
BIOTIN IS A WATER-SOLUBLE
VITAMIN.
AND THEN THE MAIN -- ONE OF THE
MAIN EXCLUSION CRITERIAS IS
BEING ON THE BIOTIN
SUPPLEMENTATION.
SO WE INCLUDED 20 PARTICIPANTS,
OF WHICH SIX WERE PRETRANSPLANT,
FIVE WERE POST TRANSPLANT, SIX
WERE AS AND THREE HAD AA.
HALF OF OUR COHORT HAD A SINGLE
ALPHA GLOBIN MUTATION.
IN OUR PRETRANSPLANT POPULATION,
WE HAD THREE SS, TWO SC AND ONE
S BETA PLUS, TWO THIRDS, ON
HYDROXYUREA AND OUR POST
TRANSPLANT GROUP, WE HAD THREE
MATCHED SIBLING DONORS, TWO
HAPLOAND ALL DONORS WERE AS
EXCEPT FOR ONE, WITH THREE
MIXED -- EXCUSE ME -- THREE FULL
CHIMERISM AND TWO MIXED
CHIMERISM.
SO IN OUR STUDY, WE INCLUDED 20
ADULTS WHERE WE WERE ABLE TO EX
VIVO LABEL THE PATIENTS' RED
CELLS WITH BIOTIN AND REINFUSE
THE BIOTIN RED BLOOD CELLS BACK
TO THE PATIENT AND DO PERIPHERAL
BLOOD SAMPLING UNTIL BIOTIN WAS
BELOW THE DETECTION LEVEL.
YOU CAN GET THESE SIMPLE BUT
ELEGANT FLOW PLOTS WHERE YOU CAN
SEE IN THE PATIENT PREBIOTIN YOU
MIGHT HAVE HAD SOME AUTO
FLUORESCENCE.
WE HAD IN THE BIOTIN PRODUCT
100% LABELED WITH BIOTIN, 20
MINUTES AFTER INFUSION WAS OUR
FIRST BLOOD SAMPLE WHERE YOU'D
GET A PROPORTION OF THE BLOOD
THAT WAS BIOTIN-POSITIVE AND
THEN YOU COULD TRACK THAT OVER
TIME.
SO WE COULD GENERATE THESE
SURVIVAL CURVES WHICH COULD SHOW
NORMALIZATION OF RED CELL
SURVIVAL AFTER TRANSPLANT
COMPARED TO PATIENTS BEFORE
TRANSPLANT, AND FOR FIGURE B ON
THE RIGHT, YOU CAN SEE THE
DIFFERENCES BETWEEN SS GENOTYPE
AND SCS BETA PLUS AND THE
DIFFERENCES BETWEEN FULL AND
DONOR MYELOID CHIMERISM, WHICH
BOTH OF THEM SHOW A NORMAL RED
CELL SURVIVAL CURVE.
TO GIVE YOU A LITTLE BIT OF
PERSPECTIVE ON THIS, THESE
FIGURES, THIS IS HPLC DATA.
WHAT WE COULD SHOW IS THAT ANY
TYPE OF NON-HEMOGLOBIN S
HEMOGLOBIN IS WHAT PROLONGS THE
RED CELLS IN THE PERIPHERAL
BLOOD.
SO FOR THIS COHORT, THIS IS OUR
PRETRANSPLANT COHORT, IT'S
EITHER FETAL HEMOGLOBIN OR
HEMOGLOBIN C THAT IS PERSISTENT
AT THE VERY END.
SO TO ORIENT YOU, FOR EXAMPLE,
FOR THE FIRST FIGURE ON THE TOP
LEFT, WE DID R RETICULOCYTE
ISOLATION WITH HPLC, WHICH YOU
CAN SEE ARE PRIMARILY SICKLE
GLOBIN.
WE DID HPLC ON WHOLE BLOOD WHICH
IS WHAT YOU WOULD MEASURE IN THE
CLINIC, WE DID HPLC ON THE
BIOTIN POSITIVE FRACTION AT THE
BEGINNING AND AT THE VERY END,
YOU CAN SEE ENRICHMENT FOR HBSS
IN HBF OVER TIME, AND FOR THE SC
PATIENTS INTERESTINGLY WE SAW A
HIGHER FRACTION OF HEMOGLOBIN C
COMPARED TO HEMOGLOBIN S AT THE
VERY END OF THE STUDY.
FOR OUR POST TRANSPLANT COHORT,
NOT SURPRISINGLY -- COMPLETE
DONOR A SDOH NORS, WHAT YOU GET
IN RETICULOCYTE IN THE WHOLE
BLOOD AND AT THE END OF STUDY IS
DONOR DERIVED AND STABLE AS
OPPOSED TO WHAT WE SEE WITH OUR
TWO MIXED CHIMERISM PATIENTS,
WHAT YOU SEE IS THAT THE
RETICULOCYTES ARE PRIMARILY
RECIPIENT DERIVED AND OVER TIME
OBVIOUSLY THE RED CELLS THAT ARE
LASTING THE LONGEST ARE
CONSISTENT WITH THE DONORS.
AND THIS WAS CONSISTENT WITH
WHAT WE SAW IN SINGLE CELL
WESTERN, SO THE CLOSED CIRCLES
ARE THE BIOTIN-POSITIVE
FRACTION.
IN BLUE IS THE DONOR DERIVED RED
CELLS THAT ENRICH OVER TIME, AND
IN RED ARE THE RECIPIENT DERIVED
THAT ARE MUCH LOWER OVER TIME.
AND WHEN WE CORRELATED THIS WITH
THE FINAL FRACTION OF SICKLED
RED CELLS AFTER DEOXYGENATION,
WE COULD STRONGLY CORRELATE THIS
WITH RED CELL LIFESPAN.
SO IT'S NOT SURPRISING THAT
PATIENTS' PRETRANSPLANT --
HIGHER PERCENTAGE OF RED
CELLS -- FOR EXAMPLE IN GREEN,
THE SC PATIENTS.
WHEN WE BLOT THIS AGAINST THE
RED CELL SURVIVAL, WE SEE A VERY
STRONG CORRELATION TO WHAT
SICKLES TO HOW LONG YOUR RED
CELLS LAST IN THE PERIPHERAL
BLOOD.
AND WHAT'S INTERESTING IS THAT
YOU CAN SEE THAT AT A CERTAIN
THRESHOLD, WE SEE PATIENT THAT
ARE SYMPTOMATIC VERSUS
ASYMPTOMATIC PATIENTS, SO EVEN
OUR MIXED CHIMERISM PATIENTS
WERE ASYMPTOMATIC AT THE TIME,
AND THAT SC PATIENT 23 WAS A
PATIENT WITH SC DISEASE THAT HAD
NO SYMPTOMS, AND SO SOMEWHERE IN
THERE IS SOME THRESHOLD THAT
SHOWS US WHERE PATIENTS MIGHT
REMAIN ASYMPTOMATIC.
WHEN WE PLOTTED THIS WITH
HISTORICAL DATA FROM PATIENTS
THAT WERE TREATED WITH GENE
THERAPY T87Q GENE ADDITION, WE
COULD SHOW THAT A FRACTION OF
SICKLING THAT OCCURS OVER TIME
IS OBVIOUSLY HIGH IN OUR SS
PRETRANSPLANT, AND IS STABLE AND
LOW IN THE PATIENTS THAT HAD
100% DONOR CHIMERISM, BUT WE
COULD SEE AN EQUIVALENT FRACTION
BECAUSE WE COULD SEE SOME
RETICULOCYTES, FOR EXAMPLE, THAT
WERE RECIPIENT DERIVED IN THE
PERIPHERAL BLOOD SIMILAR TO WHAT
YOU SEE WITH PATIENTS WITH T87Q
ADDITION BECAUSE WE KNOW IT'S
NOT 100% REPLACEMENT.
IN GENERAL THIS WAS SAFE AND
FEASIBLE, THERE ARE NO ADVERSE
EVENTS ATTRIBUTABLE TO USING BUY
TIN, WE HAD NO EMERGENCY ROOM
VISITS AND NO ANTIBODIES WERE
DETECT TODAY BIOTIN.
DETECTED TO PI BUY TIN.
SO IN SUMMARY, BIOTIN LABEL IS
SAFE AND FEASIBLE TO EVALUATE
RED CELL SURVIVAL BEFORE AND
AFTER TRANSPLANT IN PATIENTS
WITH SICKLE CELL.
RBC LIFESPAN STRONGLY CORRELATES
TO THAT FINAL FRACTION OF
SICKLED RED CELLS AFTER
DEOXYGENATION AND SEPARATES
WHO'S SYMPTOMATIC FROM
ASYMPTOMATIC.
THE DIFFERENCES IN RED CELL
SURVIVAL MAY INFORM THE
HEMOGLOBIN COMPOSITION
THRESHOLDS THAT WE NEED TO
REVERSE THE PHENOTYPE AFTER GENE
THERAPY, FOR EXAMPLE.
WOOR USING ONGOING WORK AND HAVE
A NEW PROTOCOL THAT'S OPEN NOW
TO STUDY RED CELL SURVIVAL
BEFORE AND AFTER THINGS LIKE
DISEASE-MODIFYING THERAPIES AND
AFTER GENE THERAPY.
I WANT TO ACKNOWLEDGE ALL OF THE
STAFF AT THE NIH AND BECAUSE
THERE IS A NEW OPEN PROTOCOL
NOW, I INCLUDED CHRISTINA'S
EMAIL AT THE TOP IF YOU HAVE A
PATIENT WHO WOULD BE INTERESTING
TO STUDY THEIR RED CELL
SURVIVAL.
AND I THANK YOU ALL FOR YOUR
TIME AND ATTENTION.
[APPLAUSE]
>> THANK YOU, DR. LEONARD.
QUESTION FROM --
>> PLEASE INTRODUCE YOURSELF.
>> MATT FROM STANFORD.
VERY NICE TALK.
SUPER INTERESTING, THE BIOTIN
LABELING OVER TIME LOOKING AT
RETICS OVER TIME.
HOW DOES THAT HELP US UNDERSTAND
WHEN WE LOOK AT A QUOTE
HETEROCELLULAR VERSUS
PANCELLULAR CHIMERISM?
IT MAY WELL BE THAT WHEN WE TAKE
A SNAPSHOT, IT APPEARS
PANCELLULAR BUT WHAT'S REALLY
HAPPENING IS IT'S A
HETEROCELLULAR PROCESS THAT
CONVERTS TO PANCELLULAR.
AM I THINKING ABOUT THAT THE
RIGHT WAY?
>> YEAH, I THINK -- I WAS JUST
THINKING ABOUT THIS THE OTHER
DAY, BUT THERE MUST BE -- YOU
KNOW, IT WAS SOMEWHAT SURPRISING
TO SEE POSITIVE FRACTION OF
DONOR -- EXCUSE ME -- RECIPIENT
RETICS IN THE PERIPHERAL BLOOD,
SO THERE MUST BE SOME THRESHOLD
WHERE THE RETICS AND THE ENTIRE
PERIPHERAL BLOOD IS THE DONOR OR
WHATEVER FRACTION OF
ANTISICKLING GLOBIN WAS INCLUDED
AFTER GENE THERAPY AND HOPEFULLY
WE'LL BE ABLE TO ELUCIDATE THAT
IN THIS LARGER STUDY WITH TWO --
ONLY TWO MIXED CHIMERISM
PATIENTS, WE CAN'T QUITE SAY FOR
SURE WHERE THAT THRESHOLD IS,
BUT IT'S SOMEWHERE THAT WE CAN
HOPEFULLY FIGURE OUT BY
MEASURING THIS IN LARGER
COHORTS.
>> GREG FROM CSL AND KIM OF
PENNSYLVANIA.
THIS IS REALLY WONDERFUL SCIENCE
AND USING A GREAT TECHNIQUE FOR
MEASURING RED CELL SURVIVAL.
THE BIOTIN LABELING IS REALLY
EFFECTIVE OVER A WIDE RANGE OF
RED CELL SURVIVALS BUT I
WONDERED IF YOU WERE ABLE TO
CORRELATE SERUM HAPP HAP GLOBIN
LEVELS TO THE MILDER DEGREES OF
HEMOLYSIS POST TRANSPLANT.
>> THAT'S A GREAT POINT AND
ACTUALLY WE HAVE DISCUSSED THAT.
IT WASN'T IN THE ORIGINAL
PROTOCOL FOR US TO OBTAIN IT.
AND I CAN'T REMEMBER IF WE PUT
IT IN THE NEW ONE, BUT IF IT'S
NOT IN THE NEW ONE, WE WILL PUT
IT IN THERE BECAUSE I AGREE IT
AN IMPORTANT CORRELATIVE THAT
WILL HELP US.
>> GREAT.
THANK YOU.
>> THANK YOU, DR. LEONARD.
WE'RE GOING TO MOVE TO OUR NEXT
SPEAKER, WHO DR. KRISH WILL
INTRODUCE.
>> AS IS EVIDENT FROM THE
CONVERSATION THIS MORNING, A LOT
OF THE WORK ON CURATIVE
THERAPIES FOR SICKLE CELL
DISEASE IS OCCURRING ALL OVER
THE WORLD, NOT ONLY THE UNITED
STATES, AND TO TALK ABOUT ONE OF
THE CONSORTIA, THE VANDERBILT
CONSORTIA THAT'S PLAYED AN
IMPORTANT ROLE IN ADVANCING
HAPLOIDENTICAL TRANSPLANT, WE
HAVE DR. ERPHAN NUR.
DR. NUR WILL BE SPEAKING TO US
FROM THE AMSTERDAM UNIVERSITY
MEDICAL CENTER AND SANQUIN
RESEARCH AND LANDSTEINER
LABORATORY AMSTERDAM, THE
NETHERLANDS, AND HE WILL TALK TO
US ABOUT THE VANDERBILT GLOBAL
HAPLOIDENTICAL CONSORTIUM
PART 2, NEXT STEPS FROM
NASHVILLE TO AMSTERDAM.
DR. NUR.
>> THANK YOU VERY MUCH, KRISH.
THANKS FOR THIS OPPORTUNITY TO
PRESENT AT THIS GREAT MEETING ON
BEHALF OF OUR VANDERBILT GLOBAL
CONSORTIUM.
YOU EXPLAINED THE TITLE VERY
WELL.
SO IT'S SAFE TO SAY THAT
ALLOGENEIC STEM CELL
TRANSPLANTATION IS AN
ESTABLISHED CURATIVE THERAPY FOR
PATIENTS WITH SICKLE CELL
DISEASE.
BUT THERE ARE TWO MAIN
CHALLENGES PARTICULARLY FOR
ADULTS WITH SICKLE CELL DISEASE.
FIRST IS THE SIGNIFICANT
TOXICITY WHICH BRINGS WITH IT
MORTALITY WITH MYELOABLATIVE
CONDITIONING REGIMENS AND SECOND
IS THE LIMITED POOL OF HLA
IDENTICAL SIBLING DONORS.
SICKLE CELL DISEASE ASSOCIATED
WITH AN ACCELERATED BIOLOGICAL
AGING OF VITAL ORGANS, INCLUDING
THE LUNGS, HEART AND KIDNEYINGS,
AND THIS KIDNEYS,AND THIS IS ASH
INCREASED MORTALITY IN SICKLE
CELL DISEASE, AND TOXICITY BY
THE CONDITIONING REGIMEN
ESPECIALLY IF IT'S
MYELOABLATIVE, THESE ORGANS
MIGHT ALSO CONTRIBUTE TO THE
INCREASED MORTALITY, ESPECIALLY
IN ADULTS WITH SICKLE CELL
DISEASE.
SO THE SECOND CHALLENGE AS I
SAID IS THAT OF LACK OF HL
IDENTICAL DONORS.
IN THE LAST 10 TO 15 YEARS,
SEVERAL STUDYS HAVE BEEN
PERFORMED TO EVALUATE
HAPLOIDENTICAL STEM CELL
TRANSPLANTATION IN PATIENTS WITH
SICKLE CELL DISEASE, WHILE
PRELIMINARY RESULTS WERE POOR,
ESPECIALLY WITH HIGH RATES OF --
FAILURE, OUTCOMES HAVE IMPROVED
GRADUALLY ESPECIALLY WITH THE
NON-MYELOOWE BLAITIVE OR REDUCED
INTENSITY REGIMENS AS IN VIVO --
HOWEVER THESE STUDIES WERE
SMALL, MOSTLY SINGLE CENTER, AND
ALSO USING DIFFERENT
CONDITIONING REGIMENS.
SO TO IMPROVE ON THESE RESULTS
BUT ALSO TO FIND MORE DEFINITIVE
EVIDENCE, OUR VANDERBILT
CONSORTIUM SET UP A STUDY WHERE
WE ADDED THIOTEPA 10 MG TO THE
EXISTING JOHNS HOPKINS PLATFORM
THAT WAS DEVELOPED FOR
NON-MALIGNANT DISEASES.
SO THIS IS OUR SCREENING AND
INCLUSION FLOW CHART.
WE HAD AS YOU CAN SEE IN THE
LOWER PART HAD 70 PATIENTS WHO
WERE ASSESSABLE, 32 CHILDREN AND
38 ADULTS.
WE HAD 62 SUCCESSFUL
ENGRAFTMENTS, 8 GRAFT FAILURES,
INTERESTINGLY ALL OF THEM WERE
IN CHILDREN, AND WE HAVE 5 TRIAL
DEATHS TO WHICH I WILL COME IN A
BIT.
HERE YOU CAN SEE HOUR EVENT-FREE
SURVIVAL WHICH WAS -- EVENT WAS
DEFINED AS GRAFT FAILURE OR
DEATH DUE TO ANY CAUSE.
AS YOU CAN SEE EVENT FREE
SURVIVAL WAS EXCELLENT IN ADULTS
BUT RATHER POOR IN THE PEDIATRIC
PATIENTS WHICH WAS PRIMARILY DUE
TO THE HIGH RATE OF GRAFT
FAILURE.
FORTUNATELY ALL PATIENTS WITH
GRAFT FAILURE DID HAVE
AUTOLOGOUS REGENERATION AND
SURVIVED.
AND THAT RESULTED IN THIS VERY
GOOD SURVIVAL IN BOTH ADULTS AND
CHILDREN, WHICH WAS AT 2 YEARS
AROUND 94%.
HERE YOU CAN SEE THE CELLULAR
RECOVERY AND CHIMERISM LEVELS.
FOR THE SAKE OF CLARITY I'M ONLY
SHOWING MEDIANS AND HAVE LEFT
OUT RANGES.
AS YOU CAN SEE IN THE LOWER PART
OF THE TABLE, WHOLE BLOOD AND
CD3 CHIMERISM WERE 100% FOR ALL
ENGRAFTED PATIENTS.
97% OF ALL ENGRAFTED PATIENTS
WERE OFF IMMUNOSUPPRESSION AT
ONE YEAR.
AS I SAID, WE HAD FIVE DEATHS,
ALL PRIMARILY DUE TO INFECTIONS.
ONE-YEAR INCIDENCE OF GRADE
III-IV ACUTE GVHD IN ADULTS WAS
7.9%, WHICH WAS SLIGHTLY LOWER
THAN IN CHILDREN.
AND TWO YEARS INCIDENCE OF
MODERATE TO SEVERE CHRONIC GVHD
WAS ONLY 2.6% IN ADULTS, WHICH
WAS SIGNIFICANTLY LOWER THAN IN
CHILDREN.
SO WE CAN CONCLUDE THAT
HAPLOIDENTICAL BMT WITH THIGH
THIOTEPAAND PTCY IS A VIABLE CUE
THERAPY FOR ADULTS WITH SICKLE
CELL DISEASE.
THERE IS NEED FOR MORE
OPTIMIZATION IN CHILDREN WHICH
OUR COLLEAGUES FROM THE
PEDIATRIC -- ARE WORKING ON, BUT
THIS PROTOCOL IS INCREASINGLY
BEING PROVIDED AS STANDARD OF
CARE TO ADULTS WITH SICKLE CELL
DISEASE.
SO THAT BRINGS US TO THE NEXT
QUESTION OF OUR CONSORTIUM, WHAT
IS THE EFFECT OF TRANSPLANT
ON -- RELATED HEALTH EFFECTS,
WHAT WILL BE THE EFFECT OF THE
TOXICITY OF THE CONDITIONING
VERSUS IMPROVEMENT OR
STABILIZATION DUE TO BEING CURED
FROM SICKLE CELL DISEASE?
WE RECENTLY DID THIS LARGE
SYSTEMATIC REVIEW OF THE EVENT
OF TRANSPLANT ON SCD-RELATED
ORGAN DYSFUNCTION.
THERE WERE MANY STUDIES THAT
HAVE LOOKED INTO THIS, MOSTLY IN
PEDIATRIC PATIENTS, AND THERE IS
SOME STABILIZATION OR MAYBE EVEN
IMPROVEMENT IN SOME ORGANS, BUT
SYSTEMATICALLY COLLECTED DATA IN
ADULTS ARE VERY SCARCE, SO THAT
BRINGS US -- I THINK THAT LEAVES
US WITH IMPORTANT REMAINING
QUESTIONS THAT WE WOULD LAKE TOO
ANSWER IN PART 2 OF THE
VANDERBILT GLOBAL CONSORTIUM.
WE WILL HAVE FOUR MAIN AIMS FOR
THIS.
THE FIRST AIM WILL BE IN THE
INTERMEDIATE AND LATE HEALTH
EFFECTS OF HAPLOBMT ON HEART,
LUNGS AND KIDNEYS BUT ALSO IN
MALE/FEMALE RELATED SYSTEM AS
FIRST SPEAKER TALKED ABOUT, ALSO
WE WILL ALSO LOOK INTO OTHER
SCD-RO-RO-RELATED FUNCTIONS BUTO
CYST AT THE MAICALLY EVALUATE
HEALTH-RELATED QUALITY OF LIFE.
AND THEN AS ALL THE DEATHS WERE
DUE TO INFECTIONS, WE WILL LOOK
EXTENSIVELY INTO IMMUNE RESPONSE
KIMMUNERECONSTITUTION, WE WILL W
THAT PROSPECTIVELY, AND ALSO
THERE ARE SOME INDICATIONS THAT
POOR IMMUNE RECONSTITUTION IS
RELATED TO GRAFT FAILURE SO WE
WILL ALSO LOOK INTO RELATION
WITH CHIMERISM.
THESE ARE OUR END POINTS.
I WILL KEEP IT SHORT.
JUST TO THE PRIMARY ENDS POINTS
OF AIM ONE, WE WILL LOOK AT
PROM -- THAT WILL INCLUDE GRAFT
FAILURE, DEATH, BUT ALSO GRADE
III TO IV AND ALSO CHRONIC TO
SEVERE, AND WE WILL -- FOR -- WE
WILL USE PROMIS MEASURE FOR THE
QUALITY OF LIFE AND PAIN WILL BE
OUR PRIMARY END POINT.
AND FOR THE IMMUNE
RECONSTITUTION, THAT WILL BE
SITE-SPECIFIC.
WE WILL COLLECT AND STORE PBMC
AT SOME CENTERS AND THEN PRIMARY
INPUT WILL BE AT 3 MONTHS.
JUST SHORTLY, THIS WILL BE AN
INTERNATIONAL RETROSPECTIVE ALSO
PROSPECTIVE STUDY USING OUR
PROTOCOL IN ADULTS.
WE WILL SET UP A REDCAP
DATABASE.
THE DATA TRANSFER COORDINATING
CENTER WILL MOVE FROM VANDERBILT
UMC TO AMSTERDAM UMC, FOR HEALTH
RELATED OUTCOMES WE WILL USE A
WEB-BASED PROMIS QUESTIONNAIRE
AVAILABLE IN DIFFERENT LANGUAGES
AND FOR PBMC WILL BE SITE
SPECIFIC, WE WILL DO BIOBANKING.
WITH THAT, I WOULD LIKE TO THANK
ALL THE PATIENTS, ALL THE
CAREGIVERS AND ALL THE PRINCIPAL
INVESTIGATORS WHO WERE TOO MANY
TO MENTION.
I WILL SUMMARIZE THE LIST OF
CENTERS WHO HAVE PARTICIPATED IN
PART 1 AND/OR WILL PARTICIPATE
IN PART 2, AND SOME OF THE
LEADING PERSONS OF OUR
CONSORTIUM, YOU CAN SEE IN THIS
PICTURE.
THANK YOU VERY MUCH.
[APPLAUSE]
>> THANK YOU VERY MUCH, DR. NUR.
WE HAVE A COUPLE OF QUESTIONS IN
THE CHAT.
DR. CHRISTINA PETERS WOULD LAKE
TO YOU COMMENT ON DONOR
SELECTION.
>> SO WE AIM FOR FIRST DEGREE
FAMILY MEMBERS, SO -- AND
YOUNGER RATHER THAN OLD EARLY,
SO IT COULD BE A SIBLING, IT
COULD BE CHILDREN, BUT IN THE
CASE OF PARENTS, WHERE MOST OF
THE DONORS WERE PARENTS, BUT
THERE WERE ALSO SOME
SECOND DEGREE FAMILY MEMBERS
LIKE AUNTS AND UNCLES.
>> THANK YOU.
DR. RAHIM HAS AN IMPORTANT
QUESTION.
THE HIGHER RATE OF GRAFT
FAILURE, RIGHT, SO WE'RE USED TO
CHILDREN DOING BETTER EVERYWHERE
BUT NOT SO HERE, SO ANY COMMENTS
ON WHAT MIGHT CONTRIBUTE TO
HIGHER GRAFT FAILURE IN
CHILDREN?
>> I THINK THAT'S THE MILLION
DOLLAR QUESTION, WHAT'S THE BEST
OPTIMAL CONDITIONING FOR WHICH
AGE, SO BY ADDING THIOTEPA, WE
HOPE THIS WILL WORK FOR ALL
AGES, BUT IT SEEMS THAT IT'S
STILL NOT ROBUST ROBUST ENOUGHY
FOR CHILDREN, WHY CHILDREN TEND
TO REJEBT M REJECT MORE EASILY O
NOT WELL-KNOWN, BUT OUR
COLLEAGUES FROM THE PEDIATRIC
STRATUM HAVE ALREADY MOVED ON BY
INTRODUCING A PRECONDITIONING
WHICH CON SENIOR INVESTIGATOR CF
HYPERTRANSFUSION EVERY TWO TO
THREE WEEKS AND KEEPING -- LEVEL
VERY HIGH, AND ALSO HYDROXYUREA
AT HIGH LEVELS, WHICH ADULTS
DON'T REALLY TOLERATE, AND THE
RESULTS SEEM TO IMPROVE.
THAT WAS PRESENTED -- THE GRAFT
FAILURE RATE HAS SIGNIFICANTLY
DECREASE.
SO WE WILL SEE HOW THAT DEVELOPS
WHEN MORE PATIENTS ARE INCLUDED.
>> DR. RAHIM ALSO WANTS TO KNOW
WHAT ABOUT PATIENTS THAT DID NOT
RECEIVE THIOTEPA.
DID THAT INCLUDE THEM AS WELL,
THE PEDIATRIC PATIENTS?
>> NO, IN THIS STUDY ALL
PATIENTS USED EXACTLY STRICTLY
THE SAME PROTOCOL.
THERE WERE THREE PATIENTS WHO
USED -- WHO HAD SOME VIOLATION
OF THE PROTOCOL.
WE EXCLUDED THEM.
SO ALL PATIENTS IN THIS -- ALL
THESE 70 PATIENTS DID USE -- DID
GET THIOTEPA.
>> THANK YOU, DR. NUR.
PLEASE ANSWER OTHER QUESTIONS IN
THE CHAT.
>> THANKS, I WILL.
>> SO WE'LL MOVE TO OUR NEXT
SPEAKER, DR. SHALINI SHENOY FROM
WASHINGTON UNIVERSITY SCHOOL OF
MEDICINE WILL BE PRESENTING
LONG-TERM OUTCOME DATA FROM THE
BMT CTN 0601 FOR SEVERE SICKLE
CELL DISEASE TRIAL.
>> THANK YOU FOR THE INVITATION
TO PRESENT.
GOOD MORNING.
I AM PRESENTING THE OUTCOMES OF
A TRIAL THAT HAPPENED SOME YEARS
AGO.
THE BMT CTN 0601 WAS A TRIAL OF
UNMATCHED DONOR TRANSPLANTS IN
CHILDREN WITH SEVERE SICKLE CELL
DISEASE.
IT WAS CONDUCTED BETWEEN 2008
AND 2014.
IT ENROLLED 30 PATIENTS, THE AGE
RANGE WAS 3 TO 19.75 YEARS.
THE SCD MANIFESTATIONS THAT WERE
ELIGIBLE WERE VASO-OCCLUSION,
ACUTE CHEST SYNDROME, A HIGH
TRANSCRANIAL VELOCITY AND STROKE
AND IT UTILIZED REDUCED
INTENSITY CONDITIONING INCLUDING
PROXIMAL/EARLY AL EMTEUZ MAN,
FLUDARABINE AND MELPHALAN.
PREDNISONE WAS GIVEN ONE MONTH
BEFORE THEY CAME FOR THE
CONDITIONING.
SHORT COURSE METHOTREXATE WAS IN
THREE DOSES AND MED ZONE WAS
ADMINISTERED FOR A MONTH TO
AVOID THE INFLAMMATORY CHANGES
THAT HAPPENED PERITRANSPLANT AS
WELL AS PROVIDE GBHD
PROPHYLAXIS.
IT WAS BASED ON A MATCHED
SIBLING DONOR TRIAL THAT WAS
PUBLISHED PREVIOUSLY.
AND IN 43 PATIENTS WITH SICKLE
CELL DISEASE, THE GRAFT
REJECTION RATE WAS 2% HERE AND
5% AND THEY HAD 93% SURVIVAL.
IN THE MATCHED UNRELATED DONOR,
WHICH WAS PREVIOUSLY PUBLISHED,
THE GRAPH ON THE RIGHT PANEL
SHOWS YOU THE EVENT-FREE
SURVIVAL AT ONE YEAR WAS 76%,
THE OVERALL SURVIVAL WAS 86%,
AND I WILL SHOW YOU THE
LONGER-TERM FOLLOW-UP DATA.
THE LESSONS THAT WE LEARNED.
THE TOP PANEL THERE WAS LOOKING
AT QUALITY OF LIFE AT ONE YEAR.
AND IT SHOWED THAT THE GENERAL
CHANGE IN HEALTH IMPROVED WITH
TIME, SO IT WAS LOOKED AT AT DAY
100, SIX MONTHS AND ONE YEAR,
AND WAS SIGNIFICANTLY DIFFERENT
OR BETTER AT ONE YEAR THAN IT
WAS EARLIER, POST TRANSPLANT.
THE GRAFT REJECTION RATE WAS
10%.
ENGRAFTED PATIENTS HAD NO
FURTHER SICKLE CELL DISEASE
COMPLICATIONS.
WITH A TWO-YEAR FOLLOW-UP THAT
WAS INCLUDED AS PART OF THE
STUDY.
THE PRESS RATE WAS 35% AND WAS
RELATED TO HYPERTENSION AND THE
STEROIDS THAT WERE USED.
THE EXTENSIVE CHRONIC GVHD RATE
WAS THE ONE THAT STOOD OUT THE
MOST, IT WAS 38% AND 6 PATIENTS
DIED OF GVHD RELATED
COMPLICATIONS.
THEY WERE ALL OVER 14 YEARS OF
AGE.
AND THAT DESCRIPTION IS INCLUDED
IN THE LONGER TERM FOLLOW-UP AS
WELL.
NEUROLOGIC FOLLOW-UP AFTER -- I
WANTED TO TALK BRIEFLY ABOUT
THAT.
THE NATURAL HISTORY OF SICKLE
CELL DISEASE HAS BEEN LOOKED AT
BY DR. KING FROM MY CENTER, AND
IT PREDICTS FOR A PROGRESSIVE
LOSS OF IQ AT ABOUT ONE POINT
PER YEAR.
ATTRIBUTABLE TO DISEASE-RELATED
VASCULOPATHY AND ENSUING THAT
POLG.
PATHOLOGY.
THE NEUROLOGIC OUTCOMES IN
0601 WAS DETERMINED IN 13
PATIENTS TREATED ON THE STUDY.
THE PROTOCOL DIRECTED -- IMAGING
BY MRI IN 11 PATIENTS AND THE
PROTOCOL DIRECTED NEUROCOGNITIVE
FUNCTION INCLUDED THE WECHSLER
PRESCHOOL AND PRIMARY SCALE OF
INTELLIGENCE AND THE WECHSLER
ABBREVIATE PRIMARY SCALE OF
INTELLIGENCE.
THAT WAS IN 13 PATIENTS.
FOR THE NEUROIMAGING STUDY, THE
AGE -- MEDIAN AGE WAS 12.5
YEARS.
SEVEN PATIENTS WERE TRANSPLANTED
AFTER OVERT STROKE AND ONE HAD
ELEVATED TCD VELOCITY.
SIX HAD STABLE MRIs, TWO HAD
MRI LESION RESOLUTION.
TWO OF THE EIGHT PATIENTS ARE
PRES AND THREE PATIENTS HAD NEW
INFARCTS.
TWO HAD STABLE IQs AND ONE HAD
A 10-POINT DROP IN THE IQ.
THE NEUROCOGNITION ASSESSMENT
SHOWED I THINK THE TABLE ON THE
RIGHT SIDE IS EASIER TO FOLLOW.
THIS IS THE MEDIAN FULL SCALE
IQ, THE PERFORMANCE IQ AND THE
VARIABLE IQ.
THE PRE AND POST TRANSPLANT AT
TWO YEARS, THE COMPARISON IS
SHOWN HERE IN NUMBERS.
AND DIDN'T LOOK MUCH DIFFERENT
PRE AND POST TRANSPLANT.
IN THE LONG-TERM FOLLOW-UP, THAT
WAS MORE RECENTLY LOOKED AT, 20
PATIENTS WERE TRACKED VAI A THE
CIBMTR DATA COLLECTION LONG TERM
FORMS.
THE MEDIAN AGE AT TRANSPLANT WAS
13, AND THE MEDIAN AGE AT THE
TIME POINT THAT WE LOOKED AT NOW
WAS AT 21.
AND THE RANGE WAS 11 TO 25 YEARS
AT THE CURRENT TIME.
THEY HAD NO LATE SCD RELATED
EERVETS, NO LATE CNS, CARDIAC,
HEPATIC, PULMONARY OR RENAL
COMPLICATIONS THAT WERE REPORTED
ON THE CIBMTR FORMS, AND IMMUNE
RECONS FUSION AS WAS COLLECTED
ON THE FORMS SEEMED TO HAVE
RECOVERED.
NOW, 86% HAD OVER FIVE YEARS OF
FOLLOW-UP AND THE PERFORMANCE
SCORE IN THOSE PATIENTS IN 13
WAS 92100 AND 70 TO 80 IN SIX OF
THE PATIENTS.
THERE WAS ONE LATE GRAFT
REJECTION, CHANGING THE GRAFT
REJECTION RATE TO 14%.
THERE WERE THREE DEATHS THAT
HAPPENED BEYOND TWO YEARS.
SOME OF THESE WERE REPORTED IN
THE INITIAL PAPER AS WELL.
TWO WERE DUE TO GVHD
COMPLICATIONS AND AGAIN BOTH
PATIENTS WERE OVER 14 YEARS OF
AGE, AND ONE WAS FOLLOWING A
SECOND MYELOABLATIVE TRANSPLANT
AFTER GRAFT REJECTION.
FIVE PATIENTS IMPORTANTLY WERE
LOST TO FOLLOW-UP POST
TRANSPLANT.
FOUR TO SIX YEARS POST
TRANSPLANT, AND I WANT TO
HIGHLIGHT THAT AS A CHALLENGE TO
LONGER-TERM FOLLOW-UP WHICH WE
ARE TRYING TO BE MORE CAREFUL
ABOUT.
SO THE SURVIVAL RATES AT FIVE
YEARS AND EIGHT YEARS ARE SHOWN
HERE.
THE OVERALL SURVIVAL THEN WAS
68% AND THE FIVE-YEAR AND
EIGHT-YEAR EVENT-FREE SURVIVAL
WAS 61 AND 57%.
AND THEN THE EFFECTS THAT WERE
SEEN, GO GONADAL DYSFUNCTION WAS
FOUR, NO PREGNANCIES REPORTED
YET BUT GIVEN THAT THE MEDIAN
AGE IS 21, IT'S HARD TO COMMENT
ON THAT.
AVASCULAR NECROSIS IS BEING
REPORTED IN FOUR PATIENTS,
PANCREATITIS IN TWO, ADRENAL
INSUFFICIENCY IN ONE, AND
DEPRESSION IN 2 PATIENTS.
OUTSIDE OF THE STUDY, LATE
HYPOTHYROIDISM HAS BEEN
DESCRIBED POST ALEMTU SEU. UMAB,
NO MALIGNANT TRANSFORMATION TO
DATE IN PATIENTS WITH MIXED
CHIMERISM OR GRAFT REJECTION.
SO IN SUMMARY, THE TRANSPLANT
CURTAILED SICKLE CELL
MANIFESTATIONS AS WELL AS
NEUROIMAGING AND NEUROCOGNITIVE
FUNCTION STABILIZED LATE
COMPLICATIONS WHEREAS I
DESCRIBED, BUT THE GVHD
PROPHYLAXIS IN THESE PATIENTS
WAS DEFINITELY INADEQUATE,
ESPECIALLY IN THE PATIENTS THAT
WERE TEENAGE AND OLDER.
AND THE PRES RISK WAS HIGH IN
RELATION TO THE GVHD, TAKING IT
DOWN TO THE HYPERTENSION AND
STEROIDS WHICH WERE POORLY
TOLERATED IN THIS POPULATION.
WE HAVE GONE ON TO CHANGE THE
GVHD PROPHYLAXIS THAT'S BEING
USED GIVEN THE NEWER AGENTS THAT
ARE NOW AVAILABLE, AND THESE
PATIENTS FOR UNRELATED AS WELL
AS MISMATCHED UNRELATED DONOR
TRANSPLANTS GET EXTENDED
DURATION ABATACEPT.
THE FIRST PANEL SHOWS OVERALL
DISEASE-FREE SURVIVAL AFTER
ADMINISTRATION OF ABATACEPT IN
14 PATIENTS AND THE SECOND PANEL
SHOWS THE SURVIVAL WITHOUT
ABATACEPT IN A MULTICENTER
FASHION.
28% -- AND CHRONIC GVHD
LOCALIZED OR MILD IS 36%,
MODERATE TO SEVERE CHRONIC GVHD
WAS 14% IN THIS POPULATION.
AND THE PRESS INCIDENCE IS DOWN
TO 7%.
IN THIS EARLY LOOK AT
THESE PATIENTS.
FOLLOW-UP WAS 1.5 YEARS.
THAT'S THE LAST OF MY DATA
SLIDES.
I WANT TO THANK THE CTN AND THE
FUNDING SOURCES THAT SUPPORTED
THIS STUDY.
THEN THE FOLLOW-UP WE WERE ABLE
TO DO AFTER, AS WELL AS ALL THE
PATIENTS AND ALL THE CENTERS
THAT PARTICIPATED, A LOT OF
THANKS DUE TO THEM.
THANK YOU.
[APPLAUSE]
>> THANK YOU, DR. SHENOY.
THERE'S ONE QUESTION IN THE
CHAT.
YOTHANK YOU FOR THE IMPORTANT LE
FOLLOW UP.
WHAT ARE YOUR STEM CELL SOURCES
IN THE CURRENT STUDY?
>> SO WE CURRENTLY USE BONE
MARROW.
THERE IS A STRATUM FOR CORD, BUT
IF IT'S PERIPHERAL BLOOD, WE ARE
DOING CD34 SELECTION WITH A
T-CELL ADD BACK.
WE'RE NOT GIVING THE WHOLE
PERIPHERAL BLOOD STEM CELLS AS
AN INFUSION.
THE MAJORITY OF PATIENTS ARE
BONE MARROW AND THERE ARE FEW
PATIENTS THAT GOT CD34 SELECTED
STEM CELLS.
THE T CELLS THAT WE ADD ARE
1 TIMES 10 TO THE 6TH PER KILO
OF CD3s.
>> THANK YOU, DR. SHENOY.
I THINK WE'LL MOVE ON TO OUR
NEXT SPEAKER.
PRESENTING ON NEUROLOGIC
COMPLICATIONS.
>> TO CONTINUE ON THE THEME OF
THE EFFECT OF TRANSPLANT ON THE
BRAIN, WE'LL NOW HEAR ABOUT
CEREBRAL HEMODYNAMIC CHANGES
AFTER HAPLOIDENTICAL TRANSPLANT
IN ADULTS WITH SICKLE CELL
DISEASE AND TO TALK TO US ABOUT
THAT IS DR. MEGAN AUMANN FROM
THE VANDERBILT UNIVERSITY
MEDICAL CENTER.
>> THANKS FOR THAT INTRODUCTION.
I APPRECIATE THE OPPORTUNITY TO
SPEAK HERE.
AND WE'LL GO AHEAD AND GET
GOING.
WE'RE TALKING ABOUT CEREBRAL
HEMODYNAMIC CHANGES AFTER
HAPLOIDENTICAL HEMATOPOIETIC
STEM CELL TRANSPLANT IN ADULTS.
SO EVERYONE IS FAMILIAR WITH
SICKLE CELL DISEASE, AND THE WAY
IT WORKS, BUT SOME OF THE LESS
COMMONLY FEATURED PROBLEMS FROM
SICKLE CELL DISEASE IS THAT IT
HAS AN ELEVATED TIMELINE RISK
FOR CEREBRAL INFARCTS AND STROKE
AND THIS CAN SIGNIFICANTLY
DECREASE PATIENTS' QUALITY OF
LIFE AND OVERALL ABILITY TO
FUNCTION.
WHAT WE SEE HERE IS A
21-YEAR-OLD AFRICAN AMERICAN
MALE WITH HBSS PHENOTYPE, AND
THE MR IMAGES COLLECTED HERE
SHOW SILENT CEREBRAL INFARCT
PRESENCE.
UNFORTUNATELY, PREVALENCE FOR
THE SILENT CEREBRAL INFARCTS
INCREASES THROUGHOUT THEIR LIFE
WITH NO OBVIOUS CEILING EFFECT
SEEN.
A STUDY THAT WAS SHOWN BY
DR. KASSIM SHOWS AS AGE
INCREASES, THE PREVALENCE FOR
THESE SILENT CEREBRAL INFARCT
ALSO INCREASES SO THAT BY AGE
30, MORE THAN 50% OF PATIENTS
HAVE A DETECTABLE SIGH LEAPT
CEREBRAL INFARCT.
UNFORTUNATELY, THE PRESENCE OF
SILENT CEREBRAL INFARCTS
INCREASES THE RISK FOR NEW OR
PROGRESSIVE INFARCTS, SO
FOLLOWING UP PATIENTS WHO HAVE
SHOWN SILENT CEREBRAL INFARCTS
AT BASELINE WHEN THEY WERE
MEASURED.
AFTER 2 1/2 YEARS, 30% OF THOSE
PATIENTS SHOWED A NEW OR
PROGRESSIVE INFARCTS, AND AT
FOLLOW-UP TIME OF UP TO FOUR
YEARS, 50% OF THESE PATIENTS
SHOWED PROGRESSION OR NEW
INFARCTS.
ONE OF THE THINGS THAT'S
IMPORTANT FOR REGULATING THE
BRAIN IS THAT IT ONLY COMPRISES
2% OF OUR BODY WEIGHT BUT IT
CONSUMES 20% OF THE ENERGY THAT
WE INTAKE THROUGHOUT OUR BODY,
AND IT DOESN'T HAVE A METABOLIC
RESERVE TO DRAW FROM UNLIKE SOME
OTHER AREAS OF OUR BODY.
SO MAINTAINING A CEREBRAL
METABOLIC RATE OF OXYGEN OR
CMRO2 IS REALLY IMPORTANT.
SO IN THE SCHEMATIC THAT I'VE
DISPLAYED HERE, THE CEREBRAL
METABOLIC RATE OF OXYGEN NEEDS
TO BE MAINTAINED AT A CONSTANT
RATE SHOWN IN GREEN, BUT FOR
SICKLE CELL PATIENTS WHO HAVE
INCREASED OXYGEN DELIVERY DUE TO
HEMOLYSIS, THE COMPLEX
MECHANISMS THAT ARE FORMED
INCLUDE -- ONCE THAT'S MAXED
OUT, BOT DE THE BODY CAN ALSO IE
THE OXYGEN EXTRACTION FRACTION
TO MAINTAIN THIS CEREBRAL
METABOLIC RATE OF OXYGEN.
THIS GETS WORSE AND WORSE AS THE
DISEASE BECOMES MORE SEVERE.
THERE'S AN EQUATION THAT YOU CAN
USE TO MEASURE THE CEREBRAL
METABOLIC RATE OF OXYGEN, AND
THAT'S BASICALLY JUST EQUAL TO
THE CEREBRAL BLOOD FLOW TIMES
THE OXYGEN EXTRACTION FRACTION
TIMES THE ARTERIAL OXYGEN
SATURATION MULTIPLIED BY THE
OXYGEN CARRYING CAPACITY OF
HEMOGLOBIN AND THE AMOUNT OF
HEMOGLOBIN A PATIENT HAS IN
THEIR BLOOD.
BUT THOSE TWO FACTORS ARE TWO
THINGS THAT HAVE BEEN IDENTIFIED
AS POSSIBLE BIOMARKERS FOR
TREATMENT SELECTION OR
EVALUATING TREATMENT RESPONSE ON
BRAIN HEALTH IN THESE PATIENTS
THAT ARE AT HIGH RISK FOR STROKE
AND CEREBRAL INFARCTS.
SO THE MOTIVATION BEHIND THIS
STUDY WAS ABOUT PATIENTS WHO
WERE RECEIVING HAPLOIDENTICAL
BONE MARROW TRANSPLANT OR I'M
JUST GOING TO CALL IT
TRANSPLANT, HAS BETTER
AVAILABILITY THAN STANDARD BONE
MARROW TRANSPLANT AND
PRELIMINARY EVIDENCE IN A GROUP
FROM OUR LAB IN FOUR ADULTS
SUGGEST THAT PATIENTS WHO
RECEIVED HAPLOIDENTICAL BONE
MARROW TRANSPLANT SHOWED MARKED
IMPROVEMENTS IN THEIR CEREBRAL
HEMODYNAMICS WHICH WOULD LIKELY
REDUCE THE RISK FOR THEIR --
DEVELOPMENT OR STROKE
OCCURRENCE.
THE THREE MAIN HYPOTHESES HERE
IS THAT CEREBRAL BLOOD FLOW
WOULD REDUCE FOLLOWING
TRANSPLANT THAT WOULD APPROACH
THAT OF HEALTHY CONTROLS.
IMAGING MARKERS FOR CAPILLARY
SHUPTING WHICH IS ANOTHER WAY TO
LOOK AT CEREBRAL BLOOD FLOW
MEASURES WOULD REDUCE FOLLOWING
TRANSPLANT, AND THAT SECOND
FACTOR OXYGEN EXTRACTION
FRACTION WOULD ALSO REDUCE
FOLLOWING TRANSPLANT.
THIS IS REALLY IMPORTANT BECAUSE
UNDERSTANDING HOW THESE CEREBRAL
HEMODYNAMIC CHANGES IMPROVE
FOLLOWING TRANSPLANT CAN AID IN
THE DECISION-MAKING FOR
THERAPEUTIC INTERVENTIONS,
ESPECIALLY BECAUSE THERE'S NO
GOLD STANDARD FOR CURRENTLY
STRATIFYING PATIENTS INTO MORE
ADDRESMOREAGGRESSIVE THERAPIES E
TRANSFUSION OR TRANSPLANT, OR AS
WE'VE ALL SEEN NOW, BRAND NEW
GENE THERAPIES.
SO UNDERSTANDING HOW THESE ARE
CHANGING CAN AID IN
DECISION-MAKING FOR THE KIND OF
THERAPEUTIC INTERVENTIONS WE
WANT TO SEE IN PATIENTS WHO ARE
AT PARTICULARLY HIGH RISK FOR
STROKE.
HERE WE HAVE 39 ADULTS
PARTICIPANT IN TOTAL.
WE HAD 11 SICKLE CELL DISEASE
PATIENTS WHO WERE ALL CANDIDATE
FOR TRANSPLANT AND 28 AGE AND
SEX-MATCHED CONTROLS.
WE GOT SOME BLOOD WORK FROM THEM
THAT LOOKED AT TOTAL HEMOGLOBIN
AND HEMOGLOBIN S FRACTION
MEASURED BY VENIPUNCTURE AND
ARTERIAL OXYGEN SATURATION
MEASURED VIA PULSE OXIMETRY AT
THE SAME TIME THEY RECEIVED
THEIR IMAGING.
ALL OF THE PATIENTS UNDERWENT
MAGNETIC RESONANCE IMAGING.
WE COLLECTED SOME STANDARD
ANATOMICAL IMAGES AND
IMPORTANTLY TO MEASURE CEREBRAL
BLOOD FLOW, WE USED A 2D
CONTINUE ONCE SPATIAL RESOLUTION
TECHNIQUE.
TO LOOK AT OUR FIRST HYPOTHESIS,
WE DO SEE CEREBRAL BLOOD FLOW
SIGNIFICANTLY DECREASES
FOLLOWING TRANSPLANT, AND YOU
CAN SEE THAT QUANTIFIED IN THE
MIDDLE AREA HERE ON THIS VIOLIN
PLOT.
EACH PATIENT IS SHOWN
INDIVIDUALLY WITH A LINE
CONNECTING THEIR PRETRANSPLANT
ON THE LEFT POST TRANSPLANT
CEREBRAL BLOOD FLOW VALUES ON
THE RIGHT.
AND REALLY IMPORTANTLY HERE, WE
SEE THAT THESE DECREASES IN
CEREBRAL BLOOD FLOW DROP TO THAT
OF HEALTHY CONTROLS, SO IN THE
PLOT ON THE FAR RIGHT-HAND SIDE,
HEALTHY CONTROLS ARE SHOWN ON
THE LEFT.
OUR PRETRANSPLANT PATIENTS ARE
SHOWN IN THE MIDDLE AND POST
TRANSPLANT ARE ON THE RIGHT
WHERE YOU CAN SEE FROM PRE TO
POST TRANSPLANT, THOSE VALUES
DROPPED TO THOSE COMPARABLE TO
PATIENTS' CEREBRAL BLOOD FLOW
WHO DON'T HAVE SICKLE CELL
DISEASE.
ANOTHER WAY TO LOOK AT THIS
INFORMATION IS TO USE THESE HEAT
MAPS FOR BLOOD FLOW, SO THESE
ARE ASCENDING AXIAL SLICES OF
THE BRAIN WHERE THE BOTTOM OF
THE BRAIN IS SHOWN IN THE TOP
LEFT AND THE TOP OF THE BRAIN IS
SHOWN ON THE BOTTOM RIGHT.
AND THIS IS AN AVERAGE LOOK AT
CEREBRAL BLOOD FLOW AYOS ALL OFL
OF OUR TRANSPLANT PATIENTS.
ON THE LEFT-HAND SIDE IS
PRETRANSPLANT, ON THE RIGHT-HAND
SIDE IS POST TRANSPLANT.
YOU CAN REALLY JUST APPRECIATE
HERE THAT ELEVATED TRANSPLANT --
OR ELEVATED BLOOD FLOW SHOWN IN
THE HOT COLORS HERE DECREASES
SIGNIFICANTLY FOLLOWING
TRANSPLANT, SO THAT THE AVERAGE
HOVERS MUCH CLOSER TO LIKE 45 OR
50.
50 FOLLOWING TRANSPLANT.
ADDITIONALLY ANOTHER WAY TO LOCK
AT CEREBRAL BLOOD FLOW IS TO
LOOK AT THIS CAPILLARY SHUNTING
EFFECT WHICH IS THE IDEA THAT
HIGH BLOOD FLOW VELOCITIES
RESULT IN RAPID BLOOD CELL
TRANSIT THROUGH CEREBRAL
CAPILLARIES.
THIS REDUCES CAPILLARY -- THAT'S
INDICATIVE WE THINK OF
SUBOPTIMAL DELIVERY WHICH IS
STRESSFUL ON THE TISSUE AND CAN
RESULT IN SOME OF THESE
INFARCTS.
SO WE CAN LOOK AT THIS ON AN
ARTERIAL SPIN LABELING SCAN BY
LOOKING AT THE SUPERIOR SAGITTAL
SINUS.
JUST AS A QUICK REVIEW FOR
ANYBODY WHO DOESN'T LOOK AT THE
BRAIN A LOT, THERE'S A HUGE
DRAINING VEIN YOU CAN SEE THAT'S
RIGHT ALONG THE MIDLINE IN THE
BRAIN.
IF YOU CUT THAT AND LOOK AT THIS
FIGURE ON THE RIGHT-HAND SIDE
HERE, YOU CAN SEE THAT EACH
PATIENT SHOWS A SIGNIFICANT
DECREASE IN THEIR SUPERIOR
SAGITTAL SINUS WILL SIGNAL FOR
SINUS SIGNAL.HIGH BLOOD FLOW VAN
IN THAT RED HOT COLOR AND LOWER
BLOOD FLOW VALUES IN THOSE BLUE
COOL COLORS.
FINALLY, WE'RE INTERESTED IN
THESE OXYGEN EXTRACTION FRACTION
CHANGES THAT WERE RELATED TO
THEIR TRANSPLANT.
WE DON'T SEE SIGNIFICANT CHANGES
FOLLOWING TRANSPLANT, BUT WE DO
SEE THAT PATIENTS WHO HAD
SIGNIFICANTLY ELEVATED OXYGEN
EXTRACTION FRACTION PERCENTAGES
PRETRANSPLANT TEND TO SHOW
IMPROVEMENTS IN OXYGEN
EXTRACTION FRACTION FOLLOWING
TRANSPLANT.
SO IF YOU LOOK AT THE GRAPH, THE
LINEAR REGRESSION GRAPH ON THE
RIGHT HERE AND YOU WERE TO DRAW
A LINE, SO AN AVERAGE HEALTHY
CONSIDERED OXYGEN EXTRACTION
FRACTION IS ABOUT 35%, AND A
STANDARD DEVIATION ABOVE THAT IS
ABOUT 42%.
SO IF YOU LOOK AT EVERYONE ON
THIS GRAPH WHO HAD AN ELEVATED
EXTRACTION FRACTION
PRETRANSPLANT THAT WAS GREATER
THAN 42%, ALMOST ALL OF THOSE
PATIENTS SHOWED DECREASES IN
THEIR OXYGEN EXTRACTION FRACTION
FOLLOWING TRANSPLANT.
PATIENTS WHO WERE ALREADY ON
THAT FAR RIGHT-HAND SHIFT OF
THAT CURVE TO TRY AND MAINTAIN
THEIR CEREBRAL METABOLIC RATE OF
OXYGEN DO SHOW IMPROVEMENTS IN
THEIR OXYGEN EXTRACTION FRACK FN
FOLLOWING TRANSPLANT.
SOME LIMITATIONS FOR THE STUDY
IS THAT IT IS, IN FACT, A SMALL
SAMPLE SIZE.
IT'S 11 PATIENTS.
SO FURTHER RESEARCH IS NEEDED TO
UNDERSTAND HOW BIOMARKERS OF
BRAIN HEALTH CAN REALLY WORK.
AND THAT CLINICAL INDICATIONS
FOR TRANSPLANT WERE VARIED FOR
OUR PATIENT POPULATION.
NOT EVERYONE HAD A NEUROLOGICAL
INDICATION FOR TRANSPLANT.
AND THAT COULD POSSIBLY VARY
EACH PATIENT'S CEREBRAL
COMPENSATION MECHANISMS.
SO LIKE I SHOWED IN THE OXYGEN
EXTRACTION FRACTION GRAPH, NOT
EVERYBODY HAD HIGHLY ELEVATED
OXYGEN FRACTION PERCENTAGES
COMPARED TO WHAT A HEALTHY
CONTROL MIGHT BE WHICH IS AROUND
35%.
AND ALTHOUGH IT IS ONLY 11
PATIENTS, IT IS NOVEL INSIGHTS
INTO WHAT WE WOULD KIND OF
CONSIDERED TO BE A LARGER COHORT
OF ADULT PATIENTS WHO ARE
UNDERGOING THIS HAPLOIDENTICAL
BONE MARROW TRANSPLANT PROTOCOL.
AND HERE WE SEE THAT ELEVATED
CEREBRAL BLOOD FLOW IN OUR
SICKLE CELL PATIENTS DECREASES
FOLLOWING TRANSPLANT BUT DOESN'T
JUST DECREASE, IT DECREASES TO
VALUES SIMILAR TO HEALTHY
ADULTS.
AND WE SEE THAT THIS CAPILLARY
SHUNTING EFFECT IS AMELIORATED
FOLLOWING TRANSPLANT IN A
SUPERIOR SAGITTAL SINUS, SO THAT
IMPROVES SIGNIFICANTLY.
WHICH WE THINK IS GOING TO HELP
WITH THAT OXYGEN OFFLOADING EE
QISH EFFICIENEFFICIENCY AND GETE
OXYGEN TO THE TISSUE.
PATIENTS WHO SHOW SIGNIFICANTLY
ELEVATED OXYGEN EJECTION
FRACTION AT BASELINE AT 42% SHOW
THE STRONGEST IMPROVEMENTS IN
THEIR OXYGEN METABOLISM OVERALL.
WE REALLY THINK THAT CEREBRAL
BLOOD FLOW CAN BE USED AS A
NONINVASIVE IMAGING BIOMARKER
FOR CEREBROVASCULAR HEALTH ON
THE WHOLE.
AND WITH THAT, I'D LIKE TO
ACKNOWLEDGE MY LAB.
NONE OF THIS IS DONE IN
ISOLATION OBVIOUSLY.
IT'S A TEAM EFFORT.
SO THANKS SO MUCH TO MY LAB AND
ALL OF THE WORK THAT EVERYONE
HAS PUT IN.
AND OUR FUNDING SOURCES.
AND SPECIAL ATTENTION TO THE
PATIENTS WHO VOLUNTEER THEIR
TIME AND EFFORT.
THIS IS A HUGE, HUGE TIME
COMMITMENT FOR THEM, AND THIS
WOULD NOT BE POSSIBLE WITHOUT
THEM.
THANK YOU.
[APPLAUSE]
>> THANK YOU, DR. AUMANN.
FOR THE SAKE OF TIME WE NEED TO
MOVE ON BUT THERE'S A COMMENT IN
THE CHAT FOR YOU FROM
DR. WALTERS.
OUR FINAL SPEAKER IS DR. STACI
MARTIN FROM THE NATIONAL CANCER
INSTITUTE CENTER FOR CANCER
RESEARCH HERE AT THE NIH AND SHE
WILL BE PRESENTING ON COGNITIVE
AND EMOTIONAL WELL-BEING IN
INDIVIDUALS WITH SICKLE CELL
DISEASE.
>> SO IN TERMS OF
NEUROPSYCHOLOGICAL FUNCTIONING,
WE KNOW FROM THE LITERATURE THAT
ADULTS WITH SICKLE CELL ANEMIA
SCORE LOWER THAN HEALTHY
INDIVIDUALS IN PARTICULAR AREAS
SUCH AS VISUAL SPATIAL SKILLS,
WORKING MEMORY WHICH IS THE
ABILITY TO HOLD INFORMATION IN
YOUR MIND, AND PRODUCE A
RESPONSE FROM IT, PROCESSING
SPEED, ATTENTION, AND EXECUTIVE
FUNCTIONING, WHICH IS OTHERWISE
KNOWN AS COGNITIVE FLEXIBILITY
OR ABILITY TO SHIFT AND KIND OF
PLAN AND ORGANIZE YOUR THOUGHTS
AND BEHAVIOR.
THERE'S OTHER AREAS WHERE THEY
PERFORM EXRA BLI TO HEALTHY
CONTROLS, SUCH AS VERBAL
COMPREHENSION AND MOTOR SPEED.
THERE ARE HAS BEEN RESEARCH
SHOWING THAT THESE AREAS OF
STRENGTHS AND WEAKNESSES ARE
CONSISTENT WITH IMAGING
ABNORMALITIES ON SCANS.
PARTICULARLY IN AREAS SUCH AS
THE BASAL GANGLIA AND THE
FRONTAL LOBE, AND THAT'S WHERE
YOU'RE GOING TO FIND DEFICITS IN
THE PROCESSING SPEED, ATTENTION,
EXECUTIVE SKILLS AND SO ON.
SO AMONG CHILDREN AND
ADOLESCENTS WITH SICKLE CELL
DISEASE WHO UNDERGO A
HAPLOIDENTICAL BONE MARROW
TRANSPLANT, RESEARCH HAS SHOWN
IMPROVEMENTS IN PROCESSING
SPEED, SO HOW QUICKLY YOU
PROCESS INFORMATION, BUT THEY
HAVEN'T SHOWN ANY SIGNIFICANT
IMPROVEMENTS IN OTHER COGNITIVE
DOMAINS.
BUT WE DON'T KNOW AS MUCH YET
ABOUT COGNITIVE FUNCTIONING PRE
TO POST TRANSPLANT AMONG ADULTS
WITH SICKLE CELL.
SO OUR GROUP, THE HEALTH
PSYCHOLOGY AND NEUROBEHAVIORAL
RESEARCH GROUP AT THE NIH, WORKS
WITH THE NHLBI HERE ON A VARIETY
OF THEIR TRANSPLANT PROTOCOLS,
AND ON THESE TRANSPLANT
PROTOCOLS, WE HAVE EXAMINED
COGNITIVE AND EMOTIONAL
WELL-BEING AMONG INDIVIDUALS
WITH SICKLE CELL DISEASE, PRIME
LEA ADULTS, SOME CHILDREN.
AND OUR PRIMARY -- ANOTHER
PRIMARY AIM WAS TO DETERMINE HOW
FUNCTIONING CHANGES FROM PRE TO
POST TRANSPLANT.
SO WE COMPLETED PREHEN SIEVE
NEUROBEHAVIORAL ASSESSMENTS WITH
PATIENTS BEFORE TRANSPLANT AND
THEN 12 MONTHS AFTER TRANSPLANT
ON THESE SEVERAL PROTOCOLS.
SO WHAT DO WE ASSESS IN A
NEUROBEHAVIORAL ASSESSMENT?
WE LOOK FIRST AT VERBAL SKILLS,
SO YOUR ABILITY TO REASON USING
WORDS AND UNDERSTAND WHAT OTHER
PEOPLE SAY TO YOU.
AND THEN NON-VERBAL SKILLS, SO
VISUAL SPATIAL SKILLS, SOLVING
PROBLEMS BASED ON VISUAL
REASONING.
ATTENTION.
AND YOU CAN GO AHEAD AND GO --
THERE YOU GO.
ATTENTION -- THANK YOU.
MEMORY, AND DIFFERENT KINDS OF
MEMORY, SHORT TERM MEMORY, LONG
TERM MEMORY, WORKING MEMORY.
PROCESSING SPEED AND THEN THAT
EXECUTIVE FUNCTIONING AREA THAT
I MENTIONED PREVIOUSLY.
THEN OTHER DOMAINS THAT WE LOOK
AT AS WELL IN THESE ASSESSMENTS
ARE THINGS LIKE A SOCIAL
EMOTIONAL WELL-BEING, SO WE GIVE
THE PROMIS, SUBSCALES FROM THE
PROMIS AND THE BRIEF SYMPTOM
INVENTORY, LOOKING AT THINGS
LIKE ANXIETY, DEPRESSION,
SOMATIZATION OR COMPLAINTS ABOUT
PHYSICAL SYMPTOMS AND SLEEP.
NOT ONLY DO WE GIVE EXECUTIVE
FUNCTIONING TESTS TO THE
PATIENTS, BUT WE ALSO GIVE THEM
A QUESTIONNAIRE, A
PATIENT-REPORTED OUTCOME MEASURE
WHERE THEY REPORT ON THEIR OWN
PERCEPTIONS OF THEIR DAY TO DAY
EXECUTIVE SKILLS.
THEN WE LOOK AT PAIN IN THE PAST
WEEK AND DURING THE TEST SESSION
AS WELL AS THE EXTENT TO WHICH
PAIN INTERFERES WITH DAILY
FUNCTIONING.
SO FOR THE FIRST STUDY THAT I'M
GOING TO BE TALKING ABOUT, WE
LOOKED AT 47 PATIENTS, AND THEN
22 OF THOSE PATIENTS HAD A
SIBLING DONOR, A MATCHED SIBLING
DONOR THAT ALSO PROVIDED DATA AT
BASE LIKE AND 12 MONTHS POST
TRANSPLANT.
AND WHAT WE'VE FOUND WAS THAT
AMONG THESE PATIENTS AND
SIBLINGS, ALL OF THE SCORES WERE
WITHIN NORMAL LIMITS.
SO FOR EXAMPLE, WHAT YOU SEE
THERE IN PERFORMANCE IQ, THE
MEASURE OF VISUAL SPATIAL
SKILLS, THE MEAN IS 100, SO
ANYTHING IN THE AVERAGE RANGE IS
90 TO 109, SO THEY'RE SOLIDLY IN
THE AVERAGE RANGE THERE.
BUT WE SEE -- AND IF YOU COULD
ADVANCE ONE MORE SLIDE -- ON THE
PROCESSING SPEED INDEX, THE
PATIENTS ARE AT 91, AND THAT'S
RIGHT AT THE LOWER END OF THE
AVERAGE RANGE, WHEREAS THE
SIBLINGS ARE SOLIDLY RIGHT
THERE, RIGHT AROUND 100.
AND SO THAT WAS A SIGNIFICANT
DIFFERENCE.
SO AGAIN, THEY'RE BOTH IN THE
AVERAGE RANGE, BUT WE DO SEE
THAT PATIENTS ARE SCORING
SIGNIFICANTLY LOWER THAN
SIBLINGS IN PROCESSING SPEED.
AND THEN THE QUESTIONNAIRE THAT
I MENTIONED BEFORE WHERE
PATIENTS PROVIDE THEIR OWN
PERCEPTIONS OF THEIR DAY TO DAY
EXECUTIVE SKILLS CALLED THE
BRIEF, ALL OF THE SCORES WERE IN
THE AVERAGE RANGE FOR BOTH
PATIENTS AND SIBLINGS BUT ALL OF
THOSE AREAS IN RED ARE WHERE THE
PATIENT SCORED SIGNIFICANTLY
HIGHER WHICH IN THIS CASE
INDICATES MORE SYMPTOMS THAN
THEIR SIBLING DONORS.
WE ALSO LOOKED AT THE
RELATIONSHIP BETWEEN OBJECTIVE
TEST SCORES AND PAIN, AND WE DID
NOT SEE ANY RELATIONSHIPS THERE,
WHICH WAS INTERESTING.
THAT WAS PAIN IN THE PAST WEEK.
BUT WE DID SEE THAT HIGHER PAIN
INTENSITY IN THE PAST WEEK WAS
RELATED TO MORE PROBLEMS IN
SEVERAL OF THE SELF-REPORT
EXECUTIVE FUNCTIONING SUBSCALES
ON THE BRIEF THAT I JUST SHOWED
YOU.
SO NOW LONGITUDALLY IN OUR
FOLLOW-UP STUDY, WE LOOKED PRE
AND POST TRANSPLANT, AS I
MENTIONED, AND WE FOUND THAT
JUST AMONG THE PATIENTS, THERE
WAS SIGNIFICANT IMPROVEMENT IN
PROCESSING SPEED WHERE THEY WENT
FROM 92 TO 97, SO THEY'RE
GETTING CLOSER TO THAT MEDIAN OF
100, MEAN OF 100.
THAT WAS A SIGNIFICANT
IMPROVEMENT.
AND THERE WERE NOT ANY
IMPROVEMENTS IN THINGS LIKE
ATTENTION AND MEMORY OR VERBAL
OR PERFORMANCE IQ.
WE ALSO LOOKED AT DEPRESSION AND
ANXIETY.
THOSE REMAINED STABLE FROM PRE
TO POST TRANSPLANT, AND THOSE
WERE ALL WITHIN NORMAL LIMITS.
THEN THE ONLY AREA IN TERMS OF
PATIENT-REPORTED OUTCOMES WHERE
THERE WAS IMPROVEMENT WAS IN THE
BRIEF SYMPTOM INVENTORY
SOMATIZATION SUBSCALE, THEY'RE
NOT REPORTING AS MANY CONCERNS
WITH PHYSICAL SYMPTOMS.
BUT WE ALSO FOUND THAT THE
SIBLINGS IMPROVED IN THEIR
PROCESSING SPEED FROM BASELINE
TO 12 MONTHS POST TRANSPLANT, SO
THERE WAS NOT A SIGNIFICANT
DIFFERENCE IN THE SLOPES HERE.
BOTH PATIENTS AND SIBLINGS
IMPROVED IN PROCESSING SPEED.
SO WHY DID THAT HAPPEN?
WE'RE NOT REALLY SURE.
ONE HYPOTHESIS IS THAT THERE
WERE PRACTICE EFFECTS.
SO THE SIBLINGS IMPROVED JUST
BECAUSE THEY HAD TAKEN THE TEST
BEFORE.
WE DON'T USUALLY SEE THAT
SIGNIFICANT IMPROVEMENT IN
PROCESSING SPEED IF THEY'VE ONLY
HAD THE TEST ONCE FROM OVER A
YEAR APART.
BUT WE CAN'T RULE THAT OUT AS A
POSSIBILITY.
ALSO WHEN THE SIBLINGS CAME IN
TO DONATE THEIR CELLS, MANY OF
THEM HAD SOME ANXIETY, NOT
CLINICALLY SIGNIFICANT BUT MAYBE
THEY WERE ANXIOUS DURING THE
TEST SESSION BECAUSE THEY WERE
CONCERNED ABOUT HOW THE CELL
DONATION PROCESS WOULD GO, AND
ALSO WHETHER THEIR SIBLING
WOULD -- OR THE PATIENT WOULD
ACTUALLY BE SUCCESSFULLY
TRANSPLANTED.
AND IN TERMS OF SOCIAL EMOTIONAL
FUNCTIONING, ANXIETY AND
DEPRESSION SCORES WERE WITHIN
NORMAL LIMITS AND THEY REMAINED
STABLE PRE TO POST TRANSPLANT.
WHILE THE SO SE SOMATIZATION SC-
SO WHAT WE CONCLUDE FROM THAT IS
THAT PEOPLE WITH SICKLE CELL
CONSISTENT WITH THE LITERATURE
DO HAVE A WEAKNESS IN PROCESSING
SPEED RELATIVE TO OTHER AREAS OF
FUNCTIONING AND COMPARED TO
SIBLINGS.
THE REASONS FOR THAT ARE
PROBABLY WELL LAID OUT IN THE
PRIOR TALK JUST BEFORE MINE.
IMPORTANTLY THERE DON'T SEEM TO
BE ANY DETRIMENTAL EFFECTS OF
TRANSPLANT ON COGNITIVE OR
EMOTIONAL WELL-BEING.
WE THINK THAT TRANSPLANT MAY
IMPROVE PROCESSING SPEED, BUT
FURTHER CONFIRMATION IS NEEDED,
PARTICULARLY WITH LARGER
SAMPLES.
WE HAD A SMALL SAMPLE OF MATCHED
PATIENTS AND SIBLINGS.
SO POTENTIALLY WITH LARGER
SAMPLES WE COULD LEARN MORE
ABOUT THAT RELATIONSHIP.
I JUST THANK MY KEY CONTRIBUTORS
AND THANK YOU FOR YOUR
ATTENTION.
[APPLAUSE]
>> THANK YOU, DR. MARTIN.
I KNOW WE'RE GETTING READY TO
END THE SESSION.
THERE'S SOME QUESTIONS IN THE
CHAT FOR YOU.
THANK YOU VERY MUCH.
MUCH APPRECIATED.
THANK YOU ALL, THANK YOU ALL FOR
ATTENDING THIS SYMPOSIUM.
WE'RE SWITCHING GEARS A LITTLE
BIT FROM TRANSPLANT TO CURATIVE
THERAPIES FOR SICKLE CELL, AND
THIS IS GOING TO REALLY COVER
THE STATE OF THE ART, WHAT'S
GOING ON IN THE FIELD OF GENE
THERAPY AND GENE EDITING, AND SO
WE WILL HAVE FOUR SEPARATE TALKS
ON CLONAL HEMATOPOIETIC,
PRECISION GENE EDITING AND
PROGRESS AND UPDATES AND ALSO AN
OVERALL VIEW FROM FYODOR.
SO LET GET STARTED.
SO WE WILL HAVE THE FIRST
SPEAKER, OUR OWN COURTNEY FIT
THACOURTNEYFITZHUGH FROM NHLBI,G
ABOUT CLONAL HEMATOPOIESIS
FOLLOWING CURATIVE THERAPIES FOR
SICKLE CELL.
COURTNEY?
>> GOOD MORNING.
I'D LIKE TO THANK THE ORGANIZERS
FOR INVITING ME TO GIVE THIS
PRESENTATION.
SO AS YOU ALL KNOW, SICKLE CELL
DISEASE IS ASSOCIATED WITH
DAMAGE TO THE BONE MARROW
MICROENVIRONMENT, HYPOXIA,
SHORTENED RED CELL SURVIVAL
WHICH LEADS TO INCREASED
ERYTHROPOETIC STRESS,
INFLAMMATION AND OXIDATIVE
STRESS.
THERE HAVE BEEN TWO LARGE
POPULATION STUDIES WHICH HAVE
SHOWN INCREASED RISK FOR
AGGRESSIVE MYELOID MALIGNANCIES
IN PATIENTS WITH SICKLE CELL
DISEASE.
THIS STUDY WAS REPORTED BY
INVESTIGATORS AT U.C. DAVIS,
WHERE THEY IDENTIFIED OVER 6400
PATIENTS WITH SICKLE CELL
DISEASE BETWEEN 1991 AND 2014.
AND THEY WERE FOLLOWED FOR OVER
140,000 PERSON-YEARS AND
COMPARED TO THE GENERAL
POPULATION.
THEY DID NOT FIND AN INCREASED
PREVALENCE OF SOLID TEU NORS,
TUMORS BUTTHEY DID FIND A 2.3 FD
INCREASED RISK FOR LEUKEMIA AND
3.6 FOLD INCREASED RISK FOR
ACUTE MYELOID LEUKEMIA OR AML.
THERE ARE MULTIPLE POSSIBLE RISK
FACTORS FOR MYELOID MALIGNANCY
DEVELOPMENT IN PATIENTS WITH
SICKLE CELL DISEASE INCLUDING
ERYTHROPOETIC STRESS,
INFLAMMATION, HI HYPOXIA AND
ACIDOSIS, TRANSFUSION-RELATED
IMMUNOMODULATION, COMPROMISED
APOPTOSIS, ENDOTHELIAL DAMAGE,
INCREASED AGE, AND CLONAL
HEMATOPOEISIS.
NON-MYELOABLATIVE HLA MATCHED
SIBLING TRANSPLANT -- THE
ORIGINAL PROTOCOL WHERE PATIENTS
RECEIVE AL EMTEUZ MAN --
ORIGINAL GOAL WOS A MIXTURE OF
DONOR RECIPIENT CELLS BECAUSE WE
WERE MOST CONCERNED AT THE TIME
FOR GRAFT-VERSUS-HOST DISEASE.
INVESTIGATORS AT THE NIH
UNIVERSITY OF ILLINOIS CHICAGO
AND RIYADH, SAUDI ARABIA
RECENTLY REPORTED 122 PATIENTS
WHO UNDERWENT THIS TRANSPLANT
WITH THIS REGIMEN.
THE MEDIAN FOLLOW-UP WAS FOUR
YEARS AND AT FIVE YEARS POST
TRANSPLANT, THE OVERALL SURVIVAL
IS 93%, THE EVENT-FREE SURVIVAL
WAS 85%.
NONE OF THE PATIENTS DEVELOPED
GRADE 3 TO 4 ACUTE GVHD, AND NO
ONE DEVELOPED CHRONIC GVHD.
UNFORTUNATELY, LESS THAN 15% OF
PATIENTS WITH SICKLE CELL
DISEASE HAVE HLA MATCHED SIBLING
DONORS.
SO THIS IS OUR ORIGINAL
HAPLOIDENTICAL TRANSPLANT STUDY
WHICH WAS WRITTEN AS A DOSE
ESCALATION OF POST TRANSPLANT
CYCCYCLO -- ALL THE PATIENTS
RECEIVED SIROLIMUS.
THE FIRST COHORT DID NOT RECEIVE
ANY CYCLOPHOSPHAMIDE.
THE SECOND COHOARD RECEIVED ONE
DOSE AND THE THIRD COHORT
RECEIVED 100MGS PER KG IN
DIVIDED DOSES.
IF TOO MANY PATIENTS DEVELOPED
GRAFT REJECTION OR MODERATE TO
SE VESEVERE GVHD, WE WOULD MOVEO
THE NEXT COHORT.
THESE ARE THE RESULTS OF THE
STUDY.
22 PATIENTS WERE TRANSPLANTED.
YOU CAN SEE IN THE LAST TWO
COLUMBUS THAT THE SICKLE CELL
DISEASE-FREE SURVIVAL IMPROVED
WITH THE ADDITION OF POST
TRANSPLANT CYCLOPHOSPHAMIDE FROM
0% IN THE FIRST COHORT TO 50% IN
THE THIRD COHORT.
SO WHILE THERE WAS AN
IMPROVEMENT IN THE GRAFT
REJECTION RATE, THE GRAFT
REJECTION RATE WAS UNACCEPTABLY
HIGH AND THE STUDY CLOSED TO
ACCRUAL.
BECAUSE OF THE HIGHER RATES OF
GRAFT-VERSUS-HOST DISEASE,
ESPECIALLY IN THE HAPLOIDENTICAL
SET, WE HAVE TWO NEWER PROTOCOLS
BOTH WHICH INCLUDE INTRAVENOUS
PENTOSTATIN AND DAILY ORAL
CYCLOPHOSPHAMIDE AND TO DATE,
BOTH STUDIES ARE ASSOCIATED WITH
DECREASED INCIDENCE OF GRAFT
REJECTION.
NEXT I WANT TO INTRODUCE A
LITTLE ABO ABOUT THE BLUEBIRD B.
THE PATIENTS WERE DIVIDED INTO
THREE DIFFERENT COHORTS.
PRECOLLECTION RED CELL
TRANSFUSION REGIMEN WAS OPTIONAL
IN GROUP A PATIENTS BUT IS
REQUIRED IN GROUPS B AND C
PATIENTS.
THE HEMATOPOIETIC STEM CELL
SOURCE WAS BONE MAR BONE MAYOR N
A AND B PATIENTS AND
PERIPHERALLIZED BLOOD IN GROUP C
PATIENTS.
THE ORIGINAL DRUG PRODUCT
MANUFACTURING PROCESS WAS USED
IN GROUP A AND SOME GROUP B
PATIENTS AND A MORE REFINED
PROCESS FOR THE REST OF GROUP B
AND ALL OF GROUP C PATIENTS.
AND WITH THESE CHANGES, THERE
WAS A HIGHER VECTOR COPY NUMBER,
A HIGHER CELL DOSE, AND SIGHER
EFFICACY IN GROUP C COMPARED TO
GROUP A PATIENTS.
AND IMPORTANTLY ALL OF THE
PATIENTS RECEIVED MYELOABLATIVE
CONDITIONING WITH BUSULFAN.
UNFORTUNATELY, WE RECENTLY
REPORTED THAT FIVE OF 120
PATIENTS WE TRANSPLANTED
DEVELOPED EITHER MYELODYSPLASTIC
SYNDROME OR MDN, ALL HAD
HOMOZYGOUS SICKLE CELL DISEASE
WITH AGES RANGING FROM 20 TO 44
YEARS.
TWO OF THE PATIENTS -- SIBLING
TRANSPLANT.
THE REMAINED DER HAPLOIDENTICAL
TRANSPLANT.
1
TWO OF THE PATIENTS HAD MDS, THE
REMAINING THREE AML THAT WAS
DIAGNOSED BETWEEN FOUR MONTHS
AND 5 1/2 YEARS POST TRANSPLANT.
FOUR OF THE PATIENTS COMPLETELY
REJECTED THEIR GRAFTS.
ONE OF THEM HAD IMPENDING GRAFT
FAILURE WITH THE DONOR MYELOID
CHIMERISM OF 16% AND A DONOR --
18% AT DIAGNOSIS.
AND ALL FIVE PATIENTS ARE
DECEASED.
THIS TABLE SHOWS THE INCIDENCE
RATE OF AGGRESSIVE MYELOID
MALIGNANCIES ACROSS STUDIES.
THE FIRST THREE COLUMBUS INCLUDE
PATIENTS WHO UNDERWENT HLA
MATCHED SIBLING TRANSPLANT.
THE FIRST TWO COLUMBUS THE
PATIENTS ONLY RECEIVED
ALEMTUZUMAB.
FROM 87-POINT A TO 518 PERSON
YEARS IN THE INCIDENCE OF MDS OR
AML RANGED FROM ZERO TO 0.8 PER
100 PERSON YEARS.
WHEN THE PRECONDITIONING WAS
ADDED, AT RISK TIME IS 96 PERSON
YEARS AND THE INCIDENCE OF MDS
OR AML IS 1.04.
THESE NEXT TWO COLUMBUS SHOW
PATIENTS WHO UNDERWENT
HAPLOIDENTICAL TRANSPLANT.
THIS COLUMN SHOWS THE PATIENTS
WHO WERE ENROLLED I IN A STUDY -
WITH AT RISK TIME OF 176 PERSON
YEARS, THE INCIDENCE OF MDS OR
AML IS 1.7 PER 100 PERSON YEARS.
AND WITH AT RISK TIME OF JUST
UNDER 50 PERSON YEARS, WE DID
NOT HAVE ANYBODY DEVELOP MDS OR
AML.
THE THERAPEUTIC GOAL FOR THESE
STUDIES AS I MENTIONED EARLIER
IS MIXED CHIMERISM.
I'D LIKE TO THANK BLUEBIRD BIO
FOR PROVIDING DATA ON THE NUMBER
OF PATIENTS IN PERSON YEARS, AND
YOU CAN SEE WITH AT RISK TIME OF
112 PERSON YEARS, THE INCIDENCE
OF MDS OR AML WAS SIMILAR TO
WHAT WE SAW ON TWO OF OUR
STUDIES.
IMPORTANTLY, MOST OF THESE
PATIENTS WERE ENROLLED IN GROUP
A.
THIS COMPARES TO TWO LARGER
STUDIES THAT INCLUDED MOSTLY
PEDIATRIC PATIENTS AND WHERE
MOST OF THEM UNDERWENT
MYELOABLATIVE HLA MATCHED
SIBLING TRANSPLANT.
YOU CAN SEE WITH AT RISK TIME
RANGING FROM 1600 TO 1800 PERSON
YEARS, NO ONE DEVELOPED MDS OR
AML, AND WITH BOTH STUDIES, THE
GOAL WAS FULL DONOR CHIMERISM.
AND I JUST -- SINCE THAT STUDY
WAS REPORTED TWO YEARS AGO, I'M
SHOWING HERE THE UPDATED
INCIDENCE RATE OF MDS OR AML AND
I'M THANKFUL TO REPORT WE HAVE
NOT HAD ANYONE DEVELOP MDS OR
AML IN THE LAST TWO YEARS.
SO I MENTIONED EARLIER THE STUDY
FROM U.C. DAVIS AND THAT OVER
6400 PATIENTS WITH SICKLE CELL
DISEASE WERE FOLLOWED FOR OVER
27 YEARS.
DURING THAT TIME, ONLY SIX
PATIENTS DEVELOPED AML, OVER
140,000 PERSON YEARS, OR 0.004
PER 100 PERSON YEARS.
DURING THAT SAME TIME, 1.67
INDIVIDUALS WITHOUT SICKLE CELL
DISEASE WERE EXPECTED TO DEVELOP
AML WHEN CONTROLLED FOR AGE,
SEX, RACE, AND ETHNICITY, OR
0.001 PER 100 PERSON YEARS.
SO WHILE THERE'S AN INCREASE
RELATIVE RISK OF LEUKEMIA
DEVELOPMENT IN PATIENTS WITH
SICKLE CELL DISEASE, THE
ABSOLUTE RISK IS LOW.
THIS COMPARES TO THREE OF OUR
PATIENTS DEVELOPING AML OVER 844
PERSON YEARS, OR 0.36 PER 100
PERSON YEARS.
SO THE RATE OF AML IS
APPROXIMATELY 89 TIMES HIGHER IN
ADULTS FOLLOWING TRANSPLANT FOR
SICKLE CELL DISEASE RESULTING IN
GRAFT FAILURE COMPARED TO THOSE
WITH SICKLE CELL DISEASE WHO DO
NOT RECEIVE CURATIVE THERAPY.
WHY IS THE IP INCIDENCE OF
AGGRESSIVE MYELOID MALIGNANCIES
HIGHER IN ADULTS AFTER GRAFT
FAILURE AND GENE THERAPY FOR
SICKLE CELL DISEASE?
THERE ARE MULTIPLE POSSIBLE
REASONS THAT NEED FURTHER
EXPLORATION.
THIS STUDY FROM U.S. DAVIS
INVESTIGATORS SHOW PATIENTS WHO
ARE OLDER AND THOSE WITH MORE
SEVERE DISEASE HAD HIGHER RISK
OF LEUKEMIA.
WE TRANSPLANT PATIENTS THAT ARE
OLDER THAN TYPICAL AND WITH MORE
SEVERE DISEASE THAN TYPICAL.
WE ALSO HAVE A LONGER DURATION
OF FOLLOW-UP AND A HIGHER
PROPORTION OF OUR PATIENTS ARE
FOLLOWED LONG TERM.
COMPARED TO THE PEDIATRIC
SETTING, WE ALSO USE TBI BASED
CONDITIONING VERSUS CHEMOTHERAPY
BASED CONDITIONING, AND BOTH
WITH OUR APPROACH AT THE NIH AND
WITH GENE THERAPY, THERE'S A
REQUIREMENT OF REGENERATIVE
HEMATOPOEISIS.
SO WE'VE HAD OF FIVE PATIENTS I
TOLD YOU DEVELOPED MDS OR AML,
FOUR OF THEM HAD NEXT GENERATION
SEQUENCING DONE AT THE TIME OF
AML OR MDS DIAGNOSIS, AND ALL
FOUR HAD DIFFERENT PATHOGENIC
TP53 MUTATIONS.
SO IN THIS FIRST PATIENT, YOU
CAN SEE AT THE TIME OF
DIAGNOSIS, HE HAD A TP53
MUTATION PRESENT WITH FREQUENCY
OF 24%.
WHEN WE WENT BACK TO THE SAMPLE
THAT WE HAD COLLECTED BEFORE
TRANSPLANT OR EVEN BEFORE
CONDITIONING, THE SAME MUTATION
WAS PRESENT AT A VERY LOW
FREQUENCY.
SIMILARLY IN THE NEXT TWO
PATIENTS WHO HAD EITHER MDS OR
AML, THE TP53 MUTATION AT THE
TIME OF DIAGNOSIS RANGED FROM
2.9% TO 508%, AND THESE SAME
MUTATIONS WERE ALSO FOUND AT
BASELINE RANGING FROM 0.06 TO
0.36%.
THIS FOURTH PATIENT DEVELOPED
AML AT 5 1/2 YEARS POST
TRANSPLANT, AND SHE WAS FOUND TO
HAVE A TP53 MUTATION WITH
FREQUENCY OF 78.8%.
WE DID NOT DETECT MUTATION AT
BASELINE OR EVEN AT 1 1/2 YEARS
POST TRANSPLANT.
WE FIRST DETECTED IT AT FOUR
YEARS POST TRANSPLANT AT 0.06%.
ONE YEAR LATER IT INCREASED TO
0.34% AND NEXT YEAR IT REELIN
CREASED TO 79%.
SO IT WAS NOT PRESENT AT
BASELINE OR WE JUST WEREN'T ABLE
TO DETECT IT.
SO WE WANTED TO KNOW IN OUR
PATIENTS WHO HAVE NOT DEVELOPED
MDS OR AML WHETHER THEY HAD TP53
MUTATIONS PRESENT AT BASELINE.
SO YOU CAN SEE HERE IN SEVEN
PATIENTS WHO DEVELOPED GRAFT
FAILURE BUT WITHOUT LEUKEMIA,
NONE OF THEM HAD TP53 MUTATIONS
AT BASELINE WITH FOLLOW-UP
RANGING FROM 4 1/2 TO 12 YEARS
POST TRANSPLANT.
AND THESE ARE EIGHT ENGRAFTED
PATIENTS WHO ALSO DID NOT
DEVELOP MDS OR AML, AND AGAIN,
NONE OF THEM WERE FOUND TO HAVE
TP53 MUTATIONS AT BASELINE WITH
FOLLOW-UP RANGING FROM FOUR TO
EIGHT YEARS.
SO I'M WORKING WITH
COLLABORATORS AT MULTIPLE
INSTITUTIONS INCLUDING HOCH KINS
AND VANDERBILT, IT'S CALLED
COALESCE.
IN OUR HYPOTHESIS, AFTER GRAFT
FAILURE OR GENE THERAPY, THE
STRESS IS SWITCHING BY
AUTOLOGOUS CELLS, DRIVES CLONAL
EXPANSION AND -- PRE-EXISTING
PREMALIGNANT CLONES EVENTUALLY
RESULTING IN AML OR MDS.
SO THIS SHOWS A THEORETICAL
MODEL FOR MYELOID MALIGNANCY
DEVELOPMENT AFTER CURATIVE
THERAPIES FOR SICKLE CELL
DISEASE AND HOW TO MITIGATE THE
RISK.
SO THIS RED CELL REPRESENTS A
STEM CELL OF A PATIENT WITH
SICKLE CELL DISEASE, AND DUE TO
AGING AND COMORBIDITIES, THE
PATIENTS MAY DEVELOP LOW LEVEL
SOMATIC MUTATIONS THAT, OVER
TIME, DO NOT EXPAND IN THE
ABSENCE OF CURATIVE THERAPY SO
THAT MOST PATIENTS WITH SICKLE
CELL DISEASE DO NOT DEVELOP
MYELOID MALIGNANCIES.
IF THE PATIENT HAS A SOMATIC
MUTATION AND THEN UNDERGOES
GRAFT REJECTION OR GENE THERAPY,
BOTH REQUIRING AUTOLOGOUS
RECONSTITUTION, THE CLONE CAN
EXPAND AND THE PATIENT CAN
DEVELOP A MYELOID MALIGNANCY,
AND IT'S POSSIBLE THE REASON WE
SAW THIS IN GROUP A PATIENTS IS
THAT THERE WAS A LOWER CELL DOSE
AND THERE MIGHT BE EVEN MORE
ERYTHROPOETIC PROLIFERATION
THAT'S NEEDED.
>> SPEAKER, 2 MINUTES LEFT.
>> OKAY.
IF THE PATIENT WAS FOUND TO HAVE
A GENETIC RISK FACTOR, WE WOULD
RECOMMEND AL JE NATION
TRANSPLANTATION WITH FULL DONOR
KIESM RISM, DONOR DERIVED
LEUKEMIA IS EXCEEDINGLY RARE IN
SICKLE CELL DISEASE WHEN DONORS
ARE YOUNGER AND NOT EXPECTED TO
HAVE CLONAL HEMATOPOEISIS.
UNFORTUNATELY -- THIS IS AN
ACTIVE AREA OF RESEARCH IN MY
LAB AND OUTSIDE.
SO IN CONCLUSION, HLA MATCHED
SIBLING AND HAPLOIDENTICAL
TRANSPLANT OFFER CURATIVE
OPTIONS FOR CHILDREN AND ADULTS
WITH SICKLE CELL.
WHILE PATIENTS WITH SICKLE CELL
HAVE A HIGHER RIX OF MYELOID
MALIGNANCIES THAN THE GENERAL
POPULATION, THE ABSOLUTE RISK IS
LOW.
THE THE INCIDENCE OF MYELOID
MALIGNANCIES IS HIGHER THAN
EXPECTED AFTER GRAFT FAILURE AND
GENE THERAPY FOR SICKLE CELL
DISEASE, AND THEREFORE THE GOAL
OF OUR FUEL TOUR PROTOCOLS HAS
SHIFTED FROM MIXED CHIMERISM TO
FULL DONOR CHIMERISM.
THERE'S NO RELIABLE BASELINE
SCREENING STUDIES CURRENTLY TO
ASSESS THE RISK OF LEUKEMIA
DEVELOPMENT.
I THINK I CAN JUST END THERE.
SO THANK YOU FOR YOUR ATTENTION.
[APPLAUSE]
>> THERE'S ONE QUESTION IN THE
CHAT.
THEY WANTED TO CLARIFY IF THESE
ARE IN THE NIH TRANSPLANT STUDY
AND NOT THE BBB STUDY.
>> SO TWO OF THE PATIENTS
DEVELOPED AML WHO WERE
TRANSPLANTED ON THE BLUEBIRD BIO
STUDY GROUP A AND THE REMAINING
WERE EITHER TRANSPLANTED HERE.
ONE WAS AT UNIVERSITY OF
ILLINOIS CHICAGO.
YES.
>> SO MANY YEARS AGO, WE
PUBLISHED THAT -- CELLS ARE
HIGHLY ACTIVATED IN SICKLE
CONDITION AND AT LEAST THREE
STUDIES FROM THREE DIFFERENT
COUNTRIES, VERY SMALL NUMBER OF
PATIENTS HAVE SHOWN THAT THEY
WERE TREATED WITH GLIVAC, WHICH
CAN INHIBIT THE -- AND THAT
RESOLVED THE SICKLE CELL CRISIS.
AND I'M JUST WONDERING IF THERE
IS MORE MYELOID DIFFERENTIATION
IN THESE PATIENTS.
LAST WEEK A VERY NICE PAPER IN
CELL WHICH PUBLISHED THAT A
HIGHER NEUTROPHIL ACTIVATION
ACTUALLY CAN BE SWALLOWED UP BY
THE MAST CELLS AND THERE IS THE
MUCH, MUCH HIGHER ACTIVATION.
AND I'M WONDERING IF MAST CELL
STABILIZERS CAN BE USED
ACCOMPANYING THE TRANSPLANT AND
OTHER THINGS AND THAT MIGHT HAVE
AN INHIBITORY EFFECT OR AT LEAST
BE CONSIDERED.
>> THAT'S SOMETHING THAT WE'LL
HAVE TO LOOK INTO MORE.
THANK YOU FOR THAT.
>> ALEXIS THOMPSON, CHILDREN'S
HOSPITAL OF PHILADELPHIA.
GREAT TALK, COURTNEY.
QUICK QUESTION FOR YOU, THOUGH.
IN YOUR CONCLUSION, YOU
MENTIONED THAT THERE IS NOT YET
CLARITY ON ANY PARTICULAR
GENETIC PREDISPOSITIONS THAT ONE
COULD SCREEN FOR.
QUESTION I GUESS FOR ME IS THAT
IT SEEMS LIKE ALMOST EVERY ONE
OF THE GENE THERAPY PROGRAMS HAS
ESTABLISHED SOME MITIGATION
STRATEGY AS REQUIRED BY THE FDA
IN RESPONSE TO THE MYELOID
MALIGNANCIES.
SO I GUESS I'M STRUGGLING A
LITTLE BIT BECAUSE I'M WORRIED
THAT WE ARE GOING DOWN A PATH
THAT IS NOT LIKELY TO ACTUALLY
GET US THE INFORMATION THAT
ACTUALLY WOULD BE ACTIONABLE.
AND SO IF I'M UNDERSTANDING YOU
RIGHT, IS THIS SOMETHING THAT WE
SHOULD CONTINUE TO PURSUE, THESE
PRETRANSPLANT PANELS?
>> I DO THINK IT'S IMPORTANT, I
GUESS CONCERNED ABOUT THAT TOO
BECAUSE THESE PANELS THAT ARE
BEING RUN DON'T LOOK AT REALLY
LOW LEVEL CLONAL HEMATOPOEISIS
AND I SHOWED YOU LEVELS AS LOW
AS 0.06% HAVE LED TO MDS IN ONE
OF OUR PATIENTS.
SO I THINK IT'S IMPORTANT TO
GATHER THE DATA.
I THINK IT'S IMPORTANT TO STORE
BLOOD IT ZO THAT ONCE WE
IDENTIFY RISK FACTORS, WE CAN
LOOK BACK.
THERE ARE LARGE STUDIES GOING ON
NOW TO LOOK AT PREVALENCE OF LOW
LEVEL CLONAL HEMATOPEE CYST, AND
WE'RE ALSO LOOKING AT CLONAL
HEMATOPOEISIS AFTER TRANSPLANT
IN OUR PATIENTS, SO STAY TUNED.
THANK YOU.
[APPLAUSE]
>> OUR NEXT SPEAKER IS VIRTUAL.
DAN IS GOING TO BE TALKING ABOUT
PRECISION GENE EDITING FOR
SICKLE CELL DISEASE.
TAKE IT AWAY.
YOU'RE MUTED, DAN.
OKAY.
>> GREAT.
>> WE CAN HEAR YOU NOW.
>> THANK YOU FOR THE OPPORTUNITY
TO PARTICIPATE IN THIS FANTASTIC
MEETING.
SO IT FEELS LIKE WE'RE FACING A
MOMENT OF COGNITIVE DISSIDENCE
WHERE ON THE ONE HAND, WE HAVE
THE REMARKABLE OPPORTUNITY TO
OFFER SICKLE CELL DISEASE
PATIENTS APPROVED GENETIC
MEDICINES, ON THE OTHER HAND,
THE THERAPIES ARE FLE -- COMPLE,
COSTLY, AND CANNOT -- OF AN
ESTIMATED 300,000 BABIES BORN
AROUND THE WORLD EACH YEAR WITH
SICKLE CELL DISEASE.
I WOULD ARGUE THIS MEANS WE
STILL NEED TO DEVELOP BETTER
APPROACHES THAT ARE SIMPLER,
SAFER, AND MORE EFFECTIVE.
HERE ARE MY DISCLOSURES.
CLINICAL OBSERVATIONS DATING
BACK TO THOSE OF JANET WATSON IN
THE 1940s INDICATE THAT
NEWBORNS WITH SICKLE CELL
DISEASE ARE PROTECTED DUE TO
HIGH LEVEL EXPRESSION OF FETAL
HEMOGLOBIN.
DISEASE ONLY BEGINS ONCE FETAL
GAMMA GLOBIN, THE PAIR LOG AND
GENOMIC NEIGHBOR OF ADULT BETA
GLOBIN HAS BEEN
TRANSCRIPTIONALLY SILENCED AFTER
BIRTH.
THE LONG-STANDING GOAL OF
HEMATOLOGY HAS BEEN TO DEEPLY
UNDERSTAND HEMOGLOBIN SWITCHING
TO ENABLE THERAPEUTIC INDUCTION
OF FETAL HEMOGLOBIN.
WHEN I JOINED STU ORKIN'S LAB AS
A FELLOW, I BECAME INTERESTED OF
HOW COMMON GENETIC VARIATION AT
BCL11A INFLUENCED FETAL
HEMOGLOBIN.
WE OBSERVED DISEASE ASSOCIA
ASSOCIATED -- BECAUSE GENE
EDITING CAN DISRUPT THE
SEQUENCES IN MOUTHY RIT ROID
CELL LINE AND OBSERVED THAT
ERYTHROID BCL11A ERYTHROID
ENHANCERS WERE ESSENTIALLY --
FOR BCL11A EXPRESSION.
NEXT, CRISPR DENSE MU TOE
GENESIS -- THAT COULD SERVE AS
THERAPEUTIC TARGETS.
WE FOUND GATA1 BINDING SITES AT
THE PLUS 50A -- THAT WERE
REQUIRED FOR ROBUST FETAL
HEMOGLOBIN SILENCING.
THIS LED TO A SIMPLE THERAPEUTIC
VISION TO DISRUPT THE BCL11A
ENHANCER IN HEMATOPOIETIC STEM
CELLS, LEADING TO REDUCTION OF
BCL11A SPECIFICALLY IN ERYTHROID
PRECURSORS, AND SUBSEQUENT D
REPRESSION OF FETAL HEMOGLOBIN.
EX-VO VO MODIFIED LP STEM CELLS
COULD SERVE AS AN AUTOLOGOUS
GRAFT FOR HEMATOPOIETIC
TRANSPLANT.
RECENT CLINICAL TRIALS SPONSORED
BY CRISPR THERAPEUTICS AND
VERTEX HAVE SHOWN THAT IN 43
SICKLE CELL DISEASE PATIENTS, EX
VIVO GENE EDITING CAN PRODUCE
EFFICIENT INDELLS IN BLOOD
CELLS.
POTENT FETAL HEMOGLOBIN
INDUCTION COMPRISING ABOUT 40%
OF TOTAL HEMOGLOBIN, IMPROVEMENT
IN HEMOLYSIS AND REDUCTION IN
VASO-OCCLUSIVE CRISIS FREQUENCY
LEADING TO THE FDA AKROFL IN
DECEMBER OF 2023 OF CASGEVY.
NONNONT LESS, PATIENTS HAD SOME
RESIDUAL HEMOLYSIS AND -- THE
IMPACT ON THE INSIDIOUS
DETERIORATION CHARACTERISTIC OF
SICKLE CELL DISEASE ORGAN
FUNCTION IN LONG TERM OUTCOMES
REMAIN UNKNOWN.
THIS STUDY REPORTS A BRAZILIAN
COHORT OF HEMOGLOBIN S HPFH
COMPOUND HETEROSIGH JUST
CHILDREN WITH MEAN HEMOGLOBIN --
AND FETAL ABOUT 42%, SIMILAR
VALUES AS REPORTED IN THE RECENT
CLINICAL TRIAL REVEALED GREAT
AMELIORATION OF SICKLE CELL
DISEASE, BUT STILL SOME EPISODES
OF ACUTE CHEST SYNDROME, ACUTE
PAIN CRISES AND TRANSFUSION
REQUIREMENTS SUGGESTING CLINICAL
MANIFESTATIONS OF SICKLE CELL
DISEASE WERE NOT COMPLETELY
REVERSED.
WE KNOW THAT INDIVIDUALS WITH
SICKLE CELL TRAIT WITH A
HETEROZYGOUS HBS MUTATION ARE
LARGELY HEALTHY.
UNDER VENOUS OXYGEN TENSION OF
ABOUT 4%, IT TAKES ABOUT 65%
ADULT HEMOGLOBIN TO PREVENT
SICKLING, WHICH IS THE PRECISE
DX OF ADULT HEMOGLOBIN FOUND IN
SICKLE CELL TRAIT.
50% FETAL HEMOGLOBIN WOULD BE
EXPECTED TO ACHIEVE A
SIMILAR DEGREE OF SICKLING
PROTECTION.
SUGGESTING THAT SLIGHTLY MORE
ROBUST FETAL HEMOGLOBIN
INDUCTION MIGHT YIELD CLINICAL
OUTCOMES NON-INFERIOR TO SICKLE
CELL TRAIT.
RECENT WORK FROM MY LAB LED BY
JIN DP. ZENG SHOWS THE COMBINED
TARGETING OF THE TWO MAJOR
BCLA11 ENHANCERS PRODUCES
SUPERIOR ENHANCER DISRUPTION.
COMPARED TO SINGLE ENHANCER
DISRUPTION OR ALTERNATIVE
APPROACHES LIKE BCL11A KNOCKDOWN
OR TARGET THE PROMOTER 115 SITE
COMBINED BCR11A ENHANCER EDITING
PRODUCED THE GREATEST FETAL
HEMOGLOBIN INDUCTION AND
PREVENTION OF IN VITRO OR
ERYTHROCYTE SICKLING.
ATTRIBUTABLE TO -- UP TO FOUR
TOTAL BINDING SITES DISRUPTED
PER CELL.
WITH OUR COLLEAGUES AT NHLBI, WE
TESTED THIS COMBINED ENHANCER
GENE EDITING PROTOCOL IN THE
RHESUS MACAQUE GENE EDITING --
INCLUDING MOBILIZING,
COLLECTING, PURIFYING
HEMATOPOIETIC STEM CELLS PRIOR
TO GENE EDITING EX VIVO AND YOU
AUTOLOGOUS INFUSION.
WE TESTED TWO COHORTS, ONE
TREATED WITH STANDARD BUSULFAN
CHEMOTHERAPY, AND THE OTHER
TREATED WITH AN ANTICD45
ANTIBODY DRUG CONGUGATE.
>> WITH OR WITHOUT CHEMOTHERAPY
OVER AT LEAST A YEAR FOLLOW-UP,
PROVIDING PROOF OF CONCEPT THAT
CHEMOTHERAPY IS NOT REQUIRED FOR
EFFECTIVE HEMATOPOIETIC
RECONSTITUTION BY GENE EDITED
CELLS.
ONE POSSIBLE RISK OF GENE ID
ITING IS OFF TARGET EFFECTS.
WITH OUR BIOINFORMATIC
COLLEAGUES, WE BUILT A TOOL
CALLED CRISPRME.
THE GENETIC VARIANT SHOWN ON THE
LEFT IN BLUE WHICH CREATES A PAN
SEQUENCE WHICH ALLOWS TO BIND AT
THE ADJACENT SITE WITH JUST
THREE MISMATCHES.
THIS VARIANT IS FOUND IN ABOUT
5% ALLELE FREQUENCY IN AFRICAN
ANCESTRY INDIVIDUALS, SUGGESTING
THAT UP TO 1 IN 10 SICKLE CELL
DISEASE PATIENTS MIGHT CARRY
THIS VARIANT.
SINCE THE OFF-TARGET SITE IS ON
THE Q ARM OF CHROMOSOME 2, MORE
THAN 150 MEGA BASES FROM THE
BCL11A TARGET SITE ON THE P ARM,
WE HYPOTHESIZE THAT SIMULTANEOUS
CLEAVAGE OF THE SITES COULD
RESULT IN PERICENTRIC INVERSIONS
WHICH INDEED WE CONFIRMED WERE
PRESENT AT ABOUT 1 IN 600 ALLELE
FREQUENCY AFTER GENE EDITING IN
DONOR HEMATOPOIETIC CELLS
CARRYING A HETEROZYGOUS RISK
VARIANT.
WE THINK GENETIC VARIANT
ASSOCIATED OFF-TARGET EDITING IS
A GENERIC RISK OF GENE EDITING
AND SHOULD BE CONSIDERED IN
EDITING DESIGN, PATIENT
SCREENING AND CLINICAL
FOLLOW-UP.
ALONGSIDE ITS APPROVAL OF
CASGEVY IN DECEMBER 2023, THE
FDA MANDATED A POST MARKETING
SURVEILLANCE STUDY TO SCREEN
PATIENTS FOR THE CPS1 VARIANT
AND ASSESS FOR GENETIC
VARIANT-ASSOCIATED OFF TARGET
EDITING.
MANY POTENTIAL GENETIC VARIANT
ASSOCIATED OFF-TARGET EFFECTS
ARE DUE TO MUCH RARER VARIANTS
THAN THE CPS1 VARIANT WHICH
MIGHT MAKE IT INFEASIBLE TO FIND
DONORS FOR EXPERIMENTAL TESTING.
HERE I'M SHOWING THE MINOR
ALLELE FREQUENCY OF 72 CANDIDATE
VARIANT ASSOCIATED OFF TARGETS
WITH A SCORE OF AT LEAST 0.4.
MOST ASSOCIATED WITH VERY RARE
GENETIC VARIANTS.
IT WOULD NOT BE FEASIBLE TO
OBTAIN CD34 CELLS IN DONORS
CARRYING EACH OF THESE VARIANTS
FOR DIRECT OFF-TARGET
ASSESSMENT.
TO ADDRESS THIS CHALLENGE, WE'VE
DEVELOPED AN ASSAY THAT CAN
ASSESS THESE
EDITED FOR MAINTAINING
CLINICALLY RELEVANT CELLULAR AND
GENE EDITING DELIVERY CONTEXT.
THE EXPERIMENTAL DESIGN OF OUR
SO-CALLED ABSOLVE SEQ ASSAY
INTRODUCED ALTERNATIVE ALLELE
SEQUENCES TO CD34 CELLS AND
PERFORMING EDITING WITH
CLINICALLY RELEVANT PROTOCOLS
AND MOLECULAR IDENTIFIERS TO
DETECT SINGLE EDITING EVENTS AND
PULLED THEM TOGETHER AND
INCLUDED BAR CODES TO
DIFFERENTIATE TARGETS AND
DEVELOPED A COMPUTATIONAL
PIPELINE IN TO ASSESS THE
TARGETING SITE.
HERE'S THE RESULTS WITH 72 PROXY
OFF TARGETS TO CD34 CELLS
FOLLOWED BY THE KAS 9 AND GUIDE
RNAs AND THE TWO ON TARGET PROXY
SEQUENCES AND THE ONE KNOWN
VARIANT OFF TARGET AT CPS1
SHOWING SIGNIFICANT INCREASE IN
THE TREATED SAMPLE.
OF THE 72 VARIANT ASSOCIATED
CANDIDATE OFF TARGETS NONE
SHOWED SIGNIFICANT PROXY
EDITING.
THOUGH THIS WAS REASSURING FOR
OUR EDITING APPROACH WE HOPE
MORE BROADLY IT SHOWS A STRATEGY
FOR NOVEL CANDIDATE GENE
EDITORS.
WE HAVE GREAT OPPORTUNITIES
AHEAD FOR SICKLE CELL DISEASE
THERAPY TO GENE EDITING.
WITH GENETIC MEDICINE WE CAN
AASPIRE TO PUBLIC A LARGE IMPACT
ON THE CLINICAL UNMET NEED.
DUE TO THE ACCESSIBILITY OF THE
BLOOD SYSTEM WE CAN EXPECT TO
DEEPLY UNDERSTAND THE IMPACT OF
GENE EDITING AT MOLECULAR,
CELLULAR AND PHYSIOLOGIC LEVELS
WITH INDEFINITE FOLLOW-UP.
I'M EXTREMELY GRATEFUL TO
CURRENT AND FORMER LAB MEMBERS
AND MENTORS, COLLABORATORS AND
SICKLE CELL DISEASE PATIENTS.
THANK YOU.
>> QUESTIONS ONLINE OR HERE IN
THE AUDIENCE?
THERE'S ONE.
>> VERY ELEGANT WORK BUT I'M
INTRIGUED BY ONE OBSERVATION
WHICH HAS COME TO LIGHT MORE
RECENTLY THAT IN INDIA MOST THE
SICKLE CELL PATIENTS HAVE VERY
HIGH HEMOGLOBIN F WHICH PERSISTS
THROUGHOUT THEIR LIFE UP TO IN
30% OR SO.
SO, THEY HAVE COMORBIDITIES
SIMILAR TO THOSE WHO HAVE LOWER
HPF IN OTHER PARTS OF THE WORLD.
SO HOW WOULD THIS WORK IN THOSE
AND HOW DO WE REALLY EXPLAIN
THAT?
>> YEAH.
IT'S A GREAT QUESTION.
I THINK IT HIGHLIGHTS THE NEED
FOR LONG-TERM FOLLOW-UP IN
SICKLE CELL DISEASE BOTH TO
REALLY UNDERSTAND THE NATURAL
HISTORY OF HETEROGENEOUS DISEASE
AND THE RESPONSE OF NOVEL
THERAPIES AND WE'RE SORT OF
BLESSED TO HAVE MANY THERAPIES
COMING ON BOARD BUT REQUIRES AN
ONUS ON US TO FOLLOW PATIENTS
AND UNDERSTAND THE OUTCOME.
FETAL HEMOGLOBIN LEVEL DEPENDS
ON THE ABSOLUTE LEVEL WITHIN THE
RED CELL AND DISTRIBUTION OF THE
RED CELLS AND POPULATION OF THE
RED CELLS AND THE SURVIVAL OF
THOSE RED CELLS AS DR. LEONARD
INTRODUCED EARLIER TODAY.
AND SO I THINK WE HAVE AN
UNDERSTANDING OF HOW THE
DISTRIBUTIONS ARE PRESENT IN
VARIOUS PATIENTS AND HOW THEY'RE
ASSOCIATED WITH CLINICAL OUTCOME
BUT MAY NEED HIGHER LEVELS OF
FETAL HEMOGLOBIN TO REALLY HAVE
THE BEST POSSIBLE OUTCOMES WHICH
I WOULD SAY ARE NON INFERIOR TO
THOSE WITH SICKLE CELL TRAIT.
>> THANK YOU FOR A WONDERFUL
TALK.
WE HAVE OUR NEXT TALK IS GENE
CORRECTION OF THE NUCLEOTIDE
VARIANT OF SICKLE CELL DISEASE
PROGRESS AND UPDATES.
MATTHEW PORTEUS.
>> THANK YOU FOR INVITING ME AND
THANK YOU FOR BEING HERE.
I'M GOING TO GIVE AN UPDATE ON A
SINGLE PATIENT CLINICAL TRIAL
AND WHERE WE'RE GOING.
THESE ARE MY DISCLOSURES FOR
THERAPEUTICS WHO HAVE TAKEN OVER
SPONSORSHIP OF A CLINICAL TRIAL
I'M GOING TO DESCRIBE.
WE'RE INTERESTED IN HARNESSING
THE PATHWAY OF GENE EDITING IN
WHICH A CRISPR IS USED TO MAKE A
BREAK BUT INSTEAD OF ALLOWING IT
TO BE REPAIRED WE PROVIDED A
DONOR THAT ALLOWS THE REPAIR TO
BE TEMPLATED BY THE DONOR AND
INTRODUCED PRECISELY FOR THE
CHANGES.
THE FLEXIBILITY OF
MULTI-DIRECTIVE REPAIR IS
FANTASTIC.
YOU CAN PUT IN LARGE SETS AND
REVERSING TO A NON-PATH LOGIC
AND THIS IS HIGHLY RELEVANT TO
SICKLE CELL DISEASE WHERE EVERY
PATIENT CARRIES AND THE GAG
MAKING TO A POLAR INSTEAD OF A
CHARGE ACID.
SO 2016 WE PUBLISHED A CONCEPT
PAPER IN NATURE SHOWING WE CAN
HARNESS THE PROTEIN DELIVERY OF
THE CRISPR KAS 9 FOR TEMPLATE TO
REPAIR.
WHAT I WANT TO HIGHLIGHT IS THE
REVERSE TO THE NON-PATHOLOGIC A
AND SILENCE MUE TAILITIONS AND A
PAPER IN SCIENCE AND MEDICINE IN
2021 WE PUBLISHED ON OUR SCALE
UP AND STUDIES.
IN THIS WORK WE ACTUALLY SHOWED
IN VITRO WHEN RED BLOOD CELLS
WERE DIFFERENTIATED FROM CD34
CELLS FROM PATIENTS WITH SICKLE
CELL DISEASE AND UNMODIFIED
CELLS GENERATED HIGH AMOUNTS OF
HEMOGLOBIN S AND WE GOT HIGH
LEVELS OF HEMOGLOBIN A AND FETAL
HEMOGLOBIN I ATTRIBUTED TO THE
ARTIFACT OF DIFFERENT SYSTEMS
AND IT MAY BE RELATED TO OUR
FIRST PATIENT.
SO WE TRANSFERRED THE PROTOCOL
TO GRAPHITE BIO WHO TREATED A
PATIENT WITH THE PROTOCOL ALMOST
TWO YEARS TO THE DAY AND I WANT
TO GIVE AN UPDATE.
WE DON'T QUITE HAVE THE TWO YEAR
FOLLOW UP AND IS COMING NEXT
WEEK FOR EXAMS.
UP THROUGH MONTH 21 THIS IS WHAT
HER PARAMETERS LOOK LIKE.
SHE HAD SLOW ENGRAFTMENT AND
REQUIRED PLATELET TRANSFUSIONS
THROUGH MONTH SIX AND
TRANSFUS
TRANSFUSIONS AND WAS STARTING ON
AN AGONIST INCREASINGLY USED TO
TREAT AND THAT IS CONTINUED FROM
DAY 108 TO APPROXIMATELY 320.
AFTER THE DISCONTINUATION HER
HEMOGLOBIN IS NOW STABLE AND THE
PLATELET COUNT HAS STILL
INCREASED BUT STILL NOT NORMAL.
THE WHITE BLOOD CELL COUNT IS
NORMAL AND HEALTHY AND DOESN'T
SHOW HYPERLEUKO CYTOSIS AND HER
GENE MARKING SHOWS SIGNIFICANT
INDELS AND SMALL PERCENTAGE OF
HDL BUT REMARKABLY AS THE
PRESENCE OF SMALL AMOUNT OF
HEMOGLOBIN A AND RESIDUAL AMOUNT
OF HEMOGLOBIN S AND AN
UNEXPECTED OUTCOME FROM A
PROCESS DESIGN TO CREATE HEME
ZBLOEB --
HEMOGLOBIN A NOT F AND WHEN WE
PUT THE LABORATORY VALUES
TOGETHER LOW HC HER PICTURE IS
CONSISTENT WITH A TRANSFUSION
INDEPENDENT OF THE FETAL
HEMOGLOBIN AND WE TOOK THIS FROM
DIFFERENT GENE EDITING PROGRAMS
AND THIS IS UNIQUELY CREATING
LOW HEMOGLOBIN S WHICH
HIGHLIGHTS ARE KEY FEATURES OF
THE DECREASE OF THE SYMPTOMS OF
SICKLE CELL DISEASE.
WE SEE MULTIDIRECTIVE REPAIR
FROM THE AC DONOR TEMPLATE AND
THAT'S HERE BUT WE ALSO SEE AND
THIS HAS BEEN DESCRIBED BY
SEVERAL DIFFERENT GROUPS IS A
PATCH OF THE DELTA HEMOGLOBIN
INTO THE BETA HEMOGLOBIN GENE
WHICH REVERTS THE SICKLE CELL
MUTATION BUT ADDS A COUPLE
ADDITIONAL AMINO ACID CHANGES.
SO IF WE LOOK AT THE ALLELE
FREQUENCIES OVER TIME WHAT WE
SEE IS FIRST OF ALL A SORT OF
DECLINE IN VARIOUS ALLELE
FREQUENCIES AND THEN AROUND
MONTH SIX WE SEE THE SLOW
INCREASE OF THE MINUS 2 DELETION
IN THE BETA GLOBIN GENE AND
INCREASE FROM MONTH SIX TO MONTH
21.
SORRY, YEAH, MONTH 12 AND SINCE
THAT TIME SLOWED AND I FORGOT TO
COMMENT ON THE PREVIOUS SLIDE BY
MONTH SIX WE DETECTED A SPLICE
SITE VARIANT IN THE B CORE GENE
AND THAT HAS INCREASED AS WELL.
IT SEEMS THAT WHETHER IT WAS A
DRIVER OR THE INEFFECTIVE
HEMATOPOIESIS WE SELECTED FOR
THE CLONE.
THE CLONE HAS NOW SLOWLY DRIFTED
DOWN OVER TIME AND WITH THAT
CLONE DRIFTING DOWN AND TO THE
REPAIR CLONES ARE DECREASING AND
HOPEFULLY WE'LL SEE THE DECLINE
DRIVEN BY B CLOR WITH A MORE
POLY CLONAL HEMATOPOIESIS AND
SIMILAR TO A PATIENT TREATED IN
WHICH A CLONE AN INTEGRATION
SITE SLOWLY DISSIPATED OVER
TIME.
AGAIN, NO WAY TO KNOW WHAT WILL
HAPPEN IN THIS PATIENT.
SO WE LEARNED THAT WE COULD SEE
ENGRAFTMENT OF THE CELLS AND IT
WAS SLOW BUT SHE IS NOW
CONTINUING TO DO CLINICALLY
WELL.
SO WHAT DO WE NEED TO DO TO
IMPROVE THE HDR PROCESS SO THE
OUTCOMES IN THE NEXT PATIENTS
MAY BE BETTER?
ONE OF THE THINGS WE'LL DISCOVER
OR HIGHLIGHTED BETWEEN THE BEGIN
INITIATION OF THE CLINICAL TRIAL
IS THE DONOR TEMPLATE HIGHLY
EFFECTIVE IN GETTING IT IN THE
CELLS THE NATURE OF THE GENOME
ACTIVATES THE H53 RESPONSE.
WE USED THE AAV2500 RESULTS IN
ABOUT 200 OF AAV GENOMES IN
CELLS ON AVERAGE.
WHEN WE REDUCE THE AAV TO 625
THE NUMBER OF VECTOR GENOMES PER
CELL DECREASES TO 50 AND THERE'S
A DIRECT DOSE RESPONSE BETWEEN
P21 THE DOWN STREAM TARGET OF
P53 AND THE AMOUNT OF VECTOR
GENOMES.
ONE CAN SEE IF WE COULD GET THE
VECTOR GENOME IN THE CELL TO A
MUCH LOWER AMOUNT WE MAY BE ABLE
TO IMPROVE THE CELL QUALITY THAT
IS TRANSPLANTED IN THE PATIENTS.
SO HOW CAN WE DO THAT?
SO ONE MECHANISM IS TO USE A
SMALL MOLECULE TO INHIBIT THE
CANONICAL PATHWAY AND THIS WAS
PUBLISHED BY OUR GROUP LAST YEAR
BUT I WANT TO SWITCH TO AN
ALTERNATIVE MECHANISM WHICH IS
SHOWN IN THE NEXT SLIDE.
WHICH WAS FIRST DESCRIBED SHOWED
A
DNA PLASMID INHIBITING THE 53BP1
AROUND THE SITE OF A DOUBLE
STRANDED BREAK AND THOUGHT THE
BLOCK OF THE ABILITY TO DO HDR.
THROUGH PRIOR WORK WE FELT USING
AN mRNA OR TRANSFECTION WAS NOT
GOING TO BE A VIABLE APPROACH IN
CD 34 CELLS TO MAINTAIN THAT
CELL HEALTH.
SO WE SWITCHED TO DELIVERING THE
SAME MOLECULE THAT HAS A PEPTIDE
GIVEN OUR SUCCESSES WITH
DELIVERING CAS 9 COLLABORATED
AND SHOWED WE COULD GET MAINTAIN
A HIGH FREQUENCY OF HDR BY
ADDING A PEPTIDE BUT ABLE TO
DECREASE THE MOI BY FOURFOLD.
AND WHAT YOU SEE IS ALONG THE Y
AXIS WITH THE PEPTIDE WE WERE
ABLE TO GENERATE HIGH
FREQUENCIES OF HDR AND ALONG THE
X AXIS THE PERCENT USED IN THE
ORIGINAL PROCESS WAS ABOUT 50%
TO 60% OF UNMODIFIED CELLS NOW
WITH A LOWER MOI IS 100% OF THE
UNMODIFIED CELLS.
WE INCREASED AND MAINTAINED OR
EVEN INCREASED THE HPR FREQUENCY
BUT INCREASED THE CELL HEALTH AS
MEASURED THROUGH CFUs.
SO I'M GOING TO -- THIS IS A
TABLE OUTLINING THE VARIOUS
CRITICAL ATTRIBUTES WE NOW
ACHIEVED AT CLINICAL SCALE
MANUFACTURING AND YOU CAN SEE
THAT THERE'S AN IMPROVEMENT IN
QUALITY FORMATION AND
IMPROVEMENT IN THE NUMBER OF
CLONES IN THE CFU ASSAY WITH AT
LEAST ONE ALLELE CORRECTED AN
THIS DATA SHOWN AS A TABLE WE
REDUCED THE MANUFACTURING TIME
FROM FIVE DAYS TO THREE DAYS AND
INCREASED THE CELL CORRECTION TO
75% AND INCREASED THE NUMBER OF
CFUs AND QUALITATIVELY THEY
APPEAR LARGER AND REDUCE THE
COST OF GOODS TO JUST VERY VERY
LARGE 450,000.
JUST TO SHOW WE CONTINUE TO MAKE
IMPROVEMENTS.
AGAIN, VISUALLY TO SHOW THE
DIFFERENCE BETWEEN THE VERSION 1
AND 2 WE'RE INCREASING OUR
ALLELE AND NUMBER OF COLONIES
THAT HAVE AT LEAST ONE ALLELE
CORRECTED AND WE'RE DECREASING
THE NUMBERS WITH THE EQUIVALENT
NUMBER TO ONE LESS THAN 20% IN
THE MANUFACTURING PROCESS.
SO THE IS NOW OPEN WITH THE NEW
MANUFACTURING PROCESS AT
STANFORD.
YOU CAN EITHER CONTACT STANFORD
DIRECTLY OR OUR STUDY CONTACT
JENNI HERBER AND IT WILL SOON BE
OPEN AT WASHINGTON UNIVERSITY
AND HOPING TO OPEN AT NATIONWIDE
CHILDREN'S HOSPITAL IN 2025.
SO THANK YOU AGAIN FOR THE
OPPORTUNITY TO SPEAK.
AS EVERYONE HAS HIGHLIGHTED THIS
IS TEAM SCIENCE THAT TAKES MORE
THAN A VILLAGE.
IT TAKES MAYBE A SMALL CITY,
MAYBE RENO TO DO THIS.
I WANT TO HIGHLIGHT WE WOULD
HAVE NEVER HAVE GOTTEN OFF THE
GROUND WITHOUT THE CARE SICKLE
CELL DISEASE INITIATIVE AND
FINALLY I'LL END WITH A PICTURE
OF THE PEOPLE IN MY LAB WOULD
CONTRIBUTED TO THE PROCESS.
THANK YOU VERY MUCH.
>> NO QUESTIONS.
>> I'M FROM THE UNIVERSITY OF
TORONTO.
YOU MENTIONED YOU WANT TO TALK
ABOUT THE HUMAN FETAL HEMOGLOBIN
ELEVATION BUT WASN'T SURE IF YOU
TALKED ABOUT IT.
>> SO, IT'S STILL A BIT OF A
MYSTERY TO US WHY IT'S SO HIGH.
IT'S CLEARLY COMING FROM A CLONE
I WOULD HAVE PREDICTED AHEAD OF
TIME SHOULD HAVE A MUTATION IN
BOTH ALLELES.
SOMEHOW THAT CLONE IS CAUSING
SOME FETAL HEMOGLOBIN
UPREGULATION NOT TO MAKE A FULLY
HEALTHY RED BLOOD CELL.
WHETHER IT'S BECAUSE THE
TRANSPLANT FETAL HEMOGLOBIN WAS
8% SO IT'S NOT LIKE SHE HAD HPF8
WHETHER THERE'S A CRYPTIC FETAL
HEMOGLOBIN POLYMORPHISM WE WANT
TO UNDERSTAND AND WILL DO THAT
FIRST BY DOING WHOLE GENOME
SEQUENCING AND WORK OUR WAY
THROUGH THE VARIOUS HYPOTHESES
BUT VERY INTERESTED IN ANYONE
HAVING IDEAS.
>> YOU MENTIONED THE CLONE.
BEFORE YOU MENTIONED THE CLONE I
THOUGHT IT WAS SLOWING OF THE
CYCLING AND A LAB HAS SHOWN YOU
CAN INCREASE FETAL HEMOGLOBIN.
>> SO WE HAVEN'T DONE ANY DIRECT
MEASURES OF CELL CYCLE.
WHAT I WILL SAY IS THE MARROW
WENT FROM LESS THAN 5% CELLULAR
TO FULLY CELLULAR AND THE FETAL
HEMOGLOBIN CAME UP AT THE SAME
TIME CERTAINLY STRESSED
ERYTHROEPOIESIS.
>> OUR NEXT TALK IS AGAIN
VIRTUAL FYODOR URNOV CRISPR
CURES FOR HEMOGLOBINOPATHY A
VIEW TO 2034.
>> THANK YOU FOR THE INVITATION.
HERE ARE MY DISCLOSURES.
I KNEW I'D BE THE LAST ONE
BEFORE LUNCH AND THEREFORE I'M
GOING TO GIVE A SHORT TALK WHICH
WILL NOT HAVE A LOT OF DATA
DENSE SLIDES BUT WANT TO LEAVE
YOU WITH A SENSE OF URGENCY.
I THINK WE HAVE A BIT OF A
CRISIS IN THE GENE EDITING FIELD
IN HELPING FOLKS AND I'D LIKE TO
OFFER A POTENTIAL PATH FORWARD.
DAN BAUER AND I DID NOT
COORDINATE AND THAT SAID I'LL
START THE TALK THE SAME WAY.
OUR VIEW TO 2034 IS INFORMED BY
THE COGNITIVE DISSONANCE OF
WHERE THEY'RE WORKING AND WHERE
THE PUBLIC HEALTH CHALLENGESS
LIE.
GENE EDITING HAS A THREE DECADE
HISTORY AND BY FOLKS MENTIONED
AT THE BOTTOM OF THE SLIDE.
I'M GOING TO EXTRAPOLATE FROM
THE PAST WHICH IS THE ONE WAY WE
KNOW HOW TO DO THIS IN LOOKING
TO THE DECADE AHEAD AND IN
PARTICULAR HIGHLIGHT A PROFOUND
CHALLENGE WE AS A COMMUNITY ARE
EXPERIENCING.
EXACEL MANUFACTURE HAS
PROGENITOR CELLS USING THE
PROTEIN PARTICLE AND IN THE RNA
DAN BAUER DESCRIBED AND WE HAVE
200 MILLION IN WHICH THERE'S A
PROTEIN CREATING A DOUBLE STRAND
BREAK.
THE SUBJECT UNDER GOES
CONDITIONING IN THE CELLS.
I WANT TO HIGHLIGHT TWO KEY
PERFORMANCE METHODS OF THE
PROTEIN PARTICLE AND GUIDE RNA
AS IT GOES TO HEMOGLOBINOPATHY
AND THE PHARMACEUTICALS AND YOU
SEE THE SOME TOTAL OF CANDIDATE
OFF TARGET SITES FOR THE GUIDE
RNA IN THE HUMAN GENOME.
YOU CAN SEE NORTH OF 5,000 SITES
AND TARGET SITES.
IN A LARGE NUMBER OF EDITED WORK
LOOKING AT ALL THE OFF TARGET
SITES NO TARGETING WAS DETECTED
THAT IS AN IMPRESSIVE OUTCOME
FOR GENE EDITING.
STAYING IN MY NARROW LANE OF
GENE EDITING IN ADDITION TO THE
OR TARGET ISSUES THERE WAS
TRANSPLANTATION.
THIS IS DATA PRESENTED AND WHAT
YOU SEE AT THE TOP IS EDITING IN
THE ENHANCER MENTIONED AND THE
EDITING AT THE TARGET IN THE
BONE MARROW OF THE TARGET IS
FLAT.
IN THE BOTTOM YOU SEE IN THE
LARGER NUMBER THE INDEL
EFFICIENCY STAYS FLAT OVER TIME.
THE EDITED CELLS ONCE THEY
ENGRAFT PROVIDE STABLE
HEMATOPOIETIC CONDITION AND IN
TERMS OF THEIR SYMPTOMS OF
SICKLE CELL DISEASE IS MORE
SUCCESSFUL AND HERE I AM AT TO
THE GENE EDITOR AND HERE'S WHAT
I CAN OFFER.
THE ON-TARGET EFFICIENCY OF GENE
EDITING AT THERAPEUTIC CELL TYPE
OF CLINICAL SCALE PRODUCTION IS
AT, OR ABOVE THE THERAPEUTIC
THRESHOLD AND NO OFF-TARGET
CUTTING OBSERVED ABOVE THE LOD
IN THE LARGEST SUCH PANEL AND MY
SUMMARY CRISPR CAS 9 GENE
EDITING 1.0 HAS REDUCED AND MET
THE REQUIRED PERFORMANCE METRICS
TO DATE.
HOW IS THIS GOING?
VERTEX DISCLOSED THEY ENROLLED
20 PATIENTS TO BE TREATED AND
HERE COMES THE COGNITIVE
DISSONANCE WHAT DOES 20 PATIENTS
MEAN?
AND OBVIOUSLY THE LIMITING
FACTOR IS THE CELL CROSSING AND
TRANSPLANT AND OTHERS PURSUE
GENE EDITING FOR SICKLE CELL
DISEASE.
AND ONE HAS SHOWED IMPRESSIVE
DATA USING A DIFFERENT NUCLEASE
CAS 12A AND THE DOUBLE STRAND
BREAK MAKING OUTSTANDING
CLINICAL DATA AND THE
MANUFACTURING PROCESS EX VIVO
AND TRANSPLANT IS THE SAME.
THE PATH TO MAKING A GLOBAL
IMPACT WILL HAVE TO COME FROM
THE SYNERGISTIC INTERPLAY OF
FOUR THINGS.
EDITING INNOVATION, IN VIVO
DELIVERY AND REDUCTION OR
ELIMINATION OF CONDITIONING AND
CLINICAL TRACT.
I'LL SPEAK TO EVERYTHING OUTSIDE
CONDITIONING I DON'T WANT TO
SPEAK ABOUT CONDITIONING.
WHO CAN SPEAK ABOUT AND I CAN'T.
LET ME SPEAK ABOUT THE CLINICAL
TRACK RECORD BECAUSE I THINK
IT'S RELEVANT TO WHAT AS GENE
EDITORS SHOULD BE THINKING
ABOUT.
THESE ARE PUBLISHED DATA AND IN
THE STUDY THEY ARE USED NANO
PARTICLE DELIVERY IN VIVO AND
GUIDE RNA THAT TARGETS CAS 9 TO
A GENE CALLED ATTR.
IT'S SHOWN ON THE SCHEMATIC FROM
TO THE JOURNAL PAPER IT DELIVERS
THE mRNA TRANSLATED TO CAS 9 AND
IT GOES TO THE NUCLEUS AND
CREATES A DOUBLE STRAND BREAK
BUT IN A DIFFERENT GENE AND
SMALL INVERSIONS IN DELETIONS
AND WE HOPE THE SUBJECT
EXPERIENCED A REDUCTION IN THE
AMOUNT OF TOXIC PROTEIN IN THEIR
BLOODSTREAM.
AS AN EDITOR I CONTINUE TO WORRY
ABOUT THE TARGET SITES.
IT'S COMFORTING BUT NOT
COMPLETELY SATISFIED UNTIL WE
KNOW ABOUT THE LARGE PANEL OF
SUBJECTS ON THE CLINICAL TRIAL
BUT THERE ARE NOW CLINICAL DATA
FOR SPECIFICITY OF THIS GUIDE
FOR DIFFERENT EXPERIMENTS IS
QUITE COMPELLING.
THEY LOOKED AT A LARGE NUMBER OF
SITES AND SAW ZERO DETECTION.
TWO DIFFERENT TEAMS, TWO
DIFFERENT GUIDE RNAs AND ATTR
AND ON TARGET EFFICIENCY ROBUST
AND LOOKING AT TARGETS, NO
MEASURABLE TARGET CUTTING.
HOW ARE THE SUBJECTS DOING
CLINICALLY?
I'LL SHOW THE BIOMARKER IS THE
TOXIC PROTEIN SEVERAL COHORTS OF
SUBJECTS ON TO DIFFERENT
INDICATIONS AND WITHIN TWO
MONTHS OF DOSING THE GENE
THEY'RE TRYING TO KNOCK OUT GOES
DOWN TO JUST ABOUT THE LEVEL OF
DETECTION.
FORMIDABLE THE SUBJECT RESPONSE.
FOLKS, INTELIA IS DOING A
CLINICAL TRIAL WITH 765 SUBJECTS
WITH THIS APPROACH.
AS A GENE EDITOR AS I LOOK BACK
AT OUR 20 PLUS YEAR HISTORY IT'S
FORMIDABLE A TRIAL OF SUCH SIZE
IS ABOUT TO TAKE PLACE BUT
NOTABLY NOT FOR SICKLE CELL
DISEASE BUT FOR DOSES.
WITH RESPECT TO IN VIVO NON
VIRAL DELIVERY OF GENE EDITORING
A FORMIDABLE AMOUNT OF WORK IS
GOING AND THERE'S DIFFERENT GENE
EDITING BUT THE DELIVERY IS THE
SAME, LNP.
I MENTIONED VICTORIA GRAY SHOWN
HERE THE FIRST WITH THE EXACELL
ARE USING THIS AND THERE'S OTHER
TOOLS THAT DO NOT REQUIRE THE
CLASSICAL DOUBLE STRAND BREAK
AND THESE ARE ADVANCING TO THE
CLINICAL IN FACT SUBJECTS ARE
BEING DOSED AND THIS REALLY
UNDER LIES THE FACT AS DELIVERY
IMPROVES SO DOES THE EDITING
TOOLBOX AND IT'S MOVING TO THE
CLINIC.
WHY AM I TELLING YOU THIS?
WHAT IS THE RELEVANCE OF THE
EDITING THE RELEVANCE IS THE
LNP.
THERE WAS A LOVELY PAPER IN
SCIENCE MAYBE A MONTH AGO
DEMONSTRATING THAT LIPID NANO
PARTICLE DELIVERY TO
HEMATOPOIETIC STEM AND
PROGENITOR CELLS IS FEASIBLE AND
THE DATA ON THE RIGHT IS FROM A
BIOTECHNOLOGY COMPANY AND THEY
HAVE SHOWN A LIPID NANO PARTICLE
DELIVERY OF THE MESSENGER RNA TO
THE LT IN THE MARROW OF
HUMANIZED MICE AND CRITICALLY
NON-HUMAN PRIMATES AND LOOK AT
THE EFFICIENCY WITH WHICH THE
mRNA HAS BEEN DELIVERED.
BEFORE WE CELEBRATE LET ME
SPRINKLE A HEALTHY DOSE OF NOT
NEGATIVE NANCY BUT THERE'S DATA
BUT THEY HAD TO CUT THEIR
WORKFORCE AND I WILL EXPLAIN WHY
AND WHAT IMPLICATIONS THAT HAS
FOR OUR COMMUNITIES OF EDITOR
FOR THE HEMOGLOBINOPATHIES IN A
SECOND.
THE POSITIVE NEWS IS PEOPLE
ACTIVELY ACTING TO USE IN VIVO
NANO PARTICLE ENCAPSULATION AND
THIS PAST YEAR THEY DESCRIBED AN
INNOVATIVE APPROACH ON USING
GENE EDITING TO SHIELD THE
EDITED HEMATOPOIETIC STEM CELL
AND KEEP THE EDITED CELLS
INTACT.
A DIFFERENT BIO TECHNOLOGY
COMPANY HAS DISCLOSED AN ELEGANT
APPROACH AND IN SICKLE THEY'RE
PROPOSING WITH ONE EDITOR EDIT
THE MUTATION AND WITH THE SAME
CELL CREATE THE SHIELDING
MUTATION SUCH THAT WHEN THE
CELLS ARE TRANSPLANTED BACK YOU
CAN CONDITION THE PATIENT WITH
AN ANTIBODY AND HOW EXCITING.
WELL, THEY JUST HAD A MAJOR
WORKFORCE REDUCTION.
FOLKS, WRAPPING UP, I'VE TOLD
YOU THE PATH TO 2034 LIES
THROUGH THESE FOUR THINGS AND
I'VE GIVEN YOU THE FOLLOWING
EXAMPLES.
PEOPLE ARE ACTIVELY DEPLOYING
LNP DELIVERY OF CAS 9 IN VIVO TO
HSCs IN THE NON-HUMAN PRIMATES.
EDITING INNOVATION FROM 1.0 TO
2.0 TO 3.0 IS GROWING GIVING US
GENE EDITORS MORE OPTIONS HOW TO
CREATE.
ALL OF THIS IS HAPPENING AT THE
TIME WHEN LIPID NANO PARTICLE
DELIVERY OF THE EDITING
MODALITIES IS GROWING IN
CLINICAL SCALE.
IN THREE YEARS THEY'LL HAVE
COMPLETED THE PHASE 3.
THERE'LL BE MORE THAN 1,000
SUBJECTS DOSED AND IT WILL
PROVIDE INFORMATION IN TERMS OF
WHAT THE SAFETY PROFILE IS OF
THIS APPROACH AND FINALLY I
MENTIONED THE POTENTIAL FOR
DOUBLE EDITING TO REDUCE THE
CONDITION.
AND SO MY LAST SLIDE THANK YOU
FOR THE OPPORTUNITY TO SPEAK
WITH YOU IS THE FOLLOWING.
I MENTIONED WORKFORCE REDUCTION.
THERE'S NO SIMPLER WORD THAN IT
GRIEVES ME.
THAT OUR ENTIRE SECTOR IS
EXPERIENCING FROM A WORKFORCE
REDUCTION PERSPECTIVE WHAT ONE
LEADING SCIENTIST AT THE COMPANY
DESCRIBES AT QUOTE, A BLOOD BATH
IN PRACTICAL TERMS MY
PROFESSIONAL ASSESSMENT AS
SOMEBODY WHO FORTUNATELY IS ON
THE FIRST-NAME BASIS WITH MANY
LEADERS AT EVERY ONE OF THESE
BIO TECHS NOT ONE OF THE FOR
PROFIT ENTITIES WILL
AGGRESSIVELY GO OVER GENE
EDITING WHICH WOULD BE SCALABLE
TO THE GLOBAL CHALLENGE WHICH IS
THE MARKET CONDITIONS WILL
SIMPLY NOT ALLOW THEM TO DO THAT
IN THE NEXT FIVE YEARS.
LET ME END ON THE NOTE OF HOPE.
THE FEDERAL GOVERNMENT STEPPED
IN AND PROVIDED $140 MILLION TO
THE SOMATIC GENE EDITING
CONSORTIUM BUT NOT SICKLE.
IT'S NOT THEY MEANT TO EXCLUDE
SICKLE, IT'S NOT HOW THE PROGRAM
WAS CONFIGURED.
I THEREFORE WOULD POSE FOR THE
AUDIENCE THE QUESTION WHETHER
NOW IS THE TIME IN THE FIELD TO
LEVERAGE ALL THIS AMAZING
INNOVATION FROM DAN BAUER AND
MATT THAT EVERYONE HAS SPOKEN
ABOUT AND EVERYONE IN THE FIELD
HAS DEVELOPED TO HAVE US AS A
NATION STEP FORWARD WITH RESPECT
TO SUPPORTING AN ACCELERATED
PATH FOR GENE EDITING SOLUTION
SCALABLE FOR THE GLOBAL HEALTH
CHALLENGE BY 2034.
WHY DO THIS?
IN TERMS OF DESCRIBING HOW TO
ACT AND SHE SAID WE MUST MERGE
MERCY WITH MIGHT AND MIGHT WITH
RIGHT.
THANK YOU.
>> THANK YOU, DR. URNOV WITH THE
WONDERFUL SYSTEMS APPROACH.
QUESTIONS?
ANYBODY FROM THE AUDIENCE?
NONE.
SO YOU'VE BEEN VERY CLEAR IN
YOUR MESSAGE.
THANK YOU AGAIN FOR GIVING US
THE FUTURISTIC VIEW OF WHERE WE
SHOULD BE HEADING.
THANK YOU ALL AND THANK YOU FOR
ALL THE SPEAKERS FOR THE
SESSION.
AND SO LET'S TAKE A LUNCH BREAK
AND TRY TO BE BACK PROMPTLY HERE
GOOD AFTERNOON, EVERYBODY.
WE'RE GOING TO START WITH OUR
NEXT SESSION THAT IS UPDATES ON
IN THE SESSION BUT THE NEXT
COMPONENT OF THE SESSION 1 WHICH
IS UPDATES ON TRIALS ON SICKLE
CELL DISEASE.
SO THE FIRST TALK IS GOING TO BE
BY DR. MARK WALTERS FROM
UNIVERSITY OF CALIFORNIA SAN
FRANCISCO AND HE'S GOING TO BE
TALKING ABOUT CRISPR SICKLE CELL
DISEASE GENE EDITING TRYING
UPDATES.
MARK.
>> THANKS AND THANK YOU FOR THE
OPPORTUNITY TO GIVE THIS UPDATE.
SO HERE'S MY TITLE SLIDE.
I WANTED TO ALSO ACKNOWLEDGE THE
REMARKABLE PROJECT TEAM WE'VE
ASSEMBLED AT UNIVERSITY OF
CALIFORNIA CAMPUSES.
SO CURRENTLY IT'S LED BY THE
INNOVATIVE GENOMICS INSTITUTE AT
U.C. BERKELEY AND UCLA WITH THE
MANUFACTURING COMPONENT AND UCSF
AND HUMIDITY WORK OF THE IGI.
MORE IMPORTANT OF COURSE IS THE
FUNDING STREAM.
WE'VE BENEFITTED FROM A
COMBINATION OF CALIFORNIA
REGENERATIVE MEDICINE FUNDING
AND FOLLOWING A MEMORANDUM OF
UNDERSTANDING PARTNERSHIP WITH
CURE SICKLE CELL INITIATIVE.
THIS FUNDED PRECLINICAL
DEVELOPMENT OF THE PROJECT AND
NOW IN THE CLINICAL PHASE.
THIS IS A REMINDER OF THE
SCHEMATIC OF WHAT WE'RE
ATTEMPTING TO DO THE REPAIR AND
IN THE SCHEMATIC THERE'S THE
SEQUENCE OF THE SINGLE STRANDED
OLIGO NUCLEOTIDE DONOR AND GAA
TO HELP DISTINGUISH WILD TYPE
GLUCAMIC ACID DURING THE
PRECLINICAL DEVELOPMENT.
THE SITE IS EDITED AND THE
CLEAVAGE SITE IS SOMEWHAT
UPSTREAM OF THE CORRECTION SITE
SO HDR CAN OCCUR AND CORRECT THE
PAM BUT THE STRAPPED CAN FALL
OFF BEFORE IT REACHES THE ALLELE
AND THE COMPLEMENTARY GUIDE
SEQUENCES IS HIGHLIGHTED.
SO THESE WERE DATA I'VE SHOWN
BEFORE AND EACH GRAY DOT
RESPONSES A MOUSE IN IN VIVO
GENE EDITING PRE CLINICAL WORK
AND WE HAVE THE SECOND CONTROL
LEFT TO RIGHT OF THE ORANGE
COLORED ONE IS WHEN THERE'S PAM
ONLY HDR AND NO DIFFERENCE IN
EDITING ON UNFRACTIONATED
ERYTHROID LINEAGE AND YOU SEE
THE NICE ENRICHMENT FROM THE 20%
TO 25% OR SO MARROW NC34
POSITIVE POPULATION FOLLOWING
THE PRINCIPLES OF MIXED
CHIMERISM WITH IMPROVED SURVIVAL
OF THE CORRECTED ERYTHROID
PROGENITORS IN THE NICE TALK
GIVEN EARLIER BY ALEXUS LEONARD
AND NICE WORK BY GORDON FITZHUGH
SHOULD BE SUFFICIENT FOR A
CURATIVE AFFECT.
NON-HOMOLOGOUS EN JOINING IS OUT
OF FRAME ON THE FAR RIGHT PANEL
HAPPENS ABOUT 50% TO 70% OF THE
TIME.
UNFORTUNATELY IT CREATES THE
DROP OUT OF THE PROGENITORS AS
YOU PREDICT IN THE HALOCEMIA FOR
CLINICAL AFFECT.
SO WE SUCCESSFULLY COMPLETED OUR
PRE-CLINICAL MANUFACTURING
OUTCOMES USING CLINICAL GRADE
PATIENT MATERIALS IN THE
LABORATORY AND AGAIN CIRCLED ARE
THE HGR CORRECTION IN THE SIX
MONTHS WE RAN.
AND THE FIVE RUNS WE RAN WITH A
20% TO 25% CORRECTION BALANCED
BY A HIGHER FRACTION OF
INSERTION DELETION WITH A SINGLE
OFF-TARGET GENERALLY OCCURRING
5% OF THE TIME FULFILLED OUR INA
ENABLING GOALS FOR R&D.
WE HAVE SINCE COMPLETED THE
ACQUISITION OF CLINICAL GRADE
GMP GRADE RE-AGENTS AND SHOWS
THE COMPARABILITY TESTING ONE
MOST DIFFICULT TO CURE THE
SSOEN.
EACH BAR REPRESENTS A SICKLE
CELL DISEASE DONOR THE POSITIVE
CELLS FROM TWO DIFFERENT DONORS
AND COMPARES THE RNP ALONE WITH
OUR RESEARCH-USE ONLY TO GET
CLEARANCE OF THE IND AND THE
CURRENT CITY OF HOPE CLINICAL
GRADE.
YOU CAN SEE WITH VIABILITY AND
CLONOGENIC POTENTIAL THE OLICO
NUCLEOTIDES PERFORMED COMPARABLY
AND THE HDR AND NHEJ RATES ARE
ALSO COMPARABLE.
THIS CLEARED THE CLINICAL GRADE
SSODN FOR CLINICAL
MANUFACTURING.
FINALLY WE RECENTLY COMPLETED A
CLINICAL SCALE RUN USING ALL GNP
GRADE RE-AGENTS IN THE GENE
EDITING LABORATORY AT UCLA AND
WE AND DON COMBS' TEAMS HANDS
HAD RELEASE IN GENE EDITING AND
FREQUENCY AND OFF-TARGET
EDITING.
JUST TO GO THROUGH THE TIME
LINE.
THE IND WAS OBTAINED IN 2020 AND
THE PANDEMIC OCCURRED AND GOT
FUNDING RELEASED IN LATE 2021
AND JUST COMPLETED OUR
INITIATION VISIT AT UCLA AND
UCSF AND ANTICIPATE THE FIRST
PATIENT WILL BE ENROLLED NEXT
MONTH.
THIS WILL TAKE SEVERAL YEARS TO
COMPLETE THE UP TO NINE PATIENT
TRIAL.
SO THIS IS IN GREEN THIS TIME
LINE.
THIS WAS PRE-PANDEMIC.
IT WAS VERY OPTIMISTIC.
WE THOUGHT WE'D GET CLEARED OF
OUR FDA IND BY THE FALL OF 2020
AND WOULD APPLY FOR CLINICAL
TRIAL FUNDING IMMEDIATELY AND
WOULD HAVE IT IN HAND 2021 AND
BEGIN TO ENROLL PATIENTS.
THE NEXT SLIDE IS NOT GREEN IT'S
A REDDISH HUE AND JUST
ILLUSTRATES SOME OF THE
CHALLENGES WE EXPERIENCED ON OUR
WAY TO CLINICAL READINESS TO
COMMENCE PATIENT ENROLLMENT.
SO IT DID TAKE SEVERAL TWO
ROUNDS OF GRANT SUBMISSION AND
ULTIMATELY WE WERE SUCCESSFUL IN
PROCURING FUNDS BY THE END OF
2021.
WE ENGAGED A MANUFACTURING
FACILITY TO MAKE THE CLINICAL
GRADE SSODN IN 2021 AND EXPECTED
TO HAVE IT IN ONE YEAR TIME FOR
OCTOBER '22.
UNFORTUNATELY, THERE WERE
SIGNIFICANT DELAYS DUE TO
MANUFACTURING MATERIAL SUPPLY
CHAIN PROBLEMS THAT WERE VERY
COMMON IN THE PANDEMIC AND ITS
RECOVERY, AS YOU MIGHT REMEMBER
AND KEPT PLUGGING LONG AND HAD
AMENDMENTS ADDED TO THE IND AND
A CLINICAL PROTOCOL WAS IN 2022.
THIS GETS BRIGHT RED BECAUSE WE
HAD ONGOING DELAYS WITH THE
SSODN READINESS DELAY AND FILM
FINISH ULTIMATELY THE SSODN WAS
RELEASED IN JANUARY 2024.
DURING THIS PERIOD WE ALSO
DISCOVERED SINGLE NUCLEOTIDE
ERRORS IN THE SSODN THAT
RESULTED IN OUR FILING AN
AMENDMENT IN OCTOBER 2023 WITH A
MITIGATION PLAN ACCEPTED BY THE
FDA AND THEN SET UP OUR CLINICAL
GENOMIC SEQUENCING AND PROCESSES
LOCALLY AT UCSF.
I'M HAPPY TO SAY WE COMPLETED
THE INITIATION VISIT AT BOTH
CENTERS AND SHOULD BEGIN
ENROLLMENT NEXT MONTH.
BUT IT WAS A DAUNTING EXPERIENCE
FROM THE START AS WE STARTED TO
DO THE PRE-CLINICAL TESTING
OPTIMIZING THE EDITORS IN 2015
AND HERE WE ARE NINE AND A HALF
YEARS LATER TO ILLUSTRATE THE
PACE THINGS CAN SOMETIMES GO.
THIS IS DATA LAST YEAR WHEN WE
DISCOVERED SINGLE NUCLEOTIDE
ERRORS WITHIN THE SITE WITH THE
RESEARCH GREAT OLIGO.
THE CLINICAL GRADE ERROR RATE IS
MUCH LOWER GENERALLY LESS THAN
2% COMPARING THE GREEN SPIKES
FROM THE RESEARCH USE ONLY TO
THE ORANGE AND BLUE SPIKES WITH
THE CLINICAL GRADE.
SO THAT'S VERY GOOD NEWS.
OF INTEREST THE AREAS APPEAR TO
BE OCCURRING AT THE SAME BASIS
IN THE SYNTHESIS PATTERN.
SO WHY THIS HAPPENS IS A MYSTERY
AND IS SOMETHING THAT WILL
CONTINUE TO CHALLENGE THE
SYNTHESIS OLIGO NUCLEOTIDES FOR
HDR.
THE MOST COMMON SNIPS INTRODUCED
DO CREATE VARIANT HEMOGLOBINS
BUT I WAS HAPPY TO SHOW LAST
YEAR THESE ARE FOR THE MOST PART
COMPLETELY BENIGN AND PRO
SICKLING VARIANTS.
IT PROVIDES AN OPPORTUNITY FOR
BAR CODING, IF YOU WILL, TO LOOK
AT COLONIES AND CLONES GENERATED
THROUGH THE MANUFACTURING
PROCESS THAT WE'LL COME BACK TO.
SO, WHEN THIS WAS PUBLISHED
EARLIER THIS YEAR FROM CINDY
DUMBAR'S GROUP IT RAISED
CONCERNS IN ADDITION TO THE
SINGLE ENROLLMENT BIO WHERE
PERHAPS A LIMITING NUMBER OF
STEM CELLS WERE COMMON IN BOTH
THE CLINICAL SETTING AND IN THE
RHESUS MACAQUE MODEL.
WHAT CINDY'S GROUP SHOWED IS
TARGETING CD33 THEY WERE ABLE TO
GET IN PANEL B ABOUT 15% TO 20%
IN THE DRUG PRODUCT GENERATED
FROM THESE NON-HUMAN PRIMATES
AND IN THE PRODUCT IN THE VERY
DARK COLORS ARE THE THREE
DIFFERENT HGR ALLELE ASSORTMENT
AF THE EDITING TO ACCOUNT FOR
15% TO 20%.
BY SIX MONTHS POST TRANSPLANT IN
THE MODEL ALMOST ALL THE CD33
WAS WILD TYPE WITHOUT
PERSISTENCE OF HGR HEMATOPOIETIC
STEM CELLS COMPARED WITH THE
LENITY VECTOR COMPARED TO
INDELS IN GRAY AND HGR IN BRIGHT
ORANGE AND THE HGR ACCOUNTS FOR
FAR LESS THAN 1% OF THE
LONG-TERM REPOPULATING CELLS.
SO THESE TWO EXPERIENCES GAVE US
GREAT PAUSE AND OF COURSE WE'RE
VERY CONCERNED ABOUT RELIABILITY
OF OUR MOUSE MODEL COMPARED TO
THE CLINICAL AND NON-HUMAN
PRIMATE EXPERIENCE AND GET TO
REPOPULATED STEM CELLS TO HAVE A
CLINICAL BENEFIT.
IN OUR 2016 ITERATION OF THE
MANUFACTURING PROTOCOLS WE SAW
SOMETHING SIMILAR IF YOU LOOK AT
PANEL B, 10% TO 15% HGR IN BLUE
AND IN WEEK 16, 2% TO 3% EDITING
IN THE REPOPULATING STEM CELLS.
SO A SIGNIFICANT DROP OUT AS
CINDY DUMBAR SHOWED IN THE
NON-HUMAN PRIMATES AND WITH
IMPROVEMENTS AND THE PANEL
PUBLISHED YEARS AGO EACH OPEN
CIRCLE FOR THE COHORT OF MICE
DEPICTED IS THE INPUT
INVESTIGATIONAL PRODUCT COMPARED
TO ON THE MIDDLE PANEL B THE HGR
RATE AT THE MICE IN 16 TO 18
WEEKS.
WHILE THERE'S SOME DROP OFF IN
COHORT 1 AND 3, COHORTS 2 AND 3
SHOWED LITTLE DROP OFF IN
GENERAL AND THE BOTTOM PANEL
SHOWED NON-HOMOLOGOUS END
JOINING.
SOME ENRICHMENT BUT NOT
SIGNIFICANT AND WE ARGUE THE
IMPROVEMENTS INSTITUTED IN OUR
MANUFACTURING PROTOCOL MADE STEM
CELL EDITING VIA HGR AN EVENT
THAT OCCURS.
IN FACT THIS IS ILLUSTRATED
NICELY IN THE LABORATORY
COMPARING DIFFERENT MEDIA
CONDITIONS.
THE AOF AT THE TOP IS THE GMP
GRADE MEDIA WE USE CURRENTLY IN
THE LAB.
AND EX VIVO 15 FOR YEARS HAS
BEEN THE STANDARD MEDIA USE FOR
LET'S SAY LENITY VIRAL GENE
THERAPY MANUFACTURING.
WHAT THE AOF DID AND THE SFEM
DID MOVE MORE CELLS TO G1 WHERE
HGR CAN OCCUR AND ON THE BOTTOM
LEFT THE RATIO IMPROVED WHEN AOF
WAS IMPROVED AND THIS
ILLUSTRATES ONE OF THE THINGS
WE'VE DONE TO SELECT FOR HGR.
SO, THIS JUST SHOWED USING THE
BAR CODING THAT IN COHORT 1 MICE
YOU SEE THIS POLY CLONAL
DISTRIBUTION AT 18 WEEKS.
SO WE THINK WE'RE GETTING HGR
OCCURRING IN THE STEM CELLS IS
POLY CLONAL USING THE BAR CODING
WE HAVE AVAILABLE NOW AND GIVES
US HOPE AND CONFIDENCE TO
CONDUCT THE CLINICAL TRIAL.
SO THE LAST SLIGHT JUST
SUMMARIZES WHAT I PRESENTED.
THE CRITICAL QUESTIONS WILL THE
BALANCE OF ON TARGET INSERTION
DELETIONS AND HOMOLOGOUS REPAIR
BE BENEFICIAL FOR THE TYPE AND
IS THERE RISK OCCUR AND THE COST
RESTRICT ACCESS TO CARE.
THESE ARE ALL AND THANK YOU FOR
YOUR ATTENTION.
>> THANK YOU, MARK.
WE'LL MOVE TO OUR NEXT TALK
WHICH IS UPDATE ON THE BCL11A
LENTIVIRUS TRIAL AND DR. DAVID
WILLIAMS FROM HARVARD BOSTON'S
CHILDREN'S HOSPITAL.
>> I'M IN CLINIC BUT I HOPE TO
GO IN TOMORROW MORNING ALLOWING.
I WANTED TO START BY LIKE MARK
THANKING THE BLOOD DIVISION OF
NHLBI FOR SUPPORTING OUR TWO
TRIALS I'LL TALK ABOUT TODAY.
AND THE SUPPORT OF THE GRAFT
TRIAL AND THE LARGE GROUP AT
NHLBI THAT'S BEEN HELPFUL TO US
AND CALL OUT SUPPORT OF WHAT
WE'RE TRYING TO DO.
SO I WON'T BELABOR THIS IT'S
BEEN TALKED ABOUT AND DAN BAUER
DID A GREAT JOB THIS MORNING AND
THE GROUP KNOWS THIS ALREADY I
THINK BUT THERE'S A REASON TO
FOCUS ON FETAL HEMOGLOBIN
INDUCTION IN THE DISEASE AND
LOTS OF STUDIES IN THE PAST HAVE
SHOWN THAT EARLY IN NEWBORN LIFE
AND THE FETAL HEMOGLOBIN IS HIGH
THERE'S NO SYMPTOMS OF SICKLE
CELL AND SYMPTOMS OCCUR WHEN THE
BETA CELL IS TURNED ON.
THIS HAS BEEN DOCUMENTED NOW
THROUGH MANY YEARS WITH CLINICAL
DATA.
STUDIES SHOW PAIN AND FREQUENCY
AND EVEN DURATION OF LIFE ARE
ATTENUATED BY HIGHER HEMOGLOBIN
AND I'LL POINT OUT FROM A PAPER
A LONG TIME AGO HERE WE'RE
TALKING ABOUT FETAL HEMOGLOBIN
LEVELS ABOVE AND BELOW THE 9%.
WE'LL COME BACK TO THAT IN A
MINUTE.
AS YOU PROBABLY KNOW, GWAS
STUDIES IMPLICATED THE GENE 11A
AS A REGULATOR OF HEMOGLOBIN AND
IT'S A B CELL TRANSCRIPTION
FACTOR AND STUDIES WENT ON TO
VALIDATE THIS IN MODELS OF
SICKLE CELL DISEASE.
SO AS DAN POINTED OUT ALREADY,
OUR APPROACH IS TO USE LENITY
VIRAL VECTORS TO SWITCH FROM
BETA GLOBIN BACK TO FETAL AND
THAT'S OUR GOAL AND INCREASING
THE AFFECT OF HEMOGLOBIN F WHILE
REDUCING THE CONCENTRATION IN
THE CELL SIMULTANEOUSLY AND
COORDINATEDLY.
SO BASICALLY WE'RE TREATING
BCL11 AS A BINARY SWITCH INDUCE
LARGE LEVELS OF FETAL
HEMOGLOBIN.
TO DO THIS WE GENERATED A LENTI
VIRAL VECTOR THAT KNOCKS DOWN
BCL11A AND CALL THIS A SHARER.
THE REASON IS TWO.
IT ALLOWS US TO EXPRESS THE
SHRNA AT LEVEL CONSISTENT WITH
MICRORNA AND SECOND ALLOWS US TO
EXPRESS ONLY IN THE ERYTHROID
AND BY USING MICRORNA BACKBONE
WE CAN USE THE PROMOTER AND HS2
AND HS3 WITH THE MINIMAL BETA
PROMOTER AND IT WENT QUITE WELL.
THIS LED TO OUR FIRST STUDY
WHICH WAS A FEASIBILITY STUDY AT
THE SINGLE SITE STUDY INITIALLY
SEVEN PATIENTS TO BE ENROLLED
AND WE DID 10 BECAUSE THE TRIAL
WENT SO WELL.
WE HAD THREE DIFFERENT AGE
GROUPS AND AMENDED THIS AFTER
THE STUDY WAS STARTED THE LOWER
AGE GROUP TO INCREASE IT TO H12
BASED ON DATA FROM MARY'S PAPER
ON OUTCOMES OF IMPLANTATION.
YOU COULD NOT HAVE A MATCH
SIBLING DONOR AND COULD HAVE A
PHENOTYPE THAT FAILED HYDROXY
UREA AND THE BMP VECTOR WAS
PRODUCED AS PART OF A LICENSE
AGREEM
AGREEMENT.
THIS IS THE LENTI VIRAL PROTOCOL
AND MOBILIZED STEM CELLS I'LL
COME BACK TO IN A MOMENT.
AND THE BLOOD WAS TRANSDUCED AND
AFTER CRITERIA WAS MET THE
PATIENT WAS ADMITTED.
SO OUR INITIAL DATA WERE
PUBLISHED IN 2021 IN JANUARY AND
WE CALL THIS APPROACH
POST-TRANSCRIPTIONAL GENETIC
SILENCING OPPOSED TO GENE
EDITING BECAUSE WE ARE NOT DOING
DOUBLE STRAND BREAK TO ADD IT AT
THE BCL11A LOCUS AND FIRST PROOF
AS A TARGET.
I WANT TO TALK A MINUTE ABOUT
THE ADDITIONAL SAFETY THAT CAME
UP THIS MORNING SEVERAL TIMES.
THIS WAS THE FIRST TIME A
CHIMERIC THERAPY WAS USED AND AS
SPOKE ABOUT THIS MORNING IN THE
VIRAL IT'S A DIFFERENT
LENTIVIRAL VECTOR DESIGN AND
REQUIRED US TO IMPLEMENT
ANALYSIS FOR MUTATION ASSOCIATED
AS PART OF THE PILOT STUDY.
WE USED WHAT'S CALLED THE RAPID
HEME PANEL AT BRIGHAM AND
WOMEN'S HOSPITAL TO THE
CERTIFIED PANEL AND WE PUBLISHED
ANALYSIS POST-ENROLLMENT AND
POST TREATMENT A NUMBER OF
PATIENTS USING BANK STUDIES AND
PROSPECTIVELY FROM THAT POINT ON
AND I'LL TOUCH ON THE DATA IN A
MINUTE.
SO TODAY OVER 50 SAMPLE HAVE
BEEN ANALYZED USING THE TEST
WITH LONGEST FOLLOW-UP A LITTLE
OVER FOUR YEARS AND SHORTEST LAT
OVER THREE YEARS AND DID
ANALYSIS ON THE PATIENTS AND
I'LL TOUCH ON THE SAFETY DATA
ALSO.
SO I DID WANT TO MAKE THIS POINT
WHICH HAS NOT BEEN TALKED ABOUT
VERY MUCH TODAY.
BUT USING JOHN NAS' EXPERTISE WE
WERE ABLE TO MANUFACTURE
OUTSTANDING PRODUCTS FOR THE
PATIENTS AND FOR ALL BUT ONE OF
THEM THAT OCCURRED IN JUST ONE
MOBILIZATION COLLECTION CYCLE.
ONE PATIENT REQUIRED TWO AND IN
THESE THERE WERE TWO EFOREESE
AND I'LL CALL OUT THIS IS MY
COLLEAGUE AND THIS IS FROM THE
CRISPR PAPER FROM THE NEW
ENGLAND JOURNAL AND IN CONTRAST
BECAUSE OF THE LOSS OF CELLS
DURING EDITING APHERESIS WAS UP
TO THREE CONSECUTIVE DAYS FOR
EACH CYCLE AND BOTH COHORTS
REQUIRED THE MOBILIZATION CYCLE.
THERE'S A DRAMATIC DIFFERENT
BETWEEN THE PROCEDURE AND THE
TIME IT TAKES TO GENERATE THE
CELLS WE NEED FOR MANUFACTURING
WHEN YOUR DOING GENE EDITING FOR
THE LENTIVIRAL VECTOR
TRANSDUCTION AND WE'VE HAD YEARS
NOW OF EXPERIENCE IN DOING.
AND YOU CAN SEE THE SUMMARY OF
EACH PATIENT OF TIME POINTS PRE
AND POST INFUSION.
OF THE 10 PATIENTS ONE OF THE
SUBJECTS HAD A MUTATION PRESENT
AT LOW LEVEL BEFORE COLLECTION.
IT WAS BELOW FROM THE CLIA
STANDPOINT BUT ONCE WE FOUND THE
MUTATION AFTER THE INCLUSION
OCCURRED WE WENT BECOME AND
VALIDATED IT IT WAS THERE BEFORE
HAND.
YOU CAN SEE THE MUTATION IN THE
DMAP3A GENE READILY SEEN
MUTATION IN HEMATOPOIESIS AND
REMAINS STABLE AND FOLLOW THE
PATIENTS CLOSELY AND WERE
HEALTHY AND NO ABNORMALITIES
WITH REGARD TO THEIR BONE MARROW
OR RESPONSE TO THE THERAPY.
AND YOU CAN LOOK CAREFULLY AT
THE NO INSERTION SITE AND
ABNORMALITIES ASSOCIATED WITH
THE GROWTH AND WE'VE SEEN NO
SIGNAL AT ALL IN ANY OF THESE
PATIENTS AT ANY TIME POINTS
SEEN.
TREMENDOUSLY SAFE SO FAR.
I WON'T GO IN THE DETAILS OF THE
EFFICACY OF THE TIME POINT AND
THERE'S LONG-TERM FOLLOW-UP BUT
YOU CAN SEE FETAL HEMOGLOBIN IS
ROBUST WITH THE ONE EXCEPTION
WITH THE BLUE ARROW 20% TO 40%.
THE PERCENT OF F CELLS IS HIGH,
BROAD AND STABLE OVER TIME.
EXCEPT FOR ONE PATIENT WITH A
LOW IN VIVO BCN BELOW .2.
ALL THE OTHER PATIENTS HAVE BTNs
ABOVE .3 AND GOOD INDUCTION AND
RESULTS FROM THE THERAPY.
SO THIS INITIAL PILOT RESULT
ALONG THE FOLLOW-UP NOW IS OVER
FOUR YEARS.
IT SEEMED SAFE AND GOOD
TRANSDUCTION AND NO EVENTS
RELATED TO THE VECTOR ITSELF.
AND THERE'S A HIGH CELL IN THE F
CELL AND SIGNIFICANT ATTENUATION
OF THE PHENOTYPE WITH MINIMUM
VCN.
IT DOESN'T HAVE TO BE THREE,
FOUR OR FIVE OR GET GOOD
INDUCTION.
IT'S MORE ONE TO TWO.
SO I WASN'T ASKED TO TALK ABOUT
THE PAPER BUT WANTED TO MENTION
THEM TO YOU AND POINT THEM OUT
TO YOU.
WE PUBLISHED A PAPER WITH OUR
COLLABORATOR ON SINGLE CELL
ANALYSIS COMPARING PATIENTS WITH
THE TRIAL WITH THE PROOF OF
BLOOD HEAVILY WITH HYDROXYUREA
AND LOOKED AT THE EFFECT OF
MANUFACTURING AND TRANSDUCTION
AND ENGRAFTMENT WHICH IS
ACTUALLY RELEVANT TO GENE
EDITING PROTOCOL AND LOOKED AT
THE MUTATION BURDEN OF THIS
MANUFACTURING ENGRAFTMENT
PROCEDURE AND WE'RE DOING A
STUDY FUNDED BY TO THE GATES
FOUNDATION LOOKING AT THE
LANDSCAPE IN SICKLE CELL DISEASE
PATIENTS COMPARED TO TANZANIA
AND U.K. AND BOSTON AND
DEVELOPING IN VIVO GENE
TECHNOLOGY USING NANO PARTICLES
AND ALSO USING VIRAL VECTORS AND
MODIFIED VIRAL VECTORS.
THE TRIAL I'LL TALK ABOUT IS
PART OF A LARGE SCALE GENOMIC
ANALYSIS AT BRIGHAM AND WOMEN'S
HOSPITAL.
SO THIS BROUGHT US TO THE GRAPH
STUDY WHICH IS THE PHASE 2 STUDY
TO REDUCE SICKLE PAIN IN A
PATIENT'S RECEIVING THE THERAPY.
TO WRAP UP QUICKLY THIS IS NINE
CENTERS HERE AND ALL THE SITES
ARE ACTIVATED WITH THE P.I.s
LISTED.
AND THE STUDY DESIGN IS OPEN
LABELLED AND ASKING CAN THE
SINGLE INFUSION OF THE CELLS
WITH THE VECTOR REDUCE PAIN IN
THE PATIENTS.
WE HAVE A SAMPLE SIZE OF 25
INFUSED PATIENTS AND THE TIME
LINE FOR ENROLLMENT TO INFUSION
AS YOU CAN SEE IS FROM 2022 TO
2024.
I WANT TO POINT OUT THE PILOT
STUDY.
WE INCLUDED EXCLUSION FOR CP AND
PRIAPRISM AND A SUPER NATENT AND
ADJUSTMENT OF MOY AND
INTERESTING RESULTS.
AND WE'RE CONTINUING OUR
MONITORING OF GENE PRE AND POST
INFUSION OF LEUKEMIA ASSOCIATE
ED POST INFUSION AND THREES AN
INDEPENDENT PANEL ADJUDICATING
ALL THE RESULTS WITHIN 72 HOURS
OF BEING UPLOADED.
QUICKLY, WHERE WE'RE AT.
WE MADE VERY GOOD PROGRESS.
THERE'S BEEN 31 CONSENTS, 4
SCREEN FAILURES AND 22 PATIENTS
CURRENTLY ON STUDY.
OF 22 ONE WITH DREW AND ONE
IMMOBILIZED AND OF THOSE REMAIN
13 INFUSED, TWO MANUFACTURED AND
FIVE STARTED TRANSFUSIONS AND
THERE'S FIVE CONSENTED AND
SCREENING PROGRESS AND COMPLETED
ACCRUAL ASSUMING ALL FIVE
PATIENTS IN THE SCREENING MAKE
IT INTO THE ACTUAL PROTOCOL.
SO FAR THERE'S BEEN NO SAFETY
SIGNALS OR CONCERNS TO DATE AND
NO SCREENED PATIENTS HAVE HAD
PATHOGEN BEING MUTATIONS TO
DATE.
SO FAR THE TRIAL HAS GONE QUITE
WELL.
IT'S A COMPLICATED TRIAL WITH
LOTS OF SITES AND MANUFACTURING
AND SO WE'RE VERY THRILLED WITH
THE PROGRESS WE'VE MADE AND HOPE
TO SEE EFFICACY RESULTS IN THE
NEXT TWO YEARS.
SO HUGE AMOUNT OF WORK FROM MANY
PEOPLE IN BOSTON LISTED HERE.
THIS IS FUNDED BY RO1 AT NIH AND
THE GATES FOUNDATION.
AND IN THE GRASP TRIAL MARK AND
I ARE CHAIRS AND MARIO EAPEN HAS
BEEN INSTRUMENTAL IN GETTING THE
TRIAL RUNNING AND THE MEDICAL
COLLEGE OF WISCONSIN AND THE
TRIAL BY DANA FARBER.
AND THE GENE EDITING PROGRAM AT
BOSTON'S CHILDREN HAS BEEN VERY
HELPFUL IN MANY DISEASES AND
HAVE BEEN AN INTEGRAL PART OF
THIS.
THANK YOU VERY MUCH.
>> ANY ONLINE QUESTIONS.
>> WE HAVE A FEW.
>> GIVEN THE TIME, DAVID, CAN
YOU PLEASE RESPOND TO THE ONLINE
QUESTIONS?
WE NEED TO MOVE ON HERE.
>> OKAY, SURE.
>> FOR THE SAKE OF THE PROGRAM.
SO, WE'LL MOVE ON TO THE NEXT
TALK FETAL HEMOGLOBIN
AUGMENTATION FOR NON-CYTOTOXIC
EPIGENETIC THERAPEUTICS.
>> THANK YOU FOR THE
OPPORTUNITY.
THESE ARE MY DISCLOSURES.
THIS IS NOT JUST TO IMPROVE THE
QUALITY OF LIFE BUT THE QUANTITY
OF LIFE AND ONE CLUE HOW YOU MAY
WANT TO ADDRESS THAT PROBLEM IS
ONE OF THE MOST IMPORTANT
PREDICTORS OF EARLY DEATH IN
ADULT COHORTS IS DECLINING
ABILITY TO COMPENSATE FOR THE
CHRONIC HEMOLYSIS THAT CAN BE
MEASURED BY HEMOGLOBIN LEVEL.
BASICALLY LESS THAN TENFOLD OF
THE COUNT.
AND ANOTHER CLUE IS TO LOOK AT
THE CHARACTERISTICS OF THE
PATIENTS.
THEY HAVE LOWER HEMOGLOBIN
LEVELS AND HIGHER SERUM
REACTANT.
AND UNFORTUNATELY THE DRUG WE
HAVE TRYING TO INCREASE THE
FETAL HEMOGLOBIN IS UNABLE TO
SUSTAIN THROUGH THAT FOR THE
PATIENTS.
WHAT YOU SEE HERE IS GRAPHS OF
FETAL HEMOGLOBIN OVER TIME AND
THE PATIENTS ONE THE LOWER FETAL
HEMOGLOBIN IS WHERE HIGH DROX
DROXY -- HYDROXYUREA WAS UNABLE
TO CHANGE AS SEEN IN THE GRAPH
ON THE RIGHT.
WE NEED OTHER WAYS OF INCREASING
FETAL HEMOGLOBIN.
YOU HEARD OF GENE THERAPY
TARGETING THE PROTEIN HUB
REPRESSING THE FETAL HEMOGLOBIN
GENES AND THE DNA BINDING FACTOR
BUT WE CAN POTENTIALLY USE SMALL
MOLECULES TO INHIBIT THE ENZYMES
BEING RECRUITED BY BCL11A AND
EVEN IDENTIFY THE ENZYMES.
IF WE PULL IT DOWN HERE WE CAN
USE AND IDENTIFY THE REPRESSING
ENZYMES WITHOUT MEDIATING THE
SILENCING OF THE FETAL
HEMOGLOBIN GENE.
NOT ALL THESE ENZYMES CAN BE
INHIBITED WITHOUT CAUSING
DEVASTATING EFFECTS TO SOLVE
PHYSIOLOGY BUT I'M GOING TO SHOW
YOU CLINICAL AND PRE-CLINICAL
PROOF OF PRINCIPLE TO INHIBIT
THE TRANSFERASE AND THE MARKER
AND CHG.
AND THIS IS THE MOLECULE.
IT EXTENSIVELY DESCRIBED THE
CHEMISTRY AND CELL PHYSIOLOGY
THAT ALLOWS US TO USE THE MOL
CALL TO TARGET WITHOUT
CYTOTOXICITY.
SO WE IDENTIFIED THE MINIMUM BIO
LOGICALLY AFFECTED DOSES AND USE
THEM TO TREAT PATIENTS.
MANY OF WHOM ARE IN THE COHORTS
FROM THE TRIAL WHERE HYDROXYUREA
WAS ABLE TO INCREASE FETAL AND
TOTAL HEMOGLOBIN AS YOU SEE IN
THE GRAPHS AND THE MEASUREMENTS
WERE FOUR WEEKS AND EIGHT WEEKS.
THIS GRAPH IS SHOWING WE COULD
PRODUCE WITH THIS STRATEGY FETAL
HEMOGLOBIN INCREASES IN THE
PATIENTS WHERE HYDROXYUREA WERE
UNABLE AND ON THE RIGHT IS WHERE
IT WORKED FOR A WHILE AND
DISCONTINUED FOR WHATEVER REASON
AND ALSO THIS APPROACH WAS VERY
EFFICACIOUS.
SO TO IMPROVE THE ACCESSIBILITY
AND POSSIBILITY OF USING THIS
APPROACH WORLDWIDE AND
SUSTAINABLE IN AN ACCESSIBLE WAY
WE SPENT TIME CONVERTING THE
THERAPY AND IDENTIFIED THE
MINIMUM EFFECTIVE DOSE OF THE
ORAL THERAPY TO TARGET AND THIS
IS THE FIRST LONG-TERM
DEMONSTRATION OF A SUSTAINABLE
INCREASE IN FETAL HEMOGLOBIN.
THIS RANDOMIZED THE PATIENTS TO
RECEIVE VITAMIN B3 ALONE OR ORAL
TARGETING AGENT FOR 12 WEEK AND
RECEIVED A COMBINATION THERAPY.
THERE'S ONE PATIENT IN WHOM THE
DOSE OF THE TARGETED THERAPY WAS
BELOW THE MINIMUM BIO LOGICALLY
EFFECTIVE DOSE BECAUSE OF HIGH
BODY WEIGHT NOT ANTICIPATED IN
THE PROTOCOL AND BASICALLY WE
WERE WORKING WITH THE MINIMUM
EFFECTIVE DOSE AND SUSTAINABLE
FETAL HEMOGLOBIN INCREASES IN
THE 1 TO 2 GRAM PER DECILITER
RANGE.
AND BECAUSE WE TREATED THESE
PATIENTS FOR ABOUT A YEAR, IT
GAVE US ENOUGH TIME TO LOOK AT
CRISIS FREQUENCY.
THESE PATIENTS WERE AGAIN
HYDROXY REFRACTORY MOST IN THE
CATEGORY OF PATIENTS AT RISK
ALMOST ALL OF THEM FOR EARLY
DEATH SO THERE'S COMPLICATIONS
AT BASELINE.
VERY FREQUENT ADMISSIONS IN THE
YEAR PRIOR TO THE THERAPY AND
THE CRISIS FREQUENCY WAS
SIGNIFICANTLY REDUCED IN THE
YEAR ON THIS THERAPY.
THAT WAS CLINICAL PROOF OF
PRINCIPLE FOR PATIENTS WITH THE
HIGHEST RISK OF EARLY DEATH AND
SHOW PROOF OF PRINCIPLE WE CAN
TARGET ANOTHER TAR GET AND THAT
IS THE ATP CHROMATIN REMODELS
REPOSITION NUCLEOSOMES.
AT TO THE BUSINESS END OF
EPIGENETICS AND THERE WERE NO
SMALL MOLECULES TO INHIBIT THE
ENZYMES SO WE DEVELOPED ONE.
AND THESE MOLECULES ARE NOT NON
CYTOTOXIC AND YOU CAN LOOK AT
THE VIABILITY OF HEALTHY HUMAN
CD 34 POSITIVE PROGENITOR CELLS.
THEY DON'T ACTIVATE THE FLOW
DATA YOU SEE HERE AND THE COLONY
FORMING ASSAY DATA WE DON'T SEE
A SIGNIFICANT DECREASE AND
POSITIVE CONTROL.
AND THESE MOLECULES ARE ABLE TO
INCREASE FETAL HEMOGLOBIN EVEN
IN HEMATOPOIETIC PROGENITOR
CELLS AND IN THE IN VITRO STUDY
WE SEE SEVERAL FOLD INCREASE IN
FETAL HEMOGLOBIN.
SO I GUESS PART OF THE PROBLEM
I'M ALLUDING TO IS THE
DIMINISHED PROGENITOR CELL IN
THE BONE MARROW THAT COULD BE
MEASURED SHOWN IN THE GRAPHS ON
THE LEFT THE FIRST VASO
OCCLUSION IS ONE FACTOR AND
DAMAGE CONTRIBUTING TO THE
DECLINE OF THE SITE AND ANOTHER
FACTOR IS THE STRESS IN THE BONE
MARROW THAT DEPLETES
MITOCHONDRIAL OUTPUTS SUCH AS
NAD AND NAD IS A CO-FACTOR FOR
EPIGENETIC ENZYMES THAT MEDIATE
HEMATOPOIETIC STEM CELL HEALTH
AND THAT'S PART OF THE RATIONALE
WHY WE INCLUDED IT IN THE
PROBLEM WE SHOWED EARLIER.
SO THIS IS MY FINAL SLIDE.
ONE ASPECT WE HAVE TO DEAL WITH
IS STRATEGIES TO INCREASE FETAL
HEMOGLOBIN AND IT CAN BE DONE
WITH SMALL MOLECULES THAT TARGET
ENZYMES IN THE BCL11A ITSELF.
WE SHOULDN'T NEGLECT IT'S NOT
JUST THE HEMOGLOBIN ACCESS
CONTRIBUTING TO ANEMIA LEADING
TO EARLY DEATH THERE'S INDIRECT
CONSEQUENCES.
THE DAMAGE AND REDUX STRESS AND
THE DEPLETION OF IMPORTANT
METABOLIC COFACTORS NEEDED FOR
PROGENITOR HEALTH AND THESE ARE
ALL POTENTIALLY REMEDIABLE.
I'D LIKE TO THANK THE FUNDERS
AND THE PATIENTS.
THANK YOU VERY MUCH.
>> ANY QUESTIONS?
NO ONLINE QUESTIONS?
OKAY.
THANK YOU.
SO OUR NEXT TALK IS FOR SICKLE
CELL DISEASE AND CARDIOVASCULAR
RISK-RED CELL EXCHANGE TRIAL AND
MARIA BROOKS UNIVERSITY OF
PITTSBURGH IS GOING TO TALK
ABOUT THIS.
GO AHEAD, MARIA.
>> OKAY.
NEXT SLIDE, PLEASE.
IT'S MY PRIVILEGE TO SPEAK TO
YOU ABOUT WHAT WE CALL THE SCD
CARRE TRIAL.
IT'S DONE IN COLLABORATION WITH
OUR CLINICAL COORDINATING CENTER
WHICH IS RUN THROUGH THE
UNIVERSITY OF MARYLAND WITH
DR. GLADWIN AND THE UNIVERSITY
OF PITTSBURGH.
WE'RE FORTUNATE TO BE FUNDED
THROUGH NHLBI THROUGH THE BLOOD
DIVISION AND A WONDERFUL
COLLABORATION AND WE HAVE
COLLEAGUES FROM UNIVERSITY OF
ILLINOIS AND PITTSBURGH.
THE TRIAL INCLUDES AN ALL-STAR
CAST OF SITES AND EACH SITE IS A
COLLABORATION BETWEEN THE
HEMATOLOGY CARE OF SICKLE CELL
PATIENTS AND THE ATRANSFUSION
MEDICINE FOLKS AND WORKING
TOGETHER TO DESIGN AND IMPLEMENT
THE TRIAL.
EFFECTIVELY THIS IS AGAIN A
RANDOMIZED PARALLEL TWO-ARM
CLINICAL TRIAL WHERE PATIENTS
ARE ASSIGNED TO EITHER STANDARD
OF CARE OR STANDARD OF CARE PLUS
EXCHANGE TRANSFUSION.
IT'S A 12-MONTH INTERVENTION
PLUS ANOTHER ONE-MONTH OF FOLLOW
UP WHERE WE'LL ASSESS OUTCOMES.
WE DID HAVE TO EXTEND ENROLLMENT
FOR ONE YEAR AND HAD TO GO TO
OUR NO-COST EXTENSION PERIOD BUT
DOING WELL WITH ENROLLMENT.
THE TARGET IS 150 PARTICIPANTS
RANDOMIZED IN THE AND WE'RE AT
129.
WE ANTICIPATE ENROLLMENT WILL BE
COMPLETED IN DECEMBER OF THIS
YEAR AND AN EXTRA YEAR OF
FOLLOW-UP AT BEGINNING OF 2026
WE SHOULD PUT TOGETHER THE DATA
FOR THE TRIAL.
SO JUST TO REMIND YOU, I KNOW
THIS TRIAL HAS BEEN PRESENTED A
COUPLE TIMES AT THIS MEETING BUT
THIS IS A TRIAL WHERE WE'RE
LOOKING AT AUTOMATED CELL
TRANSFUSION PLUS STANDARD OF
CAIRO OPPOSED TO STANDARD OF
CARE ALONE AND LOOKING AT
EPISODES OF WORSENING OF SICKLE
CELL DISEASE REQUIRING AN ACUTE
HEALTH CARE ENCOUNTER ORE RESULT
IN DEATH AMONG HIGH-RISK ADULT
SICKLE CELL DISEASE PATIENTS.
THE SECONDARY AIM IS TO EVALUATE
THE ADDITION OF AUTOMATED RED
BLOOD CELL AND LOOKING AT
QUALITY OF LIFE AND PAIN AS WELL
AS LOOKING AT SAFETY OUTCOMES.
IT'S A POPULATION INTERVENTION
AND OUTCOME AND I'LL BRIEFLY GO
THROUGH THAT.
THESE ARE OF COURSE ALL
PARTICIPANTS WHO HAVE SICKLE
CELL DISEASE.
THEY ARE ADULTS.
THEY COULD NOT HAVE BEEN ON
CHRONIC EXCHANGE TRANSFUSION IN
THE PAST 60 DAYS AND THEY HAVE
TO HAVE A STABLE DOSE FOR THEIR
DRUGS.
MOST IMPORTANTLY THEY ARE
DEFINED AS HIGH RISK AS EITHER
HAVING PULMONARY HYPERTENSION AS
DEFINED BY THE TRV OR CHRONIC
KIDNEY DISEASE USING EF GFR OR
ACR.
THE EXCLUDE PATIENTS WHO WOULD
HAVE RED BLOOD CELL
ALLOIMMUNIZATION OR SEVERE
TRANSFUSION REACTIONS AND ANYONE
WHO HAD A STROKE WITHIN THE LAST
SIX MONTHS IS ALSO EXCLUDED.
AND WE LOOK AT ANTIBIOTICS AND
TRANSFUSIONS IF THEY'RE
CLINICALLY INDICATED.
TRANSFUSIONS ARE ALLOWED EVEN IN
STANDARD OF CARE.
WHAT WE'RE -- AND THESE
STANDARDS ARE FROM NHLBI,
AMERICAN THORACIC SOCIETY AND
AMERICAN SOCIETY OF HEMATOLOGY.
WHAT WE'RE CONTRASTING IT WITH
IS THE SAME STANDARD OF CARE BUT
THE ADDITION OF RED BLOOD CELL
EXCHANGE TRANSFUSIONS.
THE PROTOCOL IS STRUCTURED SUCH
THE PARTICIPANT WOULD COME IN
AND HAVE A TRANSFUSION EVERY
THREE TO SIX WEEKS.
THE GOAL IS TO HAVE THE
HEMOGLOBIN LEVELS BELOW 20% AND
THEN RE-TRANSFUSE IF THEY GOT
ABOVE 30%.
IN ADDITION, WE HAVE A TARGET
HEMOGLOBIN LEVEL OF 10 GRAMS PER
DECILITER.
THE END POINT ARE ACUTE HEALTH
CARE ENCOUNTERS OR DEATHS OVER
THE 13 MONTHS OF FOLLOW-UP.
AND WE'RE LOOKING FROM BEST TO
WORSE WHICH INCLUDES DEATH AS
WELL AS THE MAJOR COMPLICATIONS
WE'RE INTERESTED IN STROKE,
ACUTE KIDNEY LEVER OR ACUTE
CHEST SYNDROME AND THE SECONDARY
END POINTS INCLUDE EXERCISE
CAPACITY, CARDIOVASCULAR
FUNCTION, CARDIOVASCULAR RISK
BIOMARKERS AND PAIN.
AGAIN, I'M A STATISTICIAN.
I RUN THE DATA COORDINATING
CENTER AND I THOUGHT SINCE I WAS
TALKING TO YOU I'D TALK ABOUT
WHAT PLAGUES US WHEN WE'RE
TRYING TO THINK OF DESIGNING
TRIALS PARTICULARLY AT THE RARE
DISEASE SETTINGS WHERE WE KNOW
WE DON'T HAVE MUCH PARTICIPANTS
AND WANT TO MAKE THE MOST FROM
THE INFORMATION WE GET FROM THE
TRIAL.
I WANTED TO FOCUS BRIEFLY ON TWO
ELEMENTS WHICH IS HOW WE THINK
ABOUT THE RANDOMIZATION AND HOW
WE THINK ABOUT SELECTING TRIAL
END POINTS AND ANALYSIS
STRATEGIES IN ORDER TO OPTIMIZE
THE POWER AND GET THE MOST
INFORMATION THAT WE CAN FROM THE
DATA WE GET IN A TRIAL.
WE HAVE AN ADAPTIVE
RANDOMIZATION RANDOMIZE
PARTICIPANTS TO EXCHANGE OR
STANDARD OF CARE IN A ONE TO ONE
RATIO AND BALANCE THE
RANDOMIZATION AS BEST AS WE CAN
WITHIN THE 150 PARTICIPANT.
WE'RE GOING TO USE AN INDIVIDUAL
PARTICIPANT COVARIATE ADAPTIVE
RANDOMIZATION AND THE IDEA IS
EACH INDIVIDUAL IS RANDOMIZED
AND OUR GOAL IS TO HAVE THE SAME
NUMBER IN EACH INTERVENTION
GROUP AS WELL AS TO BALANCE EACH
OF THE FOLLOWING COVARIANTS.
SO WE'RE INTERESTED BEFORE THEY
ARE RANDOMIZED AND UNDERSTANDING
THEY'RE HYDROXYUREA USE AND
CHRONIC KIDNEY DISEASE, SEX,
HEMOGLOBIN GENOTYPE AND THE
CLINICAL SITE.
HERE AGAIN YOU CAN TWO THROUGH A
COUPLE ADVANCEMENT.
WE TAKE THE QUALITY OF EACH
PARTICIPANT BEFORE THEY'RE
RANDOMIZED.
WE LOOK AT THE BALANCE FOR EACH
OF THE CHARACTERISTICS.
AND WHAT WE DO IS WE SAY WHAT
HAPPENS IF THEY ARE ENROLL AND
ASSIGNED TO RED BLOOD CELL.
WHAT HAPPENS IF THEY'RE ENROLLED
TO STANDARD OF CARE?
NEXT AND NEXT AND WHAT WE FIND
IS THAT HOW IN BALANCE WOULD
THEY BE IN EACH OF THE
SITUATIONS AND CREATE THE METRIC
AND BY COMPARING THE IMBALANCE
IF THEY WERE RANDOMIZED TO
STANDARD OF CARE AND RANDOMIZED
TO EXCHANGE WE SAY, LOOK, IF
IT'S ALMOST THE SAME BETWEEN 40%
AND 60%, 50/50 YOU'LL BE
RANDOMIZED TO EXCHANGE OR
STANDARD OF CARE.
HOWEVER, IF THE IMBALANCE IS
SUCH THAT THE IMBALANCE WOULD BE
WORSE IF RANDOMIZED TO STANDARD
OF CARE WE USE WHAT WE CALL THAT
BIASSED COIN DESIGN AND SAY IT
WILL BE A 75% CHANCE THEY'LL GET
RED BLOOD CELL CHANGE AND 25%
THEY'LL GET STANDARD OF CARE
CHANCE.
THE IMPORTANT THING IS THAT IT'S
NEVER DETERMINISTIC.
THERE'S ALWAYS SOME RANDOMNESS
IN THIS BUT WE BIAS THE
RANDOMIZATION IN ORDER TO
ENHANCE THE BALANCE IN THE
TRIAL.
AND WE'RE USING A NUMBER OF
OUTCOMES IN THIS TRIAL.
THE FIRST ONE IS THE PRIMARY
OUTCOME WHICH IS A COUNT OF THE
NUMBER OF ACUTE HEALTH CARE
ENCOUNTERS.
THE SECOND IS ONE THAT'S BECOME
POPULAR THESE DAYS WHICH IS THE
ORDERED OUTCOMES WE SAY ON A
SCALE 1 TO 6 FROM BETTER TO
WORSE LET'S SEE HOW BAD THINGS
WERE OVER THE 13 MONTHS OF
FOLLOW-UP AND PUT YOU ON A SCALE
1 TO 6 OF NOTHING HAPPENING ALL
THE WAY TO DEATH.
YOU CAN THINK HOW LONG ARE YOU
FREE OF AN ACUTE HEALTH CARE
ENCOUNTER AND SO THIS IS LIKE
TIME THREE OF AN EVENT AND THEN
FINALLY WE LOOK AT THOSE
LONGITUDINAL OUTCOMES OVER TIME.
FOR EXAMPLE, HOW DOES PAIN
CHANGE OVER TIME FROM BASELINE
ACROSS FOUR MONTHS, EIGHT MONTHS
AND 12 MONTHS?
AGAIN, THIS IS A CLINICAL TRIAL
SO OUR MAJOR GOAL IS TO COMPARE
THE TWO TREATMENT ARMS.
THIS IS THE PAINIMATION AND AN
INNOVATIVE OUTCOME WHERE WE TALK
ABOUT THE LOCATION OF PAIN,
INTENSITY AND DURATION.
OUR GOAL WAS TO SAY WE WANT IT
USE THESE DATA AS BEST AS
POSSIBLE.
SO LET'S DO A SIMULATION STUDY
TO COMPARE POWER FOR OUR KEY
OUTCOMES WHICH WE THINK OF AS
THE COUNT OF HEALTH CARE
ENCOUNTERS, THE TIME TO THE
FIRST ACUTE HEALTH CARE
ENCOUNTER TO THE SIXTH LEVEL
PRIORITIZED AND I SEE IT'S
ALREADY 2:00 SO I'LL GO THROUGH
THIS QUITE QUICKLY.
WE BASICALLY DID A SIMULATION
STUDY DOING 10,000 TRIALS
EFFECTIVELY EACH ONE WITH A 150
PARTICIPANTS AND SIMULATED DATA
AS THOUGH THEY HAD HEALTH CARE
ENCOUNTERS OVER TIME AND MAY OR
MAY NOT HAVE DIED OR MAY OR MAY
NOT HAVE HAD COMPLICATIONS.
I HIGHLIGHT A COUPLE EXAMPLES
AND THESE ARE SITUATIONS WE
THOUGHT WERE POSSIBLE WITHIN SCD
CARRE AND DISTINGUISH BETWEEN
3.68 HEALTH CARE ENCOUNTERS IN
ONE ARM COMPARED TO A 26%
REDUCTION WHICH IS 2.72 HEALTH
CARE ENCOUNTERS.
THE QUESTION IS, HOW DOES THE
POWER WORK FOR DETECT THE
CHANGES IF THIS WERE THE
SITUATION?
THE DIFFERENCE BETWEEN SCENARIO
2 AND 3 ARE WHAT IF COMPLICATION
IN THE RANGE OF 10% TO 8% PER
HEALTH CARE ENCOUNTER OR IF
THERE ARE A WHOPPING 37%.
YOU'LL SEE IN THE PICTURES THE
COUNT IS ACTUALLY QUITE
EFFECTIVE IN TERMS OF
DISTINGUISHING BETWEEN ONE
SCENARIO AND ANOTHER.
AT THE RIGHT THE PRIORITIZED IN
OTHER WORDS GOING FROM A 1 TO 6
DOESN'T DISTINGUISH MUCH IF SOME
HAVE ENCOUNTERS OR 1 OR 0
COMPLICATIONS WHERE IT DOES
DISTINGUISH THE MORE SPREAD
THERE IS.
IF THERE'S AN ORDERED OUTCOME
WHERE YOU HAVE PEOPLE WITH MILD
OUTCOMES AS WELL AS SEVERE
OUTCOMES.
I HAVE TWO MORE SLIDES.
THAT'S BASICALLY WHAT WE
CONCLUDED WAS THAT TO THE COUNT
OUTCOME HAD THE HIGHEST
STATISTICAL POWER THE COUNT OF
ACUTE HEALTH CARE ENCOUNTERS.
I WAS PERSONALLY SURPRISED THAT
TIME TO EVENT DID NOT EXCEED 90%
POIR IN ANY OF OUR SCENARIOS AND
THAT AND ORDERED RANK OUTCOME
WHICH HAS BECOME POPULAR WORKS
WELL IF YOU HAVE A WIDE
DISTRIBUTION OF DATA BUT DID NOT
ACTUALLY DO SO WELL IF PEOPLE
ARE CLUSTERED ON ONE END OR THE
OTHER.
WE RECOGNIZE THE GENERALIZE ARE
BASED ON THE SITUATION.
I CONCLUDE SCDCARRE IS THE BEST
OPTION FOR HIGH RISK PATIENTS
WITH SICKLE CELL DISEASE AND
BOTH INTERVENTION STRATEGIES
CONSISTENT WITH STANDARD OF CARE
OR STANDARD OF CARE PLUS RED
BLOOD CELL EXCHANGE.
OUR GOAL AS WE IMPLEMENT THE
TRIAL IS TO GET TO THE MOST OUT
OF THE DATA WE HAVE IN THE
TRIAL.
AND FOCUS ON MAKING SURE OUR TWO
INTERVENTION GROUPS ARE AS
COMPARABLE AS POSSIBLE AND WE'RE
USING A COVARIATE ADAPTIVE
RANDOMIZATION EXTREME TO DO THAT
AND TRYING TO IDENTIFY CLINICAL
AND PATIENT-CENTERED OUTCOMES
THAT ARE IMPORTANT TO
PARTICIPANTS BUT ALSO HAVE A
VARIETY OF ANALYTIC APPROACHES
AND FOCUSSING ON THOSE THAT HAVE
GOOD STATISTICAL POWER SO WE'RE
IN A POSITION TO DETECT
CLINICALLY MEANINGFUL TREATMENT
DIFFERENCES.
THANK YOU.
>> THANK YOU, MARIA?
ANY CALLING QUESTIONS?
>> WALLY SMITH FROM RICHMOND.
SO I THINK OF EVENTS AS
HURRICANES AND THINK OF SUB
CLINICAL PAIN CRISES AT HOME AND
OTHER PAIN AS OTHER EVENTS LIKE
TORNADOS AND PREVAILING WINDS.
SO THE STACK INTRIGUES ME BUT
NOT SURPRISED HURRICANES CAUSE
DEATH AND CURIOUS ABOUT THE
STACK AND THE METAPHOR I GOT
THROUGH TALKING ABOUT THE
ORDERED RANKING AND TRY TO PUT
SOME WEIGHT ON THOSE.
>> YEAH, SO I HEAR WHAT YOU'RE
SAYING.
WHEN YOU JUST COUNT HEALTH CARE
ENCOUNTERS IT DOESN'T FEEL LIKE
THEY SHOULD ALL HAVE EQUAL
WEIGHT, RIGHT.
SO WORSE LIKE WHEN WE TRY TO
DEFINE THOSE AS THE END ORGAN
COMPLICATIONS IT MEANS SOMETHING
WORSE THAN JUST THOUGH WE KNOW
THE VASO OCCLUSIVE CRISIS ARE
VERY BAD, WE THOUGHT THOSE MAYBE
ARE LIKE THE HURRICANES THAT MAY
LEAD TO DEATH.
THAT WAS OUR ATTEMPT AT TRYING
TO SAY NOT ALL HEALTH CARE
ENCOUNTERS ARE EQUALLY BAD AND
TRYING TO SEPARATE OUT.
THE QUESTION IS IS THERE ENOUGH
DIFFERENTIATION OF PARTICIPANTS
IN A TRIAL LIKE THIS TO SEE THAT
AND ARE WE FOLLOWING THEM LONG
ENOUGH SO THAT AGAIN WE ARE
SEEING THEM ALL THE WAY THROUGH
TO THESE UNFORTUNATE HURRICANES.
WE'LL HAVE TO PUT THAT IN.
>> THANK YOU FOR A WONDERFUL
TALK.
WE'RE GOING TO TAKE A SHORT
BREAK UNTIL 2:15.
AND PLEASE COME IN HERE PROMPTLY
AT 2:15 OR EARLIER.
WE HAVE SYMPOSIUM 2 GENE THERAPY
TO BE GENE THERAPY CLINICAL
IMPLEMENTATIONS.
PATIENT AND PROVIDER PERSPECTIVE.
TALK ABOUT GENE THERAPY FOR
SICKLE CELL DISEASE, WHO, HOW,
WHERE AND WHEN.
CHAIRS ARE DR. FITZHUGH AND
DR. STROUSE FOR THIS TALK.
>> ALL RIGHT.
THANK YOU.
SO I WANT TO THANK THE NHLBI FOR
INVITING US TO DO THIS
SYMPOSIUM.
OUR SYMPOSIUM IS GENE THERAPY,
CLINICAL IMPLEMENTATION.
THIS IS THE SICKLE CELL ADULT
PROVIDER SYMPOSIUM.
I WANT TO START WITH THE MISSION
TO ESTABLISH AND SUPPORT AN
INTERACTIVE NETWORK FOR HEALTH
CARE PROVIDERS AND INVESTIGATORS
WHO SERVE ADULTS WITH SICKLE
CELL DISEASE AND WELCOME
PARTICIPATION FOR ANY PROVIDER
WITH AN INTEREST IN SICKLE CELL
DISEASE AND FAMILIES MEMBERS
LIVING WITH SICKLE CELL DISEASE.
SO THE GOALS ARE TO ESTABLISH
COMMUNICATION AND SUPPORT AMONG
ADULT SICKLE CELL DISEASE
PROVIDERS AND HAVE A WHAT'S APP
GROUP AND TO DEVELOP AND
DISSEMINATE ADULT SICKLE CELL
DISEASE INFORMATION AND ATTRACT
AND FOSTER CAREERS AND SCAPN WAS
INCORPORATED IN 2003 AND WE HAVE
ASSIST AN FOR CAREER DEVELOPMENT
AND HAVE THE WHAT'S APP GROUP
WHICH REQUIRES AN ADMINISTRATOR
APPROVAL AND LIMITED TO
PROVIDERS WITH SICKLE CELL
DISEASE HELP.
TODAY WE ARE GOING HAVE TWO
CASES OF PEOPLE THAT ARE
REQUESTING THERAPY.
THE FIRST CASE THE DISCUSSANTS
WILL BE SOPHIE LANZKRON AND RABI
HANNA AND WE'LL ANSWER QUESTIONS
ABOUT THE CASES AND DISCUSSION
AND JOINED WITH AN A PERSON WITH
SICKLE CELL DISEASE WHOSE UNDER
GONE CURATIVE THERAPY AND
JOINING US JULIE KANTER WILL
PRESENT ON GENE THERAPY
PROGRAMS.
WITH THAT I'LL PRESENT THE FIRST
CASE AND THEN WE'RE GOING TO GO
BACK AND FORTH WITH THE
QUESTIONS BETWEEN OUR TWO
DISCUSS IN THE JA -- DISCUSSANTS
AND A 26-YEAR-OLD WOMAN WITH
HBSS AND ISCHEMIC STROKE AND HAS
HAD DIFFICULTY MAINTAINING
REGULAR RED BLOOD CELL
TRANSFUSIONS SECONDARY TO
TRANSPORTATION AND OTHER
BARRIERS.
SHE HAD A RECURRENT STROKE AFTER
THREE MONTH SYMPTOM IN
TRANSFUSION.
SHE'S BEEN ON INTERMITTENT
TRANSFUSION AND CONTINUOUS HI
HYDROXYUREA AND HAD AN INITIAL
STROKE IN 2015 AND ANOTHER IN
2023 WITH A MILD RIGHT HEMI
PARESIS AND HOSPITALIZED ON
AVERAGE ONCE A YEAR WITH VASO
OCCLUSIVE ADVOCATES AND HAD
ACUTE CHEST SYNDROME TWICE AND
ADMISSION BUT TRANSFUSED AND HAS
SIGNIFICANT TRANSFUSIONAL IRON
OVERLOAD AND SICKLE CELL
RETINOP
RETINOPATHY.
SHE HAS NORMAL CARDIAC FUNCTION
AND ATRIAL SHUNTING AND HAD
ARTERY OCCLUSION AND MOYAMOYA
AND HAD THE INDICATED DRY WEIGHT
LIVER AND HAD AN ALT IN THE
UPPER
UPPER 40s AND HAS NO MICR
MICROALBUMINURIA.
I'LL GIVE THE FIRST DISCUSSION
QUESTION THE EFFICACY OF GENE
THERAPY VERSUS TRANSPLANTATION
FOR PEOPLE WITH SICKLE CELL
DISEASE IN CNS DISEASE.
DR. LANZKRON.
>> WE DON'T HAVE A LOT OF DATA.
THIS IS A 26-YEAR-OLD ONE OF THE
KEY THINGS MENTIONED WAS HER
COGNITIVE DISFUNCTION AND
NON-ADHERENCE TO HER THERAPY
RELATED TO HER COGNITIVE
DYSFUNCTION.
WE KNOW AND HEARD THIS MORNING
HEMATOPOIETIC STEM CELL ENHANCES
BLOOD FLOW AND WE LOOKED AT
CEREBRAL FLOOD FLOW AND THE
META-ANALYSIS FOR ALL THE TRIALS
IMPROVE AFTER HEMATOPOIETIC STEM
CELL AND KNOW FROM THE FRENCH
THE RISK OF RECURRENT STROKE IS
ABOUT 5.5% OR SO AFTER A HEE
HEEMENT --
HEMATOPOIETIC EVENT AND WE NEED
SOME FORM OF CURATIVE THERAPY
SINCE THE PERSON IS 26.
THE KEY IS THEY NEED A COMMUNITY
HEALTH WORKER
NAVIGATE THE HEALTH CARE SYSTEM
BECAUSE THE COGNITIVE DEFICITS
ARE CAUSING SOME OF THE
CHALLENGES.
THE QUESTION IS HEMATOPOIETIC
STEM CELL VERSUS GENE THERAPY.
WE WANT IT TO BE PROTECTIVE BUT
I THINK THERE ARE ONGOING
CONCERNS.
WE DON'T KNOW IT'S NOT AS IF
THEY STOP HEMOLIES YZE --
HEMOLYZING AND THE GRAFMENT OF
THEIR PLATELETS.
>> WE HAVE LITTLE KNOWLEDGE FROM
THE GENE THERAPY PERSPECTIVE.
MANY OF THE CLINICAL TRIAL YOU
HAVE SEEN ESPECIALLY IN GENE
EDITING THE PATIENT WHO HAVE
EVIDENCE OF STROKE WERE EXCLUDED
FROM THAT SO WE TRULY DO NOT
HAVE EVIDENCE.
THE ONLY DATA WE HAVE IS IN THE
EARLIER PHASES OF THIS GENE
ADDITION.
THEY HAD FIVE PATIENTS OF
EVIDENCE OF REMOTE STROKE
INCLUDED IN THAT PATIENT
POPULATION AMONG THEIR 40
PATIENTS THEY PUBLISHED ON BUT
WE DON'T REALLY HAVE ANY
SPECIFIC DATA IN TERMS OF THE
NEUROLOGICAL OUTCOME OR
REOCCURRENCE OR NOT IN THE GENE
THERAPY.
ON THE OTHER HAND AS YOU HEARD
FROM MANY PREVIOUS STUDIES MORE
FROM WHAT I THINK ARE THE MOST
PROSPECT OF DATA WERE THE
EUROPEAN AND GROUP SHOWED
IMPROVEMENT IN THE CNS VASCULAR
ONOPATHY AND THE MOST RECENT
1507 THEY HAD PATIENT WITH
EVIDENCE OF ADDING MORE STROKE
THAT WAS INCLUDED OR SILENT
STROKE WHETHER CLINICAL OR SOME
STROKE INCLUDED ON IT.
AND AS WAS PUBLISHED FROM THE
VANDERBILT CONSORTIUM ALMOST 52%
OF PATIENTS WERE ENROLLED ON
THEIR CLINICAL TRIAL THEY HAD
EVIDENCE OF CNS DISEASE AND
THERE WAS NO REOCCURRENCE OF THE
STROKE IN THE PATIENT.
SO FROM A SAFETY OF BONE MARROW
TRANSPLANT I FEEL COMFORTABLE TO
OFFER IT FOR A PATIENT IF THEY
REALLY HAVE WHAT YOU HEARD OF
THE IMPORTANCE OF BEING PREPARED
FOR THE TRANSPLANT AND THIS
PATIENT I WOULD HAVE CONCERNS
ABOUT IT BUT AS A PHYSICIAN OR
TRANSPLANTER I WOULD NOT OFFER
GENE THERAPY FOR THIS PATIENT.
I WOULD DISCUSS THEIR ELIGI
ELIGIBILITY OF THE PROCESS OR
HAPLO TRANSPLANT AND SEE IF THEY
WOULD UNDERSTAND AND SOMEONE I
CONSIDER FOR ALLO GENIC
TRANSPLANT.
>> THERE'S RISK AND BENEFITS OF
THE HAPLO.
>> THAT'S A VERY GOOD QUESTION.
SO THE QUESTION TO REPEAT IS
RISK AND BENEFIT OF THE
CONDITIONAL THERAPY.
SO THIS PATIENT REVIEWING THE
SUMMARY SLIDE THAT WAS YOU'LL
REMEMBER EVIDENCE OF HIGH IRON
OVERLOAD AS EVIDENCED BY THE
IRON IN TERMS OF WAS 11.7 PER
DESI -- DECILITER AND IT'S A
COMPLICATION IN HEMOGLOBINOPATHY
AND IN OTHER ON INSTRUCTIVE
SYNDROME.
I WOULD LIKE TO KNOW IF YOU HAVE
DATA BECAUSE YOU MEASURE THE
IRON AND WOULD LIKE TO KNOW IF
THERE'S EVIDENCE IN THE LIVER
BECAUSE THAT TO ME IS MORE
IMPORTANT THAN THE PERCENTAGE OF
HOW MUCH IRON THERE IS AND YOU
COULD GET THAT DATA FROM THE MRI
OF THE LIVER TO SEE EVIDENCE OF
FIBROSIS OR OCCASIONALLY SEE A
SCAN OR ANOTHER METHOD TO DETECT
IF THERE'S FIBROSIS BECAUSE THAT
WOULD MAKE ME DEFINITELY PUSH
TOWARDS REDUCE INTENSITY IN
CONDITIONAL REGIMENT AND WANT TO
HIGHLIGHT THE CR TN1507 SHOULD
LOW MORTALITY EVEN FOR MANY
PATIENT WHO HAVE HIGH
COMORBIDITY AND THAT WOULD BE
THE REGIMENT I WOULD CHOOSE FOR
THE PATIENT AND WHENEVER WE USE
REDUCE INTENSITY WE GET
CONCERNED ABOUT EITHER GRAPH
FAILURE AND WE COULD MITIGATE
THAT RISK.
THE SECOND RISK IS THE MIXED
CHIMERISM IN ADULT.
WE'RE SEEING LOWER RISK OF MIXED
CRIMER SIX USING THE CONDITIONED
THERAPY VERSUS THE REGIMENT AND
I WOULD RECOMMEND TO REDUCE
INTENSITY CONDITIONING THROUGH
THERAPY AND TBR AND IF YOU HAVE
ACCESS TO IT.
IF NOT YOU THEN INCREASE THE TBI
TO 400 PLUS THE ATG WITH THE
POST TRANSPLANT SITE AS THE
PROPHYLACTIC RENIMENT.
-- REGIMENT.
>> WITH THE UNDERLYING
TRANSPLANT IS WORRISOME.
I THINK HER IRON OVERLOAD SAY
BIG CONCERN.
THERE'S NO DATA I COULD FIND IN
SICKLE CELL DISEASE BUT LOTS OF
DATA THAT PEOPLE WITH IRON
OVERLOAD HAVE REDUCED OVER ALL
SURVIVAL AND IN THE POPULATION
HAVE MORE NON-RELAPSE RELATED
MORTALITY.
I THINK IT INCREASES THE RISK.
AGAIN, SHE'S ONLY 26 YEARS OLD
AND TRYING TO FIGURE OUT HOW TO
NAVIGATE IMPROVING HER IRON
SITUATION IN ORDER TO GO TO
TRANSPLANT IS KEY.
SHE ALREADY HAS AMOYAMOYA AND
NUMEROUS COMPLICATIONS.
SHE NEEDS AGGRESSIVE MANAGEMENT
TO HELP HER SURVIVE TO A RIPE
OLD AGE.
ARE
>> ARE THERE OTHER THERAPIES
OTHER THAN CURATIVE THERAPIES
YOU'D RECOMMEND FOR THIS PERSON?
>> WELL, TO ME HER SECOND BEST
THERAPY WOULD BE CHRONIC
TRANSFUSION THERAPY.
WE SEE THIS ALL THE TIME WHERE
PEOPLE WITH COGNITIVE DEFICITS
AND SHE'S HAD MORE THAN ONE
STROKE.
IT'S NOT A SURPRISE SHE HAS
COGNITIVE DEFICIT AND CONCERNED
AND SHOULD BE ABLE TO NAVIGATE
THIS WITHOUT ANY PROBLEM BUT
THAT'S NOT HOW IT WORKS IN THE
REAL WORLD.
THIS IS SOMEONE WHO I WOULD
ASSIGN A COMMUNITY HEALTH WORKER
TEXTING HER AND MAKING SURE
SHE'S MAKING HER APPOINTMENT AND
USE ALL THESE THINGS FOR HER
COMPLEX MEDICAL CONDITION.
>> IN PEDIATRICS WHERE WE HAVE A
PATIENT WHO HAD STROKE AND THEN
DEVELOP MOYAMOYA THEY TRY TO DO
SURGERY BEFORE THEY CAN BE
CONSIDERED FOR OTHER THERAPIES.
AND NOT DO THE SURGERY BECAUSE
IT'S COMPLICATED AND I TRY NOT
TO DO TRANS PLANT FOR AT LEAST
AROUND ONE YEAR AFTER SURGICAL
INTERVENTION LIKE THAT.
IT WOULD BE IMPORTANT TO BE
CAUTIOUS AND CONSULT THE FAMILY
ABOUT THAT BECAUSE AND WE WOULD
NEED TO KEEP HER FOR SUPPORT.
IF YOU DON'T DISCUSS THE
SURGICAL APPROACH I THINK THREE
MONTHS USUALLY OF RED BLOOD CELL
EXCHANGE TRYING DO THAT
PRECONDITIONING THERAPY WOULD BE
IMPORTANT FOR THE PATIENT TO GET
INTO A BETTER CLINICAL STATUS
AND DO THAT FOR REHEARSAL TO SEE
IF THEY CAN ADHERE WITH THE
COMPLEXITY OF BONE MARROW
TRANSPLANT PROCESS.
I TRY TO GIVE THEM THREE MONTHS
TO SEE IF THEY CAN FOLLOW THE
STANDARDS AND RED BLOOD CELL
EXCHANGE PLUS I WOULD ADD
HYDROXYUREA AND IF THE
COMBINATION THERAPY WOULD BE
POSSIBLE BECAUSE FOR ALL THE
HAPLO TRANSPLANT WE TRY TO GET
THE HYDROXYUREA AS HIGH AS 30
MILLIGRAM PER KILO.
IT COULD BE A CHALLENGE
SOMETIMES BUT TO DEMONSTRATE
COMPLIANCE WITH THERAPY WOULD BE
GOOD.
>> WE DIDN'T TALK ABOUT
FERTILITY PRESERVATION AND PART
OF THE CONVERSATION AND PLANNING
AND MAYBE A REASON WHY YOU WOULD
HOLD OFF POTENTIALLY ON DOING
HYDROXYUREA AND SOMETHING THAT
NEEDS TO BE DISCUSSED AND
ADDRESSED BEFORE MOVING FORWARD.
>> DO YOU HAVE A PREFERRED
TIMING IN RELATIONSHIP TO
TRANSFUSION WITH THE FERTILITY
PRESERVATION?
FOR SOMEONE WHO WOULDN'T
OTHERWISE BE ON TRANSFUSION.
>> OFF HYDROXYUREA?
ABOUT THREE MONTHS.
THERE'S NO DATA BUT OUT SEEMS
LIKE A GOOD NUMBER OF HALF LIVES
TO GET OUT OF THE SYSTEM AND
THEN SORT OF AS THEY PLAN FOR
TRANSPLANT AND FERTILITY
PRESERVATION AND MOVE TO
TRANSPLANT.
>> WELL, THANK YOU.
WE'RE GOING TO TAKE QUESTIONS
FOR BOTH QUESTIONS AFTER.
>> I WANTED TO SAY THIS IS CLOSE
TO MY HEART IT'S IMPORTANT NO
MATTER WHAT CHOICE SHE CHOOSES
TO FOLLOW LONG TERM WE HAVE A
PATIENT WHO WAS TRANSPLANTED SO
YEARS AND HER SYMPTOMS WERE
REVERSES AND SHE WOUND UP HAVING
AN INTRACRANIAL HEMORRHAGE 10
YEARS AFTER THE TRANSPLANT SO
IT'S IMPORTANT TO FOLLOW THE
PATIENT NO MATTER WHAT OPTION
YOU CHOOSE.
>> THANK YOU.
CAN I HAVE SLIDES BACK, PLEASE.
>> I'M GOING TO PRESENT OUR
SECOND CASE AND AFTER THIS WE'LL
HAVE GOOD FITZHUGH DOING THE
DISCUSSION.
THIS IS 40-YEAR-OLD WOMAN WITH
HEMOGLOBIN SC DISEASE AND IDDM
SINCE A TEENAGER AND WANTS TO
IMPROVE QUALITY AND FUNCTION OF
LIFE AND PREVENT EPISODES OF
SEVERE PAINFUL VASO OCCLUSIVE
EVENT.
SHE OFTEN HAS EPISODES OF
HYPERGLYCEMIA AND PREFERS GENE
THERAPY DESPITE NO DATA IN
PEOPLE WITH HEMOGLOBIN SC
DISEASE.
SHE CURRENTLY IS ON TWO DISEASE
MODIFYING THERAPIES,
CRIZANLIZUMAM AND HU AND
HOSPITALIZED FOR THREE AND THREE
SICKLE CELL VISITS PER YEAR FOR
PAIN AND HAS ACUTE CHEST
SYNDROME THREE TIMES BUT NOT
REQUIRED INTENSIVE CARE UNIT
ADMISSION OR RED CELL EXCHANGE
AND HAD A LEFT HIP REPLACEMENT
IN 2023 THAT SHOULD BE 2022 AND
RIGHT IN 2023.
AND LASER TREATMENT OF SICKLE
CELL RETINOPATHY.
AND HAD NORM AL CARDIAC FUNCTIO
AND SHOW HAS EGFR OF 117.
SO OUR FIRST DISCUSSION QUESTION
IS THE EFFICACY OF GENE THERAPY
VERSUS HAPLO IDENTICAL STEM CELL
THERAPY.
>> PEOPLE WITH HEMOGLOBIN SC
DISEASE HAVE BEEN EXCLUDED FROM
THE TRIALS SO WE HAVE NO DATA TO
KNOW WHETHER SHE WOULD BENEFIT
OR NOT OR EVEN WITH INCREASING
FETAL HEMOGLOBIN BECAUSE WE
CAN'T GET THEIR FETAL HEMOGLOBIN
HIGH SO WE DON'T KNOW IF IT WILL
BE BENEFICIAL.
I FOUND ONE CASE REPORT OF
SOMEONE WITH A PERSISTENCE OF
FETAL HEMOGLOBIN OF 25% A
28-YEAR-OLD AROUND THE
HEMOGLOBIN WAS NORMAL.
IT'S POSSIBLE SHE MAY BENEFIT
FROM A HIGHER HEMOGLOBIN LEVEL
BUT WE JUST DON'T KNOW WHERE
THERE'S MORE DATA WITH HAPLO
TRANSPLANTATION AND MANY HAVE
GONE THROUGH THE TRANSPLANT WITH
REVERSAL OF SICKLE CELL DISEASE
AND WOULD FEEL MORE COMFORTABLE
RECOMMENDING THAT THAN GENE
THERAPY FOR THE PATIENT.
>> I'LL TAKE THE CONTRARIAN
APPROACH WHILE THERE'S NO DATA I
DON'T THINK THERE'S CLINICAL
TRIAL DATA FOR PEOPLE WITH SC.
WHEN THE FDA APPROVED THE
PRODUCT THEY INCLUDED SICKLE
CELL DISEASE NOT JUST PEOPLE
WITH SS AND BETA CELL ALLO
THEMIA AND I THINK WE NEED TO
EXPLORE WHAT HER INTEREST IS IN
GENE THERAPY AND MAKE SURE WE
LISTEN TO HER VOICE AND
INCORPORATE THAT INTO THE
DECISION MAKING AND TRY TO
UNDERSTAND WHY SHE HAS A STRONG
PREFERENCE.
I'M NOT SURE.
I WASN'T THERE WHEN SHE MET WITH
THE CELLULAR THERAPY EXPERT IF
THAT'S WHAT CAME FROM THE
MEETING.
IT'S A FOLLOW UP TO ONE EARLIER.
>> THE SAFETY OF GENE THERAPY
VERSUS HAP LOW TRANSPLANT IN
SOMEONE AGE 40, I LOOKED AT THE
LITERATURE IN PEOPLE WITH SICKLE
CELL DISEASE AND THERE'S A LACK
OF INSUFFICIENT DATA HOW MILO
ABLATIVE CONDITIONS AFFECTS
ADULTS WITH SICKLE CELL DISEASE.
WE KNOW THEY'VE BEEN ENROLLED
WITH ANY SIGNIFICANT ORGAN
DAMAGE HAVE BEEN EXCLUDED FROM
THE STUDY.
WE DO KNOW IN THE BIO STUDY DID
PASS AWAY BUT THAT PATIENT HAD A
HISTORY OF PULMONARY
HYPERTENSION THEY DON'T HAVE
SIGNIFICANT ORGAN DAMAGE
REPORTED.
WE KNOW OLDER PATIENTS WHEN THE
TRANSPLANTS INCLUDED ABLATIVE
CONDITIONS MORTALITY WAS HIGHER
IN ADULTS IN GRAPH VERSUS
ADULTS.
I DON'T THINK THERE'S ENOUGH
DATA TO KNOW HOW MANY
40-YEAR-OLDS UNDER GO THE
CONDITION WILL SURVIVE AND
THERE'S MORE DATA WITH
CONDITIONING AND NON-ABLATIVE
CONDITIONING WHERE ADULTS HAVE
SUCCESSFULLY GONE THROUGH
TRANSPLANT WHO ARE DOING WELL
WITHOUT SICKLE CELL DISEASE.
FOR THAT REASON I FEEL MORE
COMFORTABLE BUT I DO THINK IT'S
IMPORTANT TO TALK TO THE PATIENT
EVEN IF THE PATIENT HAD SS
DISEASE ABOUT THE LACK OF DATA
AND INCORPORATE THEIR
PREFERENCES.
>> I SHARE YOUR OPINION WITH
SOMEONE 40 WITH SICKLE CELL
DISEASE AND WONDER IF IT'S
EASIER WITH SC VERSUS SS.
I THINK THE EXPERIENCE MOVING
FROM YOUNG ADULTS TO SLIGHTLY
OLDER THAN YOUNG ADULTS MORE
MYELOABLAH YOU -- MYELOABLATIVE
CONDITIONS AND THEY DO POORLY
AND I REALLY RECOMMEND CAUTION
IN THAT AREA AND I THINK ONE OF
THE THINGS THAT WE NEED TO LEARN
AS WE EXPAND FROM CLINICAL
TRIALS TO CLINICAL EXPERIENCE
WITH MORE DIVERSE PATIENT
POPULATION HOW WELL DO PEOPLE
TOLERATE IT AND HOW MUCH ORGAN
FUNCTION CAN WE GET AWAY WITH
FOR OLDER AGED PEOPLE BEFORE WE
GET INTO TROUBLE AND I THINK
THERE'S AN ISSUE BROUGHT UP OF
HEMATOPOIESIS.
>> I TALKED EARLIER ABOUT THE
RISK OF CLINICAL HEMATOPOIESIS
AND WE DON'T KNOW THAT IN
PATIENTS WITH SICKLE CELL
DISEASE AND THERE'S THOUSANDS OF
PATIENTS BEING SEQUENCED FROM
CHILDREN TO OLDER ADULTS.
SO WE'RE GOING TO HAVE THE
ANSWER SOON BUT WE KNOW IN THE
GENERAL POPULATION OLDER PEOPLE
ARE MORE AT RISK FOR CLINICAL
HEMATOPOIESIS AND IF THE PATIENT
HAS THIS THERE WILL BE A RISK
POTENTIALLY WITH GENE THERAPY
AND CLONAL EVOLUTION WITH THE
PROLIFERATIVE STRESS ASSOCIATED
WITH THE RECONSTITUTION AND
RECOMMEND THE REDUCED CHIMERISM
IN THIS PATIENT.
>> WE DON'T KNOW ABOUT THE RISK
OF HEMATOPOIESIS FOR SC.
PEOPLE WITH SS HAVE BEEN OVER
REPRESENTED.
IF THINK OF THE
PATHOPHYSIOLOGICAL MECHANISMS
YOU REFERRED TO IN YOUR TALK,
MANY ARE LESS INTENSE FOR PEOPLE
WITH SC SO PERHAPS THEIR RISK IS
LOWER BUT THE LARGE POPULATION
STUDY LOOKING AT ACUTE MYELOID
LEUKEMIA SEPARATES THAT OUT.
I DON'T THINK WE KNOW ABOUT HER
RISK SPECIFICALLY COMPARED TO
OTHER PEOPLE WITH SICKLE CELL
DISEASE.
AND THE FINAL QUESTION WELL,
THERE'S TWO MORE.
THE NEXT ONE WAS HOW DOES HER
HISTORY OF INSULIN DEPENDENT
DIABETES MYELITIS CHANGE HER
RISK FOR CURATIVE THERAPIES.
>> I DON'T KNOW AS MUCH AND SURE
THERE HAVEN'T BEEN A LOT OF
PEOPLE WITH DIABETES WHO
RECEIVED GENE THERAPY SO I CAN'T
SPEAK TO THAT RISK AS MUCH.
THERE'S MORE ORGAN DAMAGE
POSSIBLE WITH DIABETES.
IT'S POSSIBLE SHE MAY HAVE MORE
SUBCLINICAL ORGAN DAMAGE RELATED
TO DIABETES WE DON'T KNOW ABOUT
BUT WITH HAPLO IDENTICAL
TRANSPLANT WITH THE
IMMUNOSUPPRESSANT GIVEN THERE'S
A RISK FOR DIABETES SO IT COULD
POTENTIALLY MAKE THE DIABETES
WORSE IF SHE WERE TO DEVELOP
GRAFT VERSUS HOST DISEASE AND
START STEROIDS THAT WOULD BE A
CORNER WITH SOMEBODY WITH
DIABETES BUT WE COLLABORATE
CLOSELY WITH OUR ENDOCRINE TEAM
AND GIVE APPROPRIATE TREATMENT.
I WOULDN'T HAVE A CONCERN FOR
SPECIALLY HOW THIS IS FOR
SOMEBODY WITH DIABETES.
>> I TRIED TO ADDRESS THE
QUESTION BY LOOKING AT THE
GENERAL TRANSPLANT LITERATURE.
AT LEAST IN ONE LARGE ADULT
SERIES ABOUT 6% OF PATIENTS HAD
DIABETES PRIOR TO TRANSPLANT
LOOKING MOSTLY AT MOSTLY OLDER
ADULTS AND THE MEAN AGE WAS 60%
WITH DIABETES AND THE GROUP THAT
DEVELOPED AND SOME MAY BE THE
DIABETES, SOME MAY BE THE REASON
THEY DEVELOP MORE FOCUSSED
IMMUNOSUPPRESSION BUT THE
INCIDENT OF DIABETES AFTER
TRANSPLANT IS ASSOCIATED WITH
SUBSTANTIALLY WORSE OUTCOMES
RELATED TO MORTALITY AND THE
PEOPLE THAT WENT TO TRANSPLANT
DID HAVE SOME INCREASED RISK OF
OTHER CARDIOVASCULAR
COMPLICATIONS SUCH AS
HYPERTENSION AND STROKE.
SO I THINK IT MY INCREASE THE
RISK SOME.
SHE USES INSULIN PUMP AND IT'S
BASED ON THERAPY AND HOW CLEARLY
EVEN THE NON-MYELOABLATIVE
CONDITION CONDITION AFFECT YOUR
ABILITY TO EAT OVER TIME BUT MAY
BE MANAGEABLE OVER TIME.
THE LAST TOPIC FOR DISCUSSION IS
WHETHER THERE'S OTHER THERAPIES
WE CAN CONSIDER OTHER THAN
CURATIVE THERAPIES THAT MAY
AFFECT SICKLE CELL DISEASE.
CURRENTLY SHE'S ON OUR BEST
COMBINATION OF MEDICATIONS SHORT
OF TRANSFUSION FOR MANAGING
ACUTE COMPLICATIONS OF SICKLE
CELL DISEASE AND WE COULD NINK
-- THINK OF RED CELL EXCHANGES
FOR SICKLE CELL.
>> RELATED TO THE AGE OF THE
PATIENT, 40, I PERSONALLY THINK
WE SHOULDN'T DISCRIMINATE BASED
ON AGE AND LOOK AT
COMORBIDITIES.
IN BONE MARROW TRANSPLANT WE
HAVE A COMORBIDITY INDEX THAT
MAYBE WE CAN EXTRAPOLATE FOR
THIS PATIENT AND SEE IF THEY'RE
AT RISK FOR ANY TRANSPLANT
MORTALITY AND I WOULD PUT BOTH
GENE THERAPY AND HAPLO IN THE
SAME CATEGORY AND HAVING
DIABETES THAT WOULD BE COUNTED
AS ONE AND PUT HER IN TERMS OF
2% TO 5% OF THE RISK.
THIS WOULD BE EQUAL IN MY
OPINION.
AND I WOULD ALSO HIGHLIGHT THAT
MANY PATIENTS COME TO GENE
THERAPY THINKING IT'S SIMILAR TO
AN AUTOLOGOUS TRANSPLANT BUT THE
DIYNAMIC IS DIFFERENT.
YOU NEED SOMEONE WITH EXPERIENCE
AND BONE MARROW TRANSPLANT FOR
SICKLE CELL DISEASE BECAUSE THEY
REPRESENT ANECDOTALLY FROM MY
OWN EXPERIENCE WE HAD A PATIENT
THAT DEVELOPED PRESS WITH THE
USE OF GENE THERAPY.
WE HAVE TO BE CAREFUL WITH THE
PATIENT AND NOT JUST THINK THE
OTHER COMPLICATION RELATED TO
ALLO GENIC TRANSPLANT IN SICKLE
CELL AND THE PERIOD OF
NEUTROPENIA AND THEY ARE DON'T
ENGRAPH UNTIL DAY 24, 26.
THERE'S A SHIFT IN THE PERIOD
WHERE THERE'S A RISK OF
INFECTION AND OTHERS SEEM TO BE
POTENTIALLY DIFFERENT AND YOU
HAVE TO PAY ATTENTION TO THAT
AND LOOK MORE LIKE AN ALLO IN
HAPLO TRANSPLANT VERSUS GENE
THERAPY.
>> DO YOU THINK OF SICKLE CELL
DISEASE AS A COMORBIDITY WHEN
YOU THINK OF THE COMORBIDITY
INDEX?
YOU MENTIONED PEOPLE GETTING
PRESSED RELATED TO SICKLE CELL
DISEASE AND CHANGING IN THEIR
CEREBRAL HEMODYNAMICS IN
ADDITION TO THE MEDICATIONS
USED?
>> THAT'S WHERE WE NEED MORE
DATA.
THE COMORBIDITY INDEX IS MORE
FROM THE MALIGNANT AND PATIENTS
ANALYZED FROM THE DATA AND
DEVELOP A MORBIDITY INDEX THAT
COULD HELP FOR THE SHARED
MEDICAL DECISION.
IT'S GREAT WE HAVE OPTION.
ONE THING WE SHOULD HAVE IS
THERE'S MANY OPTION AND WE
SHOULD TALK TO THE PATIENT ABOUT
ALL THIS AND WHERE THERE'S
CONCERN BECAUSE EVEN GENE
THERAPY IS NOT THE SAME.
THERE'S SO MANY MODALITY THAT
NEED TO BE TAKEN INTO
CONSIDERATION.
>> THANK YOU.
I WANTED TO INVITE UP WE HAVE
ONE MORE IMPORTANT TO JOIN OUR
PANEL BEFORE WE UP -- OPEN IT
UP TO QUESTIONS AND THAT'S RAPI
DANIELS.
THANK YOU FOR COMING AND JOINING
US.
MS. SAMUELS IS OUR ONE EXPERT ON
GENE THERAPY AND SICKLE CELL
DISEASE THAT HAD GENE THERAPY SO
THANK YOU FOR COMING AND JOINING
US AND THEN I WANT TO OPEN IT UP
TO QUESTIONS.
>> THAT WAS A WONDERFUL LOVELY
CONVERSATION WITH EXPERTS.
THERE'S NOT A BETTER GROUP I'D
LOVE TO HEAR FROM.
SO SOPHI MADE THE POINT
ELOQUENTLY IN THE BEGINNING.
WE DON'T HAVE DATA.
WE DON'T KNOW.
THAT'S USUALLY TO THE ENDS OF A
CONVERSATION NOT THE BEGINNING
OF A LONG ONE.
THAT'S SOMETHING WE OUGHT TO
HAVE WITH HUMILITY TO ACCEPT WE
DON'T KNOW AND NOT LIKELY TO
KNOW.
SOME OF THE THINGS NOT BROUGHT
UP WAS THE BURDEN OF CARE OF SIX
MONTHS OR ONE YEAR OF
IMMUNOSUPPRESSION MAY BE VIEWED
DIFFERENTLY BY PATIENTS.
THEY'RE NOT JUST CONSIDERING
HAPLO VERSUS GENE THERAPY,
SECOND, OUTCOMES MAY ALSO BE
DISPARATE IN TERMS OF WHAT
THEY'RE LOOK BEING FOR.
SOME ARE SAYING MAYBE I'M STILL
GOING TO BE AT RISK FOR STROKE
BUT TODAY I'LL BE FREE OF PAIN
AND IF I CHOOSE TO DO THE GENE
THERAPY WHICH IS MORE ACCEPTABLE
TO ME AND PEOPLE MAY BREAK A
PART THE PIECES AND MAKE
DECISIONS DIFFERENTLY.
SO I WOULD AGREE WITH RABBI AND
MAYBE GO FURTHER I WOULD NOT
MAKE A RECOMMENDATION ONE WAY OR
THE OTHER IN CASE ONE BUT
DISCUSS ALL OF THE ABOUT AND A
QUICK COMMENT ABOUT PRESS.
PRESS IS A FAILURE OF CEREBRAL
AUTO REGULATION AND IN THE DATA
ON PRESS IN SICKLE CELL DISEASE
IT MOSTLY HAPPENED WITHOUT HIGH
CYCLOSPORIN LEVELS AND LIKE A
TRANSPLANT PEOPLE UNDERGOING
GENE THERAPY SHOULD BE CARED FOR
BY TEAMS THAT KNOW WHAT THEY'RE
DOING.
THANK YOU.
>> I THINK CHRIS YOU BRING UP AN
EXCELLENT POINT WE SHOULD TALK
ABOUT THE NEED FOR COMBINED
MANAGEMENT OF PATIENTS FROM
BEGINNING, MIDDLE AND END AND
POST END THE HEMATOLOGISTS AND
TRANSPLANTERS NEED TO WORK
TOGETHER IN A COMPREHENSIVE
APPROACH WITH POLICIES AND
PROCEDURES FOR ALL THIS BEFORE
YOU START.
>> I'LL DISCUSS EFFICACY AND
THEN WHAT MADE YOU DECIDE
BETWEEN GENE THERAPY AND HAPLO
TRANSPLANT.
>> THANK YOU FOR IF HE QUESTION.
I MADE THE DECISION AT THE TIME
I HAD TWO BROTHERS THAT WERE 10
AND 6, I BELIEVE.
FOR MANY YEARS I HAD BEEN
LOOKING FOR THE CURE.
SO WHEN I REACHED OUT TO NIH AND
THEY TOLD ME THESE TWO JUST
READING THE AMOUNT OF PAPERWORK
AND THINKING ABOUT WHAT MY
BROTHERS WOULD HAVE TO GO
THROUGH, LIKE MANY PLACES IN MY
LIFE I JUST FELT I'D LAY ON THAT
SWORD.
I FELT I DIDN'T WANT TO GO WITH
GRAPH VERSUS HOST.
THAT SCARED ME A BIT AND TAKING
THE RISK OF HAVING MY OWN CELLS
RETURNED TO ME SOUNDED BETTER.
FROM A CLINICAL PERSPECTIVE I
FELT DESPERATE FEELING LIKE ARE
THERE AS MANY OPTIONS IN 2018,
THERE WEREN'T MANY AS THERE ARE
NOW AND THERE WERE THERAPY I
TRIED.
I HAD DONE THE BLOOD
TRANSFUSIONS EVERY THREE OR FOUR
WEEKS AND STILL DIDN'T HAVE THE
QUALITY OF LIFE I CARED FOR AND
TOOK MY A YEAR TO PONDER HOW
THAT LOOKED FOR MY FAMILY.
THAT WAS ONE OF THE DRIVING
FORCES.
YOU MENTIONED THE SIX MONTHS TO
A YEAR AND HOW DOES THAT LOOK
FROM A PATIENT PERSPECTIVE ALSO
ONE OF THE THINGS I THOUGHT
ABOUT AS WELL AS WITH MY FAMILY,
HOW DOES THAT LEVEL OF CARE LOOK
BEFORE, DURING AND AFTER.
BUT AGAIN MY QUALITY OF LIFE
WASN'T WA I WANTED IT TO BE
ANYWAY SO THAT WAS A FAMILY
DECISION.
>> FOR THE SECOND PATIENT I
WONDER IF ENGAGING WITH A
PATIENT ABOUT OPTIMIZING
GLYCEMIC CONTROL WOULD BE THE
FURTHER STEP EVEN BEFORE TALKING
ABOUT GENE THERAPY VERSUS
TRANSPLANT?
I THINK REGARDLESS OF THE
DIRECTION YOU GO, I THINK
FIGURING OUT GLYCEMIC CONTROL
WOULD PROBABLY BE IMPORTANT
WHETHER A PATIENT HAS TO PURSUE
IT OR NOT.
I DO WONDER.
OBVIOUSLY PATIENTS ON
HYDROXYUREA AND IS IT BECAUSE OF
COST THEY WEREN'T ABLE TO AFFORD
THE NEWER THERAPIES FOR GLYCEMIC
CONTROL TO MORE FINE TUNE LIKE
THE BIO FEEDBACK AND THE PUMPS
AND SO FORTH.
>> SHE REPORTS CHALLENGE WITH
HER SICKLE CELL DISEASE ACTS UP
AND BLOOD SUGAR AND REGULATING
IN TIMES OF ILLNESS ARE THE
FEEDBACK LOOP AND WE ARE
INVOLVED IN THAT ASPECT OF CARE.
>> YET SHE IS STILL EXPERIENCING
HYPERGLYCEMIC EPISODES?
THAT'S FASCINATING.
YOU WONDER WHICH IS THE CHICKEN
AND THE EGG THEN.
THANKS.
>> THIS QUESTION IS FOR
COURTNEY.
QUESTION ABOUT THE PATIENT YOU
MENTIONED WITH THE INTRACRANIAL
HEMORRHAGE.
WERE THERE CHANGES THAT COULD
HAVE PREDICTED THAT WOULD
HAPPEN?
>> GOOD QUESTION.
SHE HAD 100% CHIMERISM.
SHE WAS HAVING SOME HEADACHES
AND WAS MOVING SO THERE MAY HAVE
BEEN MORE STRESS AND HIGH BLOOD
PRESSURE BUT DIDN'T PRESENT TO
THE NIH SO I DON'T HAVE ALL THE
DETAILS AT THE TIME.
TO SAY EVEN WITH REVERSAL OF
SICKLE CELL DISEASE AND SURGERY
WOULDN'T BE INDICATED BUT IT'S
IMPORTANT TO HAVE THE
CONVERSATIONS AND INDICATIONS
FOR THE SYNDROME AND WE NEED TO
KNOW HOW TO KEEP THE PATIENTS AS
SAFE AS POSSIBLE AND
PERITRANSPLANT AND AFTERWARDS.
>> I'M WONDERING EVEN LONG-TERM
SOME PATIENTS ESPECIALLY AFTER
GENE THERAPY WE DON'T HAVE PAST
TWO, THREE FOLLOW-UP SHOULD WE
CAN BE CONCERNED OF THE
HEMOGLOBIN DROPPED SHOULD WE
HAVE A LOW THRESHOLD FOR
PATIENTS FOR DISEASE MODIFYING
THERAPY RATHER THAN JUST
FOLLOWING AND SEE HOW THEY DO.
>> WE DON'T HAVE THE DATA TO
KNOW HOW BEST TO TREAT THEM BUT
SOMETHING TO THINK ABOUT.
>> I'M FROM BOSTON UNIVERSITY
AND MY QUESTION IS ABOUT THE
FIRST CASE.
AS WE ROLL OUT CLINICAL GENE
THERAPY ACROSS CENTERS, THERE IS
AND I SAY THIS AS A
NON-HEMATOLOGIST, THERE'S A
VARIABILITY IN HOW THE DATA ON
HOW GENE THERAPY MAY OR MAY NOT
BE PROTECTIVE IN PATIENTS WITH
PRIOR STROKES IS BEING INTER
INTERPRETED.
THE QUESTION I HAVE FOR THE
PANEL IS HOW WE'RE GOING TO
APPROACH AS A COMMUNITY
GATHERING DATA ON THE IMPACT OF
GENE THERAPY ON THE RISK OF
CEREBRAL VAS VASCULOPATHY AND
THOSE PRIOR TO GENE THERAPY IF
THEY WERE TO GET IT.
>> I'LL SPOKE FOR THE NATIONAL
ALLIANCE AND THE USE OF A
REGISTRY.
WE HAVE THE GRAND DAD REGISTRY
AT OVER 50 SITES ACROSS THE
COUNTRY AND THINK ANYONE GOING
TO THE THERAPY SHOULD BE IN SOME
REGISTRY AND WE NEED TO COLLECT
THIS DATA BECAUSE THOSE ARE
REALLY IMPORTANT QUESTIONS.
AND AT THE RECENT NATIONAL
ALLIANCE MEETING WE STARTED THE
DISCUSSION OF HAVING A CONCENSUS
WHO SHOULD BE THOUGHT ABOUT --
CONSENSUS FOR WHO SHOULD GO
THROUGH THERAPY AND INITIAL
CONVERSATIONS AND HOPING TO
REGROUP AT NEXT YEAR'S MEETING
TO HAVE CONSENSUS HAVING THE
MEMBER CENTERS VOTE ON
RECOMMENDATIONS FOR GENE
THERAPY.
>> I THINK IT'S IMPORTANT TO
RECOGNIZE IT IS NOT SICKLE CELL
DOCTORS THAT ARE THE GATE
KEEPERS OF THERAPY OR
TRANSPLANT.
IT'S OUR CELLULAR COLLEAGUES WE
DON'T REFER OR SEE ALL THE
PATIENTS.
IT'S GOING TO MAKE IT
HETEROGENEOUS WHO GOES IN THE
FIRST COUPLE YEARS AS WE HAVE
CLINICAL IMPLEMENTATION.
I AGREE IT'S IMPORTANT TO
UNDERSTAND ABOUT CEREBRAL
VASCULOPATHY AND SHOULD HAVE
CENTRAL READING AND THE LEVEL OF
STANDARD OF CARE BECAUSE I THINK
WE'RE GOING TO FIND THAT SOME
PEOPLE GET BETTER WITH CURATIVE
THERAPIES OR TRANSFORMATIVE
THERAPIES WHEN IT COMES TO
CEREBRAL DISEASE AND SOME MAY
NOT GET BETTER IN TRYING TO
UNDERSTAND WHAT PREDICTS THAT
WOULD BE VALUABLE.
I AGREE IF SOMEONE HAD A PRIOR
STROKE AND WERE LOSING THEIR
AFFECT AND HEMOGLOBIN IS
DROPPING AND HAVING MORE
HOMOLYSIS THEY ARE SHOULD BE
BACK.
>> CMS IS OFFERING TO RESEARCH
ORGANIZATIONS FOR COLLECTING
OUTCOME SO THAT'S ALREADY GOING
TO HAPPEN.
AND TOE SOPHI'S POINT I WANT TO
BRING OUT THAT THE PRESCRIBING
INFORMATION SAYS
CONTRAINDICATIONS, NONE.
>> REGINA CRAWFORD, OHIO STATE
UNIVERSITY.
A QUESTION ON THE SECOND CASE
THE HEMOGLOBIN SC PATIENT AND MY
QUESTION RELATES TO AT BASELINE
DOES SHE HAVE ANY SEQUESTRATION
OR KNOWN THROMBOCYTOPENIA AND
DOES THAT PLAY A ROLE FOR GENE
THERAPY OR HAPLO OR THE
MYELOABLATIVE?
>> SHE DOESN'T HAVE AMEGALLY OR
CYTOPENIA AND YOU HAVE TO MAKE
SURE THE PATIENT DOESN'T HAVE
HLA ALLO IMMUNIZATION.
IT'S IMPORTANT UNLIKE LEUKEMIA
THEY HAVEN'T HAD FAILURES
BEFORE.
>> WHEN I SEE THROMBOCYTOPENIA
AND IT WILL TAKE CYCLES TO GET
ENOUGH CD.
>> I'VE WORKED WITH REGISTRIES
ALL MY CAREER.
THEY'RE EXCELLENT FOR LOOKING
FOR THE RARE UNUSUAL EVENTS AND
BECAUSE OF THE HETEROGENEITY IN
SELECTION CRITERIA AND
APPROACHES YOU WILL FIND OUT
FROM REGISTRY DATA INFORMATION
IN THE FUTURE TO HELP YOU SELECT
PATIENTS BETTER BUT THERE'S ONE
PROBLEM, REC STRIS DON'T FUND
RESEARCH TESTS.
WE CAN ONLY COLLECT DET ON TESTS
THAT PEOPLE GET.
WE DON'T TELL PEOPLE WHAT TO DO
BUT TELL US WHAT THEY DID BUT
CAN ONLY DO THINGS PAID FOR BY
INSURANCE.
ONE THING THAT WOULD HELP THE
FIELD WOULD BE A CLEAR STATEMENT
ABOUT WHAT WE CONSIDER THE
DIAGNOSTIC TEST TO FOLLOW
PATIENTS OVER TIME SO WE CAN
UNDERSTAND WHAT'S GOING ON IN A
WAY TO JUSTIFY PAYMENT BY
INSURANCE COMPANIES.
>> AND WE'RE INTERESTED IN
LOOKING INTO THE ONLY FOR
GENETIC RISK FACTORS FOR
LONG-TERM HEALTH EFFECTS OF
CURATIVE THERAPIES FOR SICKLE
CELL DISEASE AND FORTUNATE TO
HAVE CENTERS AROUND THE
U.S. TRANSPLANTING THE LARGEST
POPULATION WITH SICKLE CELL
DISEASE AND ONE THING WE'RE
INTERESTED IN IS THE CNS EFFECTS
AND ADULTS VERSUS CHILDREN AND
TRANSPLANTING THERAPIES SCO I
THINK IT'S IMPORTANT TO USE AS
PRELIMINARY DATA TO TRY TO HELP
WITH DEVELOPING SUGGESTS AND
GUIDELINES FOR PATIENTS LONG
TERM.
>> WE'LL HAVE THIS BE THE LAST
QUESTION.
>> I TIMED THAT PERFECTLY.
MY QUESTION IS FOR THE REAL
EXPERT ON THE PANEL, THE PERSON
WHO'S HAD THE PROCEDURE DONE.
WALK US THROUGH ADULT REASONING.
SOME ADULTS HAVE COGNITIVE
DYSFUNCTION, SOME DON'T.
THEIR ABILITY TO REASON AND USE
THE TERMINOLOGY TO MAKE A COGENT
DECISION VARIES PROBABLY BY
THEIR AMOUNT OF COGNITIVE
DYSFUNCTION.
HELP US AS PROVIDERS SORT THAT
THROUGH AS WE DEAL WITH OUR
PATIENTS BECAUSE WE'RE TRYING TO
COMMUNICATE ALL THIS COMPLICATED
STUFF EVEN THE DOCTORS DON'T
UNDERSTAND TO A PATIENT TO HELP
THEM MAKE DECISIONS.
>> THANK YOU.
IT IS A CONCERTED EFFORT ON THE
PROVIDER, THE PATIENT AND THAT
GROUP MUCH -- OF PEOPLE THAT IS
SURROUNDING THEM, THEIR
COMMUNITY.
I WOULD SAY AS YOU'RE RIGHT, I
SPENT SO MUCH TIME IN THE
HOSPITAL SOMETIMES THE MEDICAL
TERMINOLOGY BECAME SECOND NATURE
TO ME.
THOSE ARE PROBABLY THE SAT WORDS
I KNEW PRIOR IT TAKING THE SAT
BUT BREAKING IT DOWN AND COMING
FROM A HUMAN PERSPECTIVE I THINK
SOMETIMES PROVIDERS CAN GET SO
STUCK TO THE DATA AND THE
PROVIDER PORTION OF IT THAT THEY
FORGET THEY'RE TALKING TO A
PATIENT WITH A LIFE.
BEFORE BEING A SICKLE CELL
PATIENT I'M A CHILD, I AM A
DAUGHTER, I'M A WIFE, I'M A
BONUS MOTHER, EMPLOYEE.
ALL THOSE THINGS MAKE UP THE
PATIENT AND I THINK TAKING THAT
INTO CONSIDERATION WHEN YOU ARE
PRESENTING ALL THE OPTIONS AND
AGAIN IT'S ABOUT FINDING AND
EXPLAINING ALL THE OPTIONS
AVAILABLE TO THE PATIENT AND TO
THAT FAMILY BECAUSE THERE ARE
TIMES THAT YOU'RE IN SO MUCH
PAIN YOU'RE NOT THINKING ABOUT
ANYTHING ABOUT ANYTHING BUT PAIN
MEDICATION OR TREATMENT.
HAVING THAT ONE PERSON YOU CAN
TALK TO AS THE PROVIDER WHEN THE
PATIENT IS JUST NOT IN A HEAD
SPACE, TO TALK ABOUT THOSE
THINGS IS VERY HELPFUL.
ALSO TALKING ABOUT THE REAL
THINGS THAT AFFECT THEM
DEPENDING ON THE METHODOLOGY.
BEING OUT OF WORK FOR MY
PROVIDER, MY CAREGIVER, FOR
MYSELF.
TRANSPORTATION, FOOD, ALL THOSE
INSECURITIES THAT COME ALONG
WITH THAT PATIENT AND BEING ABLE
TO SIT DOWN WITH THEM.
THE 15-MINUTE CONVERSATION WHERE
YOU'RE IN THEN GONE WITH THE
PATIENT AND SOMETIMES IT CAN
FEEL LIKE YOU'RE JUST A NUMBER
AND WE JUST WANT TO BE HEARD.
WE WANT TO BE ABLE TO EXPLAIN
OURSELVES AND WHERE WE ARE AS AN
ADULT AND WHERE WE'RE TRYING TO
GO.
A QUICK STORY.
I WAS MARRIED AND WANTED
CHILDREN THOUGHT THAT BEING ON
ONE OF THESE THERAPIES WOULD
HELP ME GET TO THAT BUT GETTING
TO THAT TABLE AND REALIZING THIS
PARTICULAR TREATMENT WOULD
SOMEWHAT TAKE THAT ABILITY FROM
ME.
THERE WAS PRESERVATION BUT THAT
WAS ANOTHER TIME IN MY LIFE
FEELING I HAD TO GRIEF THAT.
SICKLE CELL HAD TAKEN SO MUCH
FROM ME I WANTED TO CLAIM
SOMETHING I WANTED.
SO I HAD TO GRIEVE THAT AND EVEN
IF IT DIDN'T WORK FOR ME AS AN
OPPORTUNITY THE PROVIDERS
SOMEONE COULD FIND OUT WHAT HAD
HAPPENED TO ME TO HELP
GENERATIONS.
THAT WAS MY MIND SET GOING
FORWARD.
ONCE I DECIDED TO MAKE THIS
DECISION, IF NOTHING ELSE WAS
LEARNED BUT DATA, THEN IT WAS
DATA THAT WOULD HELP FUTURE
GENERATIONS.
ALL OF THAT WENT TO ME MAKING
THE DECISION TO DO THIS.
>> SO THANK YOU VERY MUCH.
BEFORE WE END THIS SESSION WE DO
HAVE A QUESTION ON LINE AND SOME
COMMENTS ONLINE THAT I WANT TO
MAKE SURE GET ADDRESSED.
>> SO, I WANTED TO INTRODUCE
DR. JULIE KANTER CLOSING THE
SESSION WITH THE PRACTICAL
ASPECTS OF CLINICAL GENE THERAPY
PROGRAMS WITH SICKLE CELL
DISEASE.
>> SORRY I'M NOT THERE IN
PERSON.
I HAD PLANNED TO BE BUT IT
DOESN'T WORK OUT THAT WE.
-- WAY.
I'M HOPING I'LL BE ABLE TO
ANSWER QUESTIONS AND ABOUT HALF
THE COMMENTS IN CHAT WERE FROM
ME SO I'LL COVER SOME OF THOSE
THINGS.
SO I'M GOING TO TALK MORE ABOUT
HOW WE SET THINGS UP FOR GENE
THERAPY.
WHAT IT LOOKS LIKE AND I'LL
TOUCH ON SOME OF THE POINTS ON
THE NEED FOR A TEAM AS WE
APPROACH GENE THERAPY IN THE
REAL WORLD.
THESE ARE MY DISCLOSURES.
NEXT SLIDE.
SO YOU'VE HEARD ALL ABOUT THIS
TODAY.
WE DON'T REALLY NEED TO GO BACK
THROUGH THE PROCESS.
I WANT TO MAKE SURE PEOPLE
RECOGNIZE IS THERE'S MULTIPLE
POINTS IN THE PROCESS IN WHICH
THE PERSON LIVING WITH SICKLE
CELL DISEASE ARE WAITING AND
NICINITIATING TRANSFUSION THERA
AND HAVE TO STOP HYDROXYUREA AND
HOW TO OPTIMIZE THAT AND ONCE
STEM CELLS ARE COLLECTED IT
COULD BE SIX MONTHS UNTIL THEY
GET THE CELLS BACK.
WHO IS MANAGING THE PATIENT IS
KEY TO MAKING SURE WE HAVE GOOD
OUTCOMES FROM GENE THERAPY AND
LONG-TERM FOLLOW-UP, 15 YEARS IS
A LONG TIME.
WHAT'S THAT LOOK LIKE AND WHERE
IS THIS INDIVIDUAL GOING TO BE
FOLLOWED?
THESE ARE TRANSFORMATIVE AND NOT
YET CURATIVE PROCESS AND NEED TO
BE FOLLOWED BY SOMEONE WHO KNOWS
OF SICKLE CELL DISEASE.
WE ASKED THE QUESTION SO SAY,
OKAY, WE HAVE 90 CENTERS NOW
113.
THERE'S 113 SICKLE CELL CENTERS
GIVING MULTIDISCIPLINARY CARE.
WE RECOGNIZE WE'RE CARING FOR
THE MAJORITY OF INDIVIDUALS WITH
SICKLE CELL DISEASE SEEN BY
SPECIALISTS.
WE NEEDED TO BE IN THE ROOM TO
DISCUSS WHAT GUIDANCE IS NEEDED
AND HOW TO OPTIMIZE INDIVIDUALS
PRETREATMENT AND LONG-TERM.
HOW TO MAKE IT FINANCIALLY AND
HOLISTICALLY WORTHWHILE.
THEY TAKE LONGER THAN THE ONE
TIME TREATMENT.
WE RECOGNIZE THERE'S ISSUES AND
SPECIFICALLY IN THE PAST WE KNOW
THERE'S A DISCONNECT BETWEEN
HEMATOLOGY AND TRANSPLANT.
SPECIFICALLY OFTEN TRANSPLANT
TREATS -- NOT ALL OF YOU.
WE HAVE FABULOUS COLLEAGUES IN
THE ROOM BUT SOMETIMES THE
TRANSPLANT IS LIKE THE SURGEON.
THEY WANT TO TAKE CARE OF THE
PERSON AND GET THE JOB DONE AND
SEND THE PERSON BACK WHERE THEY
CAME FROM AND THERE'S NOT A
DISTINGUISHING POINT OF
TRANSITION BEFORE, DURING AND
AFTER.
THERE'S SO MUCH TIME IN BETWEEN
THINKING ABOUT GENE THERAPY WE
HAVE TO BE PREPARED TO MANAGE
THE PATIENTS EFFECTIVELY.
WE WANTED TO UNDERSTAND THE
BARRIERS TO TRANSFORMATIVE
THERAPIES.
WHAT IF YOU DON'T HAVE A
TRANSPLANT PROGRAM?
WE FOUND BARRIERS AS THOSE
LIVING WITH BARRIERS AND NEEDS
FOR PSYCHOLOGISTS AND MENTAL
HEALTH SUPPORT.
AND THEN THERE'S OFTEN HOSPITAL
ADMINISTRATIVE-BASED ISSUES WITH
FINANCIAL BARRIERS WHEN
NEGOTIATING CONTRACTS.
WE ALL KNOW ABOUT THE
LIMITATIONS OF INSURANCE.
WE DON'T WANT TO GET TOO FAR
DOWN ROAD OR WE'LL NEVER GET
OUT.
TO THE ALLIANCE WAS TO SUPPORT
AND PROVIDE ACCESS TO CARE.
IT'S OUR OPINION NO ONE SHOULD
HAVE SICKLE CELL DISEASE AND NOT
HAVE THE OPPORTUNITY TO SEE A
SPECIALIST.
THAT'S WHAT WE CAN OFFER IS
SUPPORT MORE SICKLE CELL DISEASE
CENTERS TO PROVIDE EQUITABLE
ACCESS TO HEALTH CARE.
THERE'S 113 AND YOU CAN GO HERE
TO SEE THE MAP.
WE DEVELOPED A CONSENSUS
PROCESS.
WE'RE LOOKING AREAS OF DATA IN
MANY AREAS.
WE CAN'T WAIT FOR DATA AND
STARTED WITH LITERATURE REVIEW
AND UNDERSTAND HOW THEY'RE
PRACTICING NOW.
IF IT'S TALKING ABOUT HOW OFTEN
YOU GET AN ECHO WHAT ARE YOU
DOING AND WHAT DO GUIDELINES
SAY.
WE MEET IN PERSON TO COMPROMISE
AND HAVE A FINAL VOTE ONE VOTE
PER CENTER IS PERMITTED.
YOU CAN SEE INDIVIDUALS WITH
SICKLE CELL DISEASE AND WE
STARTED THE DISCUSSION OF WHO
SHOULD GET THE THERAPIES BUT
THAT'S NOT UNTIL NEXT YEAR.
SOW WE TALKED IN BUCKETS.
WE SAID COMPONENTS OF
RECOMMENDATIONS.
WHO SHOULD BE AT YOUR
TRANSFORMATIVE CENTER AND WHO
NEEDS TO BE ON YOUR TEAM AND
WHAT PROCESSES NEED TO BE IN
PLACE.
WE NEED TO HAVE DEFINED PRE,
DURING AND POST CARE.
WHO DOES THE PATIENT CALL WHEN
THEY NEED SOMETHING AT THIS
STAGE AND WHAT PRIOR EXPERIENCE
IS NEEDED AND MAKING SURE THE
PROTOCOLS ARE IN PLACE.
THIS GOES FOR ALLO GENEIC
TRANSPLANT AS WELL.
WE CAME UP WITH TWO IMPORTANT
RECOMMENDATIONS STATEMENTS.
ONE IS DESPITE A DECADE OF
CLINICAL TRIALS WE KNOW GENE
THERAPIES HAS ONLY BEEN DONE IN
A SMALL NUMBER OF INDIVIDUALS
WITH FOLLOW-UP AND.
AND WE ALSO KNOW THE GENE
THERAPY NEEDS TO BE INTERESTED
AS TRANSFORMATIVE INSTEAD OF
CURATIVE AND UNTIL WE HAVE DATA
WE CANNOT CALL IT CURATIVE IT'S
NOT FAIR TO PROMISE A CURE WITH
WHAT HAS NOT BEEN IDENTIFIED.
AND TRANSPLANTATION FOR SICKLE
CELL DISEASE IN DISEASE
AUTOLOGOUS TREATMENT AND THESE
WERE IMPORTANT ON VOTING.
I SHOWED YOU THIS EARLIER AND
PULLED IT APART TO TALK ABOUT
HOW THERE ARE SEVERAL PIECES AND
PARTS OF WHAT'S GOING ON IN THE
PROCESS OF GENE THERAPY AND
MANAGED BY HEMATOLOGISTS AND
MAKE SURE THEY SEE SPECIALISTS
NOT JUST A TRANSPLANT SPECIALIST
AND THIS IS HOURS UPON HOURS AND
MONTHS OF CONSIDERATION.
IT USUALLY TAKES ME 10 TO 15
HOURS WITH SOMEONE, FACE TO FACE
BEFORE WE TALK ABOUT GOING
THROUGH THIS THERAPY FROM TOP TO
BOTTOM.
WE HAVE TO TALK ABOUT
HYDROXYUREA AND TRANSFUSIONS AN
INPUT FROM A MULTIDISCIPLINARY
TEAM AND HAD A PANEL TO AGREE ON
TREATMENT AND TOGETHER YOU HAVE
TO DISCUSS THIS IS AN INDIVIDUAL
WHO SHOULD UNDER GO THE THERAPY
THEN A CONFIRMED ELIGIBILITY TO
PROCEED AND MAKE SURE THEY
CONTINUE TO GET THE
MULTI-DISCIPLINARY CARE WHILE
ADMITTED.
WHEN INDIVIDUALS COME TO OUR
CENTER FOR GENE THERAPY THEY'RE
ON THE TRANSPLANT TEAM AND
UNDERSTAND THE TRANSPLANT
PHYSICIAN IS IN CHARGE AND
UNDERSTAND I'LL DROP BY AND SEE
THEM AND COMMENTING ON THEIR
CARE AND MANAGE THEIR OPIOIDS
CARE AND THE 15-YEAR FOLLOW-UP
SHOULD BE LED BY SICKLE CELL
DISEASE AND PATIENTS STILL NEED
EYE EXAMS AND STILL NEED MRIs
AND MRAs.
NOT BECAUSE WE BELIEVE THEY'LL
HAVE ANOTHER STROKE BUT
ENDOTHELIAL DYSFUNCTION MAY NOT
BE REVERSED BY THIS THERAPY.
WE CAME UP WITH TWO LEVEL OF
RECOMMENDATIONS.
ONE OF STANDARDS AND ONE OF
RECOMMENDATIONS.
AND WE MANAGE THE INDIVIDUAL UP
TO THE MOMENT THEY COME UP FOR
TRANSPLANT AS A SICKLE CELL
SPECIALIST AND DURING STEM CELL
COLLECTION WE DO CO-MANAGEMENT.
A COORDINATOR MUST BE AVAILABLE
OND ON THE SICKLE CELL SIDE OF
THINGS BECAUSE THEY'LL BE IN THE
CLINIC AND CENTER FOR A SOLID
SIX MONTHS BEFORE THEY EVER MAKE
IT TO TRANSPLANT.
THEY NEED TO BE WHERE THEY'RE
COMFORTABLE AND SOMEBODY WHO
KNOWS THE PATIENT AND
MULTIDISCIPLINARY MEETING FOR
FINALLY REVIEW TO MAKE SURE
PATIENTS ARE READY AND
EVERYTHING SOCIALLY IS ALSO
ALIGNED.
THEY HAVE A PLACE TO LIVE AND
FOOD AND ALL THE THINGS THAT CAN
BE HARD DURING A LONG PROCESS
LIKE THIS.
AGAIN I WANT YOU TO SEE THE
NUMBER OF SPECIALISTS THAT WERE
STANDARD IN ENSURING GOOD
OUTCOME IN THE GENE THERAPY.
SOCIAL WORKER DEDICATED TO
INDIVIDUALS UNDERGOING THE
THERAPY A PATIENT NAVIGATOR A
CHW OR NAVIGATOR OR OTHER PEOPLE
OR PSYCHOLOGIST.
I GIVE A TALK ON WHERE GENE
THERAPY SAVES SICKLE CELL
DISEASE AND ENSURING WE HAVE THE
RESOURCES OUR PATIENTS HAVE
NEEDED FOR A LONG TIME INCLUDING
PSYCHOLOGY AND PSYCHIATRY AND
IMPROVED SOCIAL WORK AND PATIENT
NAVIGATION THAT LIVES WITHIN THE
SICKLE CELL CENTER.
YOU HAVE TO HAVE BLOOD BANK
EXPERIENCE AND THE KNOWLEDGE AND
ABILITY TO DO APHERESIS AND
TREAT PAIN AND THE ABILITY TO
FOLLOW PATIENTS 15 YEARS.
FACILITY RESOURCES, MOST GO
WITHOUT QUESTION HOWEVER, YOU'D
BE SURPRISED THE NUMBER OF
PLACES DON'T HAVE THE ABILITY TO
DO IN-HOUSE HEMOGLOBIN
QUANTIFICATION THAT CAN MAKE
REAL TIME TRANSFUSIONS MORE
DIFFICULT AND AS WE GET TO THE
REAL WORLD WE HAVE TO FOLLOW ALL
THE RULES DURING THE TREATMENT
IN THE GENE THERAPY TRIALS.
JUST BECAUSE YOU'RE NOW IN THE
REAL WORLD DOESN'T MEAN YOU
DON'T HAVE APHERESIS TO GET IT
LOW AS POSSIBLE PRIOR TO STEM
CELL COLLECTION.
WE ALSO WANT TO ENSURE
INDIVIDUALS HAVE APPROPRIATE
EQUITABLE AND ETHICAL ACCESS TO
SPERM BANKING, OVARIAN AND EGG
COLLECTION AND HOUSING FOR
NON-LOCAL PATIENTS WHO WILL COME
TO YOUR CENTER.
THEN WE STARTED TALKING ABOUT
THE SPECIALIZED LONG-TERM
FOLLOW-UP THAT'S ALSO KEY AND
IMPORTANT MAKING SURE WE HAVE
THOSE PEOPLE IN PLACE IN A
TRANSFORMATIVE CARE CLINIC TO
SEE THE SICKLE CELL AND
TRANSPLANT SPECIALIST.
TO MAKE SURE THEY CONTINUE TO
FOLLOW UP EVEN AFTER THE INITIAL
PERIOD AND THEIR PAIN MEDICINE
TO ENSURE THEY'RE STILL BEING
SCREENED FOR ALL THE POTENTIAL
SICKLE CELL DISEASE RELATED
ISSUES THAT MAY STILL HAPPEN
BECAUSE WE DON'T HAVE THE DATA
YET.
WE NEED TO WORK ON OUR MENTAL
HEALTH GAME.
WE DON'T KNOW YET HOW TO
OPTIMIZE THE MENTAL HEALTH
PREPARATION AND TREATMENT DURING
THIS PROCESS FOR INDIVIDUALS
LIVING WITH SICKLE CELL DISEASE.
I HAVE NO DOUBT THOSE
INDIVIDUALS WHO ALREADY
INDIVIDUALS WHO RECEIVED THE
TREATMENT WILL HELP TEACH US AND
CRAFT THIS FOR FUTURE PATIENTS.
SO WE DO BELIEVE GENE THERAPY
CAN IMPROVE CARE FOR EVERYONE
LIVING WITH SICKLE CELL DISEASE
AND MOST PEOPLE WON'T GET GENE
THERAPY FOR THE NEXT FEW YEARS.
SO ANYONE REFERRED BE REFERRED
TO SEE A SICKLE CELL DISEASE
SPECIALIST.
THAT SHOULD BE THE FIRST PERSON
THEY MEET TO TALK ABOUT THE
VARIOUS OPTIONS AND THEN THE
TRANSPLANT PHYSICIAN.
SICKLE CELL DISEASE CENTERS NEED
STAFFING AND CARE COORDINATOR,
PSYCHOLOGIST, SOCIAL WORKER,
ACCESS TO PSYCHIATRY AND THIS
WILL INCREASE INTEREST FROM
OTHER INTERDISCIPLINARY TEAM
MEMBERS.
SUDDENLY WE'RE THE SHINY NEW TOY
IN THE ROOM AND IMPROVE THIS FOR
PEOPLE WITH SICKLE CELL DISEASE
AND NOT JUST GENE THERAPY.
AND OF COURSE WE'LL FINALLY
COLLECT LONGITUDINAL DATA ON
PEOPLE LIVING WITH SECRETARY OF
DEFENSE.
IT'S SO IMPORTANT THIS DATA
INCLUDES PRE AND POST NOT JUST
POST DATA ON WHO HAS RECEIVED
THE DIFFERENT THERAPIES.
WE NEED A REGISTRY SUCH AS GRAND
DAD THE NATIONAL REGISTRY OVER
50 CENTERS SOON TO BE 60 TO MAKE
SURE WE INCLUDE ACTUAL CHART
REVIEWED DATA COLLECTED TO
COMPARE PATIENTS WHO DO AND
DON'T GET THE THERAPY AND THOSE
INDIVIDUALS ON STANDARD OF CARE.
WE ALSO NEED THIS BECAUSE WHAT'S
HAPPENED IN THE PAST WHEN YOU
HAVE A GRANT OR PROJECT, THAT
DATA GOES AWAY.
IT DISAPPEARS WITH THE PROJECT.
BUT IF YOU EMBEDDED WITHIN AN
ALREADY PRESENT REGISTRY IT WILL
CONTINUE TO COLLECT AND TELL US
THE DATA WE NEED TO KNOW WE LOST
OVER THE LAST 50 YEARS.
SO YOU HAVE YOUR WHOLE TEAM AND
EVERYBODY IN THE ROOM AND NOW
YOU DO THE PAPERWORK.
THERE'S AT LEAST FOUR TO EIGHT
CONTRACTS AND WHETHER YOU'RE A
QUALIFIED OR AUTHORIZED
TREATMENT CENTER.
I HAVE THEM ALL LISTED.
YOU NEED TO BE AWARE TO FOCUS ON
WHO WILL ENSURE THEY'LL HAPPEN
AND TAKE CONTRACTS FROM POINT A
TO B.
WE KNOW HOW DIFFICULT SPONSORED
PROJECTS CAN BE.
WAIT UNTIL IT'S REAL WORLD AND
YOU HAVE TO MAKE IT THROUGH ALL
THE DIFFERENT STEPS TO GET
APPROVALS.
FIGURE OUT WHO WILL SIGN THE
CONTRACT AND WHO WILL REVIEW THE
CONTRACT AND DO YOU HAVE A ROLE?
I DON'T GET TO SIGN THEM AT MY
INSTITUTION BUT MY ROLE IS TO
MAKE SURE THEY KEEP MOVING FROM
POINT A TO B AND C AND SOMETIMES
BACK TO A AND CDAs, TERMS OF
ENGAGEMENT, QUALITY ARGUMENTS
AND I.T. AGREEMENTS.
THERE'S MULTIPLE PROCESSES THAT
HAVE TO BE EVALUATED AND YOU
STILL HAVE TO GO THROUGH A
QUALITY EVALUATION AND APHERESIS
LABS HAVE TO GO THROUGH THIS AND
WHAT'S YOUR ROLE IN THE PROCESS.
WE ALSO DISCUSSED WHAT IF
THERE'S GAP ANALYSIS THAT
RECOGNIZES A PROBLEM?
WHO WILL MAKE SURE THE PROBLEM
GETS FIXED TO MOVE THINGS ALONG.
YOU'LL DO A TEST RUN TO MOVE IT
FROM PLACE TO PLACE WHERE IT
NEEDS TO BE.
ENGAGEMENT.
MANY CENTERS WILL REQUIRE
ENGAGEMENT AND A PLAN FROM YOUR
PAYERS BEFORE THEY'LL EVEN ALLOW
YOU TO BECOME A QUALIFIED
TREATMENT CENTER.
I RECOMMEND YOU TRY IT AVOID
THAT IF POSSIBLE AND THERE'S
MORE DETAILS I CAN EXPLAIN BUT
ME -- THE MAIN THING IS TO BE A
TREATMENT CENTER THEY WANT A
PAYER AND WE NEED TO MAKE SURE
THIS DOESN'T BECOME CIRCULAR AND
YOU NEVER GET APPROVE TO THREE
THE THERAPIES.
SO THERE'S SEVERAL PARTS TO THE
REIMBURSEMENT.
EVERYBODY HEARS THE $1.2 MILLION
AND FORGET YOU HAVE TO COLLECT
IT AND DO THE FERTILITY
PRESERVATION AND DO THE
TRANSPLANT.
SO MAKING SURE THEY'RE ALL
ALIGNED AND THE PEOPLE
NEGOTIATING THE PEOPLE KNOW
ABOUT WHAT THEY'RE NEGOTIATING
FOR AND YOU HAVE THE
COORDINATION IN PLACE.
IN SUMMARY GENE THERAPY IS A
ONE-TIME PROCESS THAT REQUIRES
SIGNIFICANT TIME AND DEDICATION.
THIS A TEAM EFFORT AND HAS TO
INCLUDE THE SICKLE CELL DISEASE
SPECIALIST.
THE ALLIANCE IS DEVELOPED
RECOMMENDATIONS TO ENSURE YOU
HAVE THE RIGHT PEOPLE AND
PROCESSES IN PLACE.
THIS WILL HELP ENSURE YOU HAVE A
COORDINATOR E OR DEDICATED TO T
INDIVIDUALS AND PSYCHOLOGISTS
AND MENTAL HEALTH CARE FOR
INDIVIDUALS GOING THROUGH THESE
PROCEDURES.
THE PAPERWORK AN C SUITE
ENGAGEMENT I CAN TELL YOU MORE
BUT YOU'D BE ASLEEP AND IT'S NOT
THAT FUN HOWEVER, IT TAKES
SOMEBODY TO SHEPHERD IT ALL THE
WAY THROUGH AND KNOW WE CAN GET
OUR PATIENTS TO THE
TRANSFORMATIVE CARE THEY
DESERVE.
THAT SHOULD BE IT.
I THINK WE HAVE A FEW MINUTES
FOR QUESTIONS.
THANK YOU AGAIN AND AGAIN, SORRY
I'M NOT THERE IN PERSON.
>> IN YOU DISCUSS THE OPTIMIZED
POINT LINE OF GENE THERAPY IN
THE USA?
IT DEPENDS ON WHAT YOU MEAN BY
PIPELINE AND I'LL PUT MY E-MAIL
IN THE DISCUSSION AND IT DEPENDS
IF YOU INCLUDE COMMERCIAL
THERAPY AT YOUR SITE VERSUS THE
PROCESS AND PIPELINE.
>> DR. FEIN.
>> JULIA, THAT WAS GREAT SORRY I
MISSED THE LAST MEETING BUT I
FEEL CAUGHT UP AND AS A
CARDIOLOGIST AND PULL MOB --
PULMONOLOGIST MANAGING SICKLE
CELL DISEASE WHAT IS THE
APPROPRIATE PRE GENE THERAPY
EVALUATION FOR OUR PATIENTS AND
I WOULD BE HAPPY TO HELP WITH
THAT PROCESS AS WE MOVE TOWARDS
THAT BECAUSE I GET CONCERNED
WHEN THERE'S TOO MUCH HAND
WAVING GOING ON HOW TO PROPERLY
EVALUATE OUR PATIENTS.
>> THIS IS FROM THE 2023 MEETING
AN NOT THE MOST RECENT.
SO YOU HAVE MORE TO CATCH UP ON
BUT WE'LL BE HAPPY TO TALK TO
YOU ABOUT THAT MORE TOMORROW OR
WEDNESDAY.
THE OTHER PART WE DID START
TALKING ABOUT THIS YEAR IS
IDENTIFYING THE RIGHT PATIENT
AND THE BEGINNING OF THIS
QUESTION OR THE BEGINNING LED TO
AN INTERESTING IDEA OF A
SIX-MONTH OPTIMIZATION PERIOD.
HOW CAN WE OPTIMIZE INDIVIDUALS
TO GET THE BEST OUTCOMES FROM
THE THERAPIES AND WE'D LOVE TO
HAVE YOU ON BOARD FOR THAT.
>> GREG KATO.
THANK YOU FOR THE TALK AND
EDUCATING US ON THE BUREAUCRATIC
PROCESS TO GET THINGS SET UP.
CAN YOU TELL US ABOUT THE
COMPLEXITIES ABOUT DEPARTMENTAL
STAKEHOLDERS.
>> GREAT QUESTION.
THERE'S ALWAYS COMPLEXITIES AND
POLITICAL MANEUVERING.
WHEN I CAME TO UAB I SET US UP
OUTSIDE THE CANCER CENTER TO
WORK MORE INDEPENDENTLY BUT IT'S
A JOINT EFFORT AND I PARTNERED
WITH OUR TRANSPLANT PERFORM
WITHIN THE CANCER CENTER.
THAT'S DIFFERENT FROM AN
ACADEMIC STANDPOINT.
IN ACADEMIC STANDPOINT UNDER THE
DEPARTMENT OF MEDICINE BUT IN
THE HOSPITAL WE LIVE UNDER THE
CANCER SERVICE LINE.
YOU HAVE TO HAVE ALL THE
DIFFERENT PEOPLE ON BOARD AND
EVERYONE KNOWS THEIR ROLE AND
RRE
PREDEFINE IT UP FRONT AND NOT A
QUESTION OF WHO IS SUPPOSED TO
DO WHAT.
>> I ENJOYED THE COMMENT ABOUT
PATIENTS TALKING ABOUT OTHER
THERAPIES.
ARE YOU SEEING INTEREST IN ORAL
THERAPIES STILL IN CLINICAL
DEVELOPMENT?
>> WE SEE TREMENDOUS INTEREST IN
ALL THERAPIES.
IN ALABAMA IN THE LAST 18 MONTHS
WE HAD 190 NEW PATIENTS COMING
TO OUR CENTER, ONLY ADULTS, WITH
SICKLE CELL DISEASE.
THE MAJORITY OF THESE WERE
PREVIOUSLY UNAFFILIATED MEANING
THEY'D NEVER SEEN A SICKLE CELL
SPECIALIST IN THE LAST TWO YEARS
AND MANY DIDN'T UNDERSTAND WHY
ANYBODY WOULD TAKE HYDROXYUREA
AND HAVE INTEREST IN OTHER
THERAPIES AND THE BENEFIT IS
GETTING THEM TO WALK IN THE
DOOR.
NOW THEY CAN ASK ABOUT OTHER
THERAPIES.
THE LAST WOMAN WHO CAME IN IS A
41-YEAR-OLD WOMAN WITH A HISTORY
OF THREE STROKES AND PULMONARY
HYPERTENSION AND WAS NOT ON
CHRONIC TRANSFUSION THERAPY.
OBVIOUSLY THERAPY IS NOT RIGHT
FOR HER BUT GETTING HER TO THE
RIGHT SPECIALIZED THERAPY SO
HELP HER IMPROVE IS AND THERE'S
GREAT OPPORTUNITY.
BY NO MEANS SHOULD WE COUNT THE
IMPORTANCE OF NEW THERAPEUTICS.
IT WILL BE A LONG TIME UNTIL
EVERYBODY CAN GET THE THERAPY.
>> ANY OTHER QUESTIONS?
THANK YOU, JULIE.
THAT WAS AN EXCELLENT TALK.
I'M EXCITED ABOUT THE GROWING
NUMBER OF SICKLE CELL CENTERS
ACROSS THE COUNTRY.
THANK YOU.
>>
>> OKAY.
LOOKS LIKE WE'RE A COUPLE
MINUTES AHEAD BUT THAT'S GREAT.
SO OUR NEXT TALK ACTUALLY WAS
SCHEDULED FOR 2:45 BUT WE'RE A
LITTLE EARLY.
THAT'S OKAY.
THE NEXT TALK WILL BE GENE
THERAPY FOR SICKLE CELL FROM
CLINICAL DEVELOPMENT TO
LONG-TERM FOLLOW-UP.
DR. ON ATH THTH THTH THTHEN -- N
AND DR. ALEXIS LEONARD.
>> I'LL MAKE THIS PRESENTATION
ON BEHALF OF THE ST. JUDE STAGES
TEAM AND DR. YEN.
WHAT I'LL TALK TO YOU ABOUT
TODAY IS THE UPCOMING CLINICAL
TRIAL THAT ST. JUDE HAS BEEN
WORKING ON FROM PRE CLINICAL
DEVELOPMENT TO OUR FOR LONG-TERM
FOLLOW-UP.
THIS IS KIND OF HOPEFULLY A NICE
COME TOGETHER OF THIS MORNING OF
THE BASIC SCIENCE TALKS AND THIS
GREAT CONVERSATION WE JUST HAD
ABOUT THE PLANS HOW TO INVOLVE
THE PATIENT IN THE PROCESS AND
THE MOVING FORWARD.
I'LL TELL YOU WHAT WE INTEND TO
DO AT ST. JUDE.
I WANT TO TALK ABOUT SICKLE CELL
DISEASE AT ST. JUDE.
AND WE SEE DISEASE THROUGH
TREATMENT.
SO ST. JUDE HAS A ROBUST HISTORY
OF SICKLE CELL DISEASE SINCE ITS
FOUNDING IN THE 1960s.
WE WERE ONE OF THE FIRST
COMPREHENSIVE RESEARCH CENTERS
ON BEHALF OF DR. DIGS AND
JACKSON AND WERE THE HOSPITAL
THAT TREATED THE FIRST PATIENT
CURED OF SICKLE CELL DISEASE
FROM A BONE MARROW TRANSPLANT IN
THE EARLY 1980s.
WE CURRENTLY TREAT ABOUT 900
PATIENTS WITH SICKLE CELL
DISEASE ACROSS FOUR STATES.
THE VAST MAJORITY OF OUR
PATIENTS PARTICIPATE IN RESEARCH
WHETHER THAT'S NEW DRUGS OR
DIAGNOSTIC TOOLS OR CURATIVE
THERAPIES WHICH WE'LL TALK ABOUT
TODAY AND IMPORTANTLY WE HAVE
THE SICKLE CELL RESEARCH AND
INTERVENTION PROGRAM STARTED BY
DR. HINKENS AND WE'RE STARTING
WITH HER LEADERSHIP TO BUILD A
GLOBAL PRESENCE IN SECOND
HALFED.
-- IN SICKLE CELL DISEASE.
I WANT TO TALK ABOUT OUR
UPCOMING STUDY AND PRECLINICAL
WORK FOR STUDY FOR SICKLE CELL
DISEASE THROUGH FETAL HEMOGLOBIN
INDUCTION.
THIS HAS ALL BEEN TALKED ABOUT
TODAY BUT THE IDEA IS TO MIMIC
THE VARIANTS IN WHAT CAUSES HPFH
AND TURNING FETAL HEMOGLOBIN IN
A PAIN CELLULAR DISTRIBUTION.
THIS STUDY IS TARGETING
SPECIFICALLY THE GAMMA GLOBIN
PROMOTER.
YOU HEARD ABOUT THIS THIS
MORNING FROM DR. BAUER AND USING
CAS 9 AND THE ERYTHROID ENHANCER
WITH THE TARGET BEING DISRUPTION
OF THE ENHANCER WITH THE CELL
AND WE'RE TALK BEING ABOUT USING
CAS 9 OR ANOTHER ONGOING TRIAL
TO CREATE INDELS AT THE GAMMA
GLOBIN PROMOTER.
IT BLOCKED THE BCL11A AND THE
TRIAL WE'RE TALKING ABOUT
REFERRED TO AS SAGES THE
ST. JUDE TARGETED SICKLE CELL
DISEASE FUNDED BY THE UL1 GRANT.
THE PROCESS OF CLINICAL TRIAL
TRIAL WAS TO GET THE IND
APPROVAL THE PAST SPRING.
I WANT TO SHOW SOME PRE
CLINICALS FROM THE CMC DATA TO
OPTIMIZE AND SCALE UP.
SO FIRST GENOME EDITING AT THE
MINUS 115 SITE TO INDUCE
HEMOGLOBIN AND AFTER
TRANSPLANTING TO THE HEALTHY
CELLS IN MICE WE COULD SHOW AND
COMPARE TO OTHER HEMOGLOBIN
STRATEGIES LIKE THE ENHANCER OR
TARGETING MOTIF THAT ACROSS THE
BOARD IN THE INPUT AND 17 WEEKS
LATER IN MICE YOU GET HIGH
EDITING RATIOS.
THE FETAL HEMOGLOBIN INDUCTION
WAS HIGHEST USING THE SITE IN
COMPARISON TO THE OTHER BINDING
MOTIFS OR ENHANCERS.
YOU HAVE SIGNIFICANT REDUCTION
IN SICKLING.
AS WE TRANSFERRED THIS TO SCALE
UP AND OPTIMIZE THERE'S
VARIABLES THAT GO INTO THIS YOU
CAN SEE LISTED HERE AND
ULTIMATELY A DESIGN OF
EXPERIMENT STUDIES WE CAN
EXAMINE MULTIPLE PARAMETERS
SIMULTANEOUSLY AND WE FOUND THE
CAS 9 CONCENTRATION AND CELL
CONCENTRATION AND WE USED
HEALTHY DONORS HECs WITH
ELECTROPORATED WITH OUR CAS 9
SHOWING INDUCTION IN VIVO ACROSS
DONORS.
AND AS A MEMBER OF ST. JUDE WE
FOUND NO DETECTABLE OFF TARGET
MUTATIONS FROM AFRICAN AMERICAN
DONORS AND WHEN WE TRANSPLANTED
WE HAD NO ADVERSE OUTCOMES IN
OUR MICE.
AND NOW I WANT TO TRANSFER TO
THE WORK WE FELT WE WERE ABLE TO
MOVE FORWARD FROM THE CLINICAL
TO HEMATOLOGY TO PATIENTS.
THIS STUDY REFERRED TO IS A CAS
9 TRIAL AT THE HEMOGLOBIN
PROMOTER AND THE PRODUCT IS
BEING MANUFACTURED ON SITE AT
THE ST. JUDE CHILDREN'S AMP AND
WILL START THE STUDY ONCE A FEW
PATIENTS HAVE BEEN TREATED WILL
BE ABLE TO EXPAND TO MULTIPLE
CENTERS.
IN BRIEF THE EXCLUSIONARY
CRITERIA ARE SIMILAR TO THE
CLINICAL TRIALS CURRENTLY BEING
RUN.
BRIEFLY THESE ARE STARTING WITH
ADULT PATIENTS.
WE ARE EXCLUDING SC PATIENTS AT
THIS TIME AND EXCLUDEING
PATIENTS WITH CURRENT VOEs OR ON
CHRONIC TRAN FUSIONS EXCEPT FOR
PRIMARY OR SECONDARY STROKE
PREVENTION AND THOSE WITH A
MATCHED SIBLING OR HISTORY OF
STROKE.
THIS LOOKS FUNNY BUT WHAT I WANT
TO DESCRIBE TO YOU IS PART OF
SUPPLEMENTING THE DISCUSSION
WITH DR. KANTER AND WE DEVELOPED
THE ST. JUDE HEMATOLOGY GENE AND
CHROME THERAPY PROGRAM RUN BY
MYSELF AND MY COLLEAGUE
DR. SHARMA.
AT THE BOTTOM IN THE SMALL FONT
YOU CAN SEE ALL THE MANY
MULTI-DISCIPLINARY TEAM MEMBERS.
ULTIMATELY THE PATIENT WAS AT
THE CENTER.
IT'S CENTERED AROUND SHARED
DECISION MAKING.
OF COURSE PATIENTS COME IN AND
THE CONSULTATION HAS BEEN
MENTIONED WE'LL TALK ABOUT THIS
CLINICAL TRIAL AND THE FDA
APPROVED OPTIONS AND ALLO GENEIC
TRANSPLANT OR NOT DOING THESE
AND THE RIGHT TIME.
AND AS PATIENTS MOVE ALONG THE
PROCESS WE INTEND TO FOLLOW FOR
15 YEARS IN OUR COMBINED
TRANSFORMATIVE CELL THERAPY
CROSSING THE GENE THERAPY
CLINIC.
ONE IMPORTANT DISTINCTION I WANT
TO MAKE SINCE IT'S A PRODUCT
WE'RE ABLE TO MANUFACTURE
OURSELVES IN CONTRAST TO THE
CLINICAL TRIALS WHERE THE WAIT
TIME BETWEEN DRUG PRODUCT
MANUFACTURER AND TRANSPLANT CAN
BE UPWARDS OF SIX MONTHS WE
ANTICIPATE ONE OR TWO MONTHS
FROM DRUG MANUFACTURE GOING
TOWARDS TRANSPLANT.
THE BIGGEST QUESTION IN THE ROOM
AND FOR ALL OF US IS HOW TO
FOLLOW THESE PATIENTS LONG-TERM
AND HOW CAN WE AT ST. JUDE DO
THIS AND HARMONIZE WITH
EVERYBODY ELSE WANTING TO DO
THIS BECAUSE GENE THERAPY IS
TRANSFORMATIVE UNTIL ALL THE
OUTCOMES ARE BETTER UNDERSTOOD.
WHAT WE INTEND TO DO AT ST. JUDE
AND I THINK THE WHOLE AUDIENCE
WOULD AGREE WE NEED TO KNOW MORE
THAN WHAT HAPPENS TO PAIN.
WE NEED TO KNOW IS THERE ONE
PRODUCT BETTER THAN THE OTHER.
WE NEED TO KNOW AS WE START TO
MAKE ALL THE PROCESS
IMPROVEMENTS GET RID OF DIFULSAN
AND WE INTEND TO DO THIS THROUGH
OUR SCCRIP COHORT STARTED IN
2014.
THIS IS OUR LONGITUDINAL AND BIO
REPOSITORY COHORT OF ALL OF OUR
PATIENTS WITH SECRETARY OF
DEFENSE FROM PEDIATRICS THROUGH
THE ADULT POPULATION AS THEY'RE
TRANSITIONED OUT OF ST. JUDE.
WE HAVE JUST OVER 1500 PATIENTS
ENROLLED AND IMPORTANTLY WE HAVE
SEPARATED IT OUT INTO MULTIPLE
WORKING GROUPS THAT HAVE
ORGAN-SPECIFIC EXPERTS FROM
ACROSS THE COUNTRY.
WE HAVE ABOUT 70 PEOPLE
INTERESTED AND PART OF THE
WORKING GROUPS.
IT HAS A PLACE FOR ROBUST
ABILITY TO GENERATE AND ANALYZE
THE DATA.
WE'RE INVOLVED IN THE TOP MED
CONSORTIUM WITH ST. JUDE AND
VANDERBILT AND THE UNIVERSITY OF
ILLINOIS TO LOOK AT THE THINGS
DR. FITZHUGH DISCUSSED IN GERM
LIN AND HEMATOPOIESIS.
OUR INTENT IS ALL PATIENTS WHO
RECEIVE A TRANSFORMATIVE THERAPY
WILL WILL BE FOLLOWED WITHIN THE
INFRASTRUCTURE WHICH ALREADY
INCLUDES THE PATIENTS RECEIVING
STANDARD OF CARE.
AND SO WITH THIS WE ARE OPEN TO
THE COLLABORATIONS THAT CAN
OCCUR AND CERTAINLY DEVELOPING A
STANDARDIZED PARAMETER TO
MEASURE THE OUTCOMES AFTER ALL
TYPES OF TRANSPLANT AND NOT
HAVING A TRANSPLANT FOR PATIENTS
WITH SICKLE CELL DISEASE.
THIS IS TO SHOW IS TAKES A LARGE
TEAM TO THE SUB SPECIALISTS AND
THE ENTIRE CLINICAL TRIALS TEAM
AND HEMATOLOGISTS WHO GOT THIS
OFF THE GROUND.
FROM HERE, WE WANT TO
ACKNOWLEDGE ALL THE IMPORTANT
PARTIES.
OUR COLLABORATORS AND NHLBI
FUNDING AND THEN AT THE TOP IS
MY E-MAIL IF YOU HAVE A PATIENT
YOU'D LIKE TO REFER.
THIS TRIAL SHOULD BE ACTIVE AND
OPEN WITHIN THE NEXT FEW MONTHS
AND WITH THAT I'M HAPPY TO TAKE
ANY QUESTIONS.
>> WE HAVE ONE COMMENT ON LINE.
FOR ME THE CRITICAL QUESTION IS
WHETHER ONE TREATMENT IS SAFER
THAN ANOTHER WHICH HINGES ON
HAVING A UNIFORM COMPLETE
LONG-TERM FOLLOW-UP PROCESS
GATHER THE CRITICAL SAFETY DATA
WHICH VARIES FROM STUDY TO
STUDIO AND SPONSOR TO SPONSOR.
>> YES, I AGREE.
AND DR. KANTER AGREES AS WELL.
TO THE REASON WE'RE HERE IS TO
AGREE ON THE PACT WE NEED
HARMONIZATION.
WE CAN START AS SIMPLE AS MAKING
SURE YOUR STUDY THAT THESE NHLBI
STUDIES ARE ALL HARMONIZED AND
THEN WORKING WITH MAKING SURE
EVERYBODY THAT'S GOING IN IS
WHAT WE'RE FOLLOWING AND ALL OF
THESE DISPARATE REGISTRIES.
THE ONLY WAY WE'LL KNOW IS IF WE
HARMONIZE THIS MORE BROADLY AND
SO I THINK MEETINGS LIKE THIS IS
A CALL TO ACTION THAT THAT'S
WHAT NEEDS TO HAPPEN.
>> OKAY.
ANYMORE QUESTIONS FROM THE
PANEL?
THANK YOU VERY MUCH, ALEXIS FOR
A GREAT TALK.
NOW WE HAVE A WONDERFUL SESSION
THE UPDATES FROM NHLBI CURE
SICKLE CELL DISEASE INITIATIVE
CHAIRED BY HEATHER AVANT.
>> I'M GOING INTRODUCE A COUPLE
PEOPLE WHO WILL COME UP.
DR. JOHN MANIS WHO WILL TALK
ABOUT OPTIMIZING PRE-TRANSPLANT
ACCESS TO GENE THERAPY FOR
SICKLE CELL DISEASE AND PART OF
THE WORKING GROUP TO CURE SICKLE
CELL AND DR. CECELIA VALRIE AND
JERLYM PORTER TALKING ABOUT
PSYCHOSOCIAL READINESS AND
SUPPORT FOR PRE AND POST-GENE
THERAPY IN SICKLE CELL DISEASE.
I'LL BE CO-HOSTING AFTER THAT
WITH ADRIENNE SHAPIRO.
>> IT'S GREAT TO GO OVER THE
TOPIC.
IT'S BEEN GREAT TO BRING THE
PRESENTATION TODAY AND TO BE
ABLE
ABLE TO DISCUSS THE WORKING
GROUP AND WHAT WE'VE DONE AND
WHAT WE'RE THINKING ABOUT AND
WHERE WE'RE GOING.
JUST ONE DISCLOSURE THAT'S MINE.
THE WORKING GROUP IS COMPROMISED
OF INDIVIDUALS AND TRIED TO MAKE
IT INCLUSIVE ACADEMIC, INDUSTRY,
GOVERNMENT ORGANIZERS.
EVERYBODY COMING TOGETHER TO
UNDERSTAND THE CHALLENGES
ASSOCIATED WITH MOBILIZATION AND
AFER -- APHERESIS CORRUPTION AND
THERE WAS CONSIDERING IN HOW
WE'D GET SIZE BUT THE DEEP
QUESTIONS SURROUNDING
MOBILIZATION, SURROUNDING
TECHNICALLY HOW DO WE COLLECT
WASN'T KNOWN.
THAT WAS ONLY FIVE TO 10 YEARS
AGO.
IT'S NOT JUST THE PROBLEM WE'VE
BEEN THINKING ABOUT THE 20 OR
30.
IT'S SO ESTABLISH THE BEST
PRACTICE GUIDELINES AND
UNDERSTAND THE KNOWLEDGE GAPS.
AFTER FIRST WOE WE WANTED TO
UNDERSTAND THE LANDSCAPE AND
DEVELOPED A SURVEY WE
DISTRIBUTED TO COLLECTION
CENTERS TO TRY TO UNDERSTAND
WHAT IS EVERYBODY DOING FOR
COLLECTIONS FOR SICKLE CELL GENE
THERAPY AND ALSO WHAT THEY'RE
DOING DIFFERENT CENTERS FOR
PATIENTS WITH DEVELOPED.
I WANT TO TAKE ONE STEP BECOME
AT THIS POINT TO HELP YOU
UNDERSTAND WHEN WE'RE TALKING
ABOUT STEM CELL COLLECTIONS FOR
SICKLE CELL DISEASE WE'RE ALSO
TALKING ABOUT OTHER REGIMENTS
I'LL GET INTO BUT HOW CAN
APHERESIS TRANSFUSION AND THOSE
THAT COLLECT STEM CELLS IMPROVE
THE HEALTH OF SICKLE CELL
PATIENTS.
THERE'S A WIDE VARIANT IN
COLLECTS AND MOST CENTERS SOME
OF SOME HAD ZERO COLLECTIONS FOR
DEVELOPED.
IT MEANT MANY COLLECTIONS.
THERE WAS ALSO WIDE VARIATION IN
STEM CELL COLLECTION PRACTICE
STANDARDS AROUND EXACTLY HOW
APHERESIS WAS PERFORMED 37 --
PERFORMED.
THE PARAMETERS WERE NOTE
SPECIFIED.
THOSE WERE LEFT IN SOME SORT OF
RAY BECAUSE HEMATOLOGISTS WERE
THINKING ABOUT THIS IN THE WAY
OF WHY ARE WE DOING THE
EXCHANGE?
THIS IS AN EVOLVING FIELD.
WHAT ARE WE GOING TO SECOND HALF
PATIENTS TO IMPROVE THEIR HEALTH
FOR MOBILIZATION.
THAT IS A QUESTION NOT BROUGHT
UP BEFORE.
THE LAST PART IS VERY IMPORTANT
IS THERE'S A LACK OF DATA
COLLECTIONS.
HOW CAN WE SHARE THE INFORMATION
AMONGST COLLECTION CENTERS.
THE CHALLENGES OF THE PATIENTS
AND GENE THERAPY ONE IS ACCESS
TO THE RED CELL TRANSFUSION
REGIMENTS.
IN OTHER WORDS, WHO COULD GET
RED CELL EXCHANGE.
HOW PATIENTS ACCESS THIS?
ARE THEY IN SPECIALTY CENTERS
THAT UNDERSTAND WHEN TO GO TO
RED CELL EXCHANGE OR NOT TO OR
WHEN TO PULL THE TRIGGER AND
HAVE.
MOBILIZATION ACRONYMS ARE
CHALLENGING AND MANUFACTURING
MENG ODDS AND TO THE PRODUCT AND
IT'S SCALABLE.
SO TO THE PRESENT DAY CHALLENGES
ACCESS TO CENTERS OF EXCELLENCE.
THE EXTENDED WAIT PERIOD FOR
ACCESS.
IF YOU ASK FOR GENE THERAPY NOW
YOU'LL PROBABLY HAVE TO WAIT
CLOSE TO A YEAR.
AND HOW DO WE CHANGE THAT?
THAT'S SOMETHING DR. BAUER UP
EARLIER.
IF IT TAKES NINE MONTHS TO
PREPARE SOMEBODY FOR GENE
THERAPY, WHO IS TAKING CARE OF
THE PATIENT AND SCALE UP FOR
MANUFACTURING.
AND WE WILL REQUIRE A LARK
NUMBER OF CELLS AND PROBABLY YOU
WANT A LARGER DOSE.
THIS IS DIFFERENT FROM THE PAST
AND THIS DISTINCTION NEEDS STUDY
AND SPECIAL ATTENTION.
THERE'S INTRINSIC LOSS IN
MANUFACTURING.
DR. WILLIAMS BROUGHT UP THE
DIFFERENCES AMONGST THE TRIALS
AND HOW TO MANIPULATE THE CELLS
IF YOU'RE EXPANDING IN VITRO AND
HOW MANY DAYS IT TAKES TO
COLLECT AND HOW CELL COLLECTIONS
ARE PUT TOGETHER ALL THIS
MATTERS.
AND REAL LIFE LIMITATIONS TO THE
GENE THERAPY AND THERE WAS A
SIMILAR SLIDE.
AND THIS ISN'T TO POINT OUT
FAILURE OF THE GROUP BUT TO
POINT OUT THE CHALLENGE.
IF YOU LOOK AT THE TABLE ON THE
RIGHT YOU'LL SEE A THIRD OF
PATIENTS REQUIRE THREE CYCLES
AND MOBILIZATION AND COLLECTION
TO GENERATE A PRODUCT.
AND THAT MEANS GOING TO THE
HOSPITAL, STAYING SEVERAL DAYS,
COLLECTING CELLS, WAITING FOR AN
ANSWER AND FOR MOST COMING BACK
ANOTHER MONTH LATER AND MAYBE
REPEATING THAT ANOTHER MONTH.
THAT'S A WAITING PERIOD THAT WE
HAVE TO IMPROVE ON.
HOW DO WE IDENTIFY WHO WOULD BE
AT RISK FOR COLLECTION?
HALF THE PATIENTS REQUIRE
MULTIPLE SAMPLES FOR COLLECTION.
THIS IS FOR ALL TOGETHER.
IF YOU THINK ABOUT THE PATIENTS
AND WE HAVE EXPERTS AND
FANTASTIC PUBLICATIONS AND
EXPERTS IN THE ROOM SHOWING HOW
YOU APPROACH IN OTHER WORDS THE
MORE YOU HAVE GOING ON BECAUSE
SICKLE CELL DISEASE THE LESS
YOU'LL MOBILIZE WELL AND IMPACT.
IT WASN'T APPRECIATED.
I MAY SEEM OBVIOUS BUT THAT WORK
IS HIGHLY, HIGHLY IMPACTFUL.
SO CONSIDER IMPROVING OVER ALL
DISEASE AND RED CELL EXCHANGE IS
ENOUGH AND RED CELL CHANGE MAY
BE USED AND THOUGHT ABOUT AS A
THERAPEUTIC TOOL AND THE WORKING
GROUP HELPED PINPOINT THAT.
WE UNDERSTAND TECHNICAL
INTERRUPTIONS AFFECTED OUTCOME.
IF YOU'RE DOING A COLLECTION
THAT TAKES HOURS ALL THE
INTERRUPTIONS DURING THE TIME
YOU MAY FORGET ABOUT THEM BUT
TAKE THEM TOGETHER THAT MAY HAVE
IMPACT.
SELECTING THE INTERFACE.
THAT'S VERY GRANULAR TALK FOR
HOW WE'RE PROGRAMMING THE
INSTRUMENT BUT IT'S INCREDIBLY
IMPORTANT REQUIRES TRAINING AND
VASCULAR ACCESS AND PATIENT
ACCESS NEEDS TO BE STANDARDIZED.
RECURRING THEMES THAT'S PRACTICE
VARIABILITY.
I POINTED TO THE POINTS ON THE
SLIDE.
THIS WILL BE ONLINE AND THERE'S
A CHECKLIST SOMEBODY SHOULD HAVE
AND WHO THAT SOMEBODY IS MAY
VARY AT INSTITUTIONS AND THAT'S
SOMETHING ELSE THE WORKING GROUP
LOOKED AT A DIFFERENT APHERESIS
PROVIDER.
SOMETIMES TRANSPLANT, SOMETIMES
HEMATOLOGY AND TRANSFUSION OR
LABORATORY MEDICINE OR PATHOLOGY
AND HAVE TO INSURRECT AND I'M
THE ONE THAT WANTS TO PUT
APHERESIS IN THE MIDDLE OF THAT
BECAUSE THERE'S A LONG PERIOD OF
TIME WHERE YOU HAVE TO BE TRANS
FUSING AND HAVE TO THINK ABOUT
RED CELL EXCHANGE AND THINK
ABOUT THE COLLECTION.
WHO IS COORDINATING THAT AND
SEEING THE PATIENT.
YOU HAVE TO INVOLVE THE
CARETAKER IN THE PROCESS.
SO REGIMENTS TO STABILIZE VOEs
TO REDUCE ERYTHROHYPERPLASIA AND
SOMETHING WE HAVE TO UNDERSTAND
AND STUDY.
CAN RED CELL EXCHANGE IMPROVE
THE HEALTH OF A BONE MARROW.
THOUGH WE COULD DO THE STUDYUND.
CAN RED CELL EXCHANGE IMPROVE
THE HEALTH OF A BONE MARROW.
THOUGH WE COULD DO THE STUDY WOE
DON'T KNOW IF IT'S THE CASE IN
PATIENTS.
IS THE ROLE SIMPLY TO PROTECT
PATIENTS DURING THE PERIOD WHEN
THEY'RE OFF THEIR USUAL
MEDICATIONS THAT PROTECT THEM
FROM VASO OCCLUSIVE CRISIS BUT
WE SHOULD THINK THERAPEUTICALLY.
THE ACTIVITIES REQUIRE DATA
COLLECTION ASSESSMENT SO THE
REGISTRIES WE'RE DISCUSSING POST
TRANSPLANT WE HAVE TO THINK
ABOUT WHAT DO WE TAKE AS INTAKE
BEFORE TRANSPLANTATION BEFORE
GENE THERAPY FOR OUTCOMES FOR
MOBILIZATION AND COLLECTION.
THIS IS SHOWING IN THE GRASP
TRIAL FUNDED THERE'S MANY SWIM
LANES AND YOU SEE SWIM LANE
AFTER SWIM LANE OF WHAT NEEDS TO
BE DONE WITH PATIENTS BEFORE
THEY GET TRANSPLANTED.
AND THERE'S A LOT THERE.
THAT NEEDS TO BE COORDINATED.
ANOTHER THING WE UNDERSTOOD IN
THE WORKING GROUP FOR THE
COMMUNITY IS THAT PLERRI --
PLERIXAFOR AND YOU SEE THE DATA
PUBLISHED.
THE MANUSCRIPT WITH THE DATA
SHOWING A HUGE VARIATION IN
COLLECTION EFFICIENCY.
THIS IS HOW MANY CELLS WE CAN
GET TO FOR THE APHERESIS LEVEL
AS A METRIC AND IT GOES FROM 10
TO 100 AND THAT'S BOSTON
CHILDREN'S.
WE CAN SEE A WIDE VARIATION.
WE HAVE TO UNDERSTAND WE WANT
SOMETHING AT 40% OR GREATER AND
IF YOU'RE GETTING MANY PATIENTS
THAT AREN'T, WHO IS THAT PATIENT
CAN WE PREDICT THAT AND THE
BIOMARK
BIOMARKERS AND LOOK AT THEM AND
SEE EXACTLY WHAT WE'RE DOING
WITH THE INSTRUMENT OVER TIME.
SO THIS NEEDS TO BE STUDIED.
BRINGING SOMEBODY IN AND HAVING
A WAITING PERIOD BEFORE THEY ARE
GO ON, DOCUMENTING A FULL BLOOD
BANK HISTORY.
HEMOGLOBIN TARGET OF 30% BEFORE
YOU START MOBILIZATION AND
DURING THE TIME PERIOD AGAIN
YOU'RE DOING TRANSFUSION BEFORE
YOU MOBILIZE AND PERHAPS WHILE
YOU'RE MAKING A GENE THERAPY
TRIAL.
VASCULAR ACCESS TO TRANSFUSION.
SO AGAIN IMPROVING MOBILIZATION,
IMPROVING THE UNDERLYING
DISEASE.
I THINK WE MADE THAT CLEAR
THROUGH THE SLIDES.
OTHER RECOMMENDATIONS AS A
WORKING GROUP, TARGETING HPC
CELLS AND PROGENITOR CELLS AT A
DEEPER LAYER.
I THINK WE'VE BEEN ABLE TO
COMMUNICATE THIS THROUGH THE
COLLECTIONS.
AND THIS NOW PART OF THE
EDUCATION AROUND THERAPIES AND
THIS MAY SEEM GRANULAR BUT THE
TAKE HOME MESSAGE IS IT'S NOT A
REGULAR STEM CELL PRODUCTION.
SO GO TO YOUR EXPERTISE, CONTACT
A CENTER THAT KNOWS HOW TO
COLLECT STEM CELLS AND ALSO
ASKING THE COMMERCIAL
MANUFACTURERS TO MAKE SURE
THEY'RE USING THESE
RECOMMENDATIONS.
UNDERSTANDING THE COLLECTION AND
THE NEED FOR MORE.
VASCULAR ACCESS.
WE NEED THE TAKE HOME MESSAGE OF
THE SLIDE IS YOU DO NEED VESS
-- VASCULAR ACCESS.
IT'S NOT STUDIED ENOUGH.
WE DON'T HAVE MANUFACTURERS OF
IMPLANTED VASCULAR DEVICES TO BE
ABLE TO DO RED CELL EXCHANGE,
TRANSFUSION.
THIS IS NOT REALLY TELLING FOR
THE SICKLE CELL COMMUNITY THE
PATIENTS WITH SICKLE CELL AND WE
HAVE TO THINK ABOUT THIS IN THE
HEMATOPOIESIS AND STUDY IN A
BROADER LEVEL.
FUTURE DIRECTIONS FOR
TRANSFUSION MEDICINE.
THIS IS ONE OF MY LAST SLIDES.
WE NEED TO IMPROVE THE
CHALLENGES BECAUSE IF THIS
BOTTLENECK OF BEING ABLE TO
COLLECT ENOUGH CELLS TO TAKE
PATIENTS THROUGH THE JOURNEY IF
WE DON'T IMPROVE THIS, WE'RE NOT
ONLY DOING A DISSERVICE TO THE
PATIENTS WE CAN'T GET THE
THERAPY TO THE MANY PATIENTS
THAT NEED IT.
AND WHAT I MEAN BY THAT IS NOT
ONLY PATIENTS WORLDWIDE BUT HALF
LIFE STUDIES THAT WERE
BEAUTIFULLY SHOWN THIS MORNING
ALL PART OF THE TRANSFUSION TO
IMPROVE RED CELL EXCHANGE,
EDUCATION AROUND GENE THERAPY AS
BROUGHT UP AND WHAT CELLS WE'RE
COLLECTING.
HOW CAN WE PARTNER AND BE ABLE
TO DO THIS.
AND REALLY NEXT GENERATION FOR
IN VIVO HOW DOES APHERESIS
PARTNER WITH THAT.
THE WHITE PAPER WILL BE COMING
OUT AND HOPEFULLY THEY'LL GIVE
MORE INSIGHTS.
AN ACKNOWLEDGEMENT TO THE
WORKING GROUP ON THE BOTTOM
RIGHT TIRELESS WORK DONE AND
UNDERSTAND APHERESIS WAS
IMPORTANT AND TO TAKE THIS OUT
TO PUBLICATION.
THANK YOU.
>> WE DO HAVE A FEW MINUTES FOR
ANY QUESTIONS.
ARE THERE QUESTIONS ONLINE OR IN
THE AUDIENCE?
ALL RIGHT.
MOVING FORWARD.
>> SO WE ARE VERY EXCITED TO BE
HERE AND THANK YOU TO THE O
ORGIORG
ORGANIZERS FOR INVITING US FOR
THE SICKLE CELL DISEASE
INITIATIVE AND TALK ABOUT THE
WORKING GROUP AND SOME UPDATES.
>> I'M GOING TO CHECK CAN ANYONE
HEAR ME?
>> YES.
>> IT'S NICE TO BE HERE.
SAD I COULD NOT BE THERE IN
PERSON.
UNFORTUNATELY THINGS DO HAPPEN.
BUT VERY EXCITED TO BE ABLE TO
TALK ABOUT THIS TOPIC OF WHAT
OUR GROUP HAS BEEN FOCUSSED ON
FOR THE PAST NUMBER OF YEARS.
I THINK IT'S VERY IN LINE WITH
THE PREVIOUS TALKS PARTICULARLY
THE PANEL AND I APPRECIATE THE
YOUNG WOMAN WHO SPOKE ABOUT HER
EXPERIENCE AND DECISION POINTS
AND THINKING ABOUT GENE THERAPY
AND I THINK THAT'S BEEN ONE OF
THE STARTING POINTS FOR OUR
GROUP AND TEAM.
I'M NOT GOING TO SPEND AS MUCH
AS TIME AS I USUALLY DO TALKING
ABOUT THE CASE AGAINST OR THE
CASE FOR READINESS BECAUSE I
THINK A LARGE PART OF THE
CONVERSATION WE'VE BEEN HAVING
HAS HELPED TO MAKE THE CASE.
I WILL GO AHEAD AND PRESENT OUR
SIMULATED CASE STUDY A
19-YEAR-OLD FEMALE WITH-BSS WHO
HAD SIGNIFICANT COMPLICATIONS
AND REPEATED VOC AND ACS EVENTS
AND DEVELOPED CHRONIC PAIN AND
MAINTAINS FAIRLY ACTIVE
LIFESTYLE AND DOES WELL IN
SCHOOL AND DREAMS OF HAVING A
FAMILY AND BEING A HEMATOLOGIST.
HER FAMILY IS STRONGLY
ADVOCATING FOR HER TO PURSUE A
CURATIVE THERAPY.
HER FATHER COMMENTED NO MAN WILL
WANT TO MARRY HER UNLESS SHE
GETS THE TREATMENT AND DECIDES
TO PROCEED WITH THE WORKUP FOR
GENE THERAPY.
WE'RE FOCUSSED ON ALL OF OUR
UNDERLYING MEDICAL TESTS BUT AS
HAS BEEN NICELY HIGHLIGHTED THIS
IS A PERSON IN THE SPACE OF
FIGHTING SICKLE CELL DISEASE AND
THERE'S OTHER CONCERNS THAT GO
TO THE DECISION PARTICULARLY ON
THE PATIENT SIDE THAT NEED TO BE
TAKEN INTO ACCOUNT.
SOME ARE GOING TO BE EVERYTHING
FROM DEVELOPMENTALLY WHERE THE
PERSON IS TO WITHIN THEIR OWN
SPAN AND ARE WE TALKING ABOUT
PEDIATRIC OR ADULT OR SOMEONE
INTERESTED IN HAVING CHILDREN OR
DEEPLY EMBEDDED WITHIN THE
SICKLE CELL COMMUNITY?
ABOUT WHAT ARE TO THE PERSON'S
INDIVIDUAL SAFETY CONCERNS AND
PSYCHOSOCIAL RISK WITH RISK TO
EMPLOYMENT AND OTHER THINGS.
AND DECIDING TO PARTICIPATE OR
NOT PARTICIPATE IN CLINICAL
TRIAL FOR GENE THERAPY IS NOT A
SIMPLE DECISION.
AND HIGHLIGHT PSYCHOSOCIAL
FACTORS WILL INFLUENCE A
PERSON'S READINESS FOR GENE
THERAPY AND TREATMENT OUTCOMES
ON THE OTHER SIDE WILL IMPACT A
PERSON'S PSYCHOSOCIAL WELL BEING
IN THE SHORT AND LONG-TERM
WHETHER THEY'RE POSITIVE OR
NEGATIVE OR NOT WHAT WAS
ORIGINALLY EXPECTED WHEN THEY
SIGNED UP FOR GENE THERAPY.
NOW, WITH OUR TEAM AND WHAT'S
BEEN AN IMPORTANT PIECE FOR US
IS WE HAVE BEEN CREATING AND
GOING OVER GUIDELINES SPECIFIC
FOR ALL THE MEDICAL PIECES WHEN
IT COMES TO RADIOLOGY AND
CARDIOLOGY AND ALL THOSE PIECES
IN RELATION TO BEING REPAIRED
FOR GENE THERAPY AND THERE
SHOULD BE A STANDARDIZED WAY OF
ALSO THINKING ABOUT THE
PSYCHOSOCIAL, PSYCHOLOGICAL
SPIRITUAL AND CULTURAL FACTORS
SO WE CAN BOTH MAKE SURE THE
PATIENT IS FULLY INFORMED AND
OPTIMIZE BENEFITS MEDICALLY AND
PSYCHOSOCIALLY THROUGHOUT THE
PROCESS.
SO THIS IS THE GUIDING QUESTION
OUR GROUP HAS GRAPPLED WITH.
IF A PERSON WITH SICKLE CELL
DISEASE CHOOSE TO PARTICIPATE IN
CLINICAL TRIAL WHAT LEVEL OF
PSYCHOSOCIAL SUPPORT IS NEEDED
TO MINIMIZE RISK OF PSYCHOSOCIAL
BURDEN AND OPTIMIZE BENEFITS?
THINKING ABOUT THIS THROUGHOUT
THE ENTIRE COURSE OF TREATMENT
BOTH BEFORE WHEN THE PERSON IS
MAKING THE DECISION AS TO
WHETHER OR NOT TO BE A PART OF
THE GENE THERAPY CLINICAL TRIAL
DURING WHICH A LONG AND ARDUOUS
AND AFTER.
THINKING ABOUT THE 15 YEARS OF
CONTINUOUS FOLLOW-UP FROM THE
HEALTH CARE TEAM AND POSSIBLY
THE REST OF THEIR LIVES THINKING
ABOUT THE CONSEQUENCES GOING
THROUGH A TRANSFORMATIVE THERAPY
CAN HAVE.
NOW AT THIS POINT I'M GOING TO
TALK HOW WE HANDLED THIS FOR
THINGS WE CONSIDER ARE PHASE 1.
I'M GOING TO GO TO MY CO-CHAIR,
DR. JERLYM PORTER AND TALK ABOUT
THE MORE CURRENT ACTIVITIES.
DR. PORTER.
>> THANK YOU.
SO THE INITIAL FOCUS OF THE
WORKING GROUP WAS TO OUTLINE A
WORK FLOW FOR INTEGRATING
PATIENT READINESS AND RESILIENCE
ASSESSMENT TO THERAPY
PROCEDURES.
WE CONCEPTUALIZE AS EXISTING ON
THE CONTINUUM AND FOCUS ON THE
DEVELOPMENT OF TWO AREAS OF
FOCUS OR BEST PRACTICES,
ASSESSING KNOWLEDGE AND
READINESS FOR GENE THERAPY OR
GENE EDITING CLINICAL TRIALS AND
ASSESSING PSYCHOSOCIAL RISK AND
PROTECTIVE FACTORS FROM THE
CONTEXT OF CLINICAL TRIALS.
YOU'LL SEE THE QR CODE TO THE
RIGHT.
THAT WILL SEND YOU TO OUR WHITE
PAPER ON THE CURE SICKLE CELL
INITIATIVE WEBSITE.
AND IF YOU DON'T SEE IT HERE,
YOU'LL SEE IT ON THE MENU
SLIDES.
AND THE PROCESS FOR TREATING TO
INTEGRATE PREGENE THERAPY AND
INSTITUTIONS ARE ENCOURAGED TO
BEGIN BY CONDUCTING A
SELF-ASSESSMENT FOR PREPAREDNESS
TO IMPLEMENT THE READINESS
ASSESSMENT AND TAKE STEPS NEEDED
TO ENHANCE PREPAREDNESS SUCH AS
HIRING STAFF OR IDENTIFYING
RESOURCES FOR TEMPORARY HOUSING
OR TRANSPORTATION.
STAGE 2 INVOLVES THE PATIENT
PREPARATION PHASE PRIOR TO
CONDUCTING THE READINESS
ASSESSMENT AND A BRIEF COGNITIVE
AND HEALTH LITERACY SCREENING TO
INFORM PATIENT EDUCATION ABOUT
GENE THERAPY.
PATIENT READINESS AND RESILIENCE
ASSESSMENT ARE PRIMARILY A
DISCUSSION OR CLINICAL INTERVIEW
BUT MAY BE COMPLIMENTED BY
VALIDATED QUESTIONNAIRES.
AND THE ASSESSMENTS ARE STAGE 3
OF OUR MODEL.
THESE ASSESSMENTS ARE
INFORMATIONAL FOR BOTH PATIENTS
AND INVESTIGATIVE TEAM AND USED
TO GUIDE THE DELIVERY OF
SUPPORTS TO ENHANCE PATIENT
READINESS.
IT'S IMPORTANT THAT THE
ASSESSMENT IS VIEWED AS HELPING
TO INFORM PATIENTS TREATMENT
DECISIONS AND THE ASSESSMENTS
SHOULD NEVER BE USED TO PLEASURE
OR PERSUADE A PATIENT TO PUBLIC
A DECISION OR NOT TO BE USED TO
PERMANENTLY PREVENT SEEKING A
FORM DESIRED.
OUR WORKING GROUP IDENTIFIED A
SET OF BEST PRACTICES SPANNING
FOUR BROAD ACTIVITIES.
SO SUPPORTING THE EFFECTIVE
DELIVERY OF -- EXCUSE ME.
THE FIVE OVER ARCHING GOALS OF
THE ASSESSMENTS ARE ONE, TO
GATHER INFORMATION ABOUT
PATIENT'S UNDERSTANDING AND
PERCEIVED READINESS OF GENE
THERAPY.
TWO, TO ENCOURAGE DIALOGUE
REGARDING CONCERNS ABOUT GENE
THERAPY AND THREE, PROVIDE AN
OVERVIEW OF FACTORS
AND AFFECT RELEVANT OUTCOMES.
FOUR, IDENTIFY PATIENT STRENGTHS
TO BE LEVERAGED TO PROMOTE
PSYCHOSOCIAL WELL BEING, BEFORE,
DURING AND AFTER TREATMENT AND
LASTLY TO IDENTIFY RISK TO BE
CONSIDERED AND ADDRESSED IN
TAILORED EDUCATION PSYCHOSOCIAL
SUPPORT AND COMMUNITY RESOURCES.
OUR WORKING GROUP IDENTIFY A SET
OF BEST PRACTICES FOR
RECOMMENDATIONS THAT SPAN FOUR
BROAD ACTIVITIES.
EFFECTIVELY DELIVERING
EDUCATION, ASSESSING
INDIVIDUAL'S KNOWLEDGE AND
UNDERSTANDING OF GENE THERAPY.
ALSO EVALUATING YOUR INTEREST IN
AN MOTIVATION FOR GENE THERAPY
AND EVALUATING AN INDIVIDUAL'S
PSYCHOSOCIAL RISK AND RESILIENCE
FACTORS THAT COULD INFLUENCE
PSYCHOSOCIAL WELL BEING AND
HEALTH BEFORE AND AFTER GENE
THERAPY.
AS I STATED EARLIER WE PUT
TOGETHER A WHITE PAPER THAT
OUTLINES THE EVIDENCE-BASED
STRATEGIES FOR PATIENT EDUCATION
AND HAVE ASSET TOOLS AND SAMPLE
INTERVIEW QUESTIONS.
SO PLEASE ACCESS THIS THROUGH
THE QR CODE.
FINAL THOUGHTS ON ASSESSING
PATIENT READINESS.
IT'S IMPORTANT TO ASSESS
READINESS AFTER EDUCATION ABOUT
GENE THERAPY AND ALLOW TIME FOR
RESULTS TO BE USEFUL.
THE INFORMATION CAN INFORM
INFORMED CONSENT AND PRESSURES
TO PARTICIPATE AND WHETHER
PSYCHOSOCIAL RISK SHOULD BE
ADDRESSED BEFORE MOVING FORWARD
IN TREATMENT.
READINESS AND RESILIENCE WILL
LOOK DIFFERENT IN EACH SETTING.
THE BEST PRACTICES ARE INTENDED
TO BE USED AS A GUIDE.
AND SHOULD BE PERFORMED BY AN
ASSESSMENT TEAM WHO HAS
KNOWLEDGE IN SICKLE CELL AND
EXPERTISE IN INTERVIEWING.
AND INFORM DECISION AND HAVE
OPEN DIALOGUE BETWEEN THE
CLINICIAN AND PATIENT REGARDING
READINESS FOR GENE THERAPY AND
WHILE THE P.I. MAY BE THOSE WHO
LEAD THE EFFORTS TO EVALUATE FOR
READINESS, IT'S IMPORTANT THE
ATTENTION RESPONSIBILITY OF THE
TREATMENT TEAM AND THE
ASSESSMENT IS INTENDED TO
ENHANCE OUTCOMES AND OPTIMIZE
TREATMENT.
WE FOCUSSED ON GENE THERAPY AND
DR. VALRIE WILL JOIN US AGAIN
AND TALK ABOUT NEXT STEPS FOR
OUR WORKING GROUP.
SO AS WE MOVE FORWARD AND THINK
ABOUT WHAT ARE SOME IMPORTANT
NEXT STEPS WE WANT TO MAKE SURE
THE THERAPY PSYCHOSOCIAL
ASSESSMENT GUIDELINES ARE FULLY
DISSEMINATED AND IMPLEMENTS IN
RELATION TO GENE THERAPY AND
THOSE CURRENTLY DOING GENE
THERAPY.
AND GUIDELINES FOR PSYCHOSOCIAL
SUPPORTS.
DIGGING INTO ACTIVITIES WITH
PREEXISTING THERAPY GUIDELINES,
ONE IS WE'RE PLANNING A SURVEY
OF CENTERS WHAT ARE TE STAFF AND
RESOURCES THAT NEED TO BE IN
PLACE TO MAKE THE SUPPORT HAPPEN
AND WE'RE DEFINITELY LOOKING TO
DEVELOP PARTNERSHIPS WITH SICKLE
CELL RESEARCHERS AND CLINICIANS
AND NETWORKS TO CONTINUE TO
FACILITATE THE IMPLEMENTATION
ACTIVITIES.
AND WE HAVE LITERATURE REVIEW OF
PSYCHOSOCIAL CONCERNS POST GENE
THERAPY FOR OTHER CHRONICALLY
ILL POPULATIONS AS THERE'S A LOT
OF EXPERIENCE.
AND WE ALSO PLAN TO CONDUCT
FOCUS GROUPS OF PROVIDERS,
PEOPLE WITH SICKLE CELL DISEASE
WHO HAVE UNDER GONE GENE THERAPY
AND THEIR CAREGIVERS.
WE ALSO PLAN TO DEVELOP OUR
ITERATIVE PROCESS TO DEVELOP THE
LINES WITH A FOCUS ON PROVIDING
RECOMMENDATIONS FOR ONE TO TWO
YEARS AND TWO TO FIVE YEARS OUT
AND FIVE TO 15 YEARS POST GENE
THERAPY GIVEN THE MANDATE OF 15
YEARS OF POST GENE THERAPY
FOLLOW UP.
I DIDN'T MEAN TO SPEED THROUGH
SLIDES.
GO BACK TWO SLIDES, PLEASE.
OUR PLAN IS TO WORK IN
CONJUNCTION TO MAKE THIS HAPPEN
WITH THE CURES ACT COMMUNITY
INPUT PANEL AS WELL AS OTHER
PARTNERS WHO MAY BE AVAILABLE.
I ALSO WANT TO MENTION ME AND
JERLYM REPRESENT A LARGER GROUP
AND THANK YOU TO OUR PAST
MEMBERS WHO WERE A PART OF PHASE
1 IN DEVELOPING OUR THERAPY
GUIDELINES AND CURRENT AND NEW
MEMBERS WHO JOINED TO CONTINUE
TO EXPAND THE EXPERTISE ON THE
TEAM.
WE'RE A TEAM OF PSYCHOLOGISTS
AND MENTAL HEALTH PROFESSIONALS,
SOCIAL WORKERS, PATIENT
NAVIGATORS AND OTHERS WITH THOSE
EXPERIENCES AS WELL AS
IMPORTANTLY PEOPLE WHO ARE
LOVING WITH SICKLE CELL DISEASE
SOME WHO HAVE BEEN THROUGH
TRANSFORMATIVE THERAPY AS WELL
AS A CAREGIVER OF A YOUNG WOMAN
WHO EXPERIENCED A TRANSFORMATIVE
THERAPY.
A SPECIAL THANK YOU TO OUR PHASE
1 LEADER, DR. HARDY AT
CHILDREN'S NATIONAL HOSPITAL AND
FOR ALL THE SUPPORT WE'VE
RECEIVED FROM NHLBI AND STAFF.
THIS IS WHERE I'LL END AND
ANSWER QUESTIONS AND I KNOW
WE'LL GO INTO A PANEL WHERE
WE'LL ALSO BE ABLE TO ANSWER
QUESTIONS.
>> ARE THERE ANY QUESTIONS AT
THIS TIME BEFORE WE HEAD TO OUR
PANEL DISCUSSION?
OKAY.
I'M HEATHER AVANT THE CHAIR OF
THE CURE SICKLE CELL INITIATIVE
AND MY GOAL IS TO REPRESENT THE
COMMUNITY.
THE GOAL IS TO BE THE VOICE.
WE ARE A PANEL OF PATIENTS AND
CAREGIVERS AND AROUND EVERYTHING
AND ANYTHING IN DEVELOP.
IF YOU CAN THINK IT, WE'VE
DISCUSSED IT.
THE GOAL OF THIS PANEL IS TO DIG
DEEP INTO WHAT THE PATIENTS AND
CAREGIVERS IN THE COMMUNITY ARE
CURRENTLY THINKING ABOUT WHEN IT
COMES TO TRANSFORMATIONAL
THERAPIES AND MENTAL HEALTH AND
APHERESIS.
I'LL LET ADRIENNE ASK THE FIRST
QUESTION.
I'M SO EXCITED BECAUSE WE HAVE
THE TWO OF YOU HERE.
IT'S SOMETHING WE AS PARENTS AND
WARRIORS HAVE DEALT WITH FOR A
LONG TIME.
YOU'RE THERE NOW, WE'RE ALL
TOGETHER AND THERE'S QUESTIONS
ABOUT WARRIORS AND FAMILY WHERE
PEOPLE ARE GETTING BLOOD
THERAPIES.
THEY MAY BE GETTING BOLD
TRANSFUSIONS.
THEY MAY BE GETTING RED BLOOD
EXCHANGES AND THERE'S A LOT OF
CONCERN THAT BEING ON THOSE
THERAPIES WILL PREVENT THEM FROM
HAVING ACCESS.
LET'S TALK ABOUT THAT.
>> IT'S A VERY GOOD POINT
BECAUSE MANY PATIENTS ON CHRONIC
EXCHANGE PROGRAMS AND CHRONIC
TRANSFUSION PROGRAMS SUDDENLY
FEEL WELL.
IT'S VERY HARD FOR THEM TO THINK
OF OTHER THERAPIES AND
TRANSFORMATIVE THERAPIES THAT
MATTER WHEN THEY'RE IN A GOOD
PLACE IN THEIR LIFE.
THIS WAS BROUGHT UP IN THE
PREVIOUS PANEL WHEN THEIR
PATIENTS THAT HAVE BEEN ILL AND
ALL OF A SUDDEN TRANSFUSION
CHANGED THAT TRAJECTORY.
NOW THEY'RE FEELING LIKE THEY
MAY NOT BE SEEKING OUT MORE
ADVANCED THERAPIES AND MAY BE
HAPPY WHERE THEY ARE AND THE
QUESTION WE GET SOMETIMES IS IS
IT TIME TO THINK ABOUT SOMETHING
ELSE AN IT'S HARD TO MAKE THE
LEAP.
IT TAKES A LONG CONVERSATION BUT
FROM THE TRANSFUSION SIDE IT'S
JUST IMPORTANT TO KEEP THAT
DIALOGUE GOING AND KEEP THE
HEMATOLOGIST INVOLVED AND TRY TO
UNDERSTAND WHY THE PATIENT IS
EVEN ASKING THE QUESTION.
>> DR. MANIS THE QUESTION WE GET
FROM THE COMMUNITY OFTEN OR I
HEAR OFTEN IS WHAT IS THE TIME
LINE FOR PREPARING FOR IN
HOSPITAL AND PRIOR TO RECEIVING
THE PRODUCT.
PATIENTS ARE ALWAYS ASKING ABOUT
TIME.
HOW MUCH TIME DO I OWE OR WILL I
HAVE TO DO?
I KNOW THERE'S NEVER AN EXACT
ANSWER BUT WHAT WOULD BE YOUR
ANSWER TO THE COMMUNITY?
>> THIS IS A TOUGH QUESTION IN
THE FACE OF AN EVOLVING FIELD
BUT I WOULD SAY BACK OF THE
ENVELOPE FIRST ANSWER WOULD BE
TO THINK ABOUT THE EXPECTATION
OF THE PATIENT AND WHAT I'M
GETTING TO IS WHY IS TIME
IMPORTANT?
IS IT BECAUSE TO PLAN TIME AWAY
FROM WORK OR BECAUSE OF FAMILY
RESPONSIBILITIES OR TO FEEL
BETTER?
THOSE ARE ALL VERY DIFFERENT
ANSWERS FOR TIME.
BECAUSE IF YOU TELL SOMEBODY WHO
IS IN PAIN ONE YEAR BEFORE YOU
GET A TRANSPLANT, THAT MAY BE
ABOUT WHAT THEY'VE PUT A HOOK ON
TO FEEL BETTER BUT WE ALL KNOW
IT WILL TAKE SIX MONTHS AFTER
THAT OR NINE MONTHS AFTER THAT
BEFORE THEY REALLY CHANGE AND
FEEL BETTER.
TECHNICALLY I WOULD SAY NINE
MONTHS IS A GOOD ESTIMATION OF
ENTRY TO THE STUDY TO BEING
TRANSPLANTED AND DURING THAT
TIME THE MAJORITY OF THE TIME
YOU'RE GETTING TRANSFUSIONS OR
SOME TRANSFUSION THERAPY.
>> WE HEAR THIS ALL THE TIME.
I'M A WARRIOR AND WITH THE
TREATMENT AND I'M NO LONGER
HAVING THOSE DAILY CHALLENGES,
WHAT DO YOU FORESEE BEING
GUARDRAILS AND THOSE REAPING
BENEFITS AND THOSE HO DON'T.
WHERE DO YOU SEE GUARDRAILS TO
HELP US?
>> THERE'S PSYCHOSOCIAL SUPPORT
FROM THE GET GO.
IF EVER CENTER COULD HAVE A
PSYCHOLOGIST OR SOCIAL WORKER
ORE ANOTHER MENTAL HEALTH
CLINICIAN THAT IS THERE FROM THE
BEGINNING AND THROUGHOUT THE
PROCESS.
I ALSO THINK IT'S IMPORTANT WE
AS CENTERS REALLY LOOK OUTSIDE
IN THE COMMUNITY AT OTHER MENTAL
HEALTH SUPPORTS BECAUSE THEY MAY
NOT ALWAYS BE ABLE TO COME BACK
TO US AT THE INSTITUTION SO WE
NEED TO GIVE THEM THE RESOURCES
IN THE COMMUNITY.
FIND THE RESOURCES AND HAVE
THOSE INDIVIDUALS THAT CAN
PROVIDE THAT ADDITIONAL SUPPORT.
AND IT'S IMPORTANT TO TALK ABOUT
EXPECTATIONS AT THE BEGINNING.
WHAT DOES SUCCESS LOOK LIKE AND
WHAT DOES SUCCESS NOT LOOK LIKE.
IF IT DOESN'T WORK WHAT WOULD
THAT LOOK LIKE AND WHAT DOES IT
LOOK LIKE SOMEWHERE IN BETWEEN
BECAUSE YOU DON'T KNOW.
>> SO WHO IS RESPONSIBLE FOR THE
PATIENT'S MENTAL HEALTH LONG
TERM?
WE TALKED ABOUT DURING THE
PROCESS OR RIGHT AFTER BUT THE
MENTAL HEALTH IMPLICATIONS.
THE PERSON GOES FROM A WARRIOR
TO WARRIOR-SURVIVOR.
WHAT'S THAT MEAN AND WHO IS
RESPONSIBLE FOR TAKING CARE OF
THE PATIENT LONG TERM?
A LOT OF TIMES PATIENTS ARE
OFTEN DISENFRANCHISED AFTER
GOING THROUGH A THERAPY.
>> I'M A PSYCHOLOGIST SO I'M
ALWAYS PROTHE THERAPY AND
PROACTIVE.
LET'S USE THERAPY TO THINK AHEAD
OF THE CHALLENGES THAT MIGHT
COME IN THE FUTURE.
I THINK WE NEED TO -- AT OUR
INSTITUTIONS WE NEED TO DO A
BETTER JOB OF PARTNERING WITH
THE COMMUNITY TO FIND OUT WHO
ARE THE MENTAL HEALTH PROVIDERS
OUT THERE AND PROVIDING SOME
EDUCATION TO MENTAL HEALTH
PROVIDERS ABOUT SICKLE CELL
DISEASE AND GOING THROUGH
TRANSFORMATIVE THERAPY AND WHAT
THAT LOOKS LIKE AFTER THERAPY IS
FINISHED.
HOW TO BEST SUPPORT THEM IN
WHATEVER OUTCOME IT IS.
>> I'M UNSURE PEOPLE CAN HEAR ME
S&P I LIKE THE IDEA OF SHARED
RESPONSIBILITY AND I ECHO
EVERYTHING DR. PORTER HAS SAID
IN RELATION TO PROVIDING SUPPORT
WITHIN THE HEALTH CARE TEAM I
THINK MENTAL HEALTH AND
PSYCHOSOCIAL SUPPORT BOTH THE
ASSESSMENT AND THE CONNECTING
WITH RESOURCES NEEDS TO COME
FROM THE ENTIRE TEAM AS
SUPPORTED BY THE POINT PERSON.
BUT THAT WE HAVE TO REALLY ACT
AS A TEAM AROUND THIS THE SAME
WE WE ACT AS A TEAM AROUND OTHER
ASPECTS OF CARE.
I ALSO WANT TO SAY THAT THOUGH
WE SHOULD HAVE A GOOD FOCUS ON
THE PERSON LIVING WITH SICKLE
CELL SOMETIMES PROVIDING THE
SUPPORT TO THEIR SUPPORT SYSTEM
IS JUST AS IMPORTANT WHETHER
IT'S A PEDIATRIC PATIENT OR
CAREGIVER OR PATIENT OR THE
OTHER CAREGIVERS FOR ADULT
PATIENTS, WE ALSO SHOULD
SOMETIMES HAVE TO THINK OUTSIDE
THE BOX AND THE PATIENTS ARE
EMBEDDED WITHIN COMMUNITIES AND
IT'S IMPORTANT WHEN THERE'S GOOD
AND SOMETIMES POORER OUTCOMES.
I THINK THIS HAS ALSO BEEN
ECHOED BY A PARENT WHO HAS LOST
A YOUNG PERSON TO COMPLICATIONS
OF SICKLE CELL DISEASE MAKING
SURE THAT JUST BECAUSE THE
IDENTIFIED PATIENT IS NO LONGER
THERE, DOESN'T MEAN THE PEOPLE
WHO ARE SUPPORTING THEM DON'T
NEED THE SAME CARE AND SUPPORT
AS THEY TRANSITION TO A NEW
REALITY.
>> SO ABOUT WHAT DO WE HAVE IN
PLACE?
I HEAR YOU TALK ABOUT REGISTRIES
AND NARRATIVES AND ALL THAT.
ARE WE PUTTING SOMETHING IN
PLACE FOR US TO DO THAT?
>> I THINK PEOPLE NEED TO GET
THE WORD OUT.
WARRIORS AND PEOPLE WHO SUPPORT
THEM PROVIDERS AND GET IT OUT IN
A SOCIAL MEDIA PODCAST.
THE WARRIOR AN SUPPORTER
EXPERIENCE IS INVALUABLE.
I CAN TALK ABOUT SICKLE CELL
EXPERIENCE AS A PROVIDER BUT AT
THE END OF THE DAY YOU ALL ARE
THE EXPERTS.
WE AS PROVIDERS AT INSTITUTIONS,
WE CAN DO THINGS TO SUPPORT YOU
ALL TO GET THE WORD OUT.
SO THAT PEOPLE KNOW WHETHER THE
EXPERIENCE IS LIKE AND YOU QUAN
GIVE THAT KNOWLEDGE AS AN EXPERT
I THINK WE CAN ALL DO A BETTER
JOB AT THAT.
ALSO I SEE DR. SMITH.
>> YOU STOLE MY THUNDER.
I WAS GOING TO TALK ABOUT
PHONING AN A FRIEND, SPORT
GROUPS AND OTHER MEANS OF MAKING
IT REAL TO SOMEBODY CONSIDERING
THERAPY.
SOMEBODY WHO IS GOING THROUGH
AND SUCCEEDING.
SOMEBODY GOING THROUGH AND
FAILING.
I THINK PHONE A FRIEND AND
SUPPORT GROUPS, I SEE US AS
LACKING IN THAT.
WHERE HE MAY HAVE MORE
PSYCHOLOGISTS AND THERAPISTS AND
TEAM MEMBERS SURROUNDING THE
PATIENT THAN SOMEBODY GOING
THROUGH THE THERAPY.
IT WAS SORELY LACKING IN MY
CENTER AND CECELIA AND I HAVE A
PATIENT WE SHARE THAT WOULD HAVE
BENEFITTED IF THE PERSON HAD
SOMEONE LIKE THAT TO TALK TO, DO
YOU AGREE?
>> YOU STOLE MY THUNDER.
WHAT ARE WE PUTTING IN PLACE TO
ALLOW FOR PATIENTS TO SHARE
THEIR STORIES?
ARE WE LAYERING IN OTHER
PATIENTS BECAUSE WE HAVE MORE
AND MORE ALL THE TIME.
AND WE'RE HEARING ABOUT MORE
SUCCESSFUL OR UNSUCCESSFUL
TRANSPLANTS FOR THAT MATTER AND
WHAT ARE WE GOING TO LAYER THEIR
STORIES AND IT'S A QUESTION THAT
COMES UP OFTEN.
>> FROM MY PERSPECTIVE PARTLY
WHAT WE THINK NEEDS IT HAPPEN IS
RIGHT NOW THE PRIMARY STORIES
GETTING OUT THERE HITTING THE
COMMUNITY ARE COMING THROUGH
STANDARDIZED MEDIA AND THEY'RE
TALKING ABOUT THE WONDERS ON THE
OTHER SIDE OF TRANSFORMATIVE
THERAPY.
I THINK IT'S A WONDERFUL MESSAGE
BUT I THINK WE HAVE GOT TO START
CONTROLLING THE NARRATIVE MORE
TO PROVIDE A PICTURE OF THE
GOOD, BAD AND NOT SO GOOD.
AS WE TALK OF GATHERING
STANDARDIZED DATA ON THE BIO
MEDICAL SIDE WE NEED TO LAYER
THAT DATA AND BUILDING DATABASES
WHEN WE HAVE 10 PEOPLE, 12
PEOPLE GOING TO BE HUNDREDS AND
EVENTUALLY THOUSANDS, WE NEED TO
MAKE SURE WITHIN THE REGISTRIES
THAT WE'RE BUILDING WE'RE ALSO
BUILDING IN THE QUESTION AND
INFORMATION THAT IS GOING TO
GIVE A MORE COMPLETE
PSYCHOSOCIAL PICTURE TO TELL
MORE OF THESE STORIES IN
SYSTEMATIC WAYS AS WELL AS
INDIVIDUAL WAYS TO GET TO BOTH
PLACES.
I THINK THAT'S GOING TO BE
IMPORTANT SO THAT BOTH PEOPLE
LIVING WITH SICKLE CELL DISEASE
CAN MAKE FULLY INFORMED DECISION
AND HEALTH CARE PROVIDERS CAN
INFORM THEM THROUGH SHARED
DECISION MAKING.
>> IS THERE A QUESTION IN THE
AUDIENCE?
>> I'M HAVE ST. JUDE.
SO MY QUESTION IS NOW THAT
EDUCATION FOR FAMILIES ABOUT
SICKLE CELL START AT NEWBORN
SCREENING.
DOES INITIATING A CONVERSATION
AROUND TRANSFORMATIVE THERAPY
LIKE THE INITIAL CARE FOR THE
PATIENT IS THAT HELPFUL
INITIATING THE DISCUSSION THERE
IS THIS OPTION.
[NO AUDIO]
>> I THINK THAT WOULD COME FROM
THE DISCUSSION.
MY CHILD DOESN'T HAVE IT BUT I
DO AND I IMAGINE RECEIVING THE
INFORMATION AT THE NEWBORN
SCREENING AND SLIGHTLY FREAKING
OUT.
I THINK THAT WOULD BECOME A
CONVERSATION AS YOU'RE A NEW
PARENTS WITH A SICKLE CELL CHILD
GOING TO THE HEMATOLOGIST.
I DON'T KNOW IF IT'S SOMETHING
YOU WANT TO BRING UP, HI, YOUR
NEWBORN HAS SICKLE CELL AND LAY
OUT NEW TRANSFORMATIVE
THERAPIES.
I THINK IT'S A LOT OF
INFORMATION AT ONCE.
THAT'S MY OPINION AS A PARENT
AND WARRIOR MYSELF.
I WOULD THINK ADRIENNE CAN
ANSWER BETTER BECAUSE SHE'S A
MOTHER.
>> THERE'S A COUPLE TYPES OF
MOTHERS.
SOME WHO HUNT DOWN DOCTORS AND
SCIENTISTS AND EMBARRASS
THEMSELVES AND THOSE WHO
POLITELY ASK FOR INFORMATION.
BECAUSE SICKLE CELL AND I
REPRESENT FIVE GENERATIONS OF
MOTHERS.
I HAVE A LOT OF HISTORY ON MY
BACK.
WHAT I'M SEEING NOW GETTING THAT
LETTER RATHER THAN WRITING A
DEATH SENTENCE FOR YOUR CHILD
WHICH IS PRETTY MUCH WHAT MY
MOTHER GOT AND I GOT.
YOU'RE OPENED UP TO A WORLD OF
POSSIBILITIES.
I THINK THE BIGGEST PART I WOULD
SAY IS THAT WE HAVE TO MAKE SURE
THE PEDIATRICIANS ARE TRAINED
STRAIGHT AWAY TO HAVE THAT
DISCUSSION AND WE REALLY HAVE TO
DEPEND ON THEM TO DO IT.
EVEN THOUGH IN THE PAST I KNOW
THEY DIDN'T LIKE TALKING TO
PARENTS ABOUT IT BECAUSE WHO
WANTS TO TELL SOMEBODY THEIR
NEWBORN CHILD MAY NOT LIVE.
THAT'S HOW TO START.
>> THE LIGHT AT THE END OF THE
TUNNEL.
>> AND I WAJT TO -- WANT TO PUT
IN A PLUG THERE'S IN TRUSTED
SOURCES NOW AND WE HAVE TO TELL
PEOPLE AND GID THEM TO THE
AGENCY -- GUIDE THEM TO THE
AGENCIES, RESEARCH CENTERS AND
COMMUNITY-BASED ORGANIZATIONS
WHICH ARE DOING A GREAT JOB OF
HOLDING THE COMMUNITY.
I THINK WE HAVE TO TRY TO
COUNTER SOME OF THE STUFF THEY
MAY FIND ON THE INTERNET AND
TALK AMONG OURSELVES ABOUT THE
IMPORTANCE OF GETTING YOUR
INFORMATION FROM A TRUSTED
SOURCE.
>> I HAVE A QUESTION.
I'M VERY EXCITED ABOUT SOMETHING
I HEARD JULIE SAY ABOUT
APHERESIS.
AND I GUESS I WANT TO SAY I
THINK WHOEN I TALK ABOUT LESSONS
LEARNED THAT'S ONE OF THE THINGS
I'M LOOKING AT.
THOSE EXAMPLES OF THINGS WE
ALREADY HAVE ACCESS TO THAT
WHILE WE'RE IN THE IN BETWEEN
TIME WE'RE MAKING CELL THERAPY
AVAILABLE.
WHAT THINGS CAN WE BE PUTTING IN
PLACE SO THAT PEOPLE ARE LIVING
BETTER AND HAVING HEALTHIER
BODIES AS WE'RE MOVING MORE
TOWARDS ACCESS TO THE CURRENT.
CAN YOU TALK ABOUT THAT A LITTLE
BIT.
>> SURE.
THERE'S MANY PARTS TO UNPACK TO
THAT.
ONE OF THE FIRST PARTS TO UNPACK
IS WHEN TO TRANSFUSE, HOW TO
TRANSFUSE AND WHEN TO DO RED
CELL EXCHANGE AND HOW TO DO THE
RED CELL EXCHANGE.
WHAT I MEAN BY THAT IS WHAT
PATIENTS RED CELL EXCHANGE IS
GOOD FOR WHAT TIME BECAUSE IT
CAN INVOLVE A COMMITMENT.
TAKING AN OVERVIEW OF THE WHOLE
PROCESS I WOULD SAY THERE'S A
LOT OF ROOM TO IMPROVE ON HOW WE
DO RED CELL EXCHANGE AND
THERAPIES FOR PATIENTS WITH
SICKLE CELL.
A LOT OF THE TOOLS AND
INSTRUMENTS WERE NEVER BUILT FOR
PARTICIPANTS WITH SICKLE CELL.
I BROUGHT UP DURING THE SLIDES I
PRESENTED THAT MAYBE CATHETERS,
PORTS, WHATEVER WE NEED TO DO
RED CELL EXCHANGE, IT REALLY
HASN'T BEEN THOUGHT ABOUT WITH
HOW COULD WE DO THIS BETTER FOR
A PATIENT WITH SICKLE CELL
DISEASE AND HOW COULD WE DO IT
BETTER SO I THINK IT'S IMPORTANT
OVER ALL SO I DO THINK IT'S
IMPORTANT TO PUT PRESSURE ON
MANUFACTURERS TO IMPROVE THAT.
IN TERMS OF A MATTER OF
EDUCATION.
THE MORE WE DISCUSS THERE'S AN
OPTION THE MORE THAT WE BRING
INTO HEMATOLOGY TO TRANSPLANT
THAT THERE ARE SPECIALISTS AND
THE MORE WE TRAIN NURSING AND
PHYSICIANS IF APHERESIS IS MORE
THAN A PROCEDURE.
THINK ABOUT THE SCIENCE
BYPRODUCT -- SCIENCE BEHIND IT
AND THE IMPACT AND THEN YOU CAN
APPROACH THE PATIENT MORE THAN
JUST THE THREE HOUR PROCEDURE
AND PUT IT IN THE CONTEXT OF
HERE'S HOW IT CAN IMPROVE OR
STABILIZE YOUR DISEASE.
>> THANK YOU SO MUCH.
I WANT TO SAY THANK YOU TO THE
PANEL WHO CAME UP AND SPOKE,
DR. CECELIA VALRIE AND
DR. PORTER AND DR. MANIS.
THANK YOU ALL.
I BELIEVE WE'RE GETTING OUT OF
HERE.
>> THANK YOU SO MUCH.
THIS IS A GREAT DISCUSSION.
SO, WE'RE ADJOURNED FOR THE DAY.
WE'RE ADJOURNING FOR THE DAY
TODAY BUT WE'LL BE BACK
TOMORROW.
WE HAVE A GREAT SESSION FOR
TOMORROW THAT STARTS WITH GLOBAL
PERSPECTIVE OF SICKLE CELL FROM
DIFFERENT COUNTRIES.
I THINK IT WILL BE A VERY
INTERESTING CONVERSATION AND
HAVE TALKS ABOUT CDC AND PAIN
AND WE'LL SEE YOU ALL TOMORROW.
THANK YOU.