>>I'M JULIE, DIVISION DIRECTOR, NHLBI
>>THANK YOU, JULIE.
OKAY.
SO AFTER ALL THE FIRE DRILLS, I
THINK WE'RE ALL PUMPED UP SO
WE'RE READY, WE HAVE A FULL
AGENDA FOR THE NEXT THREE DAYS,
AND I WOULD LIKE TO MAKE SURE
THE CHAIRS OF EACH OF THESE
SESSIONS KEEP TIME FOR THEIR
SPEAKERS.
WE HAVE TIME KEEPERS TO KEEP ALL
OF US ON TIME, AND I DON'T THINK
WE NEED ANY MEETING LOGISTICS AT
THIS POINT, ADD ON THEM TO THE
BREAK TIME.
WE HAVE AN APHERESIS WORKING
GROUP THAT'S WORKING IN THE
AFTERNOON AND WE CAN FILL IN THE
DETAILS DURING THE BREAK TIME.
SO WITHOUT ANY FURTHER ADO,
DELAYS, SO I WILL INTRODUCE OUR
FIRST SYMPOSIUM, CURATIVE
THERAPIES FOR SICKLE CELL
DISEASE, PART 1.
SHARED BY DR. LAKSHMANAN
KRISHNAMURTI FROM YALE AND HE'S
GOING TO INTRODUCE THE REST OF
THE SPEAKER PANEL.
THANK YOU.
>>GOOD MORNING AND
CONGRATULATION ON REACTING
APPROPRIATELY TO THE FIRE DRILL.
I'M LAKSHMANAN KRISHNAMURTI FROM
YALE UNIVERSITY, AND IT'S MY
PLEASURE TO INTRODUCE THE
SYMPOSIUM ON CURATIVE THERAPIES,
PART 1.
>>HI, I'M CO-CHAIRING THE
SESSION WITH KRISH.
>>BY WAY OF INTRODUCTION, WE
HAVE TRIED TO BRING TOGETHER ALL
OF THE WORK THAT'S HAPPENED IN
THE LAST 365 DAYS FROM OUR
TRANSPLANT AND CURATIVE
THERAPIES FOR SICKLE CELL
DISEASE, AND WE HAVE TRIED TO
REFLECT THE DIVERSITY IN TERMS
OF YOUNG INVESTIGATORS AND
SENIOR INVESTIGATORS IN
DIFFERENT INSTITUTIONS TO BRING
TOGETHER THIS SYMPOSIUM AND OVER
TO YOU, BETH.
>>THEY'RE PULLING UP SLIDES FOR
US WITH REVIEW OF OUR AGENDA BUT
IT'S IN THE HANDOUT, SO JUST A
REMINDER FOR SPEAKERS, YOU HAVE
8 MINUTES FOR YOUR PRESENTATIONS
AND 2 MINUTE FOR QUESTIONS IF
THERE'S TIME.
AND SO WITH THAT, AS HE'S
GETTING SLIDES UP I'LL GO AHEAD
AND -- I'M SORRY?
I'LL INTRODUCE OUR FIRST
SPEAKER.
DR. CYNTHIA SINHA IS FROM EMORY
UNIVERSITY AND SHE'LL BE
PRESENTING ON PARENTAL
PERSPECTIVE ON THE RISK OF
INFERTILITY AND FERTILITY
PRESERVATION OPTIONS FOR
CHILDREN AND ADOLESCENTS WITH
SICKLE CELL DISEASE CONSIDERING
TRANSPLANT.
>>GOOD MORNING.
AS DR. STENGER SAID, MY FREN
PREN TAITION IS ENTITLED
PARENTAL PERSPECTIVE ON THE RISK
OF INFERTILITY AND FERTILITY
PRESERVATION OPTIONS FOR
CHILDREN AND ADOLESCENTS WITH
SICKLE CELL DISEASE.
SO YES, WE KNOW THEY'RE
SUCCESSFUL AND THEY DO HAVE SOME
RISK.
JUMP AHEAD REALLY QUICKLY.
WE ALSO KNOW AS A CONDITIONING
REGIMEN, PATIENT ARE EXPOSED TO
CHEMOTHERAPY WHICH RESULTS IN
OVARIAN INSUFFICIENCY IN 89% OF
PEDIATRIC AND ADOLESCENT AGED
FEMALES AND LOW SPERM COUNT.
IN OUR PREVIOUS RESEARCH WE
WANTED TO UNDERSTAND WHAT
MOTIVATED PARENTS AND FAMILIES
TO ACTUALLY WALK THROUGH THE
DOOR AND MEET WITH AN HCT
PHYSICIAN AND WE REALLY FOCUSED
ON SOME OF THEIR MOTIVATIONS AS
DIMINISHED QUALITY OF LIFE,
RECENT COMPLICATIONS, NEED TO
MAKE A MAJOR MEDICAL DECISION
LIKE A CHRONIC BLOOD
TRANSFUSION, AND ALSO CONCERNS
ABOUT FUTURE SEVERE
COMPLICATIONS.
WHILE WE DIDN'T REALLY SEE --
WHAT WE DIDN'T REALLY SEE WAS
THEIR CONCERN ABOUT WHERE DID
INFERTILITY FALL IN ALL OF THIS,
AND SO AS A KNOWLEDGE GAP, WE
WERE INTERESTED IN LEARNING, DO
PARENTS AND FAMILYS HAVE A
REALISTIC UNDERSTANDING ABOUT
THE RISK OF INFERTILITY AFTER TO
TRANSPLANT OR ARE THEY IN
DENIAL.
WHAT ARE THEIR CAREGIVERS'
PERCEPTION ABOUT FERTILITY
PRESERVATION OPTIONS, WHAT DO
THEY UNDERSTAND, AND AFTER
ATTENDING THE CONSULTATION, HOW
DO THEY PERCEIVE THE RISK OF HCT
AND HOW DOES THIS SPECIFICALLY
FIGURE IN TO THEIR
DECISION-MAKING PROCESS TO MOVE
FORWARD.
THAT'S OUR FO FORMAL RESEARCH
QUESTION, HOW DO CAREGIVERS
PERCEIVE THE RISK OF INFERTILITY
FROM HCT AND HOW HAS THIS RISK
IMPACT THEIR DECISION-MAKING.
IT'S AN IRB-APPROVED STUDY WITH
CONSENT OBTAINED AFTER THE
PRIMARY CAREGIVER HAD ATTENDED A
CONSULTATION, QUALITATIVE
INTERVIEWS WERE CONDUCTED WITH
THESE PRIMARY CAREGIVERS FROM
ONE SINGLE HCT CH CLINIC IN
ATLANTA, ALL INTERVIEWS WERE
OVER THE PHONE USING A SEMI
STRUCTURED INTERVIEW GUIDE AND
ALL AUDIO RECORDINGS OF THE
INTERVIEW WERE TRANSCRIBED VER
BAY TI. WE HAD 19 FE FEMALE ADUS
ALL IDENTIFIED AS AFRICAN
AMERICAN, CAREGIVER RANGE FROM
25 TO 506 YEARS OLD WITH A
MEDIAN AGE OF 39 AND PATIENT
FROM 2 TO 18 YEARS WITH MEDIAN
AGE OF 10 YEARS AND LINE BY LINE
ANALYSIS WAS CONDUCTED TO
IDENTIFY THE PARTICIPANT
RESPONSE GROUPED THEM TOGETHER S
ALL WERE ACCEPTED REGARDLESS OF
AVAILABILITY OF DONOR OR
ELIGIBILITY FOR AN OPEN CLINICAL
TRIAL.
AFTER ATTENDING THE HCT
CONSULTATION AT THIS PARTICULAR
CLINIC, FAMILIES MAY SCHEDULE
FERTILITY CONSULTATION
REGARDLESS OF STATUS OR
SCHEDULING OF THE HCT PROCEDURE.
NOW, IDEALLY WE WANTED FAMILIES
TO HAVE ATTENDED BOTH
CONSULTATIONS, BUT JUST WITH THE
SCHEDULING AND THE SAMPLE SIZE,
IF THEY HAD ATTENDED THE HCT
CONSULTATION, I REACHED OUT TO
THEM.
SO THIS IS A QUICK TABLE TO SAY
THAT APPROXIMATELY HALF THE
SAMPLE, ABOUT 10, HAD NOT
ATTENDED THE CONSULTATION AT
ALL, AND NINE HAD.
AND OF THOSE, THAT WERE GOING TO
MOVE FORWARD TRANSPLANT, FOUR
SAID THEY WOULD SEEK FERTILITY
PRESERVATION OPTIONS, TWO WERE
CONSIDERING AND THREE HAD SAID
NO.
CAREGIVER DEMOGRAPHICS QUICKLY,
THE MAJORITY REPORTED THEY WERE
MARRIED AND HAD SOME COLLEGE
WITH A RATHER HIGH
POSTGRADUATE DEGREE IN THE
SAMPLE.
EMPLOYMENT STATUS , ABOUT HALF
EMPLOYED FULL TIME AND HALF NOT
EMPLOYED.
LASTLY THE TYPE OF INSURANCE,
THE MAJORITY HAD UTILIZED PUBLIC
HEALTH INSURANCE.
SO WHAT WE FOUND IS THAT MOTHERS
WERE WORRIED ABOUT DEATH AND
GVHD FROM THE TRANSPLANT MORE SO
THAN THE RISK OF INFERTILITY AND
THAT THEY DID HAVE A REALISTIC
UNDERSTANDING OF THE RISK OF
INFERTILITY AFTER TRANSPLANT AND
THEY TOOK THAT INTO
CONSIDERATION.
THEY WEREN'T IN DENIAL BUT THEY
WERE HOPEFUL.
LASTLY, FOR CA CAREGIVERS WHO HA
VERY YOUNG CHILD, IT WAS SORT OF
A TRIFECTA BARRIER TO SEEKING
FERTILITY PRESERVATIONS.
THAT IS, WE FOUND THEY DIDN'T
IMMEDIATELY EMBRACE THIS OPTION
SO IT WAS PRESENTED TO THEM.
FIRST IT WAS THE INCONVENIENCE
AT THE TIME OF THE INTERVIEW,
THE TIME OF INCONVENIENCE TO
TRAVEL TO ANOTHER STATE FOR THE
PROCEDURE AND IT WAS A PROCEDURE
THEY CONSIDERED VERY INVASIVE
PRIOR TO THE WHOLE TRAN FRAN TRT
PROCEDURE AND LASTLY THE
CAREGIVERS PERCEPTION WE FOUND
IS THEY LACKED CONFIDENCE IN
FERTILITY PRESERVATION IN THESE
PATIENTS THAT THE TISSUE TAKEN
TODAY WOULD PRODUCE A BIOLOGICAL
CHILD IN THE FUTURE.
AND SOME QUOTES I'LL JUST GO
THROUGH VERY QUICKLY.
IN REGARDS TO BEING WORRIED
ABOUT GVHD FROM HCT.
THE MAIN TWO WORRIES FOR ME IS
INFERTILITY AND GVHD.
IF I HAD TO PICK BETWEEN THE
TWO, GVHD SCARES ME MORE THAN
PROBABLY LIFE ITSELF.
THAT'S RATHER STRONG.
THEY HAVE A REALISTIC
UNDERSTANDING OF THE RISK OF
INFERTILITY.
I BELIEVE IT IS ALMOST ABSOLUTE
FOR BOYS, BASED OFF WHAT THE
PHYSICIAN SAID BECAUSE WE ASKED
A BUNCH OF QUESTIONS ABOUT THAT.
I ASKED IF THEY HAD ANY STUDIES
OR KNEW OF ANY STUDIES WHERE WAS
SPONTANEOUS BIRTHS FROM THE
MALES.
THE PHYSICIAN TALKING ABOUT
THERE WERE SPONTANEOUS BIRTHS
WITH SOME OF THE FEMALE, YOU
KNOW, SO I KIND OF HAD TO GRIEVE
THE THOUGHT OF NOT HAVING
GRANDCHILDREN, AT LEAST NOT FROM
HIM.
SO YOU CAN SEE SHE'S HOPEFUL BUT
SHE'S ALSO REALISTIC.
AGAIN WITH THE BARRIERS TO THE
PREBPREPUBESCENT CHILDREN AND
SEEKING FERTILITY PRESERVATION,
IN TERMS OF THEM REMOVING SOME
OF HIS CELLS IN THE FUTURE, THET
YET SO THERE'S THE POSSIBILITY
OF HIM NOT BEING ABLE TO HAVE
CHILDREN.
FOR ONE, WE DON'T WANT HER TO
HAVE SURGERY TWO TIMES.
ANOTHER REASON, THE PHYSICIAN
WAS TELLING US THAT IT WASN'T --
IT WAS STILL LIKE A STUDY, SO IT
WASN'T 100% SURE IT WAS GOING TO
WORK.
NOW WITH AD ADOLESCENT BOYS, ITS
A RESISTANCE TO FERTILITY
PRESERVATION.
SO EVEN IF THE FAMILY HAD NOT
MET WITH A FERTILITY TEAM, AS
YOU KNOW, SPE SPERM BANKING, THT
EXPLANATION WAS PRETTY FORWARD
SO THOSE FAMILIES WOULD TAKE
THAT AWAY FROM THE HCT CONSULT.
HE IS LIKE, MOM, I DON'T WANT NO
CHILDREN.
I'M LIKE, YOU'RE GOING TO WANT
KIDS AND HE'S LIKE, WELL, IF I
DO, THEY SAID I WOULD BE ABLE TO
DO THE SPERM BANK OR SOMETHING.
HE JUST BUST OUT LAUGHING.
HE IS REALLY GOOFY ABOUT IT
RIGHT NOW, HE IS NOT THINKING
ABOUT THAT TYPE OF STUFF.
NOW UNFORTUNATELY, THE FOUR
ADOLESCENT GIRLS IN THE STUDY,
THEY HAD NOT BEEN TO THE
FERTILITY CONSULTATION, SO IT
WAS A LITTLE DIFFICULT TO
DISCUSS THAT WITH THEM AS IT
BEING A MORE COMPLEX PROCEDURE.
AND ALSO PARENTS WERE CONCERNED
ABOUT DECISIONAL REGRET LATER
AND WHY THEY DID CONSIDER
FERTILITY PRESERVATION OR
WAITING UNTIL THE CHILD WAS OLD
ENOUGH TO WEIGH IN ON WHETHER OR
NOT THEY WANTED TO PURSUE
TRANSPLANT.
I DON'T WANT HIM TO GET
HOSPITALIZED AGAIN.
THAT HAS BEEN PLAYING THROUGH MY
MIND.
THERE ARE OTHER OPTIONS.
HE STILL HAS OPTIONS TO ADOPT
BUT IS THAT -- YOU KNOW, WHAT IF
HE RESENTS YOU?
SO IN SUMMARY, WE LEARNED THAT
THE RISK OF DEATH AND/OR GVHD IS
CONSIDERED GREATER THAN THE
RISK -- CONSIDERING THE RISK OF
INFERTILITY.
CAREGIVERS OF PREPUBESCENT
CHILDREN WERE NOT IMMEDIATELY
EMBRACING OF FERTILITY
PRESERVATION OPTIONS.
ADOLESCENT MALES MAY NOT FEEL
COMFORTABLE SPERM BANKING OR MAY
NOT FEEL COMFORTABLE THINKING
ABOUT FUTURE FATHERHOOD.
LASTLY, PARENTS ARE CONCERNED
ABOUT DECISIONAL REGRET LATER IN
LIFE WHEN CHILDREN ARE INFERTILE
AS A RESULT OF TRANSPLANT.
FUTURE RESEARCH SHOULD INCLUDE
PATIENTS TO ASCERTAIN THEIR
UNDERSTANDING OF THE RISK OF
INFERTILITY, FUTURE PARENTHOOD
AND FERTILITY PRESERVATION
OPTIONS AND THE INCONVENIENCE
AND INVASIVENESS OF FERTILITY
PRESERVATION PROCEDURES ARE
MAJOR BARRIERS AND FUTURE
RESEARCH MUST AIM AT ADDRESSING
THESE BARRIERS.
THANK YOU.
>>THANK YOU, DR. SINHA, FOR
GETTING YOUR PRESERVATION DONE
IN TIME AFTER STARTING TROUBLES.
ANY QUESTIONS FOR DR. SINHA,
ANYBODY FROM THE AUDIENCE?
LOOKS LIKE YOU DID A REALLY GOOD
JOB.
THANK YOU, CINDY.
OH, THERE IS A QUESTION, SORRY.
INTRODUCE YOURSELF, PLEASE.
>>THAT WAS A RATHER INTERESTING
POINT.
IT WASN'T, REALLY.
THEY DIDN'T UNDERSTAND THAT.
IN FACT, I TRIED TO PROBE TO SEE
IF THEY UNDERSTOOD HOW SICKLE
CELL DISEASE IMPACTS FERTILITY,
WITHOUT A TRANSPLANT, AND THERE
SEEMED TO BE A HUGE KNOWLEDGE
GAB.
IN KEEPING WITH THE TIME, I
DIDN'T HAVE AN OPPORTUNITY TO
SORT OF ENCLOSE THAT, BUT I ONLY
FOUND LIKE TWO PARENTS
UNDERSTOOD THAT HYDROXYURIA MAY
BE ASSOCIATED WITH INFERTILITY
SPRELS PRIOPRISSMM AND OVERALL
DECLINE IN HEALTH BUT THAT WAS
AN INTERESTING POINT THAT MAY
NEED TO BE ADDRESSED A LITTLE
CLEARER IN THE FUTURE, IS THERE
A RUSK OF INFERTILITY FROM
TRANSPLANT, DO THEY UNDERSTAND
THE RISK OF INFERTILITY FROM
SICKLE CELL DISEASE.
>>THANK YOU VERY MUCH,
DR. SINHA.
IT'S MY PLEASURE NOW TO
INTRODUCE OUR NEXT SPEAKER,
DR. MONICA HULBERT FROM
WASHINGTON UNIVERSITY.
AND SHE WILL BE SPEAKING ON THE
NORMALIZATION OF CEREBRAL
HEMODYNAMICS AFTER HSCT IN
CHILDREN WITH SICKLE CELL
DISEASE.
DR. HULBERT.
>>THANK YOU.
THANK YOU FOR THE OPPORTUNITY TO
DISCUSS OUR WORK IN THIS FORUM.
SO WE ALL KNOW SICKLE CELL
DISEASE CAUSES MORE THAN JUST
STROKES.
BESIDES OVERT STROKES AND
ABNORMAL TCDs, THROUGHOUT THE
LIFESPAN THERE'S INCREASING
PREVALENCE OF SILENT STROKE AND
MANY PATIENTS EXPERIENCE
ACADEMIC AND COGNITIVE
IMPAIRMENTS.
SO I WORK WITH A GROUP OF
NEUROLOGISTS AND
NEURORADIOLOGISTS AND
HEMATOLOGISTS TO INVESTIGATE THE
ROLE OF CEREBRAL AUTO REGULATION
IN SICKLE CELL DISEASE.
SO BRIEFLY THIS IS A DYNAMIC
PROCESS THAT MAINTAINS CEREBRAL
OXYGEN DELIVERY AND ACCOMPLISHES
THIS THROUGH DILATION AND
CONSTRICTION OF BLOOD VESSELS TO
CHANGE GLOBAL AND REGIONAL BLOOD
FLOW AND OXYGEN DELIVERY
DEPENDING ON THE BRAIN'S NEEDS.
SO THIS IS AFFECTED BY MANY
DIFFERENT PHYSIOLOGICAL
CONDITIONS.
AND CHIEFLY HEMOGLOBIN AND
OXYGEN SATURATION ARE VERY
IMPORTANT COMPONENTS OF THE
ARTERIAL OXYGEN CONTENT, SO YOU
CAN IMAGINE THAT IN SICKLE CELL
DISEASE, THIS CAN BE
SIGNIFICANTLY IMPAIRED.
AND A STROKE OCCURS WHEN OXYGEN
DELIVERY IS INADEQUATE AND THE
BRAIN IS NOT ABLE TO COMPENSATE.
SO WHAT DO WE KNOW ABOUT
CEREBRAL HEMODYNAMICS IN SICKLE
CELL DISEASE?
CEREBRAL BLOOD FLOW AND OXYGEN
EXTRACTION FRACTION ARE THE
MEASURES MOST COMMONLY
DISCUSSED.
WE KNOW THE THEY ARE GLOBALLY AD
REGIONALLY ELEVATED IN SICKLE
CELL COMPARED WITH SIBLING
CONTROLS, AND THEY CORRELATE IP
VERSELY WITH ANEMIA.
SO THE MORE ANEMIC THE PATIENT
IS, THE HIGHER THEIR CBF AND OEF
ELEVATIONS.
BOTH MEASURES WE HAVE
DEMONSTRATED IMPROVE WITHIN 24
HOURS AFTER A TRANSFUSION, SO
WHEN WE IMPROVE THEIR HEMOGLOBIN
ACUTELY, THEN THE STRESS ON
THEIR BRAIN IMPROVES A BIT.
AND OUR GROUP HAS ALSO
IDENTIFIED AN AREA OF EXTREME
OXYGEN EXTRACTION ELEVATION IN
THE PERIVENTRICULAR WHITE MATTER
WITH COINCIDES WITH A LOW -- A
REGION OF VERY LOW CEREBRAL
BLOOD FLOW, THE WATERSHED
REGION, AND ALSO COINCIDES WITH
THE HIGHEST DENSITY OF SILENT
STROKES.
SO ONE OF MY COLLEAGUES,
DR. MELANIE FIELDS, PUBLISHED
THIS PAPER DEMONSTRATING THAT
THE AMOUNT OF BRAIN TISSUE AT
HIGHEST RISK WITH THE MOST
ELEVATED OXYGEN EXTRACTION
FRACTION DECREASES WITH
INCREASING INTENSITY OF THERAPY.
SO PATIENTS ON THE LEFT WITH NO
THERAPY HAVE A VERY HIGH VOLUME
OF BRAIN TISSUE IN THAT
PERIVENTRICULAR WHITE MATTER
REGION WHERE IS WHERE MOST
SILENT STROKES OCCUR.
THAT APPEARS TO BE AT HIGHEST
RISK.
THOSE ON HYDROXYUREA HAVE AN
IMPROVED AREA BUT THERE'S STILL
SOME THAT DOES APPEAR TO BE AT
HIGH RISK AND THOSE ON
TRANSFUSION THERAPY HAVE A MUCH
IMPROVED AMOUNT OF BRAIN TISSUE
WITH EXTREME OEF ELEVATION.
SO NATURALLY WE WANTED TO
INVESTIGATE THE CHANGES IN
CEREBRAL BLOOD FLOW AND OXYGEN
EXTRACTION FRACTION THAT HAPPEN
AFTER A TRANSPLANT.
SO WE ENROLLED 10 SUBJECTS WITH
SICKLE CELL DISEASE WITH AN
IMAGE BEFORE AND AFTER
TRANSPLANT.
SEVEN OF THEM HAD HEMOGLOBIN SS
AND THREE HAD HEMOGLOBIN S BETA
PLUS THALASSEMIA.
THEY UNDERWENT MEASURES BEFORE
AND ONE TO TWO YEARS AFTER
TRANSPLANT AND WE COMPARED THEM
WITH 20 CHRONIC TRANSFUSION
RECIPIENTS AND 20 SIBLING
CONTROLS.
SO THE TRANSPLANT PREP REGIMEN
FOR EIGHT OF THE SUBJECTS WAS
ALEMTUZUMAN -- THERE WERE TWO
SUBJECTS WHO WERE IMAGED BEFORE
AND AFTER A SECOND TRANSPLANT
HAVING REJECTED THEIR FIRST
USING THE ABOVE REGIMEN, AND
THEY WERE PREPPED WITH FLEW DARE
BEAN, CYCLOPHOSPHAMIDE AND ATG.
THE TRANSPLANT INDICATIONS,
THREE HAD OVERT STROKES, FIVE
HAD SILENT STROKES, THREE HAD
ABNORMAL TCDs, AND SEVEN HAD
FREQUENT PAIN OR OTHER RECURRENT
VASOOCCLUSIVE EVENTS.
SO YOU CAN SEE SOME PATIENTS HAD
MULTIPLE INDICATIONS.
FORTUNATELY, THERE WERE NO
NEUROLOGICAL COMPLICATIONS
DURING OR AFTER THE TRANSPLANT
AND NO NEW INFARCTIONS
IDENTIFIED ON THEIR MRI POST
TRANSPLANT.
THERE WAS NO HIGH GRADE ACUTE OR
CHRONIC GRAFT-VERSUS-HOST
DISEASE.
SO THESE ARE THE SUBJECTS.
YOU CAN SEE THEIR AGES RANGED
FROM 6 1/2 TO 21.6 YEARS.
SEVEN OF THEM HAD MATCHED
SIBLING DONORS AND THREE HAD
8 OF 8 MATCHED UNRELATED DONORS.
THEY ALL NORMALIZED THEIR
HEMOGLOBIN AND THEIR HEMOGLOBIN
S WAS CONSISTENT WITH THEIR
DONOR AFTER THE TRANSPLANT.
SO OUR MOST IMPORTANT FINDING
WAS THAT CEREBRAL BLOOD FLOW AND
OXYGEN EXTRACTION FRACTION
NORMALIZE AFTER TRANSPLANT.
SO IN THIS GRAPH, YOU CAN SEE
BEFORE THE TRANSPLANT, WHICH IS
GREEN, AND COMPARED TO THE
PATIENT'S THERAPY BEFORE
TRANSFUSION IN RED, THERE WAS NO
SIGNIFICANT DIFFERENCE IN THEIR
CBF.
AFTER THE TRANSPLANT, THE
RECIPIENTS HAD A REDUCTION IN
THEIR CEREBRAL BLOOD FLOW THAT
WAS NOT DWICIALA DISTINGUISHABLM
CONTROLS SO THEY ESSENTIALLY
NORMALIZED TO THE LEVEL OF
CONTROLS.
THEN THIS GRAPH SHOWS THE WHOLE
BRAIN OXYGEN EXTRACTION
FRACTION.
BEFORE THE TRANSPLANT THE
TRANSPLANT RECIPIENTS WERE
SIMILAR TO THE PRE-TRANSFUSION
PATIENTS.
AFTER THE TRANSPLANT, THE
RECIPIENTS HAD NORMALIZED THEIR
OXYGEN EXTRACTION FRACTION AND
IT WAS, AGAIN, NOT DIFFERENT
FROM CONTROLS.
HOWEVER, WITH OEF, ADDITIONALLY
WE WERE ABLE TO IDENTIFY THAT
AFTER THE TRANSPLANT, THE OEF
WAS EVEN LOWER COMPARED TO THE
PATIENTS AFTER A CHRONIC
TRANSFUSION.
SO ESSENTIALLY THE OEF WAS MORE
NORMAL AFTER TRANSPLANT.
AND HERE IS A MAP REPRESENTATION
OF OUR PATIENTS -- AT ONE
PATIENT WHO UNDERWENT
TRANSPLANT.
ON THE LEFT IS A SIBLING CONTROL
WITH NORMAL CBF AND OEF VALUES,
AND THEN YOU CAN SEE THE
PRE-TRANSPLANT STATE FOR THIS
SUBJECT WITH A SIGNIFICANTLY
ELEVATED CBF AND OEF, AND THEN
AFTER TRANSPLANT, THESE VALUES
HAVE NORMALIZED TO BE VERY
SIMILAR TO THE CONTROLS.
SO WE WERE ABLE TO ALSO IDENTIFY
THAT THE PRIMARY DRIVER OF THIS
AT LEAST IN OUR SAMPLE WAS
CORRECTION OF ANEMIA, AND THE
TRAJECTORY OF ANEMIA IMPROVEMENT
STRONGLY WAS CORRELATED WITH THE
CHANGE IN IMPROVEMENT IN OEF.
SO WHEN A PATIENT IS RECEIVING
CHRONIC TRANSFUSION THERAPY, WE
THINK THAT THE REASON FOR THIS
IS THAT THEIR HEMOGLOBIN
FLUCTUATES BETWEEN 1 TO 3 GRAMS
PER DECILITER ON AVERAGE BETWEEN
THEIR TRANSFUSIONS AND THIS DOES
LEAVE THEM AT RISK FOR ACUTE
SICKLE CELL EVENTS THAT COULD
ACUTELY REDUCE OXYGEN DELIVERY
AND REQUIRE CEREBRAL
COMPENSATION AND ALSO PUT THEM
AT RISK FOR STROKES.
HOWEVER, AFTER TRANSPLANT, THE
HEMOGLOBIN STABILIZES AND
NORMALIZES THEIR BLOOD OXYGEN
CONTENT, THUS ALLOWING THE CBF
AND OEF TO RETURN TO NORMAL
RANGES.
WE FOUND THAT OEF WHICH IS SHOWN
HERE HAS A STRONGER CORRELATION
THAN CBF.
AND WE ALSO, INTERESTINGLY,
FOUND THAT HEMATOCRIT CORRELATED
A LITTLE MORE -- THAN HEMOGLOBIN
DID.
CORRELATE IMPROVEMENTS WITH
COGNITION, HEALTH RELATED
QUALITY OF LIFE, FUNCTIONAL
CONNECTIVITY -- THE DIFFERENCES
BETWEEN HEMOGLOBIN AND
HEMATOCRIT I THINK ARE KIND OF
INTRIGUING AND I'D LIKE TO BE
ABLE TO INVESTIGATE THAT MORE.
WE WERE NOT ABLE TO LOOK AT
SPECIFIC TRANSPLANT-RELATED
FACTORS.
SINCE THE SAMPLE SIZE WAS PRETTY
SMALL.
THIS I THINK WOULD BE VERY
INTERESTING TO STUDY INPATIENTS
WHO RECEIVE GENE THERAPY AND
ULTIMATELY AN A REALLY IMPORTANT
QUESTION FOR OUR FIELD IS
WHETHER EARLIER CURATIVE THERAPY
CAN STABILIZE OR EVEN IMPROVE
COGNITION IN KIDS WITH SICKLE
CELL DISEASE.
SO IN CONCLUSION, ANEMIA IS A
MAJOR DRIVER OF NEUROLOGICAL
DISEASE.
HEMODYNAMICS IMPROVE
PROGRESSIVELY WITH INCREASINGLY
INTENSIVE DISEASE-MODIFYING
THERAPY AND WE'VE DEMONSTRATED
THAT WHOLE BRAIN CEREBRAL BLOOD
FLOW AND OXYGEN EJECTION
FRACTION NORMALIZE AFTER
SUCCESSFUL TRANSPLANT.
THESE ARE MY COLLEAGUES AND
COLLABORATORS AND FUNDING
SOURCES.
AND OF COURSE THIS WOULDN'T BE
POSSIBLE WITHOUT THE EAGER
PARTICIPATION OF OUR PATIENTS.
THANK YOU.
>>WE'RE ACTUALLY GOING TO SAVE
QUESTIONS TO THE VERY END NOW SO
WE'LL HAVE THE SPEAKERS AT THE
VERY END OF THE SESSION COME UP
AND TAKE QUESTIONS IF THERE'S
TIME.
OUR NEXT SPEAKER IS DR. NITYA
BAKSHI FROM EMORY UNIVERSITY AND
SHE'LL BE PRESENTING ON
MULTIMODAL PHENOTYPING AND
CORRELATES OF PAIN FOLLOWING HCT
IN CHILDREN WITH SICKLE CELL
DISEASE.
SO THIS WAS AN OBSERVATIONAL
STUDY IN CHILDREN 8 YEARS AND
OLDER WHO WERE ENGLISH-SPEAKING
AND SCHEDULED FOR HEMATOPOIETIC
CELL TRANSPLANT FOR SICKLE CELL
DISEASE.
IN THIS STUDY, WE SOUGHT TO
STUDY THE FEASIBILITY OF
COLLECTING PAIN,
PATIENT-REPORTED OUTCOMES,
HEALTH RELATED QUALITY OF LIFE,
INTERVIEWS, AND EXPERIMENTAL
PAIN SENSITIVITY DATA BEFORE AND
AFTER TRANSPLANT.
AND OUR SECONDARY GOAL WAS TO
COMPARE THESE DATA BEFORE AND
AFTER TRANSPLANT.
SO THESE WERE THE BASELINE
CHARACTERISTICS OF OUR PATIENTS.
OUR AVERAGE AGE WAS 13.5.
THE VAST MAJORITY OF PATIENTS IN
THIS STUDY WERE MALE.
AND THEY HAD FAIRLY HIGH RATES
OF HEALTHCARE UTILIZATION BEFORE
THE TIME THAT THEY WERE
CONSIDERED FOR TRANSPLANT.
ALMOST ALL OF THEM WERE ON SOME
FORM OF DISEASE MODIFYING
THERAPY AND THE VAST MAJORITY OF
THEM HAD A -- DONOR TRANSPLANT.
ALL OF THE PATIENTS IN THE
TRANSPLANT HAD DONOR DERIVED
ERYTHROPOIESIS POST TRANSPLANT
AND TWO HAD CHRONIC GBHD.
SO THIS IS A BRIEF SNAPSHOT OF
HOW MANY PEOPLE WERE ACTUALLY
ABLE TO COMPLETE PROCEDURES AT
EVERY TIME POINT TO REMIND YOU
THE TOTAL SAMPLE WAS 8 PEOPLE.
AND AS YOU CAN SEE, YOU KNOW,
PROCEDURES SUCH AS
QUESTIONNAIRES WERE COMPLETED A
LITTLE MORE FREQUENTLY THAN THE
MORE TIME-INTENSIVE ONES SUCH
AS -- INTERVIEWED.
NOT EVERYBODY WHO SIGNED UP FOR
THE STUDY ALSO SIGNED UP FOR THE
OPTIONAL EXPERIMENTAL PAIN
SENSITIVITY PROCEDURES, BUT YOU
GENERALLY CAN SEE THAT THERE IS
SOME DECLINE OVER TIME IN
COMPLETION OF PROCEDURES.
THIS IS A SNAPSHOT OF INDIVIDUAL
LEVEL OF PAIN REPORTED OUTCOMES
POST TRANSPLANT COMPARED TO
PRETRANSPLANT.
I WANTED TO SHOW THESE FIGURES
TO SHOW YOU THAT THERE IS DOMAIN
LEVEL HETEROGENEITY AND
INDIVIDUAL LEVEL HETEROGENEITY
AND CHANGE IN PATIENT-REPORTED
OUTCOMES AFTER TRANSPLANT.
SO WHILE THERE ARE OVERALL
DECREASES ACROSS GROUPS, YOU
KNOW, THE STORY MAY NOT BE THE
SAME WHEN YOU LOOK AT DATA AT
THE INDIVIDUAL LEVEL.
OVERALL, THOUGH, YOU CAN SEE
PAIN INTENSITY TEND TO
DECREASE -- TENDS TO DECREASE AS
WELL AND SO DOES -- AND A
SIMILAR STORY IS SEEN HERE, THIS
IMPROVEMENT IN PHYSICAL
FUNCTION, REDUCTION IN ANXIETY
AND DEPRESSIVE SYMPTOMS AND
IMPROVEMENT IN PEER
RELATIONSHIPS POST TRANSPLANT.
WHEN MEASURED USING THE PAIN
DIARY, YOU HAVE A MORE GRANULAR
VIEW, AND WE HAD A FAIRLY GOOD
RATE OF DIARY COMPLETION FOR OUR
STUDY.
YOU CAN SEE, THOUGH, AS SHOWN IN
THE SECOND LINE, THE PROPORTION
OF DAYS WITH PAIN REDUCES OVER
TIME, PARTICULARLY AROUND 1 AND
2 YEARS POST TRANSPLANT, AND THE
MEAN DAILY PAIN INTENSITY, WHICH
IS THE THIRD ROLE, YOU CAN ALSO
SEE DECREASES OVER TIME.
THIS IS A SMALL SAMPLE, BUT I
THINK IT JUST SHOWS US THAT EVEN
IF YOU MEASURE WITH A DIFFERENT
INSTRUMENT, THAT IN GENERAL,
WE'RE SHOWING IMPROVEMENT IN
PAIN INTENSITY AND NUMBER OF
DAYS WITH PAIN OVER TIME POST
TRANSPLANT.
I HAVE NOT SHOWN ALL THE DATA ON
CHANGES IN EXPERIMENTAL PAIN
SENSITIVITY, BUT THESE ARE ALL
AVAILABLE AND PUBLISHED IN THE
MANUSCRIPT.
I WANTED TO HIGHLIGHT THE TWO
DOMAINS THAT WE SAW A LITTLE BIT
OF A SIGNAL IN, AS YOU CAN SEE,
IT APPEARS THAT PRESSURE PAIN
THRESHOLD TENDS TO INCREASE OVER
TIME.
THESE ARE, AGAIN, SMALL SAMPLES,
BUT EVEN WITH THESE SMALLER
SAMPLES, WE HAVE REASONABLE
EFFECT SIZES, AND WE CAN SEE THE
PRESSURE PAIN THRESHOLD TENDS TO
INCREASE OVER TIME, WHICH MEANS
PEOPLE ARE LESS SENSITIVE TO
PRESSURE PAIN AND COLD PAIN
THRESHOLD TENDS TO DECREASE
WHERE COLD PAIN IS -- SO THIS
ACTUALLY MEANS THAT PEOPLE ARE
LESS SENSITIVE TO COLD PAIN OVER
TIME.
AND SO THESE WERE THE TWO
DOMAINS THAT WE SAW SOME SIGNAL
IN WHEN WE COMPARED CHILDREN PRE
TO POST TRANSPLANT.
WHEN WE LOOK AT QUALITATIVE
INTERVIEWS, AGAIN, THIS IS JUST
A VERY HIGH LEVEL SUMMARY.
IN GENERAL, OUR TAKEAWAYS WERE
THAT THERE WAS SIGNIFICANT
IMPACT OF PAIN ON QUALITY OF
LIFE PRIOR TO TRANSPLANT IN
PRETTY MUCH EVERY DOMAIN, AND
THAT -- CAN WE DI GO TO THE NEXT
SLIDE, PLEASE?
AND PAIN INFLUENCED -- THERE WAS
SIGNIFICANT IMPACT OF PAIN ON
EVERY ASPECT OF LIFE.
POST TRANSPLANT, PAIN WAS REALLY
INFLUENTIAL IN THE DECISION TO
CONSIDER TRANSPLANT.
PARTICIPANTS AND/OR THEIR PARENT
REPORTED THAT THEY WANTED TO BE
CURED OF OR HAVE NO MORE SICKLE
CELL DISEASE OR RELATED PAIN.
AND POST TRANSPLANT, EVEN THOUGH
OUR SAMPLE WAS SMALL, WE SAW
THAT MOST PARTICIPANTS DID NOT
REPORT SICKLE CELL PAIN AND
IMPORTANTLY, MANY OF THEM
MENTIONED THAT THEY DID NOT HAVE
THE SAME ACTIVITY LIMITATIONS
THAT THEY HAD PRETRANSPLANT,
THEY HAD LESS FATIGUE, MORE
ENERGY, AND OVERALL, THEIR
EXPERIENCE EVEN THOUGH WAS
CAPTURED IN A MORE GRANULAR WAY
USING THESE QUALITATIVE
INTERVIEWS.
SO OUR CONCLUSIONS ARE THAT IT
APPEARS TO BE FEASIBLE TO
CONDUCT MULTIMODAL PAIN
ASSESSMENTS BEFORE AND AFTER
TRANSPLANT, BUT THERE ARE SOME
UNIQUE CHALLENGES.
EVEN IN VERY LARGE CENTERS, IT
IS CHALLENGING TO OFFER
PARTICIPATION TO PARTICIPANTS,
THERE'S A NARROW WINDOW
PRETRANSPLANT IN WHICH TO OFFER
PARTICIPATION.
JUST GIVEN THE INTENSITY OF THE
PROCEDURE OF TRANSPLANT, EVEN
DOING THINGS LIKE SURVEYS MIGHT
BE REALLY BURDENSOME FOR
PARTICIPANTS.
THERE'S A LONG DURATION OF
FOLLOW-UP NEEDED TO STUDY
CHANGES.
THERE IS A RISK OF LOSS TO
FOLLOW-UP, WHICH MAY BE DUE TO
MEDICAL COMPLICATIONS OR JUST
PARTICIPANT BURDEN.
AND THEN OUR DATA SUGGESTS THAT
THERE IS INDIVIDUAL AND
DOMAIN-LEVEL HETEROGENEITY IN
CHANGE IN PROs AFTER
TRANSPLANT.
I THINK STUDYING PROs
SEPARATELY OR DIVIDED BY HCT
PAIN PHENOTYPES COULD PROVIDE
MORE INSIGHT.
AND OUR SAMPLE SIZE WAS SMALL
BUT STILL OUR RESULTS COULD SHED
SOME INSIGHT INTO THE WHOLE
QUESTION OF PAIN AFTER
TRANSPLANT.
I THINK BIGGER STUDIES SUCH AS
THE EXREEN RECENTLY COMPLETED S,
1503, 1505, WILL HELP ANSWER
THIS QUESTION FURTHER.
AND THANK YOU, I'D BE HAPPY TO
TAKE ANY QUESTIONS.
THE LINK TO THE PUBLICATION AND
THE INDEX IS LISTED BELOW.
>>THANK YOU, DR. BAKSHI, FOR
THAT EXCELLENT PRESENTATION ON
PAIN AND PROs.
I WANT TO CONGRATULATE ALL THE
SPEAKERS FOR STAYING ON TIME AND
WE'LL HAVE ENOUGH TIME IN THE
END I'M SURE, SO CONTINUE THE
THEME ON PAIN AND
PATIENT-REPORTED OUTCOMES, I'D
LIKE TO INTRODUCE OUR NEXT
SPEAKER, DR. ALEXIS LEONARD FROM
ST. JUDE CHILDREN'S HOSPITAL.
AND DR. LEONARD WILL BE SPEAKING
ON REDUCTION IN VASOOCCLUSIVE
EVENT FOLLOWING STEM CELL
TRANSPLANTATION IN PATIENTS WITH
SICKLE CELL DISEASE, AND
DR. LEONARD WILL BE PRESENTING
REMOTELY.
WELCOME, DR. LEONARD.
>>THANK YOU.
THANK YOU ALL FOR INVITING ME TO
SPEAK ON THIS PUBLICATION THAT
WE HAD PUT OUT EARLIER THIS
YEAR.
AS YOU CAN SEE THE TITLE THERE,
I'M ALEXIS LEONARD, A RATHER NEW
MEMBER IN THE DEPARTMENT OF
HEMATOLOGY AT ST. JUDE, HAVING
RECENTLY BEEN AT THE NIH DOING
CLINICAL WORK AT CHILDREN'S
NATIONAL.
IN D.C. .
SO AS WE ALL KNOW, TRANSPLANT IS
POTENTIALLY CURATIVE FOR THE
LONG TERM DISEASE MANAGEMENT AND
PREVENTION OF ORGAN DAMAGE SEEN
IN SICKLE CELL DISEASE, AND THAT
PATIENTS THAT DO EXPERIENCE
STABLE DONOR ENGRAFTMENT DO NOT
EXPERIENCE SICKLE-RELATED
SYMPTOMS AND CAN HAVE EITHER
STABILIZATION OR IMPROVEMENT IN
THEIR END-ORGAN PATHOLOGY.
HOWEVER, THESE LONG-TERM EFFECTS
REMAIN TO BE FULLY ESTABLISHED.
SO WHEN WE'RE TALKING ABOUT
INDICATIONS FOR TRANSPLANT,
EXCEPT FOR STROKE, THESE
INDICATIONS ARE NOT UNIVERSALLY
AGREED UPON AND VARY AMONG
STUDY, BUT TYPICALLY ARE
RESERVED FOR THOSE WITH THE MOST
SEVERE DISEASE COMPLICATIONS OR
AT RISK FOR THOSE LONG TERM
DISEASE-RELATED COMPLICATIONS.
THIS IS A TABLE A FEW YEARS OLD
BUT IT'S SHOWING VARIOUS
INDICATIONS, AS YOU CAN SEE, IT
VARIES BASED ON DONOR STATUS BUT
IN ALL OF THESE STUDIES, HAVING
RECURRENT SEVERE PAIN DESPITE
HYDROXYUREA THERAPY ARE
INDICATIONS FOR TRANSPLANT.
AND WHEN EAR TALKING ABOUT --
THESE ARE FOR ALLOGENEIC
STUDIES.
WHEN WE'RE TALKING ABOUT
AUTOLOGOUS GENE THERAPY, HAVING
SEVERE VASOOCCLUSIVE EVENTS ARE
THE REQUIREMENT.
SO WHEN YOU LOOK AT THE
LITERATURE AT LONG TERM OUTCOME,
EACH ORGAN SYSTEM HAS SOME
DEDICATED LITERATURE TO IT.
WE'VE ALREADY HEARD FROM OUR
COLLEAGUES THIS MORNING ABOUT
THE NEUROLOGIC CHANGES, THE
NORMALIZATION OF WHOLE BRAIN
HEMODYNAMICS FROM DR. HOLBERT,
AND YOU CAN SEE EACH ORGAN
SYSTEM HAS SOME DEDICATED
LITERATURE TO IT.
MORE RECENTLY, WE HAVE MORE
LITERATURE ON THE ENDOCRINE
FUNCTION.
BUT REALLY IN ALL OF THESE
STUDIES, WHETHER IT'S ON OUTCOME
FROM A TRIAL OR THESE LONG-TERM
OUTCOMES, WE REALLY ONLY GET
REPORTS THAT SIMPLY COMMENT
THERE'S A REDUCTION IN PAIN
HOWEVER THE DATA SPECIFICALLY
REPORTING PAIN AFTER TRANSPLANT
IS LACKING.
AT THE TIME WE DID THIS STUDY,
WE DIDN'T HAVE DR. BAKSHI'S DATA
THAT SHE JUST REPORTED.
PRIOR TO WRITING THIS UP AND
DOING THIS STUDY, THERE WAS
REALLY ONLY ONE STUDY THAT
SINGLE HANDEDLY LOOKED AT PAIN
AND IT WAS ONLY UP TO ONE YEAR
POST TRANSPLANT.
AND THIS WAS IN AN ADULT
POPULATION AT THE NIH OF 35
PATIENTS THAT DOCUMENTED THAT
THERE WAS A FRACTION OF PATIENTS
IN THIS COHORT, 40% STILL HAD
PERSISTENT PAIN REQUIRING
OPIATES AT ONE YEAR POST
TRANSPLANT.
AND AS WE'RE GETTING MORE DATA
ON THE AUTOLOGOUS GENE THERAPY
TRIAL, WE'RE GETTING REPORT
ABOUT REDUCTION OR RESOLUTION OF
THESE SEVERE VASO-OCCLUSIVE
EVENTS.
THESE ARE DATA THAT WE SEE FROM
THE BLOOMBERG STUDY ON THE LEFT
AND THE CRISPR STUDY ON THE
RIGHT BOTH OF WHICH ARE
CURRENTLY UNDER REVIEW.
AND SO THE RATIONALE FOR DOING
THIS ARTICLE IN THIS STUDY WAS
THAT IN ORDER FOR US TO REALLY
ADEQUATELY INFORM AND ASSESS THE
RESULTS OF THESE NEWER
AUTOLOGOUS GENE STUDY THAIRPTS,
WE NEED BETTER PUBLISHED DATA
INCLUDING VASO-OCCLUSIVE EVENTS
BEFORE AND AFTER ALLOGENEIC
TRANSPLANT.
SO THAT LED TO THIS
RETROSPECTIVE STUDY WHERE WE
LOOKED AT 163 PATIENTS WITH
SICKLE CELL DISEASE, PEDIATRIC
AND ADULT, WHO UNDERWENT AN
ALLOTRANSPLANT.
WE LOOKED AT THE NUMBER OF
VASO-OCCLUSIVE EVENTS IN THE TWO
YEARS BEFORE TRANSPLANT, AND
COMPARED THEM WITH THE NUMBER OF
EVENTS IN THE ZERO TO 12 MONTHS
AND THEN 12 TO 24 MONTHS AFTER
TRANSPLANT, AND WHAT WE REPORT
IS THAT VASO-OCCLUSIVE EVENTS
ARE SIGNIFICANTLY REDUCED IN
THIS PATIENT POPULATION AFTER
ALLOTRANSPLANT.
SO HOW DO WE DEFINE VOE?
SO WE USED -- BECAUSE WE WANTED
THIS TO BE AN IMPORTANT ABILITY
TO COMPARE TO THESE YOU AUTOLOGS
STUDIES, WE USED THE BLOOMBERG
BIOSTUDY, ONE OF THE LARGEST AT
THE TIME, WHICH IS HIGHLIGHTED
AT THE BOTTOM.
SPECIFIC DEFINITIONS FOR
OBTAINING ACUTE -- FOR PAIN THAT
MEANS MORE THAN 24 HOURS OF
HOSPITALIZATION FOR PAIN OR ER
VISITS, TWO VISITS OVER A
CERTAIN PERIOD OF TIME.
YOU CAN SEE WE INCLUDED 11
DIFFERENT CLINICAL TRIALS FOR
ALLO TRANSPLANT BETWEEN NIH AND
CHILDREN'S NATIONAL, OF WHICH
THEY HAD VARYING DEFINITIONS OF
WHAT WAS INCLUDED FOR THE STUDY
FOR PAIN OR ACUTE CHEST.
SO THIS IS A BUSY SLIDE BUT THIS
IS PATIENT CHARACTERISTICS AND
OUTCOMES.
ON THE LEFT PATIENT
CHARACTERISTICS, WE HAD 153
PATIENTS OF WHICH A MAJORITY ARE
MALE, HEMOGLOBIN SS -- AVERAGE
AGE 20 FOR THE ENTIRE COHORT,
YOUNGEST BEING 7 MONTHS, OLDEST
BEING 64.
THE MAJORITY, 75% UNDERWENT A
NON-MYELOOWE BLAITIVE
CONDITIONING REGIMEN.
YOU CAN SEE VARYING DONOR TYPES,
MAJORITY BEING MATCHED SIBLING.
PAIN WAS THE MOST FREQUENT,
FOLLOWED BY RECURRENT ACUTE
CHEST.
IN TERMS OF THE OUTCOMES OF THIS
STUDY, ENGRAFTMENT OCCURRED IN
88% OF THE PATIENT POPULATION,
WITH AN AVERAGE MYELOID
CHIMERISM OF AROUND 80% AND YOU
CAN SEE THE RATES OF GBHD.
THIS TABLE IS IN THE ARTICLE AND
I'M GOING TO GO THROUGH THE
NUMBER OF EVENTS IN THE
FOLLOWING SLIDES.
SO THIS STUDY -- THE FIGURE THAT
YOU SEE THERE ON THE LEFT IN
BLUE ARE THE NUMBER OF
VASO-OCCLUSIVE EVENTS FOR THOSE
WHO ENGRAFTED IN THE TWO YEARS
BEFORE.
IN PINK ARE THE NUMBER OF
VASO-OCCLUSIVE EVENTS
PRETRANSPLANT AND THOSE WHO
ULTIMATELY HAD GBHD AND THEN IN
GREEN ARE THE ONES THAT
REJECTED.
IN YELLOW ARE THE NUMBER OF
EVENTS THAT OCCURRED IN THE ZERO
TO 12 MONTHS AND EMBED THE 12 TO
24 MONTHS.
YOU CAN SEE THE NUMBER OF EVENTS
LISTED HERE AVERAGE TWO YEARS
BEFORE WAS 5 1/2 EVENT BUT THAT
RANGED FROM ZERO IN SOME OF THE
PEDIATRIC PATIENTS TO 502.
TO 52.
OVERALL IN THE TWO-YEAR
PERIOD -- AS YOU CAN SEE, THE
MAJORITY OF THOSE EVENTS ARE
OCCURRING IN THE ZERO TO 12
MONTHS.
THIS IS ANOTHER WAY TO REPRESENT
THAT DATA BUT REALLY SEPARATED
OUT THE ENGRAFTED WITH AND
WITHOUT GBHD IN OUR REJECTED
PATIENTS.
THOSE WHO SUCCESSFULLY ENGRAFTED
HAD A RISK OF VASO-OCCLUSIVE
EVENT REDUCTION OF 75% IN THAT
FIRST YEAR, AND IT CLIMBED TO
99% IN THE SECOND YEAR AFTER
TRANSPLANT.
INTERESTINGLY, AS HAS
SUBJECTIVELY BEEN REPORTED EVEN
IN PATIENTS THAT REJECTED THEIR
GRAFT WE FOUND THERE WAS ALSO
SIGNIFICANT REDUCTION IN EVENT
IN THE ZERO TO 12 AND 12 TO 24
MONTHS AFTER REJECTION.
SO WE KNOW YOUNGER PATIENTS
GENERALLY HAVE LESS
VASO-OCCLUSIVE EVENTS PRE AND
POST TRANSPLANT AND THAT WAS
TRUE IN OUR POPULATION.
AS YOU CAN SEE IN THE GRAPH ON
THE LEFT, THIS IS SEPARATED BY
AGE.
THE YOUNGER PATIENT HAVING
SIGNIFICANTLY LESS EVENTS
PRETRANSPLANT, MORE COMMON
INDICATIONS WERE ACUTE CHEST --
OR STROKE.
SO WHEN WE DID AGGRESSION
MODELING INCLUDING AGE, GENDER
AND NUMBER OF EVENTS
PRETRANSPLANT, WE FOUND THAT AGE
AND NUMBER OF VASO-OCCLUSIVE
EVENTS WERE PREDICTIVE OF THE
NUMBER OF EVENTS THAT WOULD
OCCUR IN THE ZERO TO 12 MONTHS
AFTER TRANSPLANT, BUT NOT THE 12
TO 24, GIVEN THERE WERE SO FEW
EVENTS.
WE ALSO DID ANOTHER ANALYSIS
LOOKING AT DONOR MY EMPLOYED MYD
CHIMERISM AT TWO YEARS.
-- AGAIN NOT SIGNIFICANT FOR 12
TO 24 MONTHS BECAUSE WE HAD SO
FEW EVENTS.
THIS FIGURE ON THE RIGHT SHOWS
THE TOP HALF OF IT IS 100% DONOR
MYELOID CHIMERISM AND AS YOU GET
LOWER IN YOUR CHIMERISM, YOU SEE
MORE EVENTS POST TRANSPLANT.
THE OTHER THING WE DID LOOK AT,
SPECIFICALLY THIS IS WHAT HAD
BEEN REPORTED, PATIENTS ON
EITHER LONG OR SHORT ACTING
OPIOIDS AT THE TIME OF
TRANSPLANT HAD SIGNIFICANTLY
MORE VOEs PRETRANSPLANT AND
WAS PREDICTIVE IN THAT ZERO TO
12 MONTH PERIOD BUT NOT THE 12
TO 24 MONTH PERIOD.
SO THIS STUDY HAS SIGNIFICANT
LIMITATIONS, NUMBER ONE BEING
RETROSPECTIVE, NUMBER TWO, THIS
WAS A TWO-CENTER STUDY AND WITH
VARYING POPULATIONS.
WE KNOW THE NIH POPULATION TENDS
TO BE OLDER, MORE SEVERE
DISEASE, SO HOW THAT TRANSLATES
TO THE REST OF THE SICKLE CELL
POPULATION IS UNKNOWN.
WE ALSO KNOW LOOKING AT PAIN IS
VERY COMPLEX, AND THAT ACUTE
PAIN IS A LOT MORE COMPLEX THAN
JUST VASOOCCLUSION SO THIS STUDY
LIKELY OVERESTIMATES THE PAIN
EXPERIENCE BOTH PRE AND POST
TRANSPLANT.
DESPITE ELIMINATION OF THE
SICKLE-RELATED VASOOCCLUSION
EVENTS, WE KNOW THAT PAIN AND
THE COMPLEXITY OF WHAT'S
REPORTED BY PATIENTS IS GOING TO
BE HARD TO UNTANGLE FROM A
LIFETIME OF THEIR SICKLE CELL
PAIN, WHETHER THAT'S THEIR PAIN
HISTORY, THEIR PAIN MEMORY,
PSYCHOLOGICAL STRESSORS OF BEING
RE-ADMITTED TO THE HOSPITAL
BECAUSE WE KNOW THAT HAPPENS
POST ALLOGENEIC TRANSPLANT, KNOW
THAT PATIENTS HAVE CHRONIC PAIN
DISORDERS, OPIATE HYPER AL JEEZ
ALGESIA --
>>IF YOU CAN WRAP UP, PLEASE.
>>YEP.
WE PREVIOUSLY REPORTED THAT 40%
OF OUR ADULTS HAD PERSISTENT
PAIN AT 12 MONTHS, AND THIS
STUDY SHOWS THAT THE MAJORITY OF
THOSE PATIENTS WERE ABLE TO COME
OFF NARCOTICS BY 24 MONTHS.
AND THE MECHANISM FOR THOSE THAT
REJECTED IS NOT FULLY
UNDERSTOOD.
SO IN SUMMARY, WE KNOW THAT
VASO-OCCLUSIVE EVENTS ARE
REDUCED AFTER ALLOTRANSPLANT
SIGNIFICANTLY IN THAT 12 TO 24
MONTH PERIOD, AND IT OCCURS IN
EVEN THOSE WHO REJECT THEIR
GRAFT AND THIS SHOULD BE ABLE TO
INFLUENCE RESULTS OF YOU AUTOLOS
GENE STUDY THERAPIES.
QUICKLY JUST WANT TO THANK MY
CO-AUTHORS, CERTAINLY
DR. TISDALE FOR SPEARHEADING
THIS AND DR. ABRAHAM FOR BRI
BRINGING STUDIES TO THE
PEDIATRIC POPULATION AT
CHILDREN'S NATIONAL.
THANK YOU.
>>THANK YOU, DR. LEONARD.
I'LL INTRODUCE OUR NEXT SPEAKER
TO THE PODIUM TO PRESENT IN
PERSON.
THIS IS DR. HANNAH KINOSHITA,
SHE'LL BE PRESENTING ON OUTCOMES
FOLLOWING POST TRANSPLANT VIRUS
SPECIFIC T-CELL THERAPY IN
PATIENTS WITH SICKLE CELL
DISEASE.
>>THANK YOU SO MUCH FOR HAVING ME
AS EVERYONE HERE KNOWS INFECTION
IS A MAJOR CAUSE OF MORBIDITY
AND MORTALITY IN PATIENTS
FOLLOWING STEM CELL TRANSPLANT.
WITH CERTAIN VIRAL INFECTIONS
BEING IMPLICATED IN INDUCING
GRAFT FAILURE.
VIRAL INFECTIONS POST TRANSPLANT
IS OF PARTICULAR CONCERN IN
PATIENTS RECEIVING ALTERNATIVE
DONOR TRANSPLANTS AS IN THE CASE
OF SICKLE CELL DISEASE.
DR. PATEL AND COLLEAGUES LOOKED
AT POST HAPLOID IDENTICAL --
SICKLE CELL DISEASE WHO RECEIVED
POST TRANSPLANT CYCLOPHOSPHAMIDE
AND SHOWED THERE WAS DELAYED
IMMUNOCONSTITUTION AND THAT
VIRAL INFECTIONS OCCURRED IN
ALMOST 70% OF THOSE PATIENTS
WITH CMV BEING THE MOST COMMON.
TREATMENT OF THESE VIRAL
INFECTIONS CAN BE CHALLENGING
PARTICULARLY IN PATIENTS WHO
HAVE RENAL OR HEPATIC
DYSFUNCTION AS THESE STANDARD
ANTIVIRAL MEDICATIONS CAN CAUSE
RENAL AND HEPATIC TOXICITY AS
WELL AS MYELOSUPPRESSION.
SO VIRUS SPECIFIC T-CELLS HAVE
BEEN SHOWN TO BE SAFE AND
EFFECTIVE POST TRANSPLANT IN THE
SETTING OF MANY DIFFERENT
UNDERLYING DISEASES.
FROM VARIOUS DONOR SOURCES
INCLUDING MATCHED,
HAPLOIDENTICAL AND UMBILICAL
CORD SOURCES AS WELL AS DONOR
DERIVED FROM THE STEM CELL
TRANSPLANT DONOR THEMSELVES AS
WELL AS THIRD PARTY DONORS.
SO THIS IS A SCHEMATIC JUST
BRIEFLY SHOWING THE RAPID
GENERATION PROTOCOL OF
VIRUS-SPECIFIC T-CELLS FOR
VARIOUS VIRUS TARGETS.
SO WE WANTED TO LOOK
SPECIFICALLY AT THE SICKLE CELL
POPULATION KNOWING THAT THEY ARE
DIFFERENT THAN OTHER PATIENTS
WHO ARE TRANSPLANTED FOR OTHER
DISEASES SUCH AS PRIMARY
IMMUNODEFICIENCIES OR
MALIGNANCIES.
AND SO THIS IS A SINGLE CENTER
RETROSPECTIVE REVIEW OF
PEDIATRIC PATIENTS WHO RECEIV
RECEIVED -- DO YOU WANT ME TO
STOP?
>>JUST TWO SECONDS.
>>SURE.
OKAY.
SO THIS IS A SINGLE CENTER
RETROSPECTIVE REVIEW OF
PEDIATRIC PATIENTS WHO RECEIVED
VIRUS SPECIFIC T-CELLS FOLLOWING
STEM CELL TRANSPLANT AT OUR
CENTER.
WE IDENTIFIED 13 PATIENTS ON SIX
CLINICAL TRIALS.
15VST PRODUCTS WERE INFUSED AND
THE DIFFERENCE IN THAT NUMBER IS
BECAUSE PATIENTS WERE ALLOWED TO
RECEIVE MULTIPLE PRO KU PRODUCTM
DIFFERENT CLINICAL TRIALS AS
LONG AS THEY WERE ELIGIBLE.
TWO OF THE TRIALS WERE VSTs
GENERATED FROM THE DONOR OF THE
TRANSPLANT THEMSELVES, TWO OF
THE TRIALS WERE FROM CORD BLOOD
DONORS AND TWO OF THE TRIALS
WERE FROM THIRD PARTY DONORS.
SO WHEN WE LOOK AT THE
SPECIFICITY OF THE PRODUCTS
AGAINST THE VIRAL TARGET
ANTIGENS, THERE'S QUITE A BIT OF
VARIABILITY AS YOU CAN SEE.
SO BETWEEN DIFFERENT VIRUSES
THAT WE TARGETED FROM CMV, EBV,
BKV VIRUS AS WELL AS WITHIN EACH
VIRUS FROM DONOR TO DONOR.
THIS IS LIKELY AT LEAST
PARTIALLY DUE TO THE DONOR'S OWN
EXPOSURE TO THESE DIFFERENT
VIRUSES.
WHEN WE LOOK AT THE CLINICAL
OUTCOMES OF VSTs IN THIS
COHORT, SO WE IDENTIFIED 13
PATIENTS, SIX OF WHOM RECEIVED
VSTs FOR TREATMENT.
FIVE OF THOSE PATIENTS ARE
ACTIVE VIREMIA AT THE TIME OF
FIRST VST INFUSION, OR IF THOSE
PATIENTS WERE IN REMISSION FOR
AT LEAST ONE OF THE TARGET
VIRUSES AFTER THAT FIRST
INFUSION WITH ONE PATIENT HAVING
PARTIAL REMISSION AFTER THE
FIRST VST INFUSION ULTIMATELY
GOING INTO SUSTAINED REMISSION
AFTER A SECOND INFUSION.
ONE PATIENT HAD ORGAN-SPECIFIC
VIRAL DISEASE, WHO UNFORTUNATELY
DID HAVE PROGRESSIVE DISEASE
AFTER THE FIRST VST INFUSION,
BUT ULTIMATELY WENT INTO
SUSTAINED REMISSION AFTER THE
SECOND VST INFUSION.
IT IS IMPORTANT TO NOTE ALL OF
THESE CLINICAL TRIALS WERE PHASE
1, PHASE 2 SO PATIENTS IN THE
TREATMENT GROUP WERE ALLOWED TO
BE RECEIVING CONCOMITANT
STANDARD ANTIVIRAL THERAPY.
IN THE -- WHEN WE WENT BACK AND
LOOKED AT THE VST PRODUCT FOR
THAT PATIENT, IT WAS IDENTIFIED
THAT IT LACKED SPECIFICITY FOR
THAT PARTICULAR VIRUS.
JUST IN TERMS OF SAFETY, NO
PATIENTS DIED FOLLOWING VST
INFUSION AND ALL REMAINED FREE
OF SICKLE CELL DISEASE.
TWO PATIENTS DID DEVELOP
GRAFT-VERSUS-HOST DISEASE GRADE
III OR HIGHER BUT -- WHEN WE
LOOKED AT THE T-CELL ANTIGEN
RESPONSE TO THE TARGET VIRUSES
IN THE PATIENTS, WE CAN SEE THAT
IN THOSE PATIENTS WHO RECEIVED
VSTs FOR TREATMENT, THE TIME
TO T-CELL ANTIGEN RESPONSE IN
VIVO, SO IN THE PATIENT'S
PERIPHERAL BLOOD POST-INFUSION,
IT WAS SHORTER THAN THOSE
PATIENTS WHO RECEIVED VSTs FOR
PROPHYLAXIS FOR CMV AND EBV.
AND SO THIS INDICATES TO US THAT
THERE'S LIKELY A ROLE FOR --
ANTIGEN PRESENTATION IN THE POST
VST INFUSION THAT ENHANCES
T-CELL EXPANSION AND PERSIST
PERSISTENCE.
THIS IS FURTHER SHOWN IN THESE
PATIENTS WHO ONLY RECEIVED
HHV6 AND HUMAN PARAINFLUENZA
VIRUS, THREE SPECIFIC T-CELLS
FOR PROPHYLAXIS, SO NONE OF
THESE PATIENTS HAD ACTIVE
DISEASE.
YOU CAN SEE THE TIME TO T-CELL
ANTIGEN RESPONSE IS QUITE LATE,
AROUND 180 DAYS POST VST
INFUSION.
SO THIS REVIEW OUTLINED
LIMITATIONS AND FUTURE
DIRECTIONS WHERE WE CAN FURTHER
THE FIELD IN THIS AREA.
PARTICULARLY WITH RESPECT TO
ANTIGEN SPECIFICITY AND THE
VARIABILITY BETWEEN DR. VST SO
CAN IMPROVE THE SPECIFICITY.
OF
THOSE PRODUCTS AND CAUSE
INCREASE IN RESPONSE, CLINICAL
RESPONSE.
BUT ALSO TO LOOK AT THE THIRD
PARTY DONOR POPULATION IN TERMS
OF EXPANDING THAT BANK OF
PATIENTS WHO WE KNOW HAVE A GOOD
RESPONSE TO THE TARGET VIRUS
ANTIGENS.
THE CHALLENGE WITH OR SICKLE
CELL POPULATION OF COURSE IS YOU
STILL ARE GOING TO HAVE A
REASONABLE HLA-MATCHED DONOR
WITHIN THAT THIRD PARTY BANK.
AND THEN FURTHER TO LOOK AT THE
OPTIMAL TIMING OF VST INFUSION
FOR PROPHYLAXIS POST TRANSPLANT,
IT HAS YET TO BE ILL LEWIS DATED
ELUCIDATED BUTLIKELY CLOSER TO F
TRANSPLANT GIVEN -- THE
PROLONGED PERIOD OF TIME BEFORE
WE SEE A T-CELL IMMUNE RESPONSE
FOLLOWING VST INFUSION.
HOWEVER, ALL OF THIS DATA DOES
ADD TO THE BODY OF EVIDENCE
FURTHER SUPPORTING THE SAFETY OF
OUR SPECIFIC T-CELL INFUSION BUT
MORE SPECIFICALLY NOW WITHIN THE
SICKLE CELL DISEASE POPULATION.
AND SHOWS THAT THESE VSTs MAY
BE EFFECTIVE IN TREATMENT AND
PROPHYLAXIS IN OUR PATIENTS.
SO I'D LIKE TO THANK ALL OF OUR
COLLABORATORS AS WELL AS
EVERYONE IN THE STUDY LAB AT
CHILDREN'S NATIONAL HOSPITAL,
PARTICULARLY DR. ALLISTAIR
ABRAHAM WHO REALLY CHAMPIONED
THIS WORK.
>>THANK YOU.
I'M REALLY AMAZED AT HOW MUCH
WORK IS GOING ON IN THIS FIELD
COVERING SO MANY DIFFERENT
THEMES.
TO ADDRESS YET ANOTHER IMPORTANT
THEME, I'D LIKE TO INVITE
DR. ELIZABETH STENGER FROM EMORY
UNIVERSITY TO SPEAK ON LONG TERM
ORGAN FUNCTION AFTER TRANSPLANT
FOR SICKLE CELL DISEASE, A
REPORT FROM THE SICKLE CELL
TRANSPLANT ADVOCACY AND RESEARCH
ALLIANCE, STAR.
BETH?
>>THANK YOU, KRISH.
THIS IS A DISCLOSURE ABOUT STAR
BUT IS NOT RELEVANT TO THE DATA
I'M PRESENTING TODAY.
SO AS BACKGROUND, WE KNOW THAT
PERSONS WITH SICKLE CELL DISEASE
HAVE SIGNIFICANT MORBIDITY AS
WELL AS EARLY MORTALITY DESPITE
MODERN MEDICAL CARE, AND THAT
HCT IS THE ONLY CURATIVE
TREATMENT SUPPORTED BY LONG-TERM
DATA AT THIS POINT.
AND JUST BY INCREASING USE OF
TRANSPLANT PARTICULARLY IN THE
MOST RECENT DECADE, THERE'S
LIMITED SPECIFIC SICKLE CELL
SPECIFIC DATA ON LONG TERM ORGAN
FUNCTION AFTER TRANSPLANT, SO WE
SOUGHT TO ASSESS THE PREVALENCE
OF RISK IN THIS POPULATION
FOLLOWING TRANSPLANT.
WE HYPOTHESIZED THAT MOST
PATIENTS WILL HAVE STABLE TO
IMPROVED ORGAN FUNCTION
FOLLOWING TRANSPLANT AND SOME OF
THE PREDICTORS FOR ORGAN
DYSFUNCTION WOULD BE THOSE
LISTED.
FOR OUR METHODS, WE USED THE
STAR ALLIANCE RETROSPECTIVE
REGISTRY, WHICH INCLUDED 300
PATIENTS WHO HAD UNDERGONE
TRANSPLANT FOR SICKLE CELL
DISEASE.
PER THIS ANALYSIS, WE EXCLUDED
PATIENTS WHO HAD DIED OR WERE
LOST TO FOLLOW-UP PRIOR TO ONE
YEAR, SO THAT REMOVED 24
PATIENTS FROM THE ANALYSIS, AND
WE REMOVED PATIENTS WHO HAD
GRAFT FAILURE SECOND TRANSPLANT,
WHICH INCLUDED 29 PATIENTS.
WHICH LEFT US WITH 247 PATIENTS
FROM 13 STAR CENTERS IN THE U.S.
AND CANADA.
IN THIS ANALYSIS.
AND WITHIN THIS COHORT, WE
EVALUATED -- FOR THE PURPOSES OF
THIS PRESENTATION, I LIMIT TO
CARDIAC, PULMONARY AND
NEUROLOGIC DYSFUNCTION.
BUT THE PAPER DOES INCLUDE OTHER
ORGANS AS WELL.
AND FOR OUR MULTIVARIABLE COX
REGRESSION ANALYSIS, WE LIMITED
TO THESE THREE ORGANS.
THESE ARE OUR DEFINITIONS FOR
CARDIAC DYSFUNCTION.
LOWY JEX OR SHORTENING FRACTION,
PULMONARY DYSFUNCTION
RESTRICTIVE LUNG DISEASE OR ON
STRUCK TOUGH LUNG DISEASE.
NEUROLOGIC DYSFUNCTION, EVENTS
WERE INCLUDED AS NEW OR
PROGRESSIVE VASCULOPATHY OR
INFARCTS FOLLOWING TRANSPLANT.
THESE ARE OUR BASELINE SICKLE
CELL PATIENT CHARACTERISTICS FOR
THIS COHORT.
MEDIAN AGE IS 9.4 YEARS, PRETTY
EVENLY SPLIT MALE VERSUS THEE
MAIL, TWO THIRDS HAD SEVERE
CLINICAL DISEASE SEVERITY COMING
INTO TRANSPLANT WITH INDICATIONS
AS LISTED.
ABOUT A THIRD HAD RECEIVED
HYDROXYUREA TREATMENT COMING
INTO TRANSPLANT AND ABOUT HALF
HAD A HISTORY OF CHRONIC RED
BLOOD CELL TRANSFUSIONS SO OVER
A LIFETIME TRANSPLANTS RECEIVED
WERE HIGH AND IN THE 52 PATIENTS
WE HAD DATA WAS A MEDIAN OF 6.
OUR TRANSPLANT CHARACTERISTICS
MEDIAN YEAR OF TRANSPLANT WAS
2012.
ABOUT THREE QUARTERS OF THE
PATIENTS HAD A MATCH-RELATED
DONOR, WITH MOST OTHER PATIENT
HAVING A MATCHED OR MISMATCHED
UNRELATED DONOR.
MOST PATIENTS RECEIVED BONE
MARROW AS THEIR STEM CELL
SOURCE.
SLIGHTLY MORE THAN HALF RECEIVED
MYELOABLATIVE CONDITIONING SO WE
HAD A PRETTY DECENT PROPORTION
WHO RECEIVED REDUCED INTENSITY
CONDITIONING.
NEARLY ALL RECEIVED T-CELL
DEPLETION, WHICH IS STANDARD IN
THIS POPULATION, AND MOST
RECEIVED INHIBITOR FOR
PROPHYLAXIS.
AT A HIGH LEVEL OF TRANSPLANT
OUTCOME, AT TIME OF LAST
FOLLOW-UP WHICH IS MEDIAN OF
THREE YEARS, DONOR CHIMERISM RAS
99 TO 100%.
ABOUT A QUARTER OF PATIENTS
OVERALL HAD ACUTE OR CHRONIC
GVHD WITH THE SE VAIRTS LISTED
THERE.
AT THE TIME OF LAST FOLLOW-UP,
14 PATIENTS OR ABOUT 6% REQUIRED
CONTINUED IMMUNE SUPPRESSION,
WITH THE PRIMARY INDICATION
BEING GVHD, AND 13 PATIENTS DIED
IN THIS COHORT, MEANING THEY
DIED BEYOND ONE YEAR POST
TRANSPLANT.
MAJORITY FROM GVHD OR FROM
INFECTIONS WITHOUT GVHD.
SO MOVING TO OUR ORGAN
DYSFUNCTION, FIRST CARDIAC.
MOST RECENT ECHO PERFORMED AND A
MEDIAN OF 2.3 YEARS POST
TRANSPLANT.
EF DECREASED SIGNIFICANTLY FROM
THE PRETO THE POST ECHO.
ONLY A SUBSET OF 31 PATIENTS --
AND THIS DID DECREASE SLIGHT
SLIETLY BUT NOT SIGNIFICANTLY.
THIS DATA IS ALSO SHOWN BY
CATEGORIZING AS LOW EF IN BLUE
OR LOW SF IN PINK PRE VERSUS
POST TRANSPLANT AND THERE WAS AN
INCREASED PROPORTION POST
TRANSPLANT OF THOSE WHO HAD LOW
EF ON THE LEFT AND LOW FF SF OE
RIGHT WHICH WAS SIGNIFICANTLY
SIGNIFICANT.
MOST RECENT PFTs PERFORMED AT
A MEDIAN OF 2.4 YEARS.
NO SIGNIFICANT CHANGE SEEN IN
FEV1, FVC OR DLCO.
WHEN WE CATEGORIZED PATIENT WE
DID NOT SEE A DIFFERENCE
PREVERSUS POST TRANSPLANT,
ALTHOUGH WE DID HAVE A SIZABLE
PROPORTION WITH RESTRICTIVE LUNG
DISEASE AT BOTH TIME POINTS.
IN TERMINGS OF NEUROLOGIC
OUTCOMES, THERE WERE NINE
STROKES THAT OCCURRED IN EIGHT
PATIENTS.
ONE HAD A HEMORRHAGIC AND AN
ISCHEMIC STROKE AND THESE
OCCURRED AT A MEDIAN OF 47 DAYS
RANGING FROM ZERO TRANSPLANT DAY
TO 243 DAYS POST.
WE HAD 159 PATIENTS THAT HAD
PREA AND POST TRANSPLANT BRAIN
MRI DATA REPORTED WITH THE POST
TRANSPLANT MRI PERFORMED AT A
MEDIAN OF 2.1 YEARS.
MAJORITY OF PATIENTS HAD NORMAL
OR STABLE FINDINGS MEANING
FINDINGS THEY HAD PRETRANSPLANT
WERE STABLE ON LAS FOLLOW-UP
MRI.
SEVEN PATIENTS HAD A NEW INFARCT
AND SIX PATIENTS EACH HAD A
PROGRESSIVE INFARCT, NEW
VASCULOPATHY OR PROGRESSIVE
VASCULOPATHY.
THESE ARE WHAT WERE COUNTED AS
EVENTS IN OUR MODELS.
SO NEXT MOVING TO OUR MODELS, I
DO NOT SHOW A FIGURE FOR
PULMONARY DYSFUNCTION BECAUSE
POST TRANSPLANT EENT WERE RARE,
SO WE DID NOT SEE ANY RISK
FACTORS THAT PREDICTED FOR
PULMONARY DYSFUNCTION POST
TRANSPLANT.
ON THE LEFT IS OUR CARDIAC
DYSFUNCTION MODEL.
THOSE WHO DEVELOPED SEVERE GRADE
3 TO 4 OR RECEIVED MYELOABLATIVE
CONDITIONING HAD A SIGNIFICANTLY
HIGHER RISK FOR DEVELOPMENT OF
CARDIAC DYSFUNCTION POST
TRANSPLANT.
ON THE RIGHT IS OUR MODEL FOR
NEW OR PROGRESSIVE CNS DISEASE
AND IN THIS MODEL WE ADJUSTED
FOR ACUTE GVHD, YEAR OF
TRANSPLANT AND CLINICAL
PHENOTYPE OR CLINICAL SEVERITY
COMING INTO TRANSPLANT, AND
THOSE WHO HAD A CNS INDICATION
FOR TRANSPLANT HAD SIGNIFICANTLY
HIGHER RISK TO DEVELOPING NEW OR
SIGNIFICANT -- POST TRANSPLANT.
WE ALSO LOOKED AT COMPOSITE
ORGAN DYSFUNCTION.
THIS SHOWS A SCORING MODEL WE
USED TO SCORE EACH SEPARATELY
FROM ZERO TO 2 SO TOTAL SCORE
RANGED FROM ZERO TO A MAXIMUM OF
6.
THAT MODEL IS SHOWN ON THE LEFT
WHERE AFTER WE ADJUSTED FOR CNS
INDICATION YEAR OF TRANSPLANT
AND ACCUSE GVHD THOSE WHO HAD A
SEVERE -- HAD SIGNIFICANTLY
HIGHER RISK FOR HAVING A HIGHER
COMPOSITE ORGAN DYSFUNCTION
SCORE.
ON THE RIGHT WE LOOKED AT AN END
POINT OF ONE OR MORE ORGAN
DYSFUNCTION AND AFTER ADJUSTING
FOR CNS INDICATION THOSE WHO
UNDERWENT TRANSPLANT AT GREATER
OR EQUAL TO 16 YEARS OF AGE HAD
A HIGHER RISK FOR HAVING ONE OR
MORE ORGAN WITH DYSFUNCTION POST
TRANSPLANT.
SO IN CONCLUSION, USING THIS
PEDIATRIC RETROSPECTIVE DATASET,
WE FOUND THE PREVALENCE OF ORGAN
DYSFUNCTION OVERALL TO BE LOW
FOLLOWING TRANSPLANT FOR SICKLE
CELL DISEASE, JUST NOTING A
SLIGHT INCREASE IN CARDIAC
DYSFUNCTION USING THE
DEFINITIONS WE USE IN STABLE
PROPORTION WITH RESTRICTIVE LUNG
DISEASE.
I'VE LISTED SOME OF THE RISK
FACTORS WE FOUND IN OUR MODELS
FOR ORGAN DYSFUNCTION AND
OVERALL, WE FELT THAT THESE
RESULTS SUPPORT CONSIDERATION OF
TRANSPLANT AT A YOUNGER AGE AND
USE OF LESS INTENSE REGIMENS TO
MINIMIZE TOXICITY.
OBVIOUSLY BALANCING RISK FOR
INCREASED RATES OF REJECTION
WITH LESS INTENSE CONDITIONING.
FOR FUTURE DIRECTIONS WE'RE
CONTINUING WORK THROUGH THIS
RETROSPECTIVE REGISTRY
HIGHLIGHTING OTHER PROSPECTIVE
REGISTRY BY OUR REJ
BIOREPOSITORY AND MRI BANK
PROJECT SICKLE CURE LED BY
DR. GREG GUILCHER.
OTHER ONGOING IMPORTANT LATE
EFFECTS STELLAR AND COALESCE.
I'D LIKE TO ACKNOWLEDGE THE
STUDY TEAM, PARTICULARLY MY
CO-PI, DR. ALISTAIR ABRAHAM,
CO-AUTHORS AND OUR FUNDING
SOURCES.
THANK YOU.
>>WE'LL INTRODUCE OUR
NEXT SPEAKER.
SO DR. LAWAL IS PRESENTING NEXT,
INCREASED INCIDENCE OF
HEMATOLOGIC MALIGNANCIES IN
SICKLE CELL DISEASE AFTER
TRANSPLANT IN ADULTS WITH GRAFT
FAILURE AND MIXED CHIMERISM.
>>GOOD MORNING, EVERYONE.
THANK YOU FOR THIS OPPORTUNITY.
IN SICKLE CELL DISEASE, WE KNOW
THAT RBCs HAVE SHORTENED LIFE
SURVIVAL, AND THIS -- INCREASED
INFLAMMATORY MEDIATORS AND
ULTIMATELY DAMAGE TO THE BONE
MARROW MICROENVIRONMENT.
FORTUNATELY WE DO HAVE
THERAPEUTIC OPTIONS.
AT THE NIH, WE HAVE PATIENTS
COME FOR HLA-MATCHED SIBLING
TRANSPLANTATION USING THIS
CONDITION REGIMEN SHOWN HERE
WHICH UTILIZED AL TEUZ MAN,
USING 300 CENTIGRADE, ALONG WI
WITH -- WE'VE SEEN GRAFT FAILURE
AT 13% IN A STUDY PUBLISHED IN
2021, WITH COLLABORATORS AT
CHICAGO, AND AT THE NIH.
WE ALSO UTILIZED HAPLOIDENTICAL
TRANSPLANTATION.
AGAIN USING AL EM -- WHICH YOU E
AND SIROLIMUS.
USING THIS CONDITION AND
REGIMEN, WE SEE GRAFT FAILURE AT
50% IN A STUDY PUBLISHED BY
DR. FITZHUGH IN 2017.
NOW WE HAVE NEWER STUDIES AND
NEWER CONDITIONS AND REGIMENS
WHICH UTILIZE INTRAVENOUS
PENTOSTATIN AND DAILY ORAL
CYCLOPHOSPHAMIDE FOR 14 DAYS.
TO DATE THE INCIDENT OF GRAFT
FAILURE IS MUCH LOWER.
AT THE NIH PATIENTS ALSO UNDERGO
GENE THERAPY WHERE THEY UNDERGO
MYELOABLATIVE CONDITIONING.
I'LL CALL ATTENTION TO GROUP A
WHERE PATIENTS RECEIVED LOWER
CELL DOSES AND THUS HAD
INADEQUATE THERAPEUTIC RESPONSE
AND HAD ONGOING ANEMIA.
IN OUR PAPER PUBLISHED IN 2022,
WE REVIEWED OUR PATIENTS THAT
HAD GRAFT FAILURE WITH SICKLE
CELL DISEASE AFTER TRANSPLANT
AND THEY ULTIMATELY DEVELOPED
MDS OR AML.
HERE I'M SHOWING YOU FIVE
PATIENTS.
THEY ALL HAD A PHENOTYPE OF
HEMOGLOBIN SS.
WE CAN SEE THAT THEIR AGES RANGE
FROM 20 TO 44.
WE HAVE THREE MALES, TWO
FEMALES, TWO MATCHED SIBLING
DONOR AND THREE HAPLOs.
THE DAY OF GRAFT FAILURE RANGED
ANYWHERE FROM 73 DAYS TO SEVEN
MONTHS.
AS YOU CAN SEE HERE, ALL THE
PATIENTS HAD AML EXCEPT FOR ONE
THAT HAD MDS.
WHEN WE LOOK AT THE TIME OF
MALIGNANCY POST TRANSPLANT, WE
SEE THAT IT RANGES FROM 0.33 TO
5.5 YEARS, AND ALL OF THESE
PATIENTS ARE CURRENTLY DECEASED.
NEXT WE'RE LOOKING AT MIXED
CHIMERISM IN OUR PATIENT
POPULATION, AND THESE PATIENTS
DEVELOPED OTHER HEMATOLOGIC
MALIGNANCIES AFTER TRANSPLANT,
WHICH WE'LL REVIEW.
WE HAVE THREE PATIENTS, ONE THAT
HAD HEMOGLOBIN S BETA --, THE
AGES RANGE FROM 19 TO 503.
WE HAVE TWO MALES AND ONE FEMALE
AND THEY WERE ALL PART OF THE
MATCHED SIBLING DONOR
TRANSPLANTATION.
AS YOU CAN SEE, THESE PATIENTS
DID NOT HAVE GRAFT FAILURE, AS
DEMONSTRATED BY THEIR CONTINUED
DONOR MYELOID AND -- CHIMERISM,
AND FOR THE FIRST PATIENT, THEY
HAD CML, THE SECOND -- AND THE
LAST, T-CELL ALL.
THE TIME OF MALIGNANCY POST
TRANSPLANT RANGED FROM THREE
YEARS TO NINE YEARS, AND ALL
THESE PATIENTS ARE CURRENTLY
ALIVE.
NOW WE'LL REVIEW THE INCIDENCE
OF MDS AND AML AT THE NIH AS
COMPARED TO OTHER INSTITUTIONS.
FIRST WE'RE LOOKING AT THE
MATCHED SIBLING CONDITION AND
REGIMEN THAT I REVIEWED FOR YOU.
YOU CAN SEE HERE IN THIS FIRST
ROW THIS, IS OUR ORIGINAL
CONDITION REGIMEN THAT I SHOWED
YOU.
IT'S ALSO USED BY COLLABORATORS
AT CHICAGO AND RIYADH AND IN
BETWEEN HERE IS THE NEW REGIMEN
I DEMONSTRATED EARLIER.
YOU CAN SEE THAT THE INCIDENCE
OF MDS TO AML RANGES FROM 1.6 TO
3.8 WITH A MEDIAN FOLLOW-UP FROM
4 TO 9.1 YEARS.
NEXT WE LOOK AT OUR
HAPLOIDENTICAL TRANSPLANT.
AGAIN STARTING WITH THE ORIGINAL
CONDITION AND REGIMEN AND THE
NEWER ONE.
WE SEE THAT WITH THE ORIGINAL
CONDITION AND REGIMEN, THE
INCIDENCE IS 14.3%, AND WITH THE
NEWER CONDITION AND REGIMEN,
THERE HAVE BEEN NO REPORTS OF
MDS OR AML TO DATE, AND THE
MEDIAN FOLLOW-UP RANGES FROM 8..
OUR GROUP A IN OUR GROUP OF
PATIENTS THAT HAD GENE THERAPY
WITH THE INADEQUATE THERAPEUTIC
RESPONSE, ALSO WENT ON TO HAVE F
4.3%.
NOW WE'LL LOOK AT FRENCH GROUP
AND CIBMTR.
FOR THE FRENCH GROUP, NO REPORT
OUT OF 234 PATIENTS, AND I
SHOULD MENTION THAT FOR BOTH
THESE GROUPS, THEY HAD A LARGER
PROPORTION OF YOUNGER PATIENTS
THAN WE'VE SEEN AT THE NIH.
THE MEDIAN FOLLOW-UP FOR THE
FRENCH WAS 7.8 AND FOR THE
CIBMTR, YOU SEE THE INCIDENCE OF
0.22% WITH THE MEDIAN FOLLOW-UP
OF 2.1 TO 3.9.
AT THE NIH, OUR THERAPEUTIC GOAL
FOR THE NIH MIXED CHIMERISM.
WHEN WE LOOK AT BASELINE, AT THE
RISK OF LEUKEMIA IN PATIENTS
WITH SICKLE CELL DISEASE, WE
REVIEW HERE THIS PAPER BY BRUN
SON ET AL. WHERE THEY LOOKED AT
ABOUT 6,400 SICKLE CELL DISEASE
PATIENTS OBSERVED OVER 140,000
PERSON YEARS, AND THEY COMPARED
THEM WITH THE GENERAL CALIFORNIA
POPULATION.
WHAT THEY FOUND WAS AN INCREASED
RISK OF HEMATOLOGIC TUMORS.
WHEN WE LOOK SPECIFICALLY AT
LEUKEMIA, WE SEE THAT THIS RISK
IS ABOUT 2.3 AND IT'S
SIGNIFICANT.
THEY ALSO FOUND THE SIGNIFICANCE
WITH AML WITH AN INCREASED RISK
OF ABOUT 4.
SO WHEN WE LOOK AT OUR PATIENTS
WITH SICKLE CELL DISEASE THAT
DEVELOPED HEMATOLOGIC
MALIGNANCIES OVER 140,000
ROUNDED OFF PERSON YEARS, WE SEE
IT'S 0.021 PER 100 PERSON YEARS.
18 INDIVIDUALS WITHOUT SICKLE
CELL DISEASE WERE EXPECTED TO
DEVELOP HEMATOLOGIC PLG MAN SEES
WHEN CONTROLLED FOR AGE, SEX,
RACE AND ETHNICITY, YOU SEE IT'S
0.013 PER 100 PERSON YEARS.
THERE WAS THE RELATIVE RISK OF
HEMATOLOGIC MALIGNANCIES IS
HIGHER IN SICKLE CELL DISEASE
BUT THE ABSOLUTE RISK IS LOW.
THIS CORRELATES WITH THE RATE OF
HEMATOLOGIC MALIGNANCIES AFTER
MIXED CHIMERISM AND GRAFT
FAILURE WE SAW FOR SICKLE CELL
DISEASE.
8 OF OUR PATIENTS DEVELOPED
HEMATOLOGIC MALIGNANCIES OVER
844 PERSON YEARS, WHICH EQUATES
TO 0.94 PER 100 PERSON YEARS.
SO WHAT IS IT ABOUT OUR PATIENT
POPULATION?
WE HAVE ONGOING WORK TO TAKE A
CLOSER LOOK HE IT AGE, THE
SOURCE OF CELLS, OUR CONDITION
AND REGIMEN, OUR THERAPEUTIC
GOAL, THE USE OF PROLONGED
IMMUNOSUPPRESSION, AND OF COURSE
LOOKING AT REGENERATIVE
HEMATOPOIETIC STRESS,
SPECIFICALLY IN THE SETTING OF
GRAFT FAILURE AND INADEQUATE
THERAPEUTIC RESPONSE.
SO WE CONCLUDE THAT HEMATOLOGIC
MALIGNANCY IS A POTENTIAL
COMPLICATION OF SICKLE CELL
DISEASE CURATIVE THERAPY, AND
ALTHOUGH THE RELATIVE RISK OF
HEMATOLOGIC MALIGNANCY IS HIGH
IN PATIENTS WITH SICKLE CELL
DISEASE, THE ABSOLUTE RISK IS
LOW.
INCREASED MALIGNANCY AFTER GRAFT
REJECTION AND LOW CELL DOSE IS
SEEN.
AND THIS HIGHER INCIDENCE OF
MDS/AML POST TRANSPLANT IS
COMPARABLE TO THE RATE AFTER
GENE THERAPY WITH MYELOABLATIVE
BUSULFAN FOR THAT PARTICULAR
GROUP I SHOWED YOU.
THUS THE INCIDENCE OF
HEMATOLOGIC MALIGNANCY WAS MUCH
LOWER WITH CONDITIONING REGIMENS
WHERE THE THERAPEUTIC GOAL WAS
FULL DONOR CHIMERISM.
AND FOR THAT REASON, THE GOAL OF
THE NIH PROTOCOLS MOVING FORWARD
FOR SICKLE CELL DISEASE HAS
CHANGED TO FULL DONOR CHIMERISM.
AGAIN THANK YOU FOR THIS
OPPORTUNITY.
>>THANK YOU, DR. LAWAL.
TO CONTINUE THE THEME ON
SECONDARY NEOPLASMS AFTER
TRANSPLANT FOR SICKLE CELL
DISEASE, IT'S MY PLEASURE TO
INVITE DR. MARY EAPEN FROM THE
MEDICAL COLLEGE OF WISCONSIN TO
TALK ABOUT SECONDARY NEOPLASMS
AFTER HEMATOPOIETIC CELL
TRANSPLANT FOR SICKLE CELL
DISEASE.
DR. EAPEN.
>>GOOD MORNING, LADIES AND
GENTLEMEN.
I WILL TRY TO HURRY ALONG AND
STAY WITHIN MY 10 MINUTES.
SO THANK YOU FOR THE INVITATION.
I HAVE NOTHING TO DISCLOSE.
IT'S CLEAR TO THE AUDIENCE IN
THIS ROOM THAT TRANSPLANTATION
FOR SICKLE CELL DISEASE RESTORES
HEMATOPOIESIS.
SURVIVAL IS HIGHEST AFTER HLA
MATCHED SIBLING TRANSPLANT BUT
THERE'S ALL TERN TI DONOR
TRANSPLANT WHICH EXTENDS ACCESS
BUT THAT INCREASES RISK FOR
TRANSPLANT-RELATED COMPLICATION.
THE PREDOMINANT
CYTOREDUCTIONTIVE REGIMEN
INCLUDES FULL DOSES OF BUSULFAN
WITH CYCLOPHOSPHAMIDE OR
FLUDARABINE.
LESS INTENSIVE CYTOREDUCTIONTIVE
THERAPY IS USED FOR
TRANSPLANTATION WHICH IS
ASSOCIATED WITH FEWER EARLY
TOXICITY BUT LONGER FOLLOW-UP IS
REQUIRED TO ASCERTAIN LONG TERM
SEQUELAE.
GENERALLY SOLID NEOPLA NEOPLAS
HIGH.
SECONDARY SOLID NEOPLASMS DOUBLE
UP AT TWICE THE RATE EXPECTED ON
THE BASIS OF THE GENERAL
POPULATION.
THOSE STUDIES HAVE IDENTIFIED
THE USE OF RADIATION CONTAINING
REGIMENS AND CHRONIC
GRAFT-VERSUS-HOST DISEASE AS
RISK FACTORS.
SPECIFICALLY WHEN YOU LOOK AT
FULL DOSE BUSULFAN AND
CYCLOPHOSPHAMIDE, THE
PREDOMINANT REGIMEN THAT IS USED
FOR MATCHED SIBLING DONOR
TRANSPLANTATION IN SICKLE CELL
DISEASE, FOR THOSE WHO HAVE
RECEIVED THIS PARTICULAR REGIMEN
FOR HEMATOLOGIC MALIGNANCY
INCLUDING MYELOID LEUKEMIA AND
MYELODYSPLASTIC SYNDROME, THE
INCIDENCE RATE IS ON 1.4 TIMES
HIGHER THAN THE GENERAL
POPULATION.
THE RISK FACTORS IDENTIFIED
INCLUDE OLDER AGE, AGE GREATER
THAN 35 AT TRANSPLANTATION, AND
A HISTORY OF CHRONIC
GRAFT-VERSUS-HOST DISEASE.
IF YOU LOOK AT NON-MALIGNANT
DISEASE, LARGELY IN THE
PEDIATRIC POPULATION, WHICH
WOULD GIVE YOU A MEDIAN AGE OF K
COMPARED TO THE GENERAL
POPULATION, LARGELY DRIVEN BY
TRANSPLANTATION FOR FANCONI
ANEMIA, WHERE THE INCIDENT IS
ABOUT 6%.
HOWEVER, THE COMMON NEOPLASMS
ENCOUNTERED ARE LEUKEMIAS AND
CANCERS OF OROPHARYNGEAL AND
SKIN.
THE LEUKEMIAS TEND TO OCCUR
EARLY, TYPICALLY LESS THAN FIVE
YEARS, AND THE OROPHARYNGEAL AND
SKIN CANCERS AFTER A LONGER
PERIOD.
SO WHAT HAPPENS IN SICKLE CELL
DISEASE?
POPULATION BASED STUDY THE IN
UNITED KINGDOM AND THE UNITED
STATES REPORT INCREASED LIFETIME
RISK FOR MYELOID LEUKEMIA, AND
THERE ARE ALSO SEVERAL CASE
REPORTS OF MYELOID MALIGNANCY IN
SICKLE CELL DISEASE ASSOCIATED
WITH MIXED CHIMERISM OR GRAFT
FAILURE, AND THE SPEAKER JUST
PRIOR TO ME HAD PRESENTED THE
DATA FROM THE NIH CLINICAL
CENTER.
SO WITH INCREASING NUMBERS OF
TRANSPLANTS FOR SICKLE CELL
DISEASE, IT IS TIMELY TO STUDY
THE INCIDENCE AND RISK FACTORS
FOR SECONDARY NEOPLASM IN A
SUBSTANTIALLY LARGER POPULATION
THAN HAS BEEN REPORTED.
THE TRANSPLANT PERIOD CHOSEN WAS
1991 TO 2016.
THE DATASET DELIBERATELY ENDED
AT 2016, AND THAT WAS REALLY TO
LIMIT INCOMPLETE ASCERTAINMENT
OF CASES AND A POTENTIAL BIAS
FOR PREFERENTIAL FOLLOW-UP OF
PATIENTS CONSIDERED TO BE AT
HIGHER RISK FOR TRANSPLANTATION.
THE COHORT INCLUDED 1,096
ELIGIBLE PATIENTS.
THE PREDOMINANT CHARACTERISTICS
OF THE COHORT WAS THAT THE
MAJORITY WERE MATCHED SIBLING
RECIPIENTS.
THEY RECEIVED A MYELOABLATIVE
REGIMEN, A BONE MARROW GRAFT A
AND -- PROPHYLAXIS.
SO SHOWN HERE ARE THE
DIFFERENCES IN THE
CHARACTERISTICS BETWEEN CASES.
THERE WERE 22 CASES OF SECONDARY
NEOPLASM AND 174 CONTROLS.
THE CASES WERE OLDER.
THEY WERE MORE LIKELY TO RECEIVE
A LOW INTENSITY REGIMEN, WHICH
INCLUDED RADIATION.
AND PERIPHERAL BLOOD WAS THE
REDOMINANT GRAFT TYPE.
SO CONSIDERING THE 1,096
ELIGIBLE PATIENTS WITH 6,631
PERSON-YEARS, 22 SECONDARY
NEOPLASMS WERE IDENTIFIED.
THE 10-YEAR INCIDENCE OF ANY
SECONDARY NEOPLASM WAS 2.4%, FOR
AML OR MDS, 1.7%, AND FOR SOLID
NEOPLASMS, .7%.
THIS TABLE IS A DESCRIPTION OF
THE TYPE OF SECONDARY PLIG PLIG
NANCY AFTER THE LOW DOSE
RADIATION CONTAINING REGIMENS.
THE PREDOMINANT MALIGNANCY BEING
HERE A LEUKEMIA.
IN CONTRAST WITH THE USE OF
NON-RADIATION REGIMENS, IT WAS
EVENLY SPLIT BETWEEN LEUKEMIA
AND SOLID TUMOR.
OUT OF THE EIGHT PATIENTS, SIX
RECEIVED WHOLE DOSE BUSULFAN,
AND THERE WERE TWO THAT RECEIVED
A REDUCED INTENSITY CONDITIONING
WITH FLUDARABENE.
WE ALSO LOOKED AT SECONDARY
NEOPLASMS IN CHILDREN, SIMPLY TO
COMPARE WHAT HAPPENS IN THE
UNITED STATES TO WHAT HAPPENS IN
EUROPE.
THERE WAS A RECENT PUBLICATION,
PROBABLY ABOUT THREE OR FOUR
YEARS AGO, FROM THE FRENCH
REGISTRY, TRANSPLANT REGISTRY,
WITH FOLLOW-UP OF AT LEAST FIVE
YEARS ON ALL OF THEIR PATIENTS
AND THERE WERE NO REPORTED CASES
OF SECONDARY NEOPLASMS.
IN CONTRAST IN THE COHORT FROM
THE UNITED STATES, THERE WERE
EIGHT SECONDARY NEOPLASMS AND I
HAVE BROKEN THEM DOWN.
WHAT WAS STRIKING IS THE
RELATIVELY SHORT TIME TO
SECONDARY NEOPLA S NEOPLASM ALLH
OCCURRED LESS THAN FIVE YEARS
AFTER TRANSPLANTATION.
SO THERE ARE DIFFERENCES BETWEEN
THE PATTERN OF SECONDARY
NEOPLASMS IN SICKLE CELL DISEASE
AND OTHER DISEASES, LARGELY THE
RELATIVELY SHORT TIME TO
DEVELOPMENT, APPROXIMATELY THREE
YEARS.
LEUKEMIA IS THE PREDOMINANT,
UNLIKE OTHER TRANSPLANTATION
WHERE SOLID TUMORS IS THE
PREDOMINANT SECOND CANCER.
60% OF THE PRIMARY NEOPLASMS
OCCURRED AFTER LOW DOSE TBI
WHEREAS THE TRANSPLANT
LITERATURE LARGELY IN THE
SETTING OF HEMATOLOGIC
MALIGNANCY IN ALLOGENEIC
TRANSPLANTATION HAVE IDENTIFIED
SINGLE DOSE TBI600 TO 1,000 CGY
AND FRACK NATEED -- AS A RISK
FACTOR.
SO WHAT ARE THE RISK FACTORS FOR
SECONDARY NEOPLASM IN SICKLE
CELL DISEASE?
OUR ANALYSIS CONFIRMED THAT LOW
INTENSITY TBI REGIMEN INCREASES
THE RISK FOR ANY SECONDARY PLIG
MALIGNANCY AND FOR LEUKEMIA AND
MYELODYSPLASTIC SYNDROME.
A MATCHED PAIR ANALYSIS WAS
CONDUCTED MATCHING FOR AGE,
DONOR TYPE AND SURVIVAL TIME.
THE CONTROLS HAD TO BE ALIVE AT
LEAST AS LONG AS THE INTERVAL TO
DEVELOPING A NEOPLASM.
THE RESULTS OF THE MAIN ANALYSES
WERE CONFIRMED.
SO TO SUMMARIZE THE HIGHER
INCIDENCE OF SECONDARY NEOPLASM
LEUKEMIA AND MDS AFTER SICKLE
CELL DISEASE IS HIGHER COMPARED
TO OTHER NON-MALIGNANT DISEASES
WITH THE EXCEPTION OF FANCONI
ANEMIA.
LOW INTENSITY REGIMENS WERE
HIGHEST RISK BUT YOU DID HAVE
OTHER DEVELOPING AFTER OTHER
REGIMENS.
THE TYPE OF SECOND -- AS OPPOSED
TO SOLID NEOPLASMS.
IN 634 CHILDREN WITH 4,342
PERSON-YEARS AND EIGHT
NEOPLASMS, THAT TRANSLATES TO
1.8 CASES PER THOUSAND
PERSON-YEARS.
SO THE PREDOMINENCE OF LEUKEMIA
AND MYELODYSPLASTIC SYNDROME MAY
BE EXPLAINED BY LOW INTENSITY
REGIMENS THAT RELY ON TOLERANCE
INDUCTION THAT LEADS TO
PERSISTENCE OF RESIDUAL HOST
CELLS THAT WERE EXPOSED TO LOW
DOSE RADIATION.
-- POST TRANSPLANT
PROLIFERATIVE STRESS OR
UNDERLYING HEMATOPOIESIS.
SO THESE DATA SHOULD PROVIDE A
FOUNDATION TO DISCUSS THE RISK
FOF SECONDARY NEOPLASMS AND IT
WILL CERTAINLY IMPROVE CANCELS
AND DETERMINING THE RISK-BENEFIT
RATIO IN LIGHT OF THE EMERGING
SUCCESS OF TRANSPLANTATION
VERSUS -- CONTINUED SURVEILLANCE
IS ENCOURAGED.
HOWEVER, CONTINUED SURVEILLANCE
REQUIRES GUIDANCE FOR SYSTEMATIC
EVALUATION THAT IS CURRENTLY NOT
AVAILABLE.
SO I CALL ON THIS AUDIENCE TO
DEVELOP A GUIDANCE DOCUMENT FOR
SURVEILLANCE FOR SECONDARY
NEOPLASM WHEN ANY CURATIVE
TREATMENT IS CONSIDERED.
SOME TREATMENT PROTOCOLS MAY
HAVE THAT INCORPORATED.
ONE EXAMPLE IS THE NHLBI-FUNDED
GRASP TRIAL LED BY DR. DAVID
WILLIAMS AT BOSTON CHILDREN'S
HOSPITAL, WHERE HE'S SCREENING
SYSTEMATICALLY FOR PATHOGENIC
MUTATIONS IN GENES ASSOCIATED
WITH MYELOID MALIGNANCY,
BEGINNING PRETRANSPLANT, AND
SERIALLY USING A COMBINATION OF
BLOOD AND BONE MARROW THROUGH 12
MONTHS POST INFUSION.
IT'S REVIEWED IN A CENTRAL CLEAR
CERTIFIED LABORATORY AND
CENTRALLY ADJUDICATED.
WITH THAT, I'D LIKE TO
ACKNOWLEDGE THE FUNDING SUPPORT
FROM THE NATIONAL INSTITUTES OF
HEALTH, THE DEPARTMENT OF HEALTH
AND HUMAN SERVICES, MY
COLLABORATORS ON THE GRASP
PROTOCOL TEAM, AND MY
STATISTICAL COLLEAGUES.
THANK YOU.
>>THANK YOU, DR. EAPEN.
>>OUR LAST SPEAKER WILL BE
PRESENTING VIRTUALLY,
DR. LILLIAN MEACHAM IS FROM
EMORY UNIVERSITY, AND SHE'LL BE
PRESENTING FEMALE REPRODUCTIVE
HEALTH OUTCOMES AFTER TRANSPLANT
FOR SICKLE CELL DISEASE, IS
REDUCED INTENSITY BETTER THAN
MYELOABLATIVE CONDITIONING.
THANKS FOR INVITING ME TO TALK
ABOUT REPRODUCTIVE HEALTH
OUTCOMES.
AND -- WITH SICKLE CELL DISEASE
AFTER TRANSPLANT.
I THINK WHEN WE CONSIDER
REPRODUCTIVE HEALTH OUTCOMES,
WHAT WE WANT TO KNOW ARE RATES
OF INFERTILITY.
INFERTILITY IS A
PATIENT-REPORTED OUTCOME OF 12
MONTHS OF UNPROTECTED
INTERCOURSE WITHOUT PREGNANCY.
THIS IS A VERY DIFFICULT OUTCOME
TO CAPTURE, BECAUSE IT IS
SELF-REPORTED AND IT'S VERY HARD
TO GET A GOOD DENOMINATOR.
THEREFORE, WE HAVE TO RELY ON
OTHER THINGS TO INFORM OUTCOMES
IN FEMALES.
PRIMARILY PREMATURE OVARIAN
INSUFFICIENCY IS WHAT WE REPORT
OR POI.
THIS IS ALSO KNOWN AS OVARIAN
FAILURE OR MENOPAUSE AND IT'S
DEFINED BY MENOPAUSAL FSH TIMES
2 AND AMEN REYA.
WE ALSO TALK ABOUT DIMINISHED
OVARIAN RESERVE.
OVARIAN RESERVE REALLY LOOKS AT
THE PRIMORDIAL FOLLICLE POOL.
HERE IS A GRAPH THAT SHOWS THAT
AT BIRTH, EACH OVARY HAS
1 MILLION PRIMORDIAL FOLLICLES.
THESE ARE LOST OVER TIME AND
WHEN YOU HIT THE THRESHOLD OF
1,000, MENOPAUSE OCCURS,
TYPICALLY AT AGE 50.
WHEN A PATIENT IS EXPOSED TO
RADIATION OR CHEMOTHERAPY,
THERE'S A LOSS IN THE PRIMORDIAL
FOLLICLE POOL AND AFTER
TREATMENT, THEY HAVE GRADUAL
LOSS BUT THIS PATIENT AND THIS
EXAMPLE WILL HAVE MENOPAUSE AT
AGE 18.
THE PRIMORDIAL FOLLICLES LIVE IN
THE CORTEX, THE OUTER SURFACE OF
THE OVARY.
EVERY MONTH A CERTAIN NUMBER
WILL DEVELOP AND GROW.
THESE ARE THE PRIMARY
PREENTERAL, SMALL ENTERAL -- ONE
IS CHOSEN TO MATURE AND RELEASED
AS THE EGG.
THESE GROWING FOLLICLES PRODUCE
A HORMONE CALLED AMH.
AMH REFLECTS THE NUMBER OF
GROWING FOLLICLES, THE NUMBER OF
GROWING FOLLICLES REFLECTS THE
SIZE AND HOW ROBUST THE FOLLICLE
POOL IS.
SO WHEN WE WANT TO LOOK AT
OVARIAN RESERVE, WE CAN EITHER
DO THAT BY GETTING AN ANTRAL
FOLLICLE COUNT WHICH TYPICALLY
HAS TO BE OBTAINED BY TRANS
VAGINAL ULTRASOUND, OR LOOK AT
AN ANTIMA L ANTIM URKTS LLERIANE
COUNT.
DIMINISHED OVARIAN RESERVE IS
DIE FINED BY AML LESS THAN 1 OR
SOME USE A LITTLE LOWER
THRESHOLD.
IN PEDIATRICS, THE VALUE VARIES
THROUGHOUT CHILDHOOD AND
ADOLESCENCE.
SO WE HAVE TO LOOK AT AN AMH
THAT IS MORE THAN 2 STANDARD
DEVIATIONS BELOW THE MEAN, OR A
VALUE THAT IS BOW L BELOW THE NL
RANGE FOR AGE AND ASSAY, BECAUSE
ASSAYS ALSO VARY.
SO WE WANTED TO BEGIN TO LOOK AT
THIS AND BACK IN 2015 WE STARTED
AND WE WANTED TO LOOK AT OVARIAN
HEALTH IN TRANSPLANT PATIENTS
AND WE WONDERED WHO SHOULD WE
COMPARE TO.
SO WE LOOKED AT PATIENTS ON
HYDROXYUREA AND PATIENTS
RECEIVING STANDARD OF CARE OR
TRANSFUSIONS.
WE FOUND NOT SURPRISINGLY THAT
WITH STANDARD OF CARE ALL
PATIENTS HAD NORMAL OVARIAN
RESERVE AND NON-IT POI
OROVAIRIAN FAILURE.
FOR PATIENTS ON HYDROXYUREA,
ALMOST A QUARTER IT DIMINISHED
OVARIAN RESERVE, WHICH WAS A BIT
SURPRISING, BUT WHEN WE LOOKED
AT THE TRANSPLANTED PATIENTS,
100% HAD DIMINISHED OVARIAN
RESERVE, THEIR AMH VALUES WERE
NOT ONLY LOW, THEY WERE
UNDETECTABLE, AND NIEP TI% HAD
OVARIAN FAILURE.
SO THEN WE ASKED THE QUESTION,
HOW HEALTHY -- WELL, WE ASKED,
IS THE RECOVERY OVER TIME?
WE KNOW THAT IN HODGKIN'S
DISEASE, IN THE FIRST TWO YEARS
YOU CAN SEE RECOVERY OF A MH.
SO WE LOOKED AT AMH
LONGITUDINALLY UP TO 13 YEARS
AND THERE WAS NO RECOVERY.
OF AMH WITHIN THAT TIME FRA FRA
FRAME.
WE HAD THREE PATIENTS IN WHOM WE
HAD BASELINE AMH.
ALL OF THOSE WERE NORMAL.
THESE ARE SI UNITS.
SO WE KNEW THAT AT LEAST IN
THESE THREE PATIENTS, THEY WERE
NORMAL AT BASELINE, DEPLETED
POST TRANSPLANT AND DID NOT
RECOVER.
SO THEN WE WANTED TO LOOK MORE
BROADLY AT AMH BEFORE TRANSPLANT
AND AFTER TRANSPLANT.
AND THIS IS A GROUP OF 19
PATIENTS.
I HAVE THEIR BONE MARROW
TRANSPLANT REGIMENS AT A THROUGH
E AND I WILL DEFINE THESE IN A
FUTURE SLIDE.
SO I KNOW THIS ISN'T HELPFUL
RIGHT NOW, BUT WE'LL COME BACK
TO THAT.
AND YOU'LL SEE THAT AT AMH PRIOR
TO TRANSPLANT, 17 WERE NORMAL
AND TWO WERE LOW AND THOSE TWO
WERE ON HYDROXYUREA, AND POST
TRANSPLANT, THEY WERE ALL
UNDETECTABLE EXCEPT FOR TWO THAT
WERE LOW.
WE LOOKED AT POI, AND POI CAN
ONLY BE MEASURED IN PATIENTS WHO
ARE OLD ENOUGH TO ACTIVATE THEIR
HYPOTHATHALAMIC ACCESS, SO THERE
WERE ONLY SIX PATIENTS ELIGIBLE
AND HALF OF THOSE AT THE TIME OF
TESTING DEMONSTRATED POI.
SO THEN WE ASKED THE QUESTION,
ARE ALL CONDITIONING REGIMENS
HIGH RISK?
OR DO THEY ALL CONFER THE SAME
LEVEL OF RISK?
OR, ARE REDUCED INTENSITY
REGIMENS LESS O OWE VO TOXIC THN
MYELOABLATIVE REGIMENS?
SO IN ORDER TO CLASSIFY
REGIMENS, WE USED THIS PAPER
WHICH WAS PUBLISHED BY LIMERICK
AND ABRAHAM TO ASSIGN WHETHER A
PROTOCOL WAS MYELOABLATIVE OR
REDUCED INTENSITY.
WE THEN LOOKED AT EACH OF THE
REGIMENS AND WE CONVERTED THE
CYCLOPHOSPHAMIDE EQUIVALENT
DOSE.
THIS IS USED EXTENSIVELY IN
ONCOLOGY AND SURVIVORSHIP SO WE
CAN GET COMPARISONS.
SO THESE ARE THE REGIMENS THAT
WE LOOKED AT.
AND THEY'RE A THROUGH I.
I'VE LISTED THE DIFFERENT AGENTS
USED, AND THEN IN RED, YOU CAN
SEE WITH THE CYCLOPHOSPHAMIDE
EQUIVALENT DOSE IS FOR EACH
REGIMEN.
THEY GO FROM 3,300 UP TO
18,000 MILLIGRAMS PER METER
SQUARED OF CYCLOPHOSPHAMIDE.
THE LAST LINE SHOWS WHETHER THIS
REGIMEN WOULD HAVE BEEN
CLASSIFIED AS MYELOABLATIVE OR
REDUCED INTENSITY.
YOU CAN SEE THE LOWEST CED IS
ACTUALLY MYELOABLATIVE, AND THE
TWO TOP HIGHEST CEDs AT
17 GRAMS PER METER SQUARED AND
18 GRAMS PER METER SQUARED ARE
ACTUALLY REDUCED INTENSITY
REGIMENS.
WE THEN WENT AND -- THIS WAS A
LITTLE BIT CONFUSING.
WE'VE DONE THREE STUDIES WHERE
WE'VE REPORTED DIMINISHED
OVARIAN RESERVE.
SO I'VE HIGHLIGHTED THE FINDINGS
IN THOSE STUDIES.
IT IS IMPORTANT TO NOTE THAT
SOME OF THESE ARE -- THEY ARE
NOT MUTUALLY EXCLUSIVE STUDIES.
BUT THE FIRST STUDY YOU'VE
ALREADY SEEN, WHICH WAS A
LONGITUDINAL STUDY PUBLISHED IN
2020.
THE PRE AND POST AMH BY GEORGE
IN 2022, AND THEN DR. GEORGE HAS
GOT ANOTHER STUDY THAT'S IN
PROGRESS.
WHAT YOU'LL NOTICE FOR
DIMINISHED OVARIAN RESERVE, THAT
IN ALMOST ALL OF THESE PATIENTS,
100% OF PATIENTS HAD DIMINISHED
OVARIAN RESERVE, AND AGAIN NOT
JUST DIMINISHED BUT DEPLETED.
IT'S UNDETECTABLE AM EXCEPT
EXCEPT FOR TWO, WHICH IS B AND
H.
AGAIN, IN ONE PLACE, IT'S CED OF
5.6, AND THE OTHER, A CED OF
17.6.
WE THEN LOOKED AT PREMATURE
OVARIAN INSUFFICIENCY.
I THINK THIS IS MESSY DATA
BECAUSE NOT ALL PATIENTS CAN BE
STUDIED BECAUSE THEY'RE NOT OLD
ENOUGH.
AND IT'S NOT AS CLEAN OR CLEAR,
BUT I'VE LISTED THE RATES OF POI
IN THESE DIFFERENT STUDIES FOR
PATIENTS THAT WERE ELIGIBLE TO
BE EVALUATED, WHICH ARE
BASICALLY PATIENTS OLDER THAN 13
WHO SHOULD HAVE ENTERED PUBERTY.
AND YOU SEE THAT THE RANGES ARE
A LITTLE BIT SCATTERED, BUT I
HIGHLIGHTED IN YELLOW THOSE THAT
WERE LESS THAN 50%.
AND AGAIN, IT'S THE MELPHALAN
STUDY, BUT IT'S ALSO THIS STUDY,
A PROTOCOL G, SO WHEN YOU LOOK
AT CED, BY CED, MYELOABLATIVE IS
NOT MORE TOXIC REDUCED INTENSITY
IF WE JUST LOOK AT CED.
THE SECOND POINT WOULD BE
DIMINISHED OVARIAN RESERVE IS
ALMOST FOUND IN ALL PATIENTS.
AND THAT PREMATURE OVARIAN
INSUFFICIENCY IS LESS UNIFORM
AND PERHAPS A DEVELOPING PICT
PICTURE.
THOSE OF US IN THE FIELD THINK
OF DIMINISHED OVARIAN RESERVE AS
A WARNING THAT IT'S COMING.
SO RECOMMENDS PROVIDE FERTILITY
CONSULTS TO ALL PATIENTS, OFFER
FERTILITY PRESERVATION AS A
HARVEST OF OVARIAN TISSUE,
MONITOR FUNCTION AFTERWARDS, AND
THERE'S A CONSIDERATION THAT WE
COULD TALK ABOUT, ALTHOUGH
UNLIKELY TO WORK BECAUSE OF THE
LOW AMH AND THAT WOULD BE POST
TRANSPLANT EGG HARVEST.
NEXT SLIDE WHICH IS MY LAST
SLIDE.
I THINK REPRODUCTIVE HEALTH IS
COMPLICATED IN PATIENTS WITH
SICKLE CELL DISEASE BUT DESERVES
ATTENTION.
I'D LIKE TO THANK MY
COLLABORATORS.
AND OUR FUNDING.
THANK YOU.
>>BIG HAND TO THE SPEAKERS.
WE WILL PREFERENTIALLY READ OUT
QUESTIONS FROM THE CHAT, PLEASE?
>>WE HAVE A COUPLE OF QUESTIONS
ON CHAT AND ALANA IS GOING TO BE
TALKING --
>>IF YOU HAVE A QUESTION FOR
THE SPEAKER, GO TO THE NEAREST
MIC.
>>SO THE FIRST QUESTION IS FOR
DR. STENGER.
WHILE THE REDUCTIONS IN LV
EJECTION FRACTION ARE
INTERESTING, THEY ARE BOTH
WITHIN NORMAL LIMITS.
IS IT POSSIBLE THAT WHAT IS
BEING OBSERVED IS A REDUCTION IN
THE CARDIAC OUTPUT WHICH WILL
OCCUR WITH THE CORRECTION OF
ANEMIA?
ARE THERE OTHER CARDIOPULMONARY
VARIABLES AVAILABLE?
>>SO THANK YOU FOR THE
QUESTION.
SO FOR THIS ANALYSIS, WE LIMITED
TO EJECTION FRACTION AND
SHORTENING FRACTION AND AGAIN
THE SUBSET THAT HAD -- BUT WE DO
HAVE SOURCE DOCUMENTS FOR THE
PULMONARY FUNCTION TESTS AND THE
ECHOES, SO WE'RE WORKING NOW ON
POOLING THAT DATA WITH MORE
DETAILED PARAMETERS FROM BOTH SO
THAT WE CAN DO SOME FUTURE
ANALYSES.
SO HOPE TO HAVE BETTER DATA.
THANK YOU FOR THE QUESTION.
>>OKAY.
I HAVE ONE MORE QUESTION FOR DR.
AND THE QUESTION IS WHETHER YOU
HAVE CONDUCTED MRA FOR
HEMODYNAMIC ANALYSIS ON CEREBRAL
VASOCULTURE.
>>I'M SORRY, CAN YOU REPEAT THE
QUESTION?
>>SURE.
THE QUESTION IS WHETHER THERE
HAS BEEN ANY CONDUCTED MRA FOR
HEMODYNAMIC ANALYSIS ON CEREBRAL
VASOCULTURE.
>>VASOOCCLUSION, I ASSUME THAT
MEANS.
THAT'S A GREAT QUESTION.
IN OUR COHORT OF TRANSPLANT
PATIENTS, ONE OF THE PATIENTS
HAD CEREBRAL VASCULOPATHY AND
HAD UNDERGONE A UNILATERAL --
REVASCULARIZATION PROCEDURE.
IN OUR TRANSFUSION POPULATION, I
BELIEVE TWO OF THE PATIENTS,
MAYBE THREE, HAD
REVASCULARIZATION -- HAD
VASCULOPATHY, ONE HAD HAD
REVASCULARIZATION, THE OTHERS
HADN'T.
WE DIDN'T SEE ANY DIFFERENCES
IS, BUT AGAIN, IT WAS A REALLY
SMALL SAMPLE SIZE.
>>WITH THAT, WE'LL GO AHEAD AND
WRAP UP OUR SESSION.
IF IN-PERSON FOLKS HAVE
QUESTIONS FOR THE SPEAKERS,
PLEASE DON'T HESITATE TO GRAB
THEM OR REACH OUT VIA EMAIL.
THANK YOU, EVERYONE, TO OUR
SPEAKERS.
GREAT SESSION.
>>THANK YOU.
BIG HAND FOR THE SPEAKERS.
SO WE MOVE ON TO THE NEXT
SESSION, WHICH IS THE CURATIVE
THERAPIES FOR SICKLE CELL TWO,
GENE THERAPY/GENE EDITING.
>>SO MAYBE WE CAN JUST START
WITH THE INTRODUCTION WITHOUT
THE SLIDES.
SO BASICALLY THIS CURATIVE
THERAPY SESSION, WE WERE GOING
TO TALK ABOUT TWO DIFFERENT
APPROACHES OF GENETIC THERAPIES.
THE FIRST ONE BEING GENE
ADDITION WITH LENTIVIRAL VECTORS
AND THE SECOND BEING GENE ID
ITEDITING USING CRISPR/CAS.
THE GENE EDITING APPROACHES THAT
WE WERE GOING TO DISCUSS WOULD
BASICALLY INVOLVE LENTIVIRAL
VECTORS AND THEY CARRY AN
ANTICYCLING GENE THAT IS UNDER
THE CONTROL OF PROMOTERS AND
ENHANCERS.
THE LENTIVIRAL VECTOR INTEGRATES
RANDOMLY INTO THE GENOME, AND SO
THERE IS A SMALL POSSIBILITY OF
IT HAVING INSERTIONAL
GENOTOXICITY IF IT INTEGRATES
AND ACTIVATES AN ONCOGENE.
THAT SAID, THAT IS OVER 15 YEARS
OF EXPERIENCE WITH LENTIVIRAL
VECTORS, GLOBAL ANTIVIRAL
VECTORS -- SPECIFIC VECTORS AND
NO SUCH EVENT HAS BEEN REPORTED.
GENE EDITING ON THE OTHER HAND
IS USING SITE-SPECIFIC NUCLEASES
TO DIRECT A CAS NINE NUCLEASE TO
CREATE A CHANGE OR EDIT SEQUENCE
OF DNA.
AND WE HAVE AN ARRAY OF REALLY
GREAT SPEAKERS WHO ARE GOING TO
TALK, OUR FIRST SPEAKER IS JOHN
TISDALE WHO WILL BE SPEAKING ON
ANTIBODY CONDITIONING REGIMENS
AND APPROACHES OF DOING CURATIVE
THERAPIES WITH SICKLE CELL
DISEASE, AND BECAUSE WE'VE LOST
SOME TIME, I'M NOT GOING TO
SPEAK ABOUT THE TITLES OF ALL
THE OTHER SPEAKERS.
I'LL JUST LET JOHN TAKE IT AWAY.
THANK YOU FOR THE OPPORTUNITY TO
PRESENT OUR WORK.
BY NOW YOU'VE SEEN THIS SLIDE.
THIS IS HGB-206 STUDY, THE BLOOK
BERG STUDY OF HIV-BASED GENE
THERAPY FOR SICKLE CELL DISEASE.
THE IMPORTANT POINT BEING THAT
THERE WAS AN EVOLUTION OF THIS
PROTOCOL GOING FROM BONE
MARROWS, THE HSC SOURCE, SO
MANUFACTURING SUCH THAT WE GOT
MUCH HIGHER TRANSDUCTION EE FISH
SE TO CONDUCTING MOBILIZED
PERIPHERAL BLOOD AS THE SOURCE.
HERE WE ARE STUCK AGAIN.
CAN YOU ADVANCE?
>>PLEASE SAY "NEXT SLIDE."
SO THE ITERATIONS OF THIS
PROTOCOL HAVE BEEN PUBLISHED,
THERE ARE GROUPS A AND B HERE,
AND GROUP C IN THE SECOND
PUBLICATION.
THE TAKE-HOME POINT IS THAT
VECTOR COPY NUMBER IMPROVED FROM
.1 IN GROUP A TO 1.5 IN GROUP C,
AND AS YOU CAN SEE, THIS IS
STABLE OVER TIME.
JUST FOR REFERENCE .1 MEANS THAT
ON AVERAGE, ABOUT 10% OF THE
CELLS HAD ONE COPY.
THIS SHOWS THE TRANSLATION OF
THOSE CHANGES INTO AMOUNT OF
HEMOGLOBIN DERIVING FROM VECTOR
SO IT WAS ABOUT 10% AS YOU MIGHT
HAVE PREDICTED FROM THE ORIGINAL
COHORT, IT'S ALMOST HALF OF THE
HEMOGLOBIN IN GROUP C.
MODEST IMPROVEMENT OF TOTAL
HEMOGLOBIN AND GROUP C THE
HEMOGLOBIN NORMALIZED.
NOT ALL TOGETHER CERTAIN HOW
THESE SLIDES ARE GOING BUT I
KEEP HITTING NEXT --
>>PLEASE SAY "NEXT SLIDE."
>>I'M SORRY?
>>PLEASE SAY "NEXT SLIDE" WHEN
YOU'RE READY.
>>NEXT.
OKAY.
SO THIS RESULTED IN A COMPLETE
RESOLUTION OF SEVERE
VASOOCCLUSIVE EVENT AS YOU SAW
EARLIER.
BUT UNFORTUNATELY THERE WAS A
SAFETY SIGNAL NOTED IN LONG-TERM
FOLLOW-UP.
SO YOU CAN SEE THE TREATMENT
EMERGING GRADE III AEs THAT
ARE TYPICAL FOR AN AUTO
TRANSPLANT, BUT WE HAD TWO CASES
OF ACS AML AS MENTIONED.
IN THE SECOND CASE, THERE WAS,
IN FACT, A VECTOR PRESENT IN THE
BLAST.
NOTABLY BOTH PATIENTS HAD
CLASSIC AML DRIVERS, AT
DIAGNOSIS, MONO SEW ME 7,
RUNX1 AND PTPN11.
WE DID AN EXHAUSTIVE EVALUATION
TO LOOK FOR WHETHER VECTOR WAS A
PASSENGER OR DRIVER IN THIS
MALIGNANT PROCESS.
AND TICKED OFF ALL OF THESE
BOXES AND FOUND THAT VECTOR
INTEGRATION, PER SE, WAS NOT
LIKELY CONTRIBUTING TO THE
LEUKEMOGENESIS.
SO WE HAD TO LOOK AT
CONDITIONING AS AT LEAST A
CONTRIBUTING FACTOR IN THE
MALIGNANCIES IN THESE PATIENTS,
AND AS YOU ARE ALL AWARE, WE'VE
MADE LOTS OF PROGRESS IN GENE
MODIFICATION.
YOU'RE GOING TO HEAR ABOUT A LOT
OF THAT, BUT WE'VE MADE VERY
LITTLE PROGRESS NE IN THE
CONDITIONING REGIMEN THAT WE
USE.
SO WE ALONG WITH HARVARD STEM
CELL INSTITUTE AND WHAT WAS MA
GENERAMAGENTA THERAPEUTICS LAUNA
BED TO BEDSIDE PROJECT TO LOOK
AT DRUG CONJUGATED CONDITIONING.
WE CHOSE ANTI-CD117, BY
ATTACHING A PAYLOAD THAT'S
KILLING BOTH QUIESCENT AND
DIVIDING CELLS AND THIS GIVES US
AN OPPORTUNITY FOR A LESS TOXIC
CONDITIONING WITH IMMUNE
PRESERVATION AND HOPEFULLY
AVOIDANCE OF SECONDARY
MALIGNANCY AND FERTILITY, BOTH
OF WHICH YOU'VE HEARD ABOUT THIS
MORNING.
SO CD117 OR C-KIT IS IDEAL
BECAUSE IT'S EXPRESSED ON -- AND
ONLY MAST CELLS BEYOND THAT, AND
A SINGLE DOSE CAN ENABLE ROBUST
ENGRAPHMENT IN MICE AS SHOWN
SOME YEARS BACK.
WE MADE AN ADC THAT'S POTENT FOR
KILLING BOTH HUMAN AND NON-HUMAN
PRIMATE CD34 CELLS AT LOW ICs.
THIS ALLOWS HSC DELIVERY OF THIS
ADC, AND YOU CAN SEE IN THE
BOTTOM PANEL HERE, AT BASELI
BASELINE -- EQUIVALENT TO WHAT
WE ACHIEVE WITH MYELOABLATIVE
BUSULFAN AT 6 MILLIGRAMS PER
COULD I GO KILOGRAM TIMES 4.
WE TESTED THIS APPROACH USING A
VECTOR THAT WE DEVELOPED
SPECIFICALLY FOR TREATMENT OF
SICKLE CELL DISEASE THAT HAS A
SMEAR FOR BC11A LIKE IN DAVID
WILLIAMS' TRIAL BUT WE ALSO
CO-EXPRESSED A TRUNCATED EE POE
RECEPTOR BECAUSE WE KNOW THAT
THIS TRUNCATED EE POE RECEPTOR
MAKES ERYTHROPROGENY MORE
SENSITIVE TO EPO AS EVIDENCED BY
THIS GUY WHO MEDALLED ACROSS
FOUR OLYMPICS WHO HAD A
TRUNCATED EPO RECEPTOR AND
HEMOGLOBIN OF ABOUT 21.
IT'S A BENIGN CONDITION WITH
ERYTHROCYTOSIS, SO WE THOUGHT
THAT WE MAY BE ABLE TO TAKE
ADVANTAGE OF THIS BY
CO-EXPRESSING THIS AND,
THEREFORE, SELECTING FOR CELLS
THAT ALSO HAD THE SMEARS.
WE MADE VECTORS WITH JUST THE
SMEAR OR THE SMEAR PLUS THE EPO
RECEPTOR, AND TRANSDUCED HUMAN
CELLS, PUT THOSE INTO
IMMUNODEFICIENT MICE AND HERE
YOU CAN SEE THE CONTROLS, THE
SMEAR ONLY WITH ABOUT 3 OR 4%
FETAL HEMOGLOBIN AT 6 MONTHS
WHEN WE TOOK THESE MICE DOWN.
WITH A GPA PROMOTOR OR THE
ANKERIN PROMOTER WE GOT REALLY
NICE FETAL HEMOGLOBIN LEVELS OF
ABOUT 40%.
WE THEN TRIED THIS VECTOR SYSTEM
IN THE NON-HUMAN PRIMATE WITH
JUST A SMEAR AND A PAIR OF
ANIMALS WHERE WE GOT PRETTY GOOD
FETAL HEMOGLOBIN INITIALLY BUT
IN ABSENCE OF DISEASE STATE,
THIS WENT DOWN TO PRE-TRANS
PLANT LEVELS.
BUT WITH THE SMEAR TO BCL11A
AND -- WE GOT NICE LEVELS OF
HEMOGLOBIN F.
SO THEN WE COMPARE THIS VECTOR
SYSTEM, THE SMEAR, WITH EPO, TOO
THESE MULTI-DOSE BUSULFAN
ANIMALS AS OPPOSED TO EITHER
.3 OR .4 MILLIGRAMS PER KILOGRAM
OF THE ANTIBODY.
HERE YOU SEE TRANSIENT
NEUTROPENIA AFTER THE ADC AT
.3 OR AT .4 MILLIGRAMS PER
KILOGRAM, AND COMPARE THAT TO
THE BUSULFAN CONDITIONING AS
SHOWN ON THE RIGHT.
HERE YOU SEE ENGRAFTMENT WITH
VECTOR COPY NUMBER, OR
HEMOGLOBIN F INDUCTION.
YOU CAN SEE IT'S EQUIVALENT
BETWEEN THE BUSULFAN ANIMALS AND
THE ANTIBODY ANIMALS WITH THE
EXCEPTION OF ONE ANIMAL DOSE,
THE LOWER DOSE.
WE SAW MINIMAL TOXICITIES WITH
THE DC117 ANTIBODY.
MOST NOTABLY WE DID NOT OBSERVE
AMENORRHEA.
SO THIS THE MENSTRUAL CYCLE PER
MONTH IN THESE ANIMALS TREATED
WITH THE ADC VERSUS CONTROL --
HISTORICAL ANIMALS TREATED WITH
EITHER BUSULFAN OR TDI.
SO YOU CAN SEE THEY WERE HAVING
ONE CYCLE PER MONTH.
SO WE PUT THESE ANIMALS INTO A
BREEDING COLONY AND IN THE FIRST
BREEDING SEASON, WE'VE HAD TWO
OF THE FOUR FEMALES THAT HAVE
GIVEN BIRTH AND TWO OF THE MALES
HAVE SIRED.
AND ACTUALLY ONE OF THE PAIRS
WAS A FEMALE ANIMAL TREATED WITH
ADC PAIRED WITH A MALE ANIMAL
THAT WAS A DC-TREATED.
SO THAT'S FOUR SUCCESSFUL AMONG
SIX ANIMALS THAT WE TRANSFERRED.
I THINK WE CAN JUST MOVE TO THE
LAST SLIDE.
WE DID SIMILAR STUDIES WITH THE
CD45-TREATED COHORT.
AND FOR THAT, WE USED A BCL11A
ERYTHROENHANCER EDITING.
YOU CAN SEE HERE THE DROP IN
COUNTS.
THE COLORED LINES ARE ANIMALS
TREATED WITH THE CD45-ADC
COMPARED TO BUSULFAN CONTROLS IN
GREY.
YOU CAN SEE OVERALL PERCENT
EDITING IS SIMILAR TO THE BEU
SUL FEIGN-TREATED ANIMALS WHEN
ANIMALS WERE DOSED AT
.3 MILLIGRAMS PER KILOGRAM.
SO WE KNOW WE CAN CURE THIS
DISEASE, GENE THERAPY THROUGH
EDITING OR GENE ADDITION AS I'VE
SHOWN YOU CAN ALSO BE CURATIVE
AND HOPEFULLY THESE NOVEL
CONDITIONING REGIMENS WILL GET
US TO THE PLACE WHERE WE CAN
ALSO DO THIS WITHOUT MUCH
TOXICITY.
I'LL JUST SHOW THE CONTRIBUTORS
ON THE NEXT SLIDE.
THANKS.
>>WE CAN HAVE ONE QUESTION FOR
JOHN.
AT THE END?
ALL RIGHT.
SO THE NEXT TALK, I'M GOING TO
SPEAK ABO ABOUT RIC LENTIVIRAL E
THERAPY WITH MODIFIED HBF,
FUTURE DIRECTIONS OF OUR TRIAL.
SO AS THIS AUDIENCE WELL KNOWS,
FETAL HEMOGLOBIN IS A POTENT
ANTICYCLANTISICKLING HEMOGLOBINO
HAS A HIGHER AFFINITY FOR OXYGEN
THAN HEMOGLOBIN A OR HEMOGLOBIN
S, THEREBY RETAINING OXYGEN AND
PREVENTING POLYMERIZATION.
BEYOND THE WILD TYPE HBF, THE
HBFG16D MUTATION THAT WE MADE
ADDS A NEGATIVE CHARGE TO THE
GAMMA GLOBIN, INCREASING THE
COMPETITIVE ADVANTAGE TO BIND TO
THE POSITIVELY CHARGED ALPHA
GLOBIN SUBUNITS.
ADDITIONALLY, WE'VE ALSO IN
PRE-CLINICAL STUDIES OBSERVED
THAT IT IS MORE POTENT
ANTISICKLING GLOBIN THAN THE
ENDOGENOUS FETAL HEMOG HEMOGLOBD
T87Q.
SO WE DESIGNED THE VECTOR
INITIALLY NAMED GBGM AND THEN
LICENSED TO ARUVANT AND RENAMED
AS ARU-1801, WHICH ENCODES THIS
MUTANT GAMMA GLOBIN THAT HAS THE
POINT MUTATION G16D.
AND FOR THE CONDITIONING, JOHN
HAS ALREADY ALLUDED TO
CONDITIONING FOR AUTOLOGOUS GENE
THERAPY TRANSPLANTS, SO UNLIKE
IMMUNE DEFICIENCIES, CORRECTION
OF SICKLE CELL DISEASE REQUIRES
A MUCH HIGHER PERCENTAGE, ABOUT
15 TO 20% GENETICALLY MODIFIED
HEMATOPOIETIC STEM CELL
ENGRAFTMENT.
AND IN GENE THERAPY OR EDITING,
THE INFUSED DRUG PRODUCT
CONTAINS BOTH THE DESIRED
GENETICALLY MODIFIED AND THE
UNMODIFIED STEM CELLS.
HENCE, GENE ADDITION AND GENE
EDITING TRIALS FOR SICKLE CELL
DISEASE USE MYELOABLATIVE
CHEMOTHERAPY CONDITIONING, USING
BUSULFAN, TO ABLATE ALL THE
ENDOGENOUS RESIDUAL YOU'LL HSC,
GIVING THE HSC IN THE DRUG
PRODUCT ENGRAFTMENT ADVANTAGE.
HOWEVER MYELOABLATIVE
CHEMOTHERAPY RESULTS IN
PROLONGED NEUTROPENIA AND
THROMBOCYTOPENIA REQUIRING
SIGNIFICANT INFECTION, NUTRITION
AND TRANSFUSION SUPPORT.
REDUCED INTENSITY CONDITIONING
OFFERS ADVANTAGES.
ALTHOUGH IN REDUCED INTENSITY
CONDITIONING, THE INFUSED DRUG
PRODUCT HSC COMPETES WITH
RESIDUAL YOU'LL ENDOGENOUS HSC.
THE ADVANTAGES INCLUDE LESS
ACUTE SIDE EFFECTS, LESS DAYS IN
HOSPITAL FOLLOWING TRANSPLANT,
LESS CHEMOTHERAPY EXPOSURE, LESS
RISK OF INFERTILITY.
I WAS ACTUALLY VERY PLEASED TO
HEAR THE PREVIOUS SPEAKER TALK
ABOUT -- HAVING THE LOWEST RISK
OF INFERTILITY, AND LESS
TECHNICAL KNOW-HOW REQUIRED.
BESIDES THERE HAVE BEEN VERY
ELEGANT STUDIES IN TRANSPLANT
SHOWING PATIENTS WITH SICKLE
CELL ANEMIA WHO DEVELOP
PERSISTENT MIXED CHIMERISM HAVE
AMELIORATION OF ALL THEIR
DISEASE SYMPTOMS.
SO WE THEREFORE HYPOTHESIZE THAT
WITH RIC, A HIGH DOSE AND POTENT
VECTOR WE CAN PROVIDE A STRONG
SELECTIVE ADVANTAGE TO
GENETICALLY MODIFIED RED BLOOD
CELLS AND THIS MAY SUFFICE.
SO THE MOMENTUM STUDY IS A PHASE
I/II TRIAL OF ARU-1801 UTILIZING
REDUCED INTENSITY CONDITIONING
IN PATIENTS WITH SEVERE SICKLE
CELL DISEASE, FROM CINCINNATI
CHILDREN'S.
HERE WE HAVE THE STANDARD
INCLUSION CRITERIA OF PATIENTS
WITH VERY SEVERE DISEASE, AND
THE KEY EXCLUSION CRITERIA WERE
HISTORY OF STROKE OR PATIENTS
WITH ALPHA THALASSEMIA, TWO OR
MORE GENE DELETIONS.
PATIENTS WERE ENROLLED, THEY
WERE GIVEN TRANSFUSIONS,
PERIPHERAL STEM CELLS WERE
COLLECTED.
THE FIRST TWO PATIENTS, WE DID
BONE MARROW COLLECTION.
SUBSEQUENT PATIENTS WERE
APHERESED, TRANSDUCED FOR 36
HOURS AND PATIENTS WERE INFUSED
ON THE SECOND DAY AFTER GETTING
MELPHALAN.
SO WE'VE DONE SEVEN PATIENTS SO
FAR, AND THIS -- THE MEDIAN CD34
PLUS CELL DOSE AND MEDIAN DRUG
PRODUCT VECTOR COPY NUMBER OF
.47.
ONE PATIENT, PATIENT 2, HAD
INADEQUATE MELPHALAN EXPOSURE
BECAUSE HE A HIGH GFR RATE.
AND CLEARED HIS MELPHALAN.
SO THIS ILLUSTRATES THAT THIS
EXPOSURE I SHOWED YOU IS
ACTUALLY A REDUCED INTENSITY
CONDITIONING EXPOSURE.
AND IT RESULTS IN A MEDIAN
NEUTROPENIA OF EIGHT DAYS, SHOWN
ON YOUR RIGHT.
AND THROMBOCYTOPENIA OF --
THROMBOCYTOPENIA OF FIVE DAYS.
WE ALSO DID -- WE HAD THE USUAL
REDUCED INTENSITY TRANSPLANT
RELATED MUCOSITIS AND THE
EXPECTED CHEMOTHERAPY-RELATED
ADVERSE EVENTS THAT WERE MILD
AND RESOLVED WITHIN A WEEK, JUST
IN PARALLEL WITH THE RESOLUTION
OF THE CYTOPENIA.
THESE PATIENTS, ALL OF THEM HAVE
HAD INTEGRATION SITE DEVELOPMENT
AND POLYCLONAL ENGRAFTMENT
AND -- LO LEUKEMIA/LYMPHOMA PAN,
FISH AND NGS FOR LEUKEMIA
ASSOCIATED -- AND THEY'RE
NEGATIVE.
SO FOR ALL SIX PATIENTS, PATIENT
2 AS I SAID HAS A DECREASING HBF
16D BECAUSE HAD INADEQUATE
EXPOSURE BUT THE REST HAD STABLE
EXPOSURE AND STABLE VCN LEVELS
AND THEY ARE ABOUT 77% OF THE
DRUG PRODUCT WE S VCN.
SO IN CONCLUSION, ARU-1801 GENE
THERAPY WITH REDUCED THERAPY
CONDITIONING HAS HIGH LEVELS OF
ANTISICKLING HEMOGLOBIN AT A
RELATIVELY MODDI MODEST GCN.
THE IN VIVO, VCN WAS ABOUT .4.
THE IMPROVEMENT IN ENGRAFTMENT,
IF WE IMPROVE THE ENGRAFTMENT OR
VCN FURTHER, IT WOULD RESULT IN
EVEN HIGHER ANTISICKLING
GLOBINS, AND IT MAY BE A
PROMISING ALTERNATIVE TO
THERAPIES REQUIRING
MYELOAPLAYTIVE CONDITIONING.
HOWEVER LATE LAST YEAR, ARUVANT
DECIDED TO STOP FURTHER
DEVELOPMENT OF ARU-1801.
AND SO THE IND IS BACK WITH
CINCINNATI CHILDREN'S AND WE'RE
GOING TO CONTINUE THIS TRIAL,
USE A NEW METHOD TO IMPROVE
HOMING AND AND ENGRAFTMENT OF
SPECIFICALLY GENETICALLY
MODIFIED HSCs.
WE'VE DEVELOPED A PACKETING
SYSTEM WHERE WE CAN DELIVER A
HOMING RECEPTOR CXCR4 AS A
PROTEIN DELIVERY IN THE LENT
VIRAL.
WE DID A PROOF OF CONCEPT IN
MICE WHERE THIS LENTIVIRAL
VECTOR, THE GENETIC -- IS THE
SAME, BUT THE VECTOR CARRIES THE
CXCR4 LATCHED ON TO THE --
PROTEIN.
WHEN WE TRANSPLANTED NSG MICE
WITH THE CONTROL GFP LENTIVIRUS
OR THE CXCR4 CARRYING
LENTIVIRUS, IF YOU SEE ON THE
LEFT, THOSE WE GAVE CD34 CELL
DOAN'S INTRAVENOUSLY OR DIRECTLY
INTO THE BONE MARROW.
AND OF COURSE WITH THE BONE
MARROW, WE ALWAYS SEE A FOUR
FOLD HIGHER ENGRAFTMENT IN THE
LONG TERM, BUT IF WE GIVE THE
CXCR4 ANTIVIRAL VECTOR, WE SEE A
FOUR FOLD HIGHER ENGRAFTMENT IF
WE DELIVER THE CD34 CELLS IV,
AND A 14 -- HIGHER ENGRAFTMENT
IF WE DELIVER THEM INTRABONE
MARROW.
THIS IS SPECIFICALLY ONLY IN THE
GFP-POSITIVE CELLS, BECAUSE
THOSE ARE THE CELLS THAT GOT THE
VECTOR.
SO WE THINK THAT THIS METHOD
WILL REALLY IMPROVE GENE THERAPY
WITH REDUCED INTENSITY
CONDITIONING TO EVEN A HIGHER
ANTISICKLING LEVEL.
AND WITH THAT, I WOULD LIKE TO
THANK MY TEAM.
IT TAKES A VILLAGE TO DO THIS,
AND I'LL END HERE.
>>SO OUR NEXT SPEAKER -- SO NOW
WE ARE GOING TO SWITCH GEARS AND
DR. MITCH WEISS IS GOING TO
INTRODUCE GENE EDITING
STRATEGIES AND TALK ABOUT HIS
DATA, HEMOGLOBIN F INDUCTION
WITH GENE EDITING.
>>HI.
THANK YOU FOR INNOVATING ME.
I'M MITCH WEISS.
I'M A RESEARCH HEMATOLOGIST AT
ST. JUDE, AND THANK YOU GUYS FOR
INVITING ME.
I'M GOING TO TALK ABOUT GENOME
EDITING TO INDUCE FETAL
HEMOGLOBIN.
THIS IS THE PROTOCOL FOR
AUTOLOGOUS STEM CELL THERAPIES.
I THINK YOU ALL KNOW THAT.
AND THE REMARKABLE THING THAT
WE'RE HEARING ABOUT TODAY IS
THAT THERE IS A TREMENDOUS
NUMBER AND GROWING OF WAYS TO
MANIPULATE AUTOLOGOUS PATIENT
CELLS GENETICALLY TO TREAT AND
HOPEFULLY CURE FETAL HEMOGLOBIN.
I WAS ASKED TO TALK ABOUT J
GENETIC INDUCTION OF FETAL
HEMOGLOBIN USING CAS NINE
NUCLEASE OR BASE EDITING.
I WANT TO EMPHASIZE THAT THERE'S
A LOT OF APPROACHES AND THE BEST
ONES AREN'T KNOWN AND THE ONLY
WAY TO FIND THAT OUT IS IN
LONG-TERM STUDIES LIKE THE ONES
WE'VE HEARD THIS MORNING WHERE
WE TRACK ORGAN OUTCOME OVER TI
TIME.
WE ALL KNOW THAT SICKLE CELL
DISEASE BECOMES SYMPTOMATIC
AROUND BIRTH, AND THIS IS COENS
DENT WITH THE GAMMA TO BAY THAT
GLOBIN SWITCH SHOWN AT THE
BOTTOM.
GAMMA GLOBIN IS TURNED OFF AND
BETA GLOBIN IS TURNED ON, AND WE
GO FROM A OR S IF YOU'RE HBB --
AND IT'S MUTATED IN SICKLE CELL
DISEASE.
WE ALSO KNOW THAT ELEVATED FETAL
HEMOGLOBIN AMELIORATES SICKLE
CELL DISEASE.
THIS IS AN OLD SLIDE FROM PLATT
SHOWING YOU LIVE HIGHER IF YOU
HAVE HIGHER HEMOTBLOA BINS IN
SICKLE CELL DISEASE.
WE ALSO KNOW THAT THERE IS A
BENIGN GENETIC CONDITION CALLED
HEREDITARY PERSISTENCE OF FETAL
HEMOGLOBIN AND IF YOU COINHERIT
IT WITH SICKLE CELL DISEASE,
YOU'RE WAY BETTER OFF AND MAYBE
CAN HAVE ALL OF THE PROBLEMS OF
SICKLE CELL DISEASE ELIMINATED.
WE KNOW THAT SOME FORMS OF HPFH,
THE KNOWN DELETIONAL FORMS ARE
CAUSED BY MUTATIONS IN GAMMA
GLOBIN GENE PROMOTERS.
POINT MUTATIONS OR SMALL
DELETION.
SO BECAUSE OF THIS, BEING ABLE
TO TURN ON FETAL HEMOGLOBIN IN
SICKLE CELL PATIENT RED BLOOD
CELLS OR RED CELL PRECURSORS HAS
BEEN A HOLY GRAIL, AND PEOPLE
HAVE BEEN WORKING AT IT FOR A
LONG TIME.
BUT NOW, TWO THINGS HAVE COME
TOGETHER TO REALLY REVOLUTIONIZE
THE FIELD.
GENETIC ENGINEERING TECHNOLOGIES
AND MECHANISTIC INSIGHTS INTO
GLOBIN GENE SWITCHING.
AND TOGETHER, THESE TWO THINGS
HAVE ACCELERATED PROGRESS
TREMENDOUSLY.
SO WHAT I'M GOING TO TELL YOU
ABOUT IS ONE OF THE MAJOR TOOLS,
WHICH IS CRISPR/CAS 9 RNA-GUIDED
NUCLEASES.
THIS WAS ADAPTED FROM A
BACTERIAL SYSTEM TO DEFEND
AGAINST VIRUSES.
AND WHAT WE MEAN, CAS9 IS A
PROMMABLE NUCLEASE AND WHAT WE
MEAN IS SHOWN ON THE RIGHT.
CAS9 COMBINES WITH SOMETHING
CALLED A GUIDE RNA THAT'S
COMPLEMENTARY TO SEQUENCES IN
THE GENOME THAT YOU WANT TO
MODIFY.
AND SO THAT'S SHOWN ON THE
RIGHT.
THE GUIDE RNA WILL TAKE CAS9 TO
A DESIRED SITE ANYWHERE IN THE
GENOME, AND ONCE THE CAS9 FINDS
ITS PLACE IN THE GENOME, IT WILL
CREATE A DOUBLE STRANDED DNA
BREAK.
I SHOULD ALSO POINT OUT, I THINK
YOU ALL KNOW THAT THE NOBEL
PRIZE IN CHEMISTRY WAS WON BY
JENNIFER -- IN 2020 FOR THIS
TECHNOLOGY.
SO CAS9 FIND ITS PLACE ON THE
DNA AND IT CREATES A DOUBLE
STRAND DNA BREAK.
CELLS DON'T LIKE DOUBLE STRAND
DNA BREAKS AND THEY TRY VERY
HARD TO CORRECT THEM QUICKLY,
AND THERE'S TWO WAYS TO CORRECT
A DOUBLE STRAND DNA BREAK.
THE FIRST ONE IS SHOWN ON YOUR
LEFT, NON-HOMOLOGOUS END
JOINING.
THIS IS A FAST WAY TO CORRECT
THINGS BUT IT'S IMPERFECT.
SO THE CELL WILL KR CREATE SMALL
INSERTIONS OR DELETIONS AT THE
SITE OF THE FUSION OF THE TWO
BROKEN ENDS.
ANOTHER MECHANISM THAT CELLS
HAVE IS CALLED HOMOLOGY DIRECTED
REPAIR OR HDR.
AND THAT OCCURS IN THE PRESENCE
OF A DONOR TEM PRAIT.
SO YOU PUT A TEMPLATE INTO THE
CELLS THAT LOOKS LIKE THE SITE
THAT NEEDS TO BE REPAIRED, BUT
IT COULD HAVE SMALL CHANGES IN
IT LIKE A NORMAL CODON AT
POSITION SIX INSTEAD OF THE
MUTATED VALENE.
THIS IS A VERY PRECISE WAY TO
CORRECT THINGS, AND YOU YOU CAN
CAN USETHIS TO CORRECT SICKLE CL
MUTATIONS.
SO NON-HOMOLOGOUS END JOINING IS
IMPRECISE.
IT OCCURS AT HIGH RATES IN
HEMATOPOIETIC STEM CELLS AND
IT'S EASY TO PERFORM.
ON THE OTHER HAND, HOMOLOGY
DIRECTED REPAIR IS VERY PRECISE,
BUT IT OCCURS AT LOW RATES IN
HEMATOPOIETIC STEM CELLS AND
IT'S TECHNICALLY DIFFICULT.
AND WE'LL HEAR MORE ABOUT THIS
LATER IN THE SESSION FROM MATT.
NON-HOMOLOGOUS END JOINING CAN
BE USED TO INDUCE FETAL
HEMOGLOBIN, AND HDR CAN BE USED
TO CORRECT THE SICKLE CELL
MUTATION.
SO NOW LET'S TALK ABOUT INSIGHTS
INTO GLOBIN SWITCHING.
WE KNOW THAT PERINATAL SILENCING
OF GAMMA GLOBIN OCCURS BY
TRANSCRIPTIONAL REPRESSION.
TWO REPRESSOR PROTEINS BIND THE
REGION OF THE GAMMA GLOBIN
PROMOTER AT BIRTH, ZBTB7A AND
BCL11A.
THEY CONTRIBUTE ABOUT 50/50 TO
REPRESSION.
WE ALSO KNOW THAT SOME NATURALLY
OCCURRING HPFH VARIANTS ARE
MUTATIONS THAT BLOCK THE ABILITY
OF THESE PROTEINS TO BIND DNA.
THESE HPFH MUTATIONS ARE SHOWN
HERE.
SO JUST LIKE THE HPFH MUTATIONS,
WE CAN USE CAS9 TO DIRECT
NON-HOMOLOGOUS END JOINING TO
DESTROY THESE REPRESSOR BINDING
SITES AND RE-CREATE THOSE HPFH
MUTATIONS.
THIS IS AN EXAMPLE FROM MY LAB
SHOWN HERE.
WE USED CAS9 AND A GUIDE RNA TO
DISRUPT THAT BCL11 BINDING SIDE
IN THE GAMMA GLOBIN -- TURN THEM
INTO RED CELLS BY IN VITRO
ERYTHROID DIFFERENTIATION AND
MEASURED FETAL HEMOGLOBIN.
WHAT YOU SEE IS THE RESULTS
HERE, THAT WHEN WE ARE EDIT CAN
CAS9 IN THE GUIDE RNA, FETAL
HEMOGLOBIN DWOAS GOES UP IN THOD
CELLS AS SHOWN BY THIS FLOW
CYTOMETRY PLOT.
SO THAT'S THE APPROACH THAT I
JUST SHOWED YOU IS ON THE LEFT.
AND THIS IS BEING TESTED IN A
CLINICAL TRIAL RIGHT NOW BY
EDITAS MEDICINE AND WE ARE
PLANNING TO DO SOMETHING SIMILAR
AT ST. JUDE.
THERE'S ALSO ANOTHER CAS9
NUCLEASE APPROACH.
AND THIS IS TO USE CAS9 TO
DISRUPT A CRITICAL SITE, A RED
CELL ERYTHROID-SPECIFIC ENHANCER
FOR THE BCL11A GENE ITSELF.
AND WHAT THIS DOES IS IT REDUCES
BCL11A EXPRESSION IN ERYTHROID
CELLS, AND THAT RAISES FETAL
HEMOGLOBIN.
AND THIS IS BEING EXAMINED IN A
CLINICAL TRIAL BY VERTEX.
I SHOULD SAY THAT THESE TWO
CLINICAL TRIALS FROM VERTEX AND
EDITAS ARE LOOKING PRETTY GOOD.
VERTEX IS FURTHER ALONG, BUT I
THINK THEY BOTH ARE PROMISING.
NOW THERE ARE THREE OTHER HPFH
VARIANTS THAT ARE DIFFERENT.
THESE INSTEAD OF BLOCKING
REPRESSOR BINDING SITES, THEY
CREATE NEW BINDING SITES FOR
TRANSCRIPTION FACTORS.
AND THESE ARE SHOWN HERE, A NEW
KLF1, TAL1 OR GATA1 MOTIF.
THEY CAN BE CREATED WITH BASE
EDITORS.
SO WHAT IS A BASE EDITOR?
A BASE EDITOR IS A CATALYTICALLY
IMPAIRED FORM OF CAS9.
IT DOESN'T CREATE DOUBLE STRAND
DNA BREAKS.
AND IT'S FUSED TO A DEAM NAIZ
THAT CAN CONVERT A TO G OR C TO
T.
SO WE USED THIS APPROACH TO
COMPARE -- WE COMPARED FIVE
DIFFERENT APPROACHES FOR FETAL
HEMOGLOBIN INDUCTION.
ALL OF THESE I'VE SHOWED YOU.
TWO CAS9 AND THREE WITH BASE
EDITORS TO CREATE NEW TRAN SCRIP
TORE BINDING SITES.
THIS IS A COLLABORATION BETWEEN
MY GROUP AND THE INDIVIDUALS
SHOWN HERE, INCLUDING DAVID LIU,
WHO INVENTED BASE EDITORS, AND
GREG NEWBY, WHO'S GOING TO TALK
IN THIS SESSION.
SO THESE ARE THE REQUIREMENTS,
WE THINK, FOR IDEAL THERAPEUTIC
INDUCTION OF FETAL HEMOGLOBIN.
MORE IS BETTER AND YOU NEED IT
IN ALL RED CELLS.
SO WE TREATED CD34 CELLS WITH
ABE, A BASE EDITORS OR CAS9 AND
WE MADE RED CELLS OUT OF THEM.
WE MEASURED FETAL HEMOGLOBIN.
YOU SEE ON THE LEFT HERE THAT
THE EDITING FREQUENCY IS HIGHER
FOR THE CAS9 APPROACHES, LOWER
FOR THE BASE EDITING APPROACHES.
BUT THE FETAL HEMOGLOBIN LEVELS
ARE ACTUALLY HIGHER COMPARED TO
BASE EDITING FORECAST 9.
IF YOU NORMALIZE FETAL
HEMOGLOBIN LEVELS PER PERCENT
EDITING YOU SEE WAY HIGHER
LEVELS FOR THESE BASE EDITING
APPROACHES.
AND WE FOUND THAT WE FOLLOWED UP
ON THE MINUS 175A TO G APPROACH
BECAUSE IT INDUCES FETAL
HEMOGLOBIN MOST POTENTLY.
WE THINK WE UNDERSTAND THE
MECHANISM OF THIS.
THIS MUTATION CREATES A NEW
BINDING SITE FOR TRANSCRIPTION
FACTOR TAL1 IN DNA THAT'S NEXT
TO A GATA1 SITE.
AND THIS CREATES A BINDING SITE
FOR A TRANSCRIPTIONAL COMPLEX
CONSISTING OF THESE MULTIPLE
PROTEINS.
THIS COMPLEX IS ALREADY PRESENT
AT THE LOCUS CONTROL REGION AND
UPSTREAM ENHANCER IN THE BETA
GLOBIN LOCUS.
AND WHEN YOU HAVE A NEW
TAL1 BINDING SITE CREATED BY
THIS MINUS 175A TO G, THIS
COMPLEX BINDS HE HERE, AND ONE F
THE COMPONENTS, LDV1, INTERACTS
WITH ITSELF.
WHAT IT DOES IS IT BRINGS THIS
STRONG ENHANCER NEXT TO THE
GAMMA GLOBIN GENES AND TURNS IT
ON.
SO WE PERFORM PROOF OF CONCEPT
STUDIES IN HEMATOPOIETIC -- TO
SEE IF WE CAN EDIT HEMATOPOIETIC
STEM CELLS.
WE ELECTROPORATEDCD34 HUSBAND
CELLS WITH -- WE PERFORMED BASE
EDITING, TRANSFERRED THESE CELLS
INTO IMMUNODEFICIENT MICE AND
ANALYZED THE DONOR CELLS AT 16
WEEKS.
WHAT WE SEE HERE AGAIN IS THE
EDITING EYE EFFICIENCIES ARE
LOWER WITH THE BASE EDITORS AND
WE'RE WORK ON THIS.
THESE HAVE TO BE IMPROVED.
BUT STILL THE FETAL HEMOGLOBIN
SELECTION IS HIGHER IN THESE
MICE.
IF WE PLOT PERCENT EDITING
VERSUS PERCENT FETAL HEMOGLOBIN,
THE BASE EDITORS DO MUCH BETTER
THAN THE CAS9 APPROACH.
WHEN WE DO CLONAL ANALYSIS OF
HEMATOPOIETIC COLONIES, WHAT WE
SEE IS THAT WITH THE CAS9
APPROACHES, ALMOST EVERY RED
CELL COLONY, EVERY PRECURSOR OR
STEM CELL GETS EDITED.
BUT WE'RE MISSING ABOUT 20%
EDITING WITH THE ABE APPROACHES
AND SO AGAIN, I THINK IN ORDER
TO REALLY MAKE THIS WORK WELL,
WE HAVE TO INCREASE THE EDITING
FREQUENCY OF THE BASE EDITOR.
I THINK THIS IS THE LAST DATA
SLIDE.
THIS IS A LITTLE COMPLICATED.
I'LL JUST GO FROM HERE.
I'LL JUST SHOW YOU THIS ONE.
THIS SHOWS PERCENT FETAL
HEMOGLOBIN IN CLONES, IN EDITED
COLONIES.
AND EVERY ONE OF THESE COLONIES
HAS FULL EDITING.
SO WE'RE JUST COMPARING THE
POTENCY OF THE EDITING.
AND WHAT WE SEE HERE IS THAT IN
THE CAS9 NUCLEASE APPROACHES,
THE PERCENT FETAL HEMOGLOBIN HAS
A BIG SPREAD.
THERE'S A LOT OF VARIABILITY.
BUT WITH THIS MINUS 175, THERE'S
A VERY TIGHT INDUCTION OF FETAL
HEMOGLOBIN THAT IS VERY HIGH.
ARE .AM I 3 MINUTES OVER?
SORRY, YOU'RE BEING VERY POLITE.
MAYBE I GOT A BREAK SINCE WE
HAVE TO SAY "NEXT SLIDE."
SO THIS IS THE CONCLUSION.
SO WHAT I SHOWED YOU IS THAT THE
BASE EDITOR APPROACHES THAT
CREATE NEW TRANSCRIPTION FACTOR
BINDING SITES ARE MORE POTENT
THAN THE CAS9 APPROACHES.
WHAT I'VE WRITTEN HERE IS THAT
THE TRANS ACTIVATION BY MINUS
175A TO G OVERRIDES DUAL
REPRESSION.
AND WHAT I MEAN IS I TOLD YOU
THAT THESE TWO REPRESSORS, EACH
REPRESS ABOUT 50/50.
HERE I HAVE 40/40.
BUT THIS GOES UP TO ABOUT 80% AT
ANY GIVEN GENE, SO IT OVERCOMES
THE ACTIVITIES OF TWO
REPRESSORS.
THIS EDIT PRODUCES MORE POTENT
FETAL HEMOGLOBIN INDUCTION WITH
MINIMAL DOUBLE STRAND DNA
BREAKS, AND WHAT I KIND OF
SHOWED YOU BUT I WENT THROUGH
QUICKLY IS NOT ALL CAS9 INDELS
RAISE FETAL HEMOGLOBIN EQUALLY.
WHAT THAT SAYS IS THE DIVERSE
INDELS, DIFFERENT SIZE DELETIONS
OR INSERTIONS GENERATED BY CAS9
NUCLEASE CAN CAUSE UNEXPECTED
VARIATIONS IN BIOLOGICAL
OUTCOMES.
AND THOSE CAN BE OVERCOME BY THE
PRECISION OF BASE EDITING.
AND FOR THAT REASON,
ADENOSINE-BASED EDITORS MAY BE A
SUPERIOR APPROACH FOR
THERAPEUTIC FETAL HEMOGLOAN
INDUCTION AN THAT'S BEING TESTED
IN A CLINICAL TRIAL RIGHT NOW BY
BEAM THERAPEUTICS.
I'M NOT SURE IF THEY'VE ENROLLED
THEIR FIRST PATIENT YET BUT
WE'LL FIND OUT.
SO AGAIN, THERE ARE A LOT OF
TECHNOLOGIES, AND WE HAVE TO
COMPARE THEM HEAD TO HEAD.
AND WHAT WE NEED TO DO THAT ARE
YOU INCLUDE NICHES OUT THERE WHO
ARE GOING TO FOLLOW THESE
PATIENTS FOR A LONG TIME.
OKAY.
I WANT TO THANK MY ORGANIZERS
FOR GIVING ME EXTRA TIME.
AND APOLOGIZE, AND THESE ARE MY
COLLABORATORS, THE MAIN ONES I
ALREADY MENTIONED, AND WE THANK
OUR FUNDING SOURCES, AND THANK
YOU GUYS.
>> THANK YOU, MITCH THE THE
NEXT SPEAKER IS PRESENTING
VIRTUALLY FROM PARIS ON
PRE-CLINICAL RESULTS ON BASE
EDITING TO REACTIVE FETAL
HEMOGLOBIN.
DR. ANNARITA MICCIO.
>>THIS IS A VIDEO TALK.
>>SO GOOD MORNING, EVERYBODY.
FIRST I WOULD LIKE TO THANK THE
ORGANIZERS FOR THE INVITATION,
AND TODAY I WILL DISCUSS EDITING
APPROACH TO SEQUENCE OF DISEASE,
IN PARTICULAR TO REACTIVATE
FETAL HEMOGLOBIN.
AS YOU HEARD, APPROACHES FOR
SICKLE CELL DISEASE HAVE BEEN
DEVELOPED USING CRISPR/CAS
9 SYSTEM BUT MORE RECENTLY ALSO
USING NOVEL EDITING PLATFORMS
SUCH AS BASE EDITORS.
SO THE CRISPR/CAS 9 NUCLEASE
SYSTEM HAS BEEN USED TO DEVELOP
THERAPEUTIC STRATEGY FOR SICKLE
CELL DISEASE AS IT GENERATES
DOUBLE STRAND BREAK IN THE
TARGET SITE THAT CAN BE REPAIRED
EITHER TO CORRECT THE GENES
THROUGH HDR OR BY GENERATING
THROUGH JOINING.
DOUBLE STRAND BREAK CAN INDUCE
RESPONSE, CAN ALSO CAUSE
REARRANGEMENTS.
STRATEGIES FOR SICKLE CELL
DISEASE, USING APPROACHES SUCH
AS BASE EDITORS THAT CAN MAKE C
TO T OR A TO G CONVERSION OR
PRIME EDITING TO CAN INDUCE
CONVERSION OR FINALLY EP GINO
EDEEPIGENOMEEDITOR FOR ACTIVE OE
TRANSCRIPTION.
IN PARTICULAR BASE EDITOR CAN
MAKE THESE PINPOINT CHANGES IN
THE DNA AS THEY CONTAIN -- THAT
MAKES ONLY SINGLE STRAND BREAKS
THAT FACILITATE CONVERSION IN C
TO G OR A TO G CONVERSION.
SO EDITING APPROACHES INCREASING
THE LEVEL OF FETAL HEMOIMLOA BI-
BY PERSISTENCE OF FETAL GAMMA
GLOBIN, TYPICALLY ASSOCIATED
WITH GENETIC VARIANCE.
SO OUR FIRST STRATEGY TO
REACTIVATE IS TO KNOCK OUT BC
BCL11, AND THIS CAN BE ACHIEVED
BY GATA1, BASICALLY BY
DELETING -- TO -- JOINING.
CURRENTLY BEING TESTED IN
CLINICAL TRIAL.
INTERESTINGLY, BASE EDITOR HAS
BEEN USED TO INACTIVATE
GATA1 ACHIEVING HIGH BASE
EDITING EFFICIENCY IN PROGENITOR
CELLS FROM SICKLE CELL DISEASE
PATIENT.
AND THIS LED TO FETAL HEMOGLOBIN
ACTIVATION IN THE PHENOTYPE.
SO TO FACTOR INCREASED FETAL
HEMOGLOBIN EXPRESSION, -- TO
ENHANCE THE BCL11 GENE USING
BASE EDITORS.
IN PARTICULAR, DUAL EDITING --
PRIMARY HSPCs FROM SICKLE CELL
DISEASE PATIENTS LED TO HIGHER
EXPRESSION COMPARED TO THE
SINGLE EDITING.
WITHOUT ALTERING THE --
POTENTIAL OF HSPCs.
AND THEN ANOTHER POTENTIAL
TARGET TO REACTIVATE FETAL
HEMOGLOBIN IS -- DISRUPT THE
BINDING SITE FOR TRANSCRIPTION
OF REPRESSOR OR GENETIC --
TRANSCRIPTION ACTIVATORS.
SO WE HAVE INITIALLY USED THE
CRISPR/CAS 9 SYSTEM FROM THE
GAMMA GLOBIN PROMOTER --
REPRESSOR BY -- INSIGHT
THROUGH -- CURRENTLY BEING
TESTED IN CLINICS.
ALSO IN THIS CASE WE DECIDED
TO -- TO TARGET THIS REGION AS
THEY CAN PRECISELY -- INHIBITING
THE BINDING OF REPRESSORS BUT --
RECRUITING TRANSCRIPTIONAL
ACTIVATORS.
AND IN PARTICULAR, CBEs CAN BE
USED TO GENERATE -- OF THE GAMMA
GLOBIN PROMOTERS THAT DISRUPT
THE REPRESSOR BINDING SITE.
AND IN THE REGION, THIS EDITOR
CAN BE USED TO MAKE T TO C
CONVERSION AND GENERATE THE --
ACTIVATOR BINDING SITE.
-- IN MY LAB -- GENERATED
THE -- IN HSPs FROM SICKLE
CELL DISEASE PATIENTS, ACHIEVING
BASE EDITING EFFICIENCY OF
BETWEEN 40 AND 50%, WITH LOW OR
ABSENT DOUBLE STRAND BREAK
INDUCED -- COMPARED TO THE
CAS9 -- WHERE WE USE THE
PREVIOUSLY DEVELOPED STRATEGY
DELETING THE -- BINDING INSIDE.
THE ANALYSIS SHOWED REACTIVATION
IN SAMPLES WHICH WAS EVEN HIGHER
THAN IN CRASS 9 TRE CAS9 TREATES
AND -- SAMPLES WAS LOWER
COMPARED TO THE CAS9 TREATED
SAMPLES.
-- SUFFICIENT TO CORRECT THE --
PHENOTYPE.
IMPORTANTLY TYPICALLY OBSERVED
UPON DOUBLE STRAND BREAK -- WAS
NOT DETECTED IN BASE EDITED
CELLS AND MODEST -- SAMPLES.
SO TO IMPROVE THIS EDITING
EFFICIENCY WE TESTED SEVERAL
DRUGS THAT COULD IMPROVE IN H
SPCs, PROTOCOLS OR IN THE CASE
OF THIS EDITOR -- ABE WHICH
INCREASED BASE EDITING
EFFICIENCY.
AND WE HOPE TO BRING THIS
APPROACH SOON TO THE CLINICS.
WE ALSO -- ENRICHING FOR EDITS
CELLS, THE GAMMA GLOBIN PROMOTER
TO GENETICALLY -- OR DISRUPT
TORE -- AND FROM THE OTHER SIDE
OF THE GENE ENCODING FOR A
SURFACE MARKERS SUCH AS CD33.
SO THE IDEA WAS THAT THE
SELECTION OF CD33 NEGATIVE CELLS
WOULD DELETE TO HIGH BASE
EDITING EFFICIENCY -- POORLY
EDITED CELLS.
MULTIPLE -- STRONGLY IMPACTED
THE -- EXPRESSION IN SICKLE CELL
DISEASE PATIENTS -- CD34, A
MARKER OF PROGENITOR CELLS.
INTERESTINGLY WE OBSERVED HIGHER
BASE EDITING EFFICIENCY AT THE
GABA GLOBIN PROMOTER IN THE --
POPULATION WHILE IMPORTANTLY --
DID NOT AFFECT THE PROGENITOR
VARIABILITY.
AND THEN I BRIEFLY MENTIONED TO
YOU OTHER STRATEGIES SUCH AS
PRIME EDITING AND EP GINO EP EE
EDITING.
-- ALL THIS CONVERSION IT CAN
ALLOW TO -- AS IT WILL BE
DISCUSSED LATER IN THE SESSION.
AND AS PRIME EDITING CAN
GENERATE MULTIPLE MODIFICATION,
WE DECIDED TO INTRODUCE MULTIPLE
HBF -- THAT TOGETHER CAN BOOST
FETAL HEMOGLOBIN EXPRESSION.
IN PARTICULAR, WE'VE CHOSEN TO
INTRODUCE TWO MUTATIONS IN
EDITING SITES AS WE DEMONSTRATED
IN THE PRESENCE OF BOTH BINDING
SITES LEADS TO HIGHER FETAL
HEMOGLOBIN EXPRESSION COMPARED
TO THE INTRODUCTION OF
INDIVIDUAL SITES.
AND WE ARE CURRENTLY OPTIMIZING
THE FREQUENCY OF CONCOMITANT
INTRODUCTION OF BOTH AND THEN
MOVE TO PRIMARY CELLS.
AND FINALLY EP JOE K EPIGENOME G
APPROACHES TO SICKLE CELL
DISEASE TO ACTIVATE THE GAMMA
GLOBIN PROMOTERS, REMOVING
REPRESSIVE HISTONE MARKS, OR DNA
METHYLATION, AND WE CAN DO THE
OPPOSITE TO BCL11 -- GENERATING
ANY TYPE OF DNA DAMAGE
WHATSOEVER AS EPIGENOME
EDITOR -- CAS9 WITH NO DNA
CLEAVAGE ACTIVITY.
SO NOW OUR LAB WE FIRST COME
FROM THE GAMMA GLOBIN PROMOTER
HIGHLY METHYLATED WHEN SILENT
WHEN EXPRESSING HIGH LEVEL OF
FETAL HEMOGLOBIN, THEN
METHYLATION IS SUBSTANTIALLY --
ALSO ACQUIRE THE HISTONE MARKS
OF THE -- TYPICALLY ASSOCIATED
WITH ACTIVE TRANSCRIPTION.
AND THEREFORE SIMONE IN MY LAB
USED THE EDITOR -- AND REMOVE
DNA METHYLATION AS ACTIVITY IN
FETAL HEMOGLOBIN EXPRESSION --
ACTIVATION OVER TIME.
AND IN CONCLUSION, I SHOWED YOU
THAT THIS EDITING CAN BE USED
FOR ACTIVATING FETAL HEMOGLOBIN
BY -- GENERATED HB -- I'M PRETTY
SURE THAT MANY MORE TARGETS WILL
BE DISCOVERED IN THE FUTURE, AND
NOVEL AND POTENTIAL SAFER --
POTENTIALLY SAFER EDITING TOOLS
COULD BE ALSO USED FOR THESE
PURPOSES.
HOWEVER I NEED TO MENTION THAT
CAS9 NUCLEASE STRATEGIES -- IN
CLINICS WITH PROMISING RESULT.
BASE EDITING STRATEGIES ARE ALSO
VERY PROMISING AND THE FIRST
CLINICAL TRIAL JUST STARTED WITH
THE FIRST PATIENT.
FINALLY I WOULD LIKE TO THANK
ALL THE MEMBERS OF MY LAB,
COLLABORATORS, FUNDING AGENCY
AND ESPECIALLY CLINICIANS AND
PATIENT AND YOU FOR YOUR
ATTENTION.
I. WILLI WILL BE HAPPY TO TAKE
QUESTIONS.
THANK YOU.
>>THANK YOU.
WITH THAT, I WOULD LIKE TO
INTRODUCE GREG NEWBY TO GIVE THE
NEXT TALK ON PRE-CLINICAL
RESULTS ON BASE EDITING AND
PRIME EDITING IN SICKLE CELL
DISEASE.
>>THANKS TO THE ORGANIZERS FOR
INVITING ME HERE TO TALK ABOUT
THIS WORK.
I JUST STARTED AS A PROFESSOR, A
NEW LAB AT JOHNS HOPKINS, BUT
THE WORK I'LL TELL YOU ABOUT
TODAY WAS DONE WHILE I WAS A
POSTDOCTORAL FELLOW IN THE LAB
OF DAVID LU AT THE BROAD
INSTITUTE IN COLLABORATION WITH
MITCH WEISS AND JONATHAN YEN AT
ST. JUDE.
SO TALKED TODAY ABOUT TWO
DIFFERENT STRATEGIES THAT WE'VE
BEEN DEVELOPING AND SHOWN IN
CELL AND ANIMAL MODELS THAT CAN
MODIFY THE SICKLE CELL MUTATION
ITSELF TO PREVENT SICKLE CELL
DISEASE OR TO TREAT -- HOPEFULLY
CURE THIS CONDITION.
WE REALLY NEED TO ENGINEER A PEE
SPOKE EDITING REAGENT.
IN THIS CASE HERE'S THE MOLECULE
THAT WE SETTLED ON FOR
MODIFICATION BY BASE EDITING OF
SICKLE CELL MUTATION.
HERE'S A SCHEMATIC SHOWING THE
SCWEENS AROUND THE SICKLE CELL
MUTATION WE CAN MAKE A TO G
POINT MUTATIONS WHICH CANNOT
PERFECTLY CORRECT THE T TO A
MUTATION THAT CAUSES SICKLE CELL
DISEASE BUT WE CAN CONVERT THE
CAUSATIVE NUCLEOTIDE INTO A G
WHICH PRODUCES A RARE FORM OF
HEMOGLOBIN CALLED HEMOGLOBIN
MAKASSAR WHICH IS DEBENI BENIGNS
NOT CAUSE DISEASE.
WE DELIVERED -- INTO CELLS FROM
SICKLE CELL PATIENTS.
THESE ARE CD34 HSPCs.
UP TO ABOUT 80% MODIFICATION OF
THE TARGET SICKLE CELL MUTATION
IN BLUE AND BYSTANDER MUTATIONS
WERE LARGELY ABSENT OR SILENT IN
GREEN AND OTHER COLORS THERE, SO
HIGH EFFICIENT EDITING OF OUR
TARGET SITE.
WE COMPARED THIS TO SOME OF THE
APPROACHES USING NUCLEASES TO
TREAT SICKLE CELL DISEASE, IN
THIS CASE, USING CAS9 --
ENHANCER.
THIS IS SHOWN IN RED UP ABOVE
AND WHAT WE'RE LOOKING AT IS
P21, MARKER FOR THE DNA DAMAGE
RESPONSE.
ONE OF THE UNINTENDED OR
UNDESIRABLE OUT OUTCOMES THAT'N
REPORTED FOREC FOR CAS9 CAS9 NUE
TREATMENT.
WITH NO EDITOR AT ALL LEADS TO
THIS TRACE OF THE BLACK LINE,
AND OUR BASE EDITOR LEADS TO THE
BLUE TRACE THERE, SO NO
INDUCTION RE RELATIVE TO A ZERO
EDITOR CONTROL.
ELECTROPELECTROPORATION LEADS TE
DAMAGE ITSELF.
LARGER THAN DESIRED DELETIONS OF
THE TARGET SAY THE CAN BE CAUSED
BY TRANSLOCATIONS OR OTHER
DELETIONS OF 100 TO MANY
KILABASES.
-- THAT'S REMAINING EITHER
NUCLEASE OR BASE EDITOR
TREATMENT.
WE SEE THAT NUCLEASE TREATMENT
LEADS TO A LOSS OF ABOUT 13% OF
ALLELES IN THE RESULTING
SUBPOPULATION WHEREAS BASE
EDITOR TREATMENT LEADS TO NO
CHANGE, SO WE DON'T OBSERVE
THESE LARGER DELETIONS OR
REARRANGEMENTS.
ON THE OTHER HAND, WE DO OBSERVE
A DIFFERENT CLASS OF UNDESIRED
OUTCOMES THAT ARE ASSOCIATED
WITH BASE EDITORS RATHER THAN
CAS9 NUCLEASES WHICH IS OFF
TARGET BASE EDITING.
TO SHOW BOTH OF THESE TOGETHER,
SORRY, BACK ONE, SO WE ASSESSED
ABOUT 700 OFF-TARGET SITES THAT
WE IDENTIFIED VIA CIRCLE SEQ,
EXPERIMENTAL METHOD AND
COMPUTATIONAL SCAN.
OF THOSE 700, WE IDENTIFIED 54
SITES WITH OFF TARGET REAL BASE
EDITING, EACH OF THOSE SITE --
THE MOST EFFICIENT OF THOSE
SITES IS SUMMARIZED AT LEFT WITH
OFF TARGET MOTIFS THEY BIND TO.
AT RIGHT I'M SHOWING THE PIE
CHART OF WHERE THOSE 54 OFF
TARGET SITES FALL.
LARGELY THEY'RE IN SPACE WHERE
WE DON'T EXPECT TO HAVE ANY
PHENOTYPIC IMPACT.
A FEW ARE UTRs BUT SEVERAL
HUNDRED BASE PAIRS AWAY FROM
WHERE WE EXPECT ANY IMPACT.
-- WE DIDN'T SEE ANY THAT SEEM
TO BE CLINICALLY PROBLEMATIC.
HERE I'M SHOWING SOME RESULTS
FOLLOWING A XENOGRAFT OF THESE
EDITED PATIENT HUMAN CELLS INTO
IMMUNOCOMPROMISED MICE TO TRACK
HOW DURABLY THESE CELLS CAN
REPOPULATE THE BONE MARROW.
WE SAW THAT AFTER FOUR MONTHS,
THE ANIMALS THAT RECEIVED OUR
EDITED CELLS MAINTAINED ABOUT
68% ALLELI, C -- THIS WAS
CONSISTENT AMONG ALL WE
ASSESSED.
USING A COLONY ASSAY, WE SAW 80
TO 90% OF CLONES HAD AT LEAST
ONE EDIT WHICH SHOULD BE
PHENOTYPICALLY NORMAL.
THE BOTTOM LEFT HERE, WE SEE
GREATLY REDUCED SICKLING
PROPENSITY QUANTIFIED HERE.
LOOKING AT THE LINEAGES OF CELLS
THAT'S GENERATED AFTER EDITING,
WE SEE NO DIFFERENCE TO THOSE
RECEIVING UNTREATED CELLS.
SO NO DEFECT IN THE CELL
LINEAGES FROM BASE EDITORS.
WE ALSO SIMULATED A AUTOLOGOUS
TRANSPLANT IN INBRED MICE.
WE EXTRACTED THEIR LIN MINUS
HSPCs AND RETRANSPLANTED INTO
MICE.
THESE MICE ARE GENETICALLY
MODIFIED SO THAT THEY CONTAIN
TWO COPIES OF THE SICKLE CELL
ALLELE.
WE ALSO DID THIS PROCEDURE
WITHOUT ANY EDITING AS A
NEGATIVE CONTROL AND USED A
SICKLE CELL TRAIT MOUSE LINE AS
A POSITIVE CONTROL FOR HEALTHY
CELLS.
HEALTHY MICE.
TRANSPLANTED THESE IN,
SACRIFICED THEM 16 WEEKS LATER.
SAW SUBSTANTIAL MAINTENANCE OF
THE EDITED GENOTYPE AND IN BLOOD
BY HPLC WE QUANTIFIED ABOUT 70
TO 80% MACOSARGLOBIN.
HERE WE'RE DOING A COMPLETE
BLOOD COUNT ON THE TRANSPLANTED
BLOOD, AND IN RED ARE THOSE
ANIMALS THAT WERE TRANSPLANTED
WITH UNMODIFIED SICKLE CELLS SO
THESE ARE DISEASE PHENOTYPES IN
TERMS OF THE TOTAL CONCENTRATION
OF HEMOGLOBIN, PERCENTAGE OF RE
RETICULOSITES, -- IN BLUE WE'RE
SHOWING OUTCOMES OF MICE WHO
RECEIVED EDITED CELLS AND THESE
ARE CORRECTED BACK TO THE LEVELS
OF HEALTHY CONTROL, SHOWN IN
PURPLE AND BROWN HERE.
SO THAT'S THE CONCLUSION OF WHAT
I WANTED TO TALK ABOUT BASE
EDITING.
THE SECOND APPROACH IS USING
PRIME EDITING TO CORRECT SICKLE
CELL DISEASE.
FOR MANY OF THESE EXPERIMENTS WE
DID THE VERY SAME ANALYSES WE
DID FOR BASE EDITING SO I'M NOT
GOING TO GO THROUGH ALL OF THEM
BUT I'LL SUMMARIZE.
SO PRIME EDITING ALSO DOES NOT
INVOLVE DOUBLE STRANDED BREAKS,
IT DOESN'T USE A DEAMINASE.
INSTEAD WE DIRECTLY WRITE IN
SEQUENCE INTO A TARGET REGION OF
THE GENOME.
SO WE TOOK CELLS FROM FOUR
SICKLE CELL DONORS HERE AND
ELECTROPROATED THESE WITH
ELECTROPRIME RNA AND
TRANSPLANTED THESE INTO
IMMUNODEFICIENT MICE AND LOOKED
FOUR MONTHS LATER AT HOW
EFFICIENTLY OUR EDITED CELLS
REPOPULATED THE BONE MARROW AND
HEMATOPOIETIC SYSTEM OF THESE
MICE.
IN THIS CASE WE'RE DOING BONE
MARROW ANALYSIS OF THE HUMAN
LINEAGES SO BETWEEN THE FOUR
DONORS, THERE IS SOME
VARIABILITY BUT IN EACH CASE,
WE'VE HAD CONSISTENT MAINTENANCE
OF THE EDITED CELLS OVER THIS
FOUR-MONTH PERIOD.
IN TOTAL, 15 TO 40% OF ALLELES
WERE DURABLY MODIFIED.
THERE'S A CLONAL ASSAY WHERE
WE'RE LOOKING AT WHETHER THIS
EDITING OCCURRED IN ZERO, ONE OR
TWO ALLELES, SO IN EACH CASE,
WE'VE GOT AT LEAST 20 AND UP TO
60% OF THE CELL POPULATION
RECEIVING AT LEAST ONE EDIT.
HERE WE'RE SHOWING THE
QUANTIFICATION OF SICKLING OF
HYPOXIA THIS THESE CELLS
DIFFERENTIATED TO ERYTHROID
CELLS IN VITRO AND RETREATED TO
HYPOXIA.
WE LOOKED AGAIN EXTENSIVELY AT
OFF-TARGET SITES AND WITH PRIME
EDITING WE DID NOT OBSERVE ANY
BEYOND THAT OF AN UNTREATED
CONTROL SO WE WERE DELIGHTED TO
SEE THIS.
AND THE REASON WHY WE EXPECT
THIS TO BE THE CASE IS DUE TO
THE UNIQUE MECHANISM OF PRIME
EDITING THAT HAS NOW THREE
QUALITY CONTROL STEPS WHERE IT
CAN REJECT OFF-TARGET EDITING
OUTCOMES OF FIRST OF THESE BEING
WITH ANY CAS9 KNEW CLEE AIZ O
OR -- MISMATCHES REDUCE THE
EFFICIENCY OF THIS INTERACTION.
THE SECOND IS THE PRIMER BINDING
SITE, SO WE NEED A COMPLEMENTARY
SEQUENCE ON THE GUIDE RNA TO
ANIL TO THE TARGET SITE TO --
ANY MISMATCHES HERE REALLY
REDUCE THE EFFICIENCY OF THIS.
ONCE YOU GET SYNTHESIS OF THE
NEW STRAND OF DNA, THERE'S AN
EQUILIBRATION BETWEEN THE
ENDOGENOUS SEQUENCE AND THE NEW
SEQUENCE WE'VE SYNTHESIZED AND
ANY MISMATCHES IN THE
SURROUNDING REGION CAN REJECT
THE EDITING OUT COME AT THIS
STAGE AS WELL.
ONLY THOSE WITH GOOD HOMOLOGY TO
THE TARGET -- THIS IS WHY WE
THINK THE EDITING WITH PRIME
EDITORS ARE SO EXCLUSIVELY
PRECISE.
SO TO SUMMARIZE WHAT I TOLD YOU,
WE USE BASE EDITING TO CONVERT
THE SICKLE CELL MUTATION TO
BENIGN MAKASSAR AND THIS
CONVERTED THE DISEASE MUTATION
TO THE HEALTHY ONE IN 80 TO 90%
OF DURABLY ENGRAFTED
HEMATOPOIETIC STEM CELLS IN
MICE.
WE ALSO USED PRIME EDITING TO
CONVERT THE SICKLE CELL MUTATION
BACK TO THE WILD TYPE ALLELE,
AND THESE ALSO REPOPULATED MOUSE
BONE MARROW 20 TO 60%
EFFICIENCY.
I EXPECT THAT THERE'S FURTHER
DEVELOPMENT ON BOTH OF THESE
PROCESSES TO GET MORE EFFICIENT
EDITING AND ALSO TO REDUCE
OFF-TARGET ID ITING IN THE CASE
OF A BASE EDITORS.
WE EMPLOYED THE STRONGEST BY FAR
KNOWN DEAMINASE AND BY
FINE-TUNING THAT, I THINK
THERE'S MORE THAN 20 DIFFERENT
VARIANTS THAT HAVE BEEN
PUBLISHED NOW, SO I THINK FUTURE
RESEARCH CAN FIND EVEN MORE
PRECISE AND STILL VERY EFFICIENT
EEDITING STRATEGIES TO IMPROVE
THESE OUTCOMES.
JUST HIGHLIGHTING THAT BOTH OF
THESE STRATEGIES CAN SUPPORT
HEALTHY MULTIPOTENT
HEMATOPOIETIC STEM CELLS.
LONG TERM FOLLOW-UP IS GOING TO
BE NEEDED TO COMPARE THESE AND
ALL THE OTHER ALTERNATIVE
THERAPIES AND REALLY FIND THE
BEST ONE.
LAST SLIDE IS MY ACKNOWLEDGMENTS
OF ALL THE MANY PEOPLE THAT
CONTRIBUTED TO THESE STUDIES.
I WANT TO THANK MITCH WEISS OUR
COLLABORATOR AT ST. JUDE AND
JONATHAN YEN, OUR POSTDOCTORAL
MENTOR WHO LED OUR TIME TEEM AND
KELSEY EVERETT, AND OTHERS WHO
COLLABORATED ON THESE STUDIES.
THANK YOU VERY MUCH.
>>THANK YOU, GREG.
WE'LL PROCEED TO THE NEXT TALK
AND HAVE MAYBE QUESTIONS AT THE
END.
SO THE NEXT TALK IS VIRTUAL BY
HANS-PETER KIEM, AND HE'LL BE
TALKING ABOUT IN VIVO GENE
EDITING TH AND GENE THERAPY FOR
SICKLE CELL DISEASE.
>>I HOPE YOU CAN HEAR ME OKAY?
>>WE CAN HEAR YOU.
>>GOOD MORNING.
THANKS FOR ALLOWING ANDRE AND ME
TO PRESENT OUR VISION HERE FOR
IN VIVO HEMATOPOIETIC STEM CELL
GENE THERAPY FOR SICKLE CELL
DISEASE.
NEXT SLIDE.
THERE ARE MANY DISEASES AND
CONDITIONS THAT COULD BE
TARGETED BY HEMATOPOIETIC STEM
CELL GENE THERAPY AND SOME OF
THOSE ARE LISTED HERE, BUT OF
COURSE THE LARGEST POPULATIONS
ARE PATIENTS WITH SICKLE CELL
DISEASE OR THALASSEMIA, OR
PEOPLE LIVING WITH HIV.
NOW USING EX VIVO GENE THERAPY
APPROACHES, THERE'S BEEN
TREMENDOUS SUCCESS AS YOU'VE NOW
HEARD FROM A NUMBER OF
PRESENTATIONS HERE AND PREVIOUS
SPEAKERS USING EX VIVO GENE
THERAPY APPROACHES AND EDITING
APPROACHES.
HOWEVER, ACCESS TO THOSE
THERAPIES IS HIGHLY LIMITED AS
WE KNOW AND OF THE ABOUT
20 MILLION PEOPLE LIVING WITH
SICKLE CELL DISEASE GLOBALLY,
ONLY ABOUT 25,000 OR SO PATIENTS
COULD BE TREATED WITH CURRENT EX
VIVO GENE THERAPY-BASED
APPROACHES.
THIS IS ALSO BASED ON ESTIMATES
BY CRISPR VERTEX AND -- PROBABLY
ONLY ABOUT 1% PATIENTS LIVING
WITH SICKLE CELL DISEASE WOULD
HAVE ACCESS.
SO MAIN REASON IS -- THE MAIN
REASON IS THE COMPLEX NATURE OF
THE KURN EX VIVO GENE THERAPY
APPROACHES AND PROTOCOLS.
SO THIS JUST OUTLINES A LITTLE
BIT OF THE CURRENT OF COURSE EX
VIVO GENE THERAPY STUDIES,
ACTUALLY -- FAIRLY INTENSIVE
CARE AND SIMILAR TO ALLOGENEIC
TRANSPLANTATION, LENGTHY --
FAIRLY LENGTHY HOSPITALIZATIONS
AND CLEARLY A SPECIALIZED
FACILITIES AND CLINICS TO BE
ABLE TO DELIVER THIS APPROACH.
NOW WE PROPOSE REALLY A --
HOPEFULLY A TRUE OFF THE
SHELF-TYPE ADMINISTRATION OF
THIS GENE THERAPY WITH A SINK EL
SHOT, HOPEFULLY AGAIN ULTIMATELY
AS AN OUTPATIENT TREATMENT
WITHOUT TOXIC PRECONDITIONING OR
PRE-TREATMENT.
SO TO ACCOMPLISH THIS, ANDRE AND
I HAVE BEEN COLLABORATING TO USE
A CAPSID-MODIFIED
HELPER-DEPENDENT ADENOVIRUS
VECTORS REALLY DEVELOPED BY AN
DREE LIEBER IN HIS LAB.
THE BASIC COMPONENTS OF THE
APPROACH ARE LISTED HERE.
THIS CAPSID IS LIKE A TROJAN
HORSE, ALL THE VIRAL GENES HAVE
BEEN REMOVED, WHICH ALLOWS US
NOW TO HAVE LIKE A 35KB CAPACITY
FOR TRANS GENES AND REGULATORS
OR ADDITIONAL COMPONENTS TO
INCORPORATE IN THIS TRANSFER
VECTOR.
THE FIBER KNOB CAN BE MODIFIED
OOR REPLACED AND CHANGED SO THE
CURRENT FIBER KNOB THAT WE HAVE
HAS HIGH AFFINITY TO CD46, WHICH
IS HIGHLY EXPRESSED IN
HEMATOPOIETIC STEM CELLS AND
OTHER BLOOD CELLS.
NOW, WITH THIS, WE CAN HAVE
EFFICIENT HEMATOPOIETIC STEM
CELL TRANSDUCTION, ESPECIALLY
THESE EARLY CD90 POSITIVE CELLS.
THERE'S MINIMAL HEPATOCYTE
TRANSDUCTION AS I WILL SHOW YOU
IN THE NEXT SLIDE AS WELL WITH
THIS FIBER MODIFICATION THAT
WE'VE INCORPORATED.
NOW OF COURSE THERE CAN BE
OTHER -- OTHER CAPSIDS CAN BE
USED AS WELL, AND ONE -- SEVERAL
ADDITIONAL ADVANTAGES ARE
THERE'S AN EP SOMOL VECTOR
SYSTEM SO WE CAN USE BASE AND
PRIME EDITORS, WE CAN USE AN
INTEGRATING SYSTEM.
I WILL SHOW YOU THIS USING A
SLEEPING BEAUTY TRANS POSASE SO
WE CAN INTEGRATE THE PAIR OR WE
CAN AGAIN SIMPLY USE ONE VECTOR
SYSTEM TO DELIVER BASE --
IMPORTANTLY IT'S SIMPLE,
SCALABLE, IT ALLOW FOR SIMPLE
AND SCALABLE MANUFACTURING TO
HOPEFULLY ENABLE GLOBAL REACH.
SO HERE AGAIN YOU CAN SEE AN
EXAMPLE FROM MOUSE STUDIES AT
HOW THIS AD35 FIBER IS TARGETING
THE LIVER.
ON THE RIGHT-HAND SIDE YOU SEE
THERE'S NO LIVER ENZYME
ABNORMALITIES WHEN WE USE THIS
AT 35 FIBER.
SO HERE WE SEE THE DIFFERENT
PLATFORMS AS WE MENTIONED.
YOU SEE THE TWO VECTOR SYSTEM,
ADDITIONAL VECTOR TO FACILITATE
THE INTEGRATION OF THE PAYLOAD
OR HE WI WE CAN SIMPLY USE A
NON-INTEGRATING AND USE A PRIME
OR BASE EDITOR.
HERE'S A GENERAL OUTLINE HOW WE
DO THESE STUDIES IN OUR MOUSE
MODELS IN SICKLE CELL DISEASE
AND THALASSEMIA.
LIKE WE WOULD ENVISION IT IN
HUMANS, WE MODIFY THE BLOOD
YELLS IN THE BLOODSTREAM WITH D
CELLS IN THE BLOOD STWREEM.
FOR FURTHER ENRICHMENT IN VIVO,
AFTER THE INITIAL VECTORED A
STRAITION, AND THEN OF COURSE TO
CONFIRM THAT, WE REALLY -- TO
HEMATOPOIETIC STEM CELL, WE ALSO
LOOK AT SECONDARY TRANSPLANTS IN
MICE.
THIS HERE NOW SHOWS THE APPROACH
WITH AN INTEGRATING VECTOR
SYSTEM TO CURE A MOUSE MODEL OF
THALASSEMIA -- MEDIA.
ABOVE GAMMA GLOBIN DRIVEN BY A
LARGE PROMOTER AND THE SELECTION
CASSETTE THAT ALLOWS US TO
ENRICH IN VIVO AND THEN TO
INTEGRATE THIS CONSTRUCT, WE
CO-ADMINISTER THIS SLEEPING
BEAUTY TRANSPOSASE.
WE FURTHER ENRICH WITH THIS
ENRICH CH STRATEGY, WE CAN
TITRATE UCH THE MODIFICATION
LEVELS TO HOPEFULLY THEN, IF
NECESSARY, GET INTO A
THERAPEUTIC RANGE FOR PATIENTS.
THE GENE MODIFICATION IS STABLE.
ON THE RIGHT-HAND SIDE WE SHOW
THE SECONDARY TRANSPLANTS AND WE
SEE PHENOTYPIC CORRECTION IN
THESE MICE WITH MARKEDLY IMPR
IMPROVED SPLEEN SIZES, POINT OUT
THIS IS HIGHLY POLYCLONAL IN
THESE MICE.
NOW HERE'S AN EXAMPLE OF A
SINGLE VECTOR TO DELIVER A BASE
EDITOR.
SO I'M GLAD WE'VE HEARD FROM
MITCH AND GREG ABOUT BASE AND
PRIME EDITING.
WHERE WE CAN SIMPLY DELIVER A
BASE EDITOR AND THE BASE EDITOR
WE USED HERE IS VERY SIMPLE TO
DISRUPT THE BCLA11 BINDING SITE
AS YOU'VE HEARD AGAIN FROM MITCH
TO PRETTY MUCH RE-CREATE THE
HEREDITARY PERSISTENCE OF FETAL
HEMOGLOBIN STATUS IN THESE MICE.
AND THE VECTOR AGAIN THE SINGLE
VECTOR SHOWN AGAIN BELOW.
IT DOES INCLUDE AGAIN THIS
ENRICHMENT CASSETTE WHERE WE
COULD EARLY ON ENRICH FOR THESE
MODIFIED CELLS DIRECTLY IN VIVO.
NOW THIS HERE SHOWS WHERE WE CAN
SEE NOW IN THE EXAMPLE OF THIS
VECTOR, WE CAN SEE THE
EFFICIENCY ON THE RIGHT-HAND
SIDE.
WE SAW EDITING FAIRLY EFFICIENT
IN THE MINUS 113 SITE, WHICH
OFFICIALLY INCREASES THE GAMMA
GLOBIN POSITIVE -- CELLS AS
SHOWN HERE, AS YOU MOVE TO THE
RIGHT THERE, WITH AGAIN VERY LOW
LEVELS OF INDELS AND NO OFF
TARGET EDITING.
WE'VE ALSO SHOWN SIMILAR
EFFICACY NOW ALSO WITH EDITING
THE 1 MINUS 75 SITE WHICH YOU'VE
JUST HEARD ABOUT FROM MITCH.
NOW IN COLLABORATION WITH THE
DAVID LU LAB, WE'VE ALSO USED A
PRIME EDITOR TO DIRECTLY CORRECT
THE SICKLE CELL DISEASE
MUTATION.
NOW BECAUSE OF THE LARGE PACKAGE
CAPACITY OF OUR VECTOR, WE COULD
DELIVER A VERY HIGHLY OPTIMIZED
16KB PRIME EDITOR DEVELOPED BY
THE LU LAB TO FIX THE SICKLE
CELL DISEASE MUTATION IN THE C
CD46/TOWNES MICE AND I'LL SHOW
YOU RESULT IN ONE SLIDE.
THIS IS AGAIN THE RESULTS.
YOU CAN SEE THE EFFICIENCY OF
THE PRIME EDITING IN VIVO, SO
PRIME EDITING IN PERIPHERAL
BLOOD AFTER ININ VIVO GENE
MODIFICATION BY SEQUENCING AND T
TO A CONVERSION RATE WHICH --
ABOUT 44% AT WEEK 16, WE ALSO
SAW EFFICIENT CORRECTION ON THE
PRONE LEVEL, ON THE RIGHT-HAND
SIDE, THEY'RE -- THE AVERAGE WE
SAW ABOUT 43% CORRECTION THERE.
WE ALSO SAW SIGNIFICANT
REDUCTION IN SICKLING IN THE
PERIPHERAL BLOOD SPLEENS AND
ALSO THE SPLEEN SIZES AS YOU CAN
SEE IN THE RIGHT LOWER SIDE.
NOW THIS IN VIVO ENRICHMENT HAS
BEEN DONE WITH A LOW DOSE OF
CHEMOTHERAPY.
OF COURSE YOU'VE HEARD A LOT OF
ANTIBODY-BASED CONDITIONING, AND
THIS IS EXACTLY ULTIMATELY WHAT
WE'D LIKE TO USE FOR IN VIVO
ENRICHMENT AS WELL, SO REPLEASE
ANY CHEMO -- THISIS JUST AN EXAN
MULTIPLEX WITH BASE EDITING TO
REALLY FACILITATE ANTIBODY-BASED
IN VIVO ENRICHMENT, SO WE MODIFY
THE STEM CELLS TO NOT BIND THE
PARTICULAR ANTIBODY THAT WE
WOULD USE FOR IN VIVO SELECTION
THEN.
HERE IS AN EXAMPLE SH, WE KNOCK
OUT CD33 AND AT THE SAME TIME
EDIT FOR FETAL HEMOGLOBIN
REACTIVATION AND SO WE CAN
MODIFY THESE CELLS IN VIVO
DIRECTLY AND THEN ENRICH FOR THE
MODIFIED CELLS USING ANTIBODY
BASED APPROACH.
AGAIN, THIS WAS DONE WITH
CD33 BUT OF COURSE WE'RE ALSO
LOOKING INTO CD117.
WE'VE TRANSLATED THIS INTO
NON-HUMAN PRIMATE STUDIES VERY
EFFICIENTLY.
WE'VE DONE PROBABLY ABOUT 20
MONKEYS WITH A SHORT TWO-DAY
IMMUNOSUPPRESSIVE REGIMEN.
WE'VE BEEN ABLE TO ADMINISTER
THIS SAFELY TO THESE PRIMATES
AND THIS IS JUST WHAT YOU SEE
DURING THE SLIDE IS THE
IL-6 LEVELS.
AGAIN, ALL THESE HAVE TOLERATED
THIS DELIVERY, VERY SAFELY WITH
ESSENTIALLY NO LIVER FUNCTION
ABNORMALITIES AND AGAIN NO
CYTOKINE REACTIVATION.
>>WE NEED TO WRAP IT UP.
>>THAT'S IT.
AND THESE ARE JUST OF COURSE THE
ACKNOWLEDGMENT HERE.
I'D LIKE TO THANK EVERYBODY
INVOLVED.
OF COURSE ESPECIALLY ANDRE
LIEBER AND HIS LAB WHOSE
PERFORMED MOST OF THESE STUDIES
AND SOME PEOPLE FROM MY LAB,
WE'VE COLLABORATED ON THIS FOR A
NUMBER OF YEARS, AND OF COURSE
THE OTHER COLLABORATORS, AND
ALSO THE FUNDING SOURCES AND I
SHOULD ALSO SAY ANDRE AND I ARE
CO-FOUNDERS OF ENSOMA, A COMPANY
THAT DEVELOPS THIS PARTICULAR
PLATFORM.
>>GREAT.
THANK YOU, HANS-PETER.
SO NOW WE HAVE THE LAST SPEAKER
WHO'S MATTHEW SPEAKING VIRTUA
VIRTUALLY.
IF WE HAVE TIME WE'LL HAVE A FEW
QUESTIONS AT THE END.
WE'LL GO AHEAD WITH MATT'S TALK.
ARE YOU THERE, MATT?
>>I AM.
THANKS FOR INVITING ME TO JOIN
THIS SESSION WHICH REALLY HAS
GIVEN A GREAT REVIEW OF THE
EXCITING NUMBER OF APPROACHES TO
SICKLE CELL DISEASE AND I'LL
CONCLUDE BY TALKING ABOUT
HOMOLOGY DIRECTOR REPAIR
EDITING.
MITCH GAVE A BRIEF SHOUT OUT
EARLIER.
I'LL JUST NOTE THAT PROBABLY
MAYBE MANY OF YOU DON'T REALIZE
THAT HDR EDITING WAS ACTUALLY
THE FIRST NOBEL PRIZE, I BECAUSE
OTHERS WON A NOBEL PRIZE FOR
WHAT WAS CALLED GENE TARGETING
WHICH IS HDR EDITING FOR -- STEM
CELLS.
HERE ARE MY POTENTIAL CONFLICTS
OF INTEREST.
THE MOST RELEVANT OF WHICH IS
GRAPHITE BIO, WHICH I'LL EXPLAIN
LATER.
SO WE'RE INTERESTED IN, AS HAS
BEEN MENTIONED BEFORE, DIRECTLY
REVERTING THE PATHOLOGIC -- OF
THE BETA GLOBIN GENE BACK TO THE
HEMOGLOBIN VERSION IN POSITION
TO CODON 6 OF THE BETA GLOBIN
GENE.
I'M NOT GOING TO GO THROUGH ALL
OF THE PATHOPHYSIOLOGY OF SICKLE
CELL DISEASE BECAUSE THIS
AUDIENCE KNOWS IT WELL.
AND SO THE SYSTEM WE USE IS A
SYSTEM THAT HAS TAKEN MANY YEARS
TO DEVELOP.
IT'S AN EX VIVO SYSTEM IN WHICH
CD34 CELLS ARE PURIFIED.
WE THEN PUT THEM INTO CELL
DIVISION BECAUSE HDR PROCESS IS
ACTIVE DURING SNG2 OF THE CELL
CYCLE.
WE DEVELOP OUR CRISPR/CAS
9 NUCLEASE AS A COLLECTION USING
A PURIFIED HIGH FIDELITY FORM OF
CAS9, COMPLEX TO A SI SYNTHETIC
GUIDE RNA.
WE THEN HAVE TO DELIVER OUR
DONOR TEMPLATE IN A WAY THAT
DOES NOT ACTIVATE THE TYPE
1 INTERFERON SYSTEM, AND WE HAVE
FOUND THAT AAV6, A
NON-INTEGRATING NATURALLY
OCCURRING VIRUS, CAN INFECT OR
TRANSDUCE CD34 CELLS WITHOUT
ACTIVATING THE TYPE 1 INTERFERON
SYSTEM.
USING -- SORRY.
THIS TRANSDUCTION OF AAV6 IS
ENHANCED BY ELECTROPORATING THE
CELLS WITHIN 15 TO 20 MINUTES OF
ADDING THE VIRUS.
AND USING THIS SYSTEM IN A WIDE
VARIETY OF CELL TYPES, WE CAN
ACHIEVE 40, 60 AND EVEN 80%
TARGETED INTEGRATION OR GENE
CORRECTION IN A WIDE VARIETY OF
CELL TYPES.
SO USING THIS SYSTEM AND A LARGE
TEAM OF PEOPLE PUBLISHED IN TWO
PAPERS, ONE IN 2016 AND THEN
MORE RECENTLY IN 2021, WE WERE
ABLE TO SHOW THAT IN CD34 CELLS
DERIVED FROM SICKLE CELL DISEASE
PATIENTS, WE COULD ACHIEVE 60 TO
70% ALLELE CORRECTION USING THE
SYSTEM I DESCRIBED BEFORE AND
USING A DOLE DONOR VECTOR THATD
OF COURSE CORRECT THE SICKLE
CELL CAUSING VARIANT, BUT ALSO
INTRODUCE SILENT SYNONYMOUS
CHANGES TO PREVENT RECUTTING OF
THE GENE AFTER CORRECTION
OCCURRED AND TO FACILITATE HIGH
FREQUENCIES OF HDR.
AND WHEN THESE CELLS ARE
DIFFERENTIATED INTO RED BLOOD
CELLS IN VITRO, WHAT YOU SEE IS
THAT INSTEAD OF COMPENSATING FOR
HEMOGLOBIN S, WE'RE DIRECTLY
REPLACING THE PATHOLOGIC
HEMOGLOBIN S WITH A
NON-PATHOLOGIC HEMOGLOBIN A AND
AFTER DIFFERENTIATION HAVE CLOSE
TO 60 TO 80% HEMOGLOBIN A, A
LITTLE BIT OF HEMOGLOBIN S, AND
ALMOST NO HEMOGLOBIN S, SO IT'S
REALLY A REPLACEMENT STRATEGY
IN -- TO A CORRECTION STRATEGY.
SO THE FIRST PATIENT WAS DOSED
JUST A LITTLE OVER A YEAR AGO.
WITH CELLS AUTOLOGOUS
4X4 MOBILIZED CELLS THAT HAVE
BEEN ENGINEERED USING AN
RMB86 SYSTEM AS I DESCRIBED.
IN JANUARY OF 2023, THAT IND AND
PROCESS WAS LICENSED TO GRAPHITE
BIO.
WE THEN TREATED THE FIRST
PATIENT AS I SAID ONE YEAR AGO.
IN JANUARY OF THIS YEAR --
SORRY, NEXT SLIDE, PLEASE.
IN JANUARY OF THIS YEAR,
GRAPHITE BIO ANNOUNCED A
VOLUNTARY PAUSE ON THE TRIAL.
THE REASON FOR THIS VOLUNTARY
PAUSE IS THAT THE PATIENT FIVE
MONTHS POST INFUSION OF THE
CELLS WAS STILL REQUIRING RED
BLOOD CELL AND PLATELET
TRANSFUSIONS AND HAD BEEN
STARTED ON ALTRAMABAG AS A WAY
SUPPORTING HSC GROWTH IN THE
MARROW.
SINCE THAT TIME, HOWEVER, THE
PATIENT HAS CONTINUED TO IMPROVE
AND SHE'S NOW BEEN
TRANSFUSION-INDEPENDENT SINCE
APRIL OF THIS YEAR.
SHE'S NO LONGER ON ANY GROWTH
FACTORS, SHE HAS NO EVIDENCE OF
M DS OR ABNORMAL HEMATOPOIESIS
NOTING IT'S ONLY ONE YEAR OUT
AND HER MOST RECENT -- SHE HAS
LESS THAN 5% HEMOGLOBIN S AND
HAS A TOTAL HEMOGLOBIN GREATER
THAN 9.
THE FIRST DETAILS WILL BE REPORT
AT ASHE IN DECEMBER OF THIS
YEAR.
ONE COULD SAY SHOULDN'T WE HAVE
GONE ON AND TREATED A SECOND
PATIENT?
BUT I THINK THE FIRST PATIENT,
THERE WAS WERE VERY FEW THINGS
THAT THE SUBSEQUENT PATIENTS
COULD DO WOULD DO MUCH BETTER.
THE CELL DOSE WAS LOWER THAN WE
ANTICIPATED BUT NONETHELESS,
THINGS WENT RELATIVELY SMOOTHLY.
SO INSTEAD OF TREATING ANOTHER
PATIENT, WE WENT BACK TO THE
DRAWING BOARD AND SAID, CAN WE
DEVELOP AN IMPROVED
MANUFACTURING PROCESS SO THAT
THE SUBSEQUENT PATIENTS WOULD
HAVE BETTER OUTCOMES OR FASTER
OUTCOMES.
OF COURSE THIS HAS BEEN NOTED
BOTH BY PU PUNHAM AND JOHN THAT
GENETIC -- ENGINEERING IS MORE
COMMON THAN NOT.
SOMETHING HAPPENED HERE, BUT
WHAT'S SHOWN IN THE RED BOX,
IT'S A MAP TO P SEA CHANGE,
WHAT'S SHOWN HERE ON THE BOTH
LEFT AND RIGHT SIDE IS THAT THE
GREEN CELLS, WHICH ARE THE CELLS
THAT HAD UNDERGONE HDR EDITING
COMPARED TO THE BLUE CELLS THAT
HAD NOT UNDERGONE HDR EDITING,
THE LEVEL OF ENGRAFTMEN ENGRAFTR
PRE-CLINICAL TUMOR TALK STUDY
WAS LOWER OVERALL THAN THE BLUE
CELLS.
NOW THERE WAS SIGNIFICANT
OVERLAP.
YOU CAN SEE SOME OF THE MICE
RECEIVING BLUE CELLS ENGRAFTED
AT THE SAME FREQUENCY AS MANY OF
THE MICE RECEIVING THE GREEN
CELLS, WHICH IS WHY THE ADA
CLEAREFDACLEARED THE IND, BUT TW
BECAME A SIGNAL FOR US TO
IMPROVE ON.
CAN WE IMPROVE THE LEVEL OF
ENGRAFTMENT OF AGR EDITED CELLS.
AND SO WHAT HAS BEEN NOTED BY
ALBINI'S LAB AND OUR LAB AND
OTHERS AND HAS BEEN MENTIONED
PRIOR IS THAT THE HDR EDITING
PROCESS CAN INDUCE A P53 STRESS
RESPONSE THROUGH TWO MECHANISMS.
ONE IS THE CREATION OF A DOUBLE
STRANDED BREAK AT THE ON-TARGET
SITE, AND THE SECOND IS BY THE
DELIVERY OF AN A AAV GENOME INTO
THE NUCLEUS OF THE CELLS SO THIS
BECAME MINIMIZING THE STRESS
RESPONSE THUS BECOMES A REAL
TARGET FOR HOW WE IMPROVE THE
MANUFACTURING PROCESS.
AND WHAT WE FOUND, AS RECENTLY
PUBLISHED IN MOLECULAR THERAPY
METHODS IN CLINICAL DEVELOPMENT
IN THE LOWER LEFT CORNER IS THE
ACTIVATION OF P21, A DOWNSTREAM
TARGET OF P53, IS DIRECTLY
CORRELATED TO THE NUMBER OF
VECTORS IN THE CELLS.
SO BY LOWERING THE AMOUNT OF AAV
USED, ONE CAN REDUCE THE
P21 STRESS RESPONSE IN THE UPPER
LEFT IS SHOWN THAT IF WE COULD
REDUCE IT BY IT FOUR FOLD, WE
COULD REDUCE THAT STRESS
RESPONSE TO THE EQUIVALENT OF
JUST USING THE NUCLEASE ALONE
AND ON THE RIGHT-HAND SIDE SHOWS
SIMILAR RESCUE NOT JUST IN THE
P21 STRESS RESPONSE BUT IN THE
FUNCTIONALITY OF THE CELLS BY
RESCUING THE NUMBER OF COLONIES
THAT ARE FORMED PER 600 INPUT
CELLS.
SO USING THIS PROCESS, THE WE
HAVE NOW RE-DOSED THE
MANUFACTURING TIME FROM FIVE
DAYS TO THREE DAYS.
WE'VE INCLUDED A SMALL MOLECULE
BOOSTER OF HOMOLOGY DIRECT
REPAIR.
THIS HAS INCREASED THE FREQUENCY
OF GENE CORRECTION FROM 35 TO
50%, INCREASED OUR FREQUENCY OF
CELL CORRECTION FROM 40% TO 75%,
RESULTED IN A 40% INCREASE IN
THE TOTAL NUMBER OF COLONIES,
AND QUALITATIVELY, THE COLONIES
LOOK LARGER AND HEALTHIER.
IT HAS INDUCED THE P53 RESPONSE
DOWN TO RNP ALONE.
ALSO HAS REDUCED THE
MANUFACTURING COST BY ABOUT --
CUT THE MANUFACTURING COST IN
HALF.
NOW THESE ARE STILL VERY HIGH
NUMBERS AND AS HAS BEEN
MENTIONED, IF WE'RE GOING TO GET
THESE SORT OF THERAPIES TO
PATIENTS AROUND THE WORLD, WE'LL
NEED TO FURTHER REDUCE THESE
COSTS, BUT I THINK MANY OF US
BELIEVE THAT THE
INDUSTRIALIZATION OF MANUFAC
MANUFACTURING AND REAGENTS FOR
ALL GENE THERAPIES HAS YET TO
OCCUR, AND WITH THAT, WE CAN
EXPECT FURTHER REDUCTIONS.
SO IN SUMMARY, WE'LL DESCRIBE AT
ASHE EVEN MORE OF THE DETAILS
ABOUT THE CLINICAL PROOF OF
CONCEPT THAT CAN -- CLEARLY ONE
YEAR IS NOT LONG-ENOUGH
FOLLOW-UP EFFICACY AND LONG TERM
SAFETY BUT REMIND YOU THE POINT
IS WE'RE NOT ONLY INCREASING
HEMOGLOBIN A BUT ALSO LOWERING
HEMOGLOBIN S.
CONVERSION OF ACADEMIC
MANUFACTURING PROCESS TO BIOTECH
PROCESS WITH IMPROVEMENTS IN ALL
METRICS, AND TAKE THIS IMPROVED
MANUFACTURING PROCESS, GET AN
IND AMENDMENT AND BEGIN TREATING
PATIENTS IN 2024.
SO WITH THAT, I WANT TO THANK
YOU, EVERYONE, FOR YOUR
ATTENTION AND OPPORTUNITY TO
PRESENT OUR WORK.
AS HAS BEEN MENTIONED PRIOR, IT
TAKES A VILLAGE, NOT ONLY WITH
TALENTED INVESTIGATORS IN MY L
LAB, MY GREAT COLLEAGUES, OUR
COLLEAGUES IN THE STANFORD
FACILITY, INDUSTRY COLLABORATORS
AROUND THE WORLD AND MONEY AND
SPONSORSHIP FROM A WIDE RANGE OF
INVESTIGATORS AND FOUNDATIONS.
SO WITH THAT, THANK YOU FOR
INCLUDING ME IN THIS SESSION,
AND I THINK I WILL END HERE AND
THAT SHOULD LEAVE TIME FOR A
COUPLE QUESTIONS.
THANK YOU VERY MUCH.
>>I THINK WE HAVE ONE OR TWO
ONLINE QUESTIONS.
>>I THINK WE'LL START WITH THE
ONLINE QUESTIONS IF THERE ARE
ANY.
CAN YOU PLEASE READ THOSE?
>>YEP.
WE HAVE ONE ONLINE QUESTION.
THE QUESTION IS FOR ANY OF THE
SPEAKERS WHO WOULD LIKE TO SHARE
THEIR OPINION ON WHETHER PATIENT
SHOULD WAIT UNTIL THERE IS
CONSENSUS ON THESE VARIOUS
APPROACHES BEFORE DECIDING ON A
SPECIFIC POTENTIALLY CURATIVE
THERAPY?
>>SINCE I'VE BEEN PINNED, I
THINK WE'VE HAD EIGHT SPEAKERS
IN THE SESSION.
I SUSPECT YOU'D GET EIGHT
DIFFERENT ANSWERS.
BUT MY ANSWER WOULD BE THAT IF
THE SEVERITY OF YOUR SICKLE CELL
DISEASE IS SUCH THAT IT IS
CAUSING SIGNIFICANT DISRUPTIONS
IN YOUR LIFE AND YOUR FUTURE
PROBABILITIES, IT IS NOT WORTH
WAITING.
IT ALSO IS CONSISTENT WITH --
THAT RECOMMENDATION IS ALSO
CONSISTENT WITH THE DATA THAT
WAS PRESENTED IN THE FIRST
SESSION, THAT THIS IS A DISEASE
THAT CAN BE RESULT IN PERMANENT
END ORGAN DAMAGE THAT'S NOT
REVERSIBLE WHETHER BY AN ALLO
TRANSPLANT OR AUTOLOGOUS GENE
THERAPY TRANSPLANT.
SO I THINK IN CONSULTATION WITH
YOUR PHYSICIAN AND YOUR SUPPORT
NETWORK, IT IS SOMETIMES
APPROPRIATE TO INITIATE
THERAPIES WITH ONE OF THESE ON A
CLINICAL TRIAL EVEN IN 2023.
HOWEVER, I THINK IF YOUR DISEASE
IS MILDER AND IS NOT IMPACTING
ON YOUR LIFE, YOU PERHAPS MAY
CHOOSE TO WAIT LATER.
BUT I'LL STOP THERE AND LISTEN
TO THE DISAGREEMENTS.
>>SO I'LL TAKE THE CHAIR'S
PREROGATIVE AND GIVE MY OPINION.
I AGREE WITH MATT THAT I THINK
WE HAVE A LOT OF PATIENTS -- THE
ELIGIBILITY CRITERIA FOR GENE
THERAPY AND GENE EDITING IS ALSO
REALLY STRICT, AND IT REALLY IS
PATIENTS WHO ARE REALLY, REALLY
SICK AND ARE NOT RESPONDING TO
CURRENT DISEASE MODIFYING
THERAPIES.
I THINK THAT THEY SHOULD -- IT'S
GOOD THAT THEY HAVE SO MANY
DIFFERENT TYPES OF STRATEGIES
AVAILABLE, AND THAT DECISION OF
WHAT THEY SHOULD CHOOSE WILL
HAPPEN WITH A DISCUSSION WITH
THEIR PHYSICIAN.
BUT I DO THINK THAT PATIENTS WHO
DON'T HAVE ANY OTHER OPTIONS,
LIKE TRANSPLANT OR OTHER
DISEASE-MODIFYING THERAPIES,
HAVEN'T WORKED -- LIKE CHRON
CHRONIC -- PATIENTS ON OUR
TRIAL, HALF OF THEM RECEIVED
GENE THERAPY BECAUSE THEY
WEREN'T RESPONDING TO THE
STANDARD THERAPIES.
SO I THINK THEY SHOULD CONSIDER
IT NOW AND AT LEAST HAVE AN
INFORMED DISCUSSION WITH THEIR
PHYSICIAN, THERE SHOULD BE AN
INFORMED DECISION-MAKING.
BUT I DO THINK THAT -- I
COMPLETELY AGREE WITH MATT ON
THE MILDER PATIENTS.
>>I WAS JUST GOING TO SAY, IT'S
NOT ONLY ABOUT RESEARCH
ANYMORE --
>>THAT'S NOT WORKING.
>>IT IS WORKING.
>>IT'S NOT JUST ABOUT RESEARCH
ANYMORE, THERE'S TWO GENE
THERAPIES THAT ARE PROBABLY
GOING TO BE APPROVED IN THE NEXT
YEAR.
AND I THINK THAT IT'S AN
INDIVIDUALIZED DECISION.
I THINK THAT IT'S AN
INDIVIDUALIZED DECISION, AND THE
MOST IMPORTANT THING IS
INFORMATION AND INFORMED
CONSENT.
AND THAT IS SO HARD TO DO, IT'S
SO HARD FOR ANYBODY TO
UNDERSTAND WHAT COULD HAPPEN,
LET ALONE PATIENTS.
SO THAT'S A HUGE ROLE OF THE
PEOPLE TAKING CARE OF THESE
PATIENTS TO REALLY EXPLAIN TO
THEM.
THAT WAS THE LAST THING THAT YOU
SAID, PUNHAM, AND I AGREE WITH
THAT.
>>ANY OTHER QUESTIONS FROM THE
AUDIENCE?
>>IS THIS ON?
YES.
THIS IS A QUESTION FORMAT
PORTEUS.
THANKS FOR GIVING THE UPDATE
ABOUT YOUR PATIENT INVOLVED IN
THE GRAPHITE BIO TRIAL.
I'M SURE YOU'LL GO INTO THIS AT
THE MEETING IN DECEMBER, BUT CAN
YOU TELL US ANY MORE ABOUT
WHETHER OR NOT THERE'S EVIDENCE
OF INEFFECTIVE ERYTHROPOIESIS
AND STRESS WITH POIESIS AND IF
THERE ARE ANY FEATURES OF
THALASSEMIA IN THAT PATIENT?
>>I CAN'T GIVE YOU A LOT --
THOSE ARE ALL EXCELLENT QUEST
QUESTIONS, MARK.
HOPEFULLY WE'LL BE ABLE TO BRING
MORE INFORMATION TO THE
COMMUNITY IN DECEMBER.
NO EXCUSES, BUT OBVIOUSLY THE
TRANSITION OF THE PROGRAM OUT OF
GRAPHITE HAS SLOWED SOME OF OUR
STUDIES OF THOSE VERY IMPORTANT
QUESTIONS, BUT HOPEFULLY WE CAN
CATCH UP ON THEM BY THE TIME
DECEMBER ROLLS AROUND.
>>THANK YOU.
ANY OTHER QUESTIONS?
>>SORRY.
>>OH, SORRY.
GO AHEAD, PLEASE.
>>I HAVE A COMMENT, AND I THINK
IT ADDRESSES BOTH THE SESSIONS
THAT WE HAD THIS MORNING AND
TIES THEM TOGETHER.
AS A CLINICIAN WHO'S PRESENTING
THESE OPPORTUNITIES TO OUR
PATIENTS, EITHER ON CLINICAL
TRIALS OR SOON TO BE PERHAPS
AVAILABLE FDA-APPROVED
THERAPIES, IT'S SO IMPORTANT FOR
US TO HAVE THE INFORMATION THAT
COMPARES OUTCOMES, LONG-TERM
OUTCOMES THAT WERE PRESENTED IN
THE FIRST SESSION, IN COMPARISON
TO MODERN CONTEMPORANEOUS
CONTROLS, AND THAT'S WHAT I URGE
PEOPLE TO THINK ABOUT WHEN THEY
PRESENT THEIR DATA OR ARE
DESIGNING STUDIES, AND EVEN THE
NIH FOR FUNDING STUDIES THAT
HAVE THE APPROPRIATE CONTROLS,
WE DO HAVE THE OPPORTUNITY TO
USE REAL REAL WORLD DATA WHERE
YOU CAN USE MACHINE LEARNING TO
CREATE A COHORT THAT IS MATCHED
IN SEVERITY TO LOOK AT SOME
OUTCOMES.
THERE ARE, YOU KNOW, LARGE
DATABASES, AND IT'S SO
IMPORTANT.
SO IT HELPFUL FOR ME TO KNOW
JUST AS AN EXAMPLE, THAT THE
RARISK OF MALIGNANCY IS 45 FOLD
HIGHER WHEN THERE'S GRAFT
REJECTION, BUT WHAT'S THE
AVERAGE, AND WHAT'S THE AVERAGE
IN SICKLE CELL PATIENTS AND WHAT
ARE THE RISK FACTORS THAT CA SO
THAT CAN BE COMPARED IN A
MEANINGFUL MANNER WHEN YOU'RE
CONSENTING PATIENTS IN THE
CLINIC.
>>YES, I COULDN'T AGREE MORE.
I THINK THAT AS THESE THERAPIES
ARE MATURING AND COMING TO THE
CLINIC, WE REALLY NEED TO NOT
JUST LOOK AT THE SHORT TERM
EFFICACY BUT THE LONG TERM
RESULTS.
I THINK NIH AND ASHE, AND YOU
WERE PROBABLY PART OF THOSE
COMMITTEES, HAS IMPANELED
SEVERAL GROUPS TO MAKE
GUIDELINES AND RECOMMENDATIONS
FOR LONG TERM FOLLOW-UP AND WHAT
SHOULD BE DONE AND TESTED ON
THESE PATIENTS.
AND THE OTHER THING I DO FEEL IS
VERY IMPORTANT IS TRANSPARENCY,
ESPECIALLY FROM TRIALS THAT GO
TO PHARMA, WE HEAR JUST, YOU
KNOW, WHAT THEY WANT TO
DISCLOSE, AND I THINK
TRANSPARENCY IS SOMETHING THAT
WOULD REALLY HELP THE FIELD.
>>QUICK QUESTION FOR
HANS-PETER.
DOES YOUR APPROACH LEND ITSELF
TO IN UTERO?
OH, HANS IS ONLINE.
>>SORRY, I WAS LISTENING.
POTENTIALLY, YES.
>>THAT COULD POTENTIALLY
REDUCE -- AND MAKE THE TARGET
REALLY SMALLER.
>>YES.
>>THANK YOU, PUN H PUNHAM, AND
EVERYONE FOR GREAT SESSIONS.
>>LET'S GET STARTED WITH
OUR NEXT SESSION, UPDATES ON
CLINICAL TRIALS, SICKLE CELL
DISEASE.
THE FIRST ONE, WE HAVE -- NEXT
FOUR TALKS ARE ALL GOING TO BE
TALKING ABOUT THE CLINICAL
TRIALS.
SO THE NEXT TALK IS GOING TO BE
PROOF OF CONCEPT STUDY OF
NICOTINAMIDE AND ORAL
THU/DECITABINE TO TREAT HIGH
RISK SICKLE CELL DISEASE.
DR. YOGEN SAUNTHARARAJAH FROM
CLEVELAND CLINIC.
>>THANK YOU.
SO THANK YOU VERY MUCH, PUNKAJ
AND THE ORGANIZERS.
SO THESE ARE MY DISCLOSURES.
I HAVE PATENTS AROUND
DECITABINE, EQUITY AND BOARD
ROLES IN A COUPLE OF STARTUP
COMPANIES, NOVO NORDISK HAS
SUBLICENSED ONE OF THESE PATENTS
AND I HAVE ISSUED PATENTS IN
SOME OTHER SMALL MOLECULE
THERAPEUTICS AS WELL.
SO WE'VE HEARD A LOT ABOUT HE
RED DRI MISSENSE AND HOW IT DOWN
REGULATES SEVERITY OF SICKLE
CELL DISEASE AND WE ALL KNOW
THAT VARIATIONS IN THE BCL11A
GENE OR REGULATORY ELEMENTS CAN
CAUSE HEREDITARY PERSISTENCE OF
FETAL HEMOGLOBIN, A LITTLE WELL
LESS RECOGNIZED IS THERE'S A
MISSENSE MUTATION IN THE GENE
FOR THIS EPIGENETIC REGULATOR,
DNA TRANSFERASE 1, DNMT1.
THEIT IS ALSO A CALLS OF HPFH.
ACTUALLY IT'S ALL PART OF THAT
SAME HUB.
DNMT1 IS KNOWN TO BE RECRUITED
AT THE BETA GLOBIN LOCUS IN
ORDER TO EFFECT TRANSCRIPTION
REPRESSING FUNCTIONS.
AND SO BASICALLY THIS IS WHAT
THE POLYMORPHISM DOES, IS IT
DECREASES THE PROTEIN HALF-LIFE
TO CAUSE HPFH AND ACTUALLY WE DO
HAVE A SMALL MOLECULE
FDA-APPROVED IN THE CLINIC FOR
TREATING MYELOID MALIGNANCIES
THAT BASICALLY DOES THE SAME
THING.
IT DEGRADES DNMT1 PROTEIN.
SO WHAT IS THIS MOLECULE AND HOW
DOES DO IT?
THE NAME OF THE MOLECULE IS
DECITABINE.
AND IT BASICALLY HAS A SINGLE
ATOM CHANGE COMP.
SO IT'S SUBSTITUTED WITH A
NITROGEN, AND THAT HAPPENS TO BE
THE CARBON THAT IS METHYLATED BY
DNA METHYL TRA TRANSFERASE 1.
IT GETS DEGRADED SO YOU GET
DNMT1 PROTEIN DEPLETION FROM
CELLS.
AS MENTIONED, THERE'S ONLY A
SINGLE ATOM CHANGE COMPARED TO
THE OXYCYTABENE.
SO UNLIKE OTHERS WE USE IN THE
HEMATOLOGY AND ONCOLOGY CLINIC,
THAT'S UNUSUAL.
SO VERY OFTEN THE SUGAR IS
MODIFIED.
THE SUGAR IS PHYSIOLOGIC.
SO WHEN IT INCORPORATES INTO THE
NEWLY SYNTHESIZED DNA STRAND
DURING S-PHASE, IT DOESN'T
TERMINATE DNA CHAIN ELONGATION.
SO YOU CAN ACTUALLY ACHIEVE THE
DNMT1 DEPLETION AT
CONCENTRATIONS THAT DO NOT
CAUSE -- WHAT YOU'RE LOOKING AT
DNA DAMAGE MEASUREMENT IN CORD
BLOOD CD34 CELLS TREATED WITH
DECITABINE, ABOUT 10 TIMES MORE
THAN WHAT YOU NEED TO DEPLETE
DNMT1, AND HERE IS ECOMOLAR --
CAUSING A LOT OF CYTOTOXICITY,
HYDROXYURIA CAUSES CYTOTOXICITY.
HIGHER CONCENTRATIONS DO PRODUCE
ANTIMETABOLITE EFFECTS,
TERMINATING OF DNA STRAND SINS
ZEST BUT A NUMBER OF OTHER
ANTIMETABOLITE EFFECTS THAT DO
CAUSE CYTOTOXICITY BUT THE
BOTTOM LINE IS THAT YOU CAN FIND
CONCENTRATIONS OR DOSES AGAINST
AN EPIGENETIC REGULATOR WITHOUT
EFFECTS OF CYTOTOXICITY.
SO YOU CAN ALSO IF YOU WANT TO
KILL STUFF, YOU CAN GIVE HIGHER
CONCENTRATIONS AND PRODUCE DNA
DAMAGE AND CYTOTOXICITY, YOU CAN
PRODUCE THIS EFFECT.
SO OBVIOUSLY THE GOAL WITH USING
DECITABINE, TALKING ABOUT
POTENTIALLY TRYING TO
RECAPITULATE THE MECHANISM, WE
ALREADY HAVE A DRUG HYDROXYUREA
TO INCREASE FETAL HEMOIMLOA BIN
IN OUR PATIENTS BUT OF COURSE
HYDROXYUREA DOES THAT
INDIRECTLY.
SO IT'S A RO RIBONUCLEOTIDE
REGULATOR, THAT PRODUCES
CYTOSTASIS, CYTOTOXICITY.
DURING THE RECOVERY PHASE FROM
THAT, SO STRESS ERYTHRO.EE CYST,
THE CHROMATIN CONFIGURATION IS
AFFECTED TO INCREASE FETAL
HEMOGLOBIN.
WHAT WE'RE TALKING ABOUT IS
CONCEPTUALLY DIFFERENT THAN
THAT, WE INTEND TO TARGET THIS
HUB DIRECTLY BY TARGETING
DNMT1 ABOUT WITH A SMALL MALL
KEUL.
A LOT OF THE GENE THERAPY WE'VE
HEARD ABOUT ARE ALSO TARGETING
THIS HUB BUT THEY'RE TARGETING
IT AT THE LEVEL OF THE BCA11
BINDING TO DNA OR TARGETING
BCLA11 LEVELS, ET CETERA, ET
CETERA.
SO WE'RE REALLY TRYING TO GO
AFTER THAT SAME HUB THAT CAUSES
DIRECTLY BUT USING A SMALL
MOLECULE INSTEAD OF GENE
THERAPY.
SO CONCEPTUAL DIFFERENCES WITH
HYDROXYUREA THAT WE USE TO TRY
TO INCREASE FETAL HEMOGLOBIN, IT
WORKS BY A STRESS
ERYTHROPOIESIS, THE
PHARMACODYNAMIC OBJECTIVES WITH
HYDROXYUREA IS RIBONUCLEOTIDE
REDUCTASE INHIBITION, WE'RE
TRYING TO DEPLETE DNMT1.
DERIVED FROM THE MAXIMUM
TOLERATED DOSE, WHEREAS WE'RE
HOPING TO OPERATE JUST BEFORE
THE THRESHOLD REQUIRED TO
DEPLETE DNMT1.
THAT'S WHY WE END UP WITH VERY
SMALL MOLAR EXPOSURES TO THE
AGENT IN THE CLINIC.
THERE ARE NEGATIVE PREDICTION
BIOMARKERS FOR RESPONSE TO
HYDROXYUREA MOST LIKELY RELATED
TO ITS MECHANISM OF ACTION AND
AS YOU WILL SEE, WE DON'T THINK
THOSE NEGATIVE PREDICTION
BIOMARKERS APPLY TO DESITE BEAN.
THERE IS SOME OVERLAP, APPLIED
IN THIS WAY YOU ALSO GET
THROMBOCYTOPENIA.
WE ACTUALLY GET HIGH PLATELET
COUNTS AS A SIDE EFFECT, BECAUSE
IT'S NOT CYTOTOXIC, AND THE WAY
THE DRUG WORKS IS BY
MANIPULATING MYELOID
DIFFERENTIATION.
IN ARE TWO OTHER IMPORTANT
PROPERTIES OF THIS MOLECULE.
ONE IS IT'S ACTUALLY A PRODRUG.
IT HAS TO BE PHOSPHORYLATED AND
THAT PHOSPHORYLATION DETERMINES
THE INTRACELLULAR HALF-LIFE AND
THE ENZYME THAT EXECUTES THAT
PHOSPHORYLATION IS DEOXYCITABINE
OR DCK, MUCH MORE HIGHLY
EXPRESSED IN THE HEMATOPOIETIC
COMPARTMENT AND WITHIN THE
MYELOID COMPARTMENT, IT'S MOST
HIGHLY EXPRESSED WITHIN
ERYTHROID PRECURSORS.
SO IN A WAY IT TARGETS THIS DRUG
TO MYELOID AND -- LINEAGE.
ANOTHER CLINICAL PROPERTY IS
IT'S RAPIDLY CATABOLIZED IN OUR
BODIES BY THIS ENZYME, CYTIDINE
DEAN MACE.
IF WE PUSH IT INTO THE VEIN OF A
HUMAN BEING, YOU CAN'T MEASURE
THE AGENT AFTER ABOUT FIVE,
MAXIMUM 10 MINUTES, AND THAT'S
BECAUSE OF THIS ENZYME CYTIDINE
DEANAMASE.
HISTORICALLY WE'VE NEVER
ADMINISTERED ANALOGS, WHETHER
DECITABINE, BY THE ORAL ROUTE,
BECAUSE THEY ALL RAPIDLY
CATABOLIZE THIS ENZYME, SO ORAL
BIOAVAILABILITY IS TRIVIAL.
NOW IT SO HAPPENS THAT THERE IS
ANOTHER AGENT CALLED
TETRAHYDROURADINE THAT INHIBITS,
WE CAN GIVE SMALL AMOUNTS OF
DECITABINE BY THE ORAL ROUTE AND
NOW WE GET BIOAVAILABILITY AND A
HALF-LIFE THAT CAN GO INTO THE
HOURS.
AND SO AS I MENTIONED IN THE --
RIGHT IN THE BEGINNING,
DECITABINE IS AN FDA-APPROVED
DRUG FOR TREATING MYELOID
MALIGNANCIES, BUT THE DOSAGE
CONCEPTS THAT KIND OF DROVE HOW
IT WAS INTRODUCED INTO THE
CLINIC FOR TREATING MYELOID
MALIGNANCIES DERIVED FROM THE
CONVENTIONAL HISTORICAL
PRINCIPLES IN ONCOLOGY OF TRYING
TO PAUSE APOPTOSIS, SO THE
DOSAGE CONCEPTS WERE MAXIMUM
TOLERATED.
WHEREAS WE ARE USING MINIMUM BAY
LOGICALLY EFFECTIVE DOSE SO WE
GIVE TINY DOSES COMPARED TO THE
FDA-APPROVED DOSES AND THEN WE
CAN DISTRIBUTE THOSE FREQUENTLY,
SO WE CAN GIVE THEM ONCE TO
TWICE A WEEK.
SO WE'VE DONE SEVERAL CLINICAL
TRIALS TO SHOW THAT ACTUALLY YOU
CAN USE DECITABINE IN NON-HUMAN
PRIMATES AND IN HUMAN BEINGS IN
THIS WAY.
SO TO TARGET DNMT1 OR THE
MOLECULAR PHARMACODYNAMIC EFFECT
WITHOUT MEASURABLE CYTOTOXICITY.
AND WE ALSO DEFINED IN PHASE
1 TRIALS THE DOSES AND SCHEDULES
FOR HOW TO COMBINE THE
TETRAHYDROURIDINE AND DESITE
BEAN FOR THIS TARGETED MOLECULAR
THERAPY CONCEPT.
HERE IS SOME EVIDENCE OF THE
EFFECT.
HERE WE'RE TREATING HEALTHY
VOLUNTEERS SO A TOTAL OF 44 MALE
AND FEMALE, SMALL AMOUNTS THAT
WE'RE TALKING ABOUT, AND YOU CAN
SEE IN THE ENCIRCLE LATING
T-CELLS IN THE BLOOD, WE GET
VERY LARGE DECREASES IN
DNMT1 PROTEIN AMOUNTS.
SO THAT'S THE INTENDED MOLECULAR
PHARMACODYNAMIC EFFECT.
SO THE CLINICAL TRIAL I'M GOING
TO SHOW YOU IS ACTUALLY THE
FIRST CLINICAL TRIAL IN WHICH
WE'RE TREATING SICKLE CELL
DISEASE PATIENTS WITH THE ORAL
TETRAHYDRO -- THIS IS THE FIRST
TO DEFINE THESE DOSES THAT
YOU'RE GOING TO BE SEEING
APPLIED HERE, AND THIS IS THE
FIRST CLINICAL TRIAL TO ACTUALLY
APPLY THESE DOSES.
AND SO WE WANTED TO KNOW, CAN WE
ACTUALLY PRODUCE SUSTAINED FETAL
HEMOGLOBIN INCREASES OVER A
PERIOD OF 48 WEEKS, CAN WE
INCREASE HEMOGLOBIN FOR OVER 48
WEEKS WITHOUT THE EXPECTED SIDE
EFFECTS OF NEUTROPENIA OR
WORRISOME INCREASE IN PLATELET
COUNTS?
AND WE ALSO EXAMINED THE
POTENTIAL ROLE OF VITAL BIN B3.
OTHER NAMES ARE NICOTINAMIDE OR
SO WE DID SEE THE EXPD
TRENDS BUT THEY DID NOT CROSS
THRESHOLDS THAT REQUIRED HOLDING
OF ANY OF THE AGENTS.
I WILL SHOW YOU THE DATA ON THE
GRADE 3 AND 4 ADVERSE EVENTS.
AND SO THESE ARE THE DEMOGRAPHIC
CHARACTERISTICS OF THE SIX
PATIENTS.
UP HERE, SO EACH COLUMN IS A
PATIENT.
AS YOU CAN SEE, THEY ARE
SEVERELY ILL SICKLE CELL DISEASE
PATIENTS IN TERMS OF THEIR
COMPLICATION PROFILE.
THESE ARE THE VASO-OCCLUSIVE --
THAT HAPPENED IN THE SIX WEEKS
PRIOR TO ENROLLMENT.
NONE OF THESE SIX PATIENTS HAD
DOSE LIMITING TOXICITY FOR THE
PROTOCOL, AND THREE OF THESE
PATIENTS HAD VASOOCCLUSIVE
CRISES ON STUDY.
ONE DURING THE FOLLOW-UP PHASE
AFTER THE STUDY DRUGS WERE
DISCONTINUED DURING THE 48-WEEK
TO 52-WEEK.
ONE WHILE THEY WERE RECEIVING
COMBINATION THERAPY AND ONE
WHILE THEY WERE RECEIVING
NICOTINAMIDE ALONE.
THERE WERE THREE OTHER GRADE
3 TO 4 ADVERSE EVENTS.
HYPOTHAT LEEHYPOKALEMIA -- AND E
OBJECTIVE LABORATORY PARAMETERS,
SO ON THE X AXIS, ON ALL THE
GRAPHS THAT I'M GOING TO SHOW IS
THE FULL STUDY PERIOD, SO 52
WEEKS IN TOTAL AND IN ORANGE IS
THE 12-WEEK PERIOD WHERE THEY
WERE RECEIVING NICOTINAMIDE
ALONE, IN BLUE IS WHERE THEY'RE
GETTING THU AND DESITE MEAN -- E
SIX PATIENTS ACTUALLY HAD A VERY
HIGH BODY WEIGHT WHICH WAS NOT
ANTICIPATED IN HOW WE WROTE THE
PROTOCOL SO THE DOSE SHE
RECEIVED OF THE THU WAS BELOW
THE MINL MEDIC MINIMALLY EFFECT.
THIS PATIENT HAD NO INCREASE IN
FETAL HEMOGLOBIN BUT EVERYBODY
ELSE, THERE WAS AN INCREASE IN
FETAL HEMOGLOBIN.
WITH THE THU DECITABINE ALONE --
INTRODUCED INTO THE REGIMEN.
THOSE LEVELS WERE SUSTAINED.
ALTHOUGH IN TWO PATIENTS, WE
OBSERVED SOME DECLINE IN THE
FETAL HEMOGLOBIN AFTER
NICOTINAMIDE WAS INTRODUCED INTO
THE REGIMEN.
WE DID SOME SUBSEQUENT WORK AND
WE THINK WE KNOW WHY AND I'LL
TALK ABOUT THAT LATER.
AND HERE ARE THE TOTAL
HEMOGLOBIN LEVELS ON THERAPY.
AGAIN, WE SEE INCREASES IN TOTAL
HEMOGLOBIN, MOST OBVIOUSLY WITH
THE THU DECITABINE.
THERE WAS SOME SMALL INCREASE
WITH THE NICOTINAMIDE ALONE IN
THIS ONE PATIENT, AND IN THE TWO
PATIENTS IN WHOM FETAL
HEMOGLOBIN WENT DOWN AFTER THE
INITIATION OF NICOTINAMIDE, HEME
LEVELS ACTUALLY KIND OF STAYED
UP.
SO THE HEMOGLOBIN LEVELS DID NOT
DECLINE TO THE EXTENT THAT ONE
MIGHT HAVE EXPECTED FROM THE
DECLINE IN THE FETAL HEMOGLOBIN.
HERE THE NEUTROPHIL COUNTS AND
THE PLATELET COUNTS, SO AS
EXPECTED, THERE WAS A DOWNWARD
TREND IN NEUTROPHIL COUNTS ON
THERAPY, BUT IT DID NOT CROSS
THRESHOLDS FOR NEUTROPENIA.
EVEN HIGHLY CONSERVATIVE
THRESHOLDS FOR NEUTROPENIA.
HERE ARE THE PLATELET COUNTS AND
THERAPIES EXPECTED.
THERE WERE TRENDS FOR INCREASING
PLATELET COUNTS ON THE THU
DECITABINE BUT -- THAT WE
TYPICALLY SEE IN PATIENTS WITH
SICKLE CELL DISEASE ANYWAY.
HERE IS THE LDH DECLINE -- WE
SAUDI KLEINS ON NICOTINAMIDE
ALONE AS WELL AS ON THE
THU/DECITABINE.
WE SAUDI KLEINS IN TOTAL
BILIRUBIN ON NICOTINAMIDE ALONE
AS WELL AS ON THU/DECITABINE.
HERE'S D-DIMERSER AND CRP,
AGAIN, WE SAW SOME -- YOU CAN
SEE FOR YOURSELF.
THE CRPs KIND OF BOUNCE AROUND
A LITTLE BIT MORE.
OKAY.
SO THIS INTERIM ANALYSIS -- THE
ON VEST -- TTHERE'S OBVIOUS LIME
BUT THU/DECITABINE IS THE FIRST
AND THE LONGEST LONG-TERM
TREATMENT OF PATIENTS WITH
SICKLE CELL DISEASE, SO WE HAVE
ABOUT A YEAR OF DATA ON THESE
SIX PATIENTS.
AND CONSISTENT WITH THE DATA,
WITH THE SUBCUTANEOUS
DECITABINE, WE DON'T SEE
NEGATIVE PREDICTION BIOMARKERS
THAT OPERATE FOR HYDROXYUREA
APPLYING FOR THIS AGENT.
WE HAVE DISCOVERED AGAIN THERE
IS A MINIMUM BIOLOGICALLY
EFFECTIVE DOSE SO IF WE GO BELOW
THAT, WE'RE NOT GOING TO SEE THE
BENEFITS.
WE SEE SUSTAINED IMPROVEMENTS IN
BOTH OBJECTIVE AND SUBJECTIVE
BIOMARKERS.
WE DO THINK THERE'S ACTIVITY
WITH NICOTINAMIDE, BUT BASED
ALSO ON IN VITRO STUDIES, WE
THINK IT DIRECTLY ANTAGONIZES
THE UPTAKE OF DECITABINE BECAUSE
IT IS AN ENERGY -- FOR CELLS AND
THEY USE IT FOR DE NOVO PEER MI
DEAN SYNTHESIS.
SO WE'RE GOING TO MODIFY/AMEND
THE PROTOCOL SUCH THAT THE
PATIENTS DO NOT TAKE VITAMIN
B3 ON THE DAY THEY TAKE THE
THU/DECITABINE.
THAT'S THE LAST POINT.
SO I THINK I'LL END THERE AND
DOES ANYBODY HAVE ANY QUESTIONS?
THANK YOU VERY MUCH.
>>THANK YOU, YOGEN.
IS THERE AN ONLINE QUESTION FOR
YOGEN?
>>YES, WE DO HAVE AN ONLINE
QUESTION.
WHAT DOSE OF NICOTINAMIDE -- ANY
LIVER TOXICITY OR FLUSHING CAN
BE CONFUSING FOR CONSUMERS
LOOKING AT -- AS SO MANY
DIFFERENT FORMS.
I'M READING DIRECTLY.
SORRY.
>>THANK YOU FOR THAT QUESTION.
SO IT EASY FOR PATIENTS TO GET
CONFUSED BETWEEN NICOTINAMIDE
AND NIACIN.
SO FOR OBVIOUS REASONS, THE
NAME.
SO VITAMIN B3, ANOTHER NAME FOR
IT IS NIACINAMIDE, WHICH IS
ACTUALLY DIFFERENT FROM NIACIN,
BUT I HAVE SEEN THIS HAPPEN
WHERE PATIENTS WILL GO TO THE
VITAMIN SHOP OR THE CVS OR
WHATEVER, AND ASK FOR NI
NIACINAMIDE AND LEAVE WITH
NIACIN AND HAVE SIDE EFFECTS.
WE DON'T SEE SIDE EFFECTS WHEN
THEY ACTUALLY TAKE VITAMIN B3.
ONE SIDE EFFECT, I DON'T SHOW IT
IN THIS TRIAL DATA, BUT JUST
FROM CLINICAL EXPERIENCES, WE
CAN SEE A DECREASE IN PLATELET
COUNTS EVEN AS HEMOGLOBIN
INCREASES.
SO THAT IS A SIDE EFFECT, BUT IN
TERM OF HOW PATIENTS FEEL,
FLUSHING, GI, WE DON'T GET
ANYTHING LIKE THAT.
WITH NIACINAMIDE.
WHICH IS NOT THE SAME ACINI SIN.
THANK YOU.
DI
[INAUDIBLE QUESTION]
>>DID YOU SAY HEPATOTOXICITY?
>>I CAN REPEAT THE QUESTION.
HI.
LYDIA PACKARD, JOHNS HOPKINS.
THANK YOU FOR YOUR VERY HOPEFUL
TALK.
AND FOR REALLY INTERESTING DATA.
I WONDERED AS WE LOOK TO A
HOPEFUL TIME WHEN PEOPLE ARE
IMAIRING WHICH TRCOMPARING WHICY
WILL USE TO TREAT THEIR SICKLE
CELL DISEASE, I WAS WONDERING IF
YOU WOULD SPEAK TO THE
ESTABLISHED OR -- GONADOTOXICITY
OF THIS THERAPY?
>>THAT'S SOMETHING WE
DEFINITELY WILL HAVE TO LOOK
FORMALLY IN THE CLINICAL TRIAL
SETTING.
MY REASONS FOR BEING HOPEFUL, NO
DATA, BUT FOR BEING HOPEFUL ARE
KIND OF WHAT I SHOWED YOU IN THE
BEGINNING.
THESE DRUGS ARE PRO DRUGS, AND
THE TISSUE COMPARTMENT THAT IS
REALLY ENRICHED FOR THE ENZYMES
THAT ACTIVATE THE PRODRUG IS THE
MYELOID COMPARTMENT.
SO IT'S NO COINCIDENCE, FOR
EXAMPLE, THAT THESE DRUGS ARE
USED TO TREAT MYELOID
MALIGNANCIES, EVEN THOUGH DN MTR
TREATING ALL SORTS OF CANCERS,
BUT THERE ARE ONLY IN THE CLINIC
FDA-APPROVED FOR MYELOID.
IT'S RELATED TO THIS METABOLIC
ASPECT, AND NOW IF YOU GIVE A
LOT OF THE DRUG, OF COURSE
YOU'RE GOING TO GET ALL SORTS OF
PLACES, AND SO WE'RE GIVING SUCH
SMALL AMOUNTS AND GIVEN THIS
TARGETED CHARACTER, I THINK
THERE IS A REASON TO HOPE THAT
THERE MAY NOT BE GONADOTOXICITY.
BUT WE NEED TO LOOK FOR IT AND
EVALUATE FOR IT.
>>THANK YOU AGAIN, YOGEN.
SO OUR NEXT SPEAKER IS GOING TO
BE TALKING ABOUT CRISPR SICKLE
CELL DISEASE GENE EDITING TRIAL
UPDATE.
SO THE NEXT TWO TALKS ARE GOING
TO BE DR. MARK WALTERS FROM
UNIVERSITY OF CALIFORNIA, AND HE
WILL BE FOLLOWED BY DR. DAVID
WILLIAMS.
>>THANK YOU VERY MUCH.
GOOD AFTERNOON, EVERYONE.
I APPRECIATE THE OPPORTUNITY TO
GIVE AN UPDATE ABOUT OUR
CLINICAL TRIAL, WHICH IS STILL
IN THE PRE-CLINICAL PHASE OF
DEVELOPMENT.
SO I WANT TO HIGHLIGHT THE
PROJECT TEAM.
THE GENE EDITING REAGENTS, THE
EDITORS THAT WE'RE USING WERE
VELLED BY JACOB CORN AND MARK
DEWITT.
THOSE CONTINUE TO BE UTILIZED IN
THE MANUFACTURING PROTOCOL.
DAWN AND ZULEMA HAVE MADE SOME
IMPROVEMENTS TO THE PROTOCOL
WHICH HAS BEEN SUBMITTED IN
AMENDMENT TO THE IND, AND I'M
GOING TO SPEND A FAIR AMOUNT OF
TIME -- YES, I CAN.
LET ME SCRUNCH DOWN HERE.
THE BULK OF WHAT I'M GOING TO
PRESENT ARE ANALYSES BY DARIO
AND STACIA, WHO HEAD THE
BIOINFORMATICS TEAM ON THE
PROJECT.
AND THIS IS, OFTE OF COURSE, FUD
IN A PARTNERSHIP BETWEEN THE
CALIFORNIA INSTITUTE OF
REGENERATIVE MEDICINE AND NIH
NHLBI CURE SICKLE CELL
INITIATIVE.
I'M GOING TO START WITH THIS
SCHEMATIC OF THE TARGET SITE FOR
CRISPR/CAS 9 EDITING.
THE SEQUENCE ENCODES FOR 168 --
IT ACTS AS THE DONOR FOR
HOMOLOGY DIRECTED REPAIR.
SO UNLIKE THE PRESENTATION THAT
MATT GAVE IN THE TRIAL LED BY
GRAPHITE BIO, THE DONOR IN THAT
PARTICULAR TRIAL IS A VIRAL
TEMPLATE, AV6.
OTHERWISE THE GUIDE RNA AND THE
KACAS9 ARE THE SAME IN BOTH.
WHAT I'VE UNDERLINED IN RED IS
WHERE THE COMPLEMENTARITY WITH
THE TEMPLATE OCCURS AND THEN THE
CLEAVAGE SITE IS THE RED
TRIANGLE.
SO THAT'S WHERE THE TEMPLATE
STRAND EXTENSION BEGINS TO
REPLACE THE SICKLE CODON WITH
THE WILD TYPE CODON, IT ADDS A
MUTATION TO THE PAM SITE SO THAT
REEDITING DOESN'T OCCUR ONCE HDR
HAS OCCURRED, AND THEN WE'VE
INCORPORATED ADDITIONAL SINGLE
BASE PAIR CHANGES TO KNOW THE
DIFFERENCE BETWEEN HGR AND
UNEDITED CELLS.
SO WHAT YOU MIGHT NOTICE IS THAT
THE SICKLE SNP IS DOWNSTREAM
FROM THE CLEAVAGE SITE, SO IT'S
POSSIBLE FOR THE TEMPLATE FORK
TO FALL OFF, EXTENDING -- THE
EXTENDING NATIVE STRAIN -- I'M
SORRY -- AS THAT EXTENSION
OCCURS BEFORE IT REACHES THE
SICKLE MUTATION.
SO THOSE WILL STILL SCORE AS HGR
EVENTS BECAUSE THE PAM HAS BEEN
MUTATED, BUT WON'T RESULT IN AN
ALTERED SICKLE SNP.
I'LL REFER TO THIS LATER IN A
SUBSEQUENT SLIDE BECAUSE IT
BECOMES IMPORTANT.
SO SEVERAL HUNDRED MICE WERE
XENOGRAFTED FOLLOWING ELECTRO
PORATION, HUMAN HEMATOPOIETIC
STEM CELLS AND RA HARVESTED 16
WEEKS LATER.
I'M GOING TO WALK FROM LEFT TO
RIGHT, SO BEGINNING WITH THE
PINK BARS, THOSE ARE THE
UNEDITED CONTROLS AND WHAT WE
DID IN THIS EXPERIMENT WAS TO
COMPARE UNFR UNFRACTION ATED BOE
MARROW, POSITIVE SELECTED HUMAN
CELLS AND -- GLYCOPORIN, SO IN
THAT INSTANCE WHERE THE
EXTENDING REPLICATION FORK FALLS
OFF BEFORE CORRECTING THE SNP
ALLELE, THE SICKLE ALLELE,
PAM-ONLY HDR LUCKILY ONLY
HAPPENS ABOUT 5% OF THE TIME,
AND THAT CONTRASTS WITH THOSE
MICE SCORED AS HAVING
SICKLE-CORRECTED HGRs.
SO THIS OCCURS ABOUT 20 TO 25%
OF THE TIME.
EACH MOUSE DEPICTED BY AN OPEN
GREY CIRCLE.
THE CORRECTION OCCURS AT EQUAL
FREQUENCY IN BOTH CELLS BUT
WHAT'S INTERESTING, THE
ERYTHROID LINEAGE, YOU SEE THIS
FOR CORRECTED ALLELES AND IT
ACCOUNTS FOR NEARLY 50% OF THE
MICE THAT WERE SCORED.
SO JUST AS OCCURS IN STABLE --
ALLOGENIC TRANSPLANTATION, EVEN
AT THE LEVEL OF INEFFECTIVE
ERYTHROPOIESIS IN THE BONE
MARROWS OF THESE MICE, THERE'S
EXPANSION OF A CORRECTED
ERYTHROID COMPARTMENT.
THE NEXT TWO PANELS IN GREEN AND
YELLOW REPRESENT NON-HOMOLOGOUS
END JOINING.
THESE CREATE INSERTION DELETIONS
THAT TYPICALLY WILL CAUSE OUT OF
FRAME MUTATIONS THAT ELICIT A
THALASSEMIA GENOTYPE.
AND IN FACT, THESE HAPPEN MORE
COMMONLY THAN HGR, ABOUT 50 TO
60% OF THE TIME IN THE YELLOW
BARS, AND INTERESTING RILY, THEE
DON'T CONTRIBUTE TO
ERYTHROPOIESIS, SO THESE DROP
OUT BECAUSE OF INEFFECTIVE
ERYTHROPOIESIS AND DON'T
CONTRIBUTE.
THE NON-HOMOLOGOUS END FRAME,
NON-HOMOLOGOUS END JOINING
INFRAME, THESE ARE COLLEAGUES CS
THAT OCCUR IN MULTIPLES OF
THREE.
THE MOST COMMON ONE, THESE DO
CONTRIBUTE TO ERYTHROPOIESIS AND
REPRESENT THE REMAINING.
SO THIS IS THE PROOF OF
PRINCIPLE THAT CORRECTING BY
HGR, 20 TO 25% OF THE ALLELES IN
AT LEAST 20 TO 25% OF THE STEM
CELLS SHOULD ELICIT THERAPEUTIC
EFFECT.
WE HAVE DONE THIS EXPERIMENT IN
A GMP SCALE, A CLINICAL SCALE,
AND IN SICKLE CELL SMALL SCALE
DONOR RUNS, AND SELECTED --
PICKED A NUMBER OF COLONIES,
812, AND THIS SHOWS THE
DISTRIBUTION BY GENOTYPE, SO
BLUE IS GOOD.
THESE ARE CLONES THAT HAVE AT
LEAST ONE CORRECTED ALLELE.
GREEN IS BAD.
THOSE HAVE NOT BEEN MODIFIED BY
THE CRISPR/CAS 9 REAGENT SO
THOSE ARE SICKLE CELL ANEMIA
CLONES STILL AND THEN THE INDELS
WHICH WOULD PREDICT A VA
THALASSEMIA GENOTYPE MOST OF THE
TIME ARE IN ORANGE.
WHAT WE OBSERVED, ON AVERAGE 40%
OF THE COLONY FORMING UNITS
DINED AT LEAST ONE CORRECTED
ALLELE FROM THE FIVE LOTS WE
ASSESSED, AND AN AVERAGE -- AN
EQUAL NUMBER, 40%, HAVE CFUs
THAT HAVE TWO INDEL ALLELES.
SO AGAIN WE'RE RELYING ON THIS
BALANCE OF THE CORRECTION OF THE
ALLELE COMPARED WITH INDELS THAT
WOULD BE DELETERIOUS.
THIS IS WHAT IT LOOKS LIKE.
THIS IS THE GMP MANUFACTURING
OUTCOMES THAT WE SUBMITTED IN
OUR IND THAT WAS ACCEPTED FOR
COMMENCING THE CLINICAL TRIAL.
THERE WAS EXCELLENT VIABILITY,
STERILITY AND ENDO TOXIC-FREE
MANUFACTURING PRODUCTS WERE
MADE.
AND THE CFE FORMATION WAS QUITE
ROBUST.
THE OVERALL CORRECTION WAS 26%,
AND THE INDE PELS AVERAGED 50%.
SO WHAT I'VE CIRCLED HERE IS
THAT RATIO COMPARING THE HGR --
THALASSEMIA GENOTYPE.
THE CRITICAL QUESTION ASKED IN
THE KRIN CAL TRIAL, THE CRITICAL
SAFETY QUESTION, WHETHER OR NOT
THESE CELLS WILL ADAPT AFTER
THEY'VE BEEN MODIFIED BY THE
CRISPR/CAS 9, IS THE RATIO OF
CORRECTION TO THALASSEMIA
FAVORABLE.
SO TWO CRITICAL SAFETY ISSUES
THAT WILL BE ANSWERED IN THIS
CLINICAL TRIAL.
SO AS ZULEMA AND -- CONTINUE TO
WORK ON FAVORRIZATION BY
CHANGING THE MEDIA CONDITIONS BY
WHICH THE CELLS ARE EXPANDED
BEFORE THE ELECTROPORATION
OCCURS.
WHAT'S COMPARED IN THESE PANELS
ARE USING THE STANDARD EX VIVO
15 MEDIA WITH TWO NEW MEDIA, AOF
WHICH IS A GMP-READY MEDIA AND
AN FEM2, WHICH IS STILL
RESEARCH-USE ONLY OR
PRE-CLINICAL, AND THE
DIFFERENCES BETWEEN EX-VO VO AND
THE OTHER TWO, THE CELLS IN
G1 APPEAR TO BE EXPANDED.
IF I CAN SHIFT YOUR ATTENTION TO
THE LOWER LEFT-HAND PANEL, THE
MEDIA, SHIFTING FROM LIGHT BLUE
TO YELLOW AND ORANGE, SHOWS THE
CHANGES IN HGR AND THE CHANGES
IN NHEJ WITH CHANGES IN THE
MEDIA.
SO AS THE CELLS EXPAND, THEY'RE
MORE LIKELY TO UNDERGO HOMOLOGY
DIRECTED REPAIR.
THE NHEJ GOES DOWN AND THEN THE
RATIO IS IMPROVED.
AND THEN THOSE TWO PANELS ON THE
RIGHT, THE FIRST ONE JUST SHOWS
THE MIX OF CELLS RIGHT AFTER THE
ELECTROPORATION OCCURS AND THEY
DON'T APPEAR TO BE DIFFERENT.
IF YOU LOOK AT THE STEM CELLS
THAT ACTUALLY ENGRAFT IN THE
XENOGRAFTS, CONTRIBUTE TO
ERYTHROPOIESIS, THE NHEJ RATIO
MARKEDLY IMPROVES COMPARED WITH
EX VIVO 15.
SO WE THINK WE HAVE AN OPTIMIZED
MANUFACTURING PROTOCOL NOW THAT
WILL PUT THAT RATIO OF HGR TO
NH EJ IN A FAVORABLE POSITION.
AND ENHANCE SAFETY, PATIENTS WHO
PARTICIPATE IN THE TRIAL.
SO THIS IS HOW IT WILL WORK.
THIS IS NOT DIFFERENT FROM WHAT
WAS PRESENTED EARLIER TODAY.
PATIENTS ARE BROUGHT IN FOR
MOBILIZATION, SINGLE AGENT,
SHIFTED TO UCLA IN THEIR
MANUFACTURING FACILITY WHERE
ELECTROPORATION WILL BE
PERFORMED.
THE GENE EDITED CELLS
CRYOPRESERVED ARE SHIPPED AND
THE PATIENT WILL UNDERGO
ABLATION AND INFUSION OF THE
THAWED CELLS.
TIMELINE IS SHOWN HERE, SO OUR
GOAL IS TO ENROLL UP TO NINE
SUBJECTS, SIX ADULTS AND AS THE
TOXICITY AND EFFICACY PROFILES
ARE FAVORABLE, WE WOULD ENROLL
THREE ADOLESCENTS, BETWEEN 12
AND 17 YEARS OF AGE.
THE IND WAS FILED AS I
MENTIONED, COMING ON THREE YEARS
AGO.
IT TOOK A BIT OF TIME TO GET THE
FUNDING LINED UP, WHICH WE HAVE
NOW, AND OUR PRINCIPAL DELAY AT
THIS POINT IS MAKING GMP GRADE
OLIGONUCLEOTIDE.
THE RESEARCH USE ONLY SUPPLIER
DROPPED OUT OF THE GMP BUSINESS
BECAUSE OF MESSENGER RNA TAKING
OVER FOR VACCINES, AND SO WE HAD
TO SCRAMBLE TO FIND A NEW
VENDOR.
NONETHELESS, WE ANTICIPATE
HAVING THAT REAGENT RE CAN I BY
THREADY BY THEEND OF THIS CALEND
ENROLLING OUR FIRST PATIENT
EARLY NEXT YEAR.
SO WHAT ELSE COULD GO WRONG?
I'VE JUST SHARED WITH YOU THIS
IMPORTANT THALASSEMIA HDR RATIO.
CHROMOTHRIPSIS IS ANOTHER
PHENOMENON THAT'S BEEN
DESCRIBED.
IN THIS EXAMPLE, USING THE BC11A
ERYTHROSPECIFIC ENHANCER
KNOCKOUT RNP, THIS LAB SHOWED
THAT THE MICRO NUCLEI OCCUR
ABOUT 2.5% OF THE TIME, SO
THERE'S A PROBE ON EITHER SIDE
OF THE CUT SITE ON CHROMOSOME
2 WHERE BC11A IS LOCATED AND
IDEALLY YOU WOULD HAVE ONE COPY
OF EACH ON EITHER SIDE OF THE
CENTROMERE AND THE MICRO NUCLEI
HAS TWO COPIES OF THE BCL11A
GENE AS DEPICTED IN THIS
PARTICULAR PHOTOMICROGRAPH.
MOST OF THE TIME THEY DON'T
CONTRIBUTE, THEY UNDERGO
APOPTOSIS AND FALL OUT, BUT THEY
ARE ASSOCIATED WITH A HIGHER
RISK OF MALIGNANCY, SO WE ARE
SCRAMBLING TO WORK OUT A
CHROMOTHRI PSI S ASSAY FOR OUR
OWN GENE REEDITING AGENTS.
THE OTHER THING WE OBSERVED WAS
THIS DISPARITY BETWEEN THE
ASSORTMENT OF ALLELES POST
EDITING, BOTH HOMOZYGOUS AND
HETEROZYGOUS THAT SHOULD OCCUR
FOLLOWING THE HARVEY WEINBERG
PREDICTIONS AND WHAT WE ACTUALLY
OBSERVED.
IN PARTICULAR, THE HOME ZYGOTES,
WE OBSERVED MORE HOME S HO HOMO-
WE WONDERED IF ONE EXPLANATION
COULD BE THESE ARE ACTUALLY
HEMIZYGOUS, WITH ONE OF THE
ALLELES ACTUALLY REPRESENTING A
VERY LARGE DELETION THAWS
OUTSIDE OF THE SMALL
AMPLIFICATION DNA SEGMENT THAT
WE DETECT FOR HDR.
SO THIS WAS A RECENT PAPER AT
RICE UNIVERSITY, A GROUP WE'RE
COLLABORATING WITH, AND HE, IN
ADDITION TO LOOKING AT THE
SHORT -- RANGE, HE CREATED A
SYSTEM FOR PICKING UP UP TO 5KB
LONG-RANGE DELETIONS ON TARGET.
SO THE TWO AMPLICONS ARE SHOWN
IN THIS DEPICTION.
AND THEN HE USED A TECHNOLOGY
RELYING ON A SINGLE MOLECULE
REALTIME SEQUENCES SYSTEM
CREATED BY PACBIO USING THE
UNIVERSAL MOLECULAR IDENTIFIERS.
WHAT THIS DOES IS IT OVERCOMES
THE PROBLEM OF RECOMBINATION
THAT OCCUR BETWEEN THE TEMPLATES
DURING THE PCR AMPLIFICATION AND
ALSO REDUCES THE PCR ERROR RATE,
SO YOU AVOID SOME OF THE
ARTIFACTS THAT ARE INTRODUCED BY
PCR.
AND USING THIS SYSTEM, HE
CREATED A DATABASE THAT SHOWED A
QUITE STRIKING RESULT.
SO USING EXACTLY OUR TEMPLATE,
THE SAME OLIGONUCLEOTIDE AND
BOTH THE RNP, HE SHOWED THAT
FIRST OF ALL, USING RNP ALONE,
THE NUMBER OF LONG-RANGE
INSERTIONS WAS IMPRESSIVE, IN
FACT IT WAS NEARLY 40% BUT WHEN
THE OLIGONUCLEOTIDE TEMPLATE WAS
REDUCED, THE RATE WENT DOWN BUT
IT STILL ACCOUNTED FOR ABOUT 10
TO 12% OF THE TOTAL THAT WAS
OBSERVED.
SO AGAIN, THESE WILL BE -- WON'T
CONTRIBUTE TO ERYTHROPOIESIS SO
THESE ARE NEGATIVE RESULTS.
THE GOOD NEWS IS THAT THEY CAN
STILL BE OVERCOME BY A ROBUST
HDR FREQUENCY, AND THEY
SHOULDN'T BE ANY MORE DIFFICULT
TO OVERCOME THAN THE SMALL
INSERTION DELETIONS DEPICTED BY
THE GREEN SEGMENT OF THE PIE.
BUT STILL SOMETHING ELSE WE WANT
TO UNDERSTAND BETTER AND WE HAVE
SENT SOME OF OUR GENOMIC DNA TO
THE LAB FOR FURTHER ANALYSIS, SO
WE UNDERSTAND BETTER WHAT'S
HAPPENING IN OUR HANDS TOO.
THE LAST THING I WANTED TO SHOW
WAS SOMETHING WE DID FOR THE
RESEARCH USE ONLY SINGLE
STRANDED OLIGONUCLEOTIDE THAT
WAS UTILIZED IN THE PRE-CLINICAL
STUDY.
SO THIS IS DIRECT DNA SEQUENCING
OF THE OLIGONUCLEOTIDE, AND THE
LENGTH OF THOSE BARS HAS TO DO
WITH THE NUMBER OF
OLIGONUCLEOTIDES THAT WERE
SEQUENCED.
NOT SURPRISINGLY, THERE'S A LOT
OF -- LESS THAN FULL LENGTH
OLIGONUCLEOTIDES, WHICH IS OKAY.
BUT WHAT ISN'T OKAY
PARTICULARLY -- IS THERE ARE
SINGLE NUCLEOTIDE CHANGES,
ERRORS IN THE SEQUENCE, THAT
WERE NOT INTENDED, THAT OCCURRED
IN THE TEMPLATE REGION OF THE
OLIGONUCLEOTIDE.
SO THIS WAS ANALYSIS DONE BY
STACIA AND DARIO ON THE TEAM.
WHAT STACIA DID WAS THEN
CONVINCINGLY DID THIS ANALYSIS
WHICH IS FROM GENOMIC DNA THAT
WERE CREATED WITH THESE
REAGENTS.
AND AT REGULAR INTERVALS AND
PREDICTED BY THE
OLIGONUCLEOTIDE, THERE ARE
SNPs THAT HAVE BEEN INTRODUCED
INTO THE CLONES THAT WE WOULD
HAVE SCORED AS HOMOLOGY DIRECTED
CLONES AND THESE OCCUR AS
REGULAR INTERVALS.
IN THE HDR CLONES WHERE ONLY THE
PAM IS MUTATED, YOU CAN SEE
DOWNSTREAM FROM THAT, THE SNPs
DISAPPEAR.
SO THESE ARE ABSOLUTE -- THIS IS
CLEAR EVIDENCE THAT THE MISTAKES
MADE IN OLIGONUCLEOTIDE TEMPLATE
ARE BEING INCORPORATED IN THE
GENOMIC DNA, AND WOULD BE PART
OF AN HDR CLONE WE CAN USE IN
THE PATIENT.
SO THAT'S SOBERING.
BUT THE GOOD NEWS IS THERE'S
QUITE A VARIABILITY IN THE ERROR
RATE BY MANUFACTURER.
WHAT'S INTERESTING, THIS HAS
SOMETHING TO DO WITH THE
BIOSYNTHETIC, THE SYNTHESIS
CHEMISTRY THAT OCCURS WHEN YOU
MAKE AN OLIGONUCLEOTIDE OF THIS
LENGTH, THAT WHATEVER IS
HAPPENING, IT'S HAPPENING
SYSTEMATICALLY, AND THE
MANUFACTURERS DON'T UNDERSTAND
IT.
EXCEPT TO SAY THAT THEY TELL US
THAT THEY'RE AT THE LIMITS OF
THE TECHNOLOGY WITH THESE KIND
OF CHANGES, BUT WHAT WAS
INTERESTING IS THAT THE SNPs,
THE ERRORS IN OLIGONUCLEOTIDE
SEQUENCE OCCUR IN THE SAME
LOCATION REGARDLESS OF
MANUFACTURER.
SO THERE'S SOMETHING ABOUT THE
SYNTHESIS CHEMISTRY ITSELF
THAT'S CREATING THESE ERRORS.
THE GOOD NEWS IS THE ERROR RATE
IS MUCH LOWER IN THE CITY OF
HOPE NUCLEOTIDE CLINICAL TRIAL,
WHERE 5% OF THE TOTAL ALLELES IN
THE FIRST MANUFACTURER.
SO WE MAPPED OUT THE AMINO ACID
CHANGES THAT WILL OCCUR.
THESE ARE ALL NON-SYNONYMOUS
MUTATIONS THAT OCCUR.
I LOOKED UP ALL THESE VARIANTS
AND I'M HAPPY TO REPORT THAT
NONE OF THEM HAS ANY CLINICAL
PHENOTYPE.
SO WHILE THESE SNPs WILL BE
INTRODUCED AND ONE SHOULD
INTERTENTERTAIN THE POSSIBILITYT
THEY WILL CONTAIN SICKLE
PHENOTYPE, PERHAPS, THIS REVIEW
WAS, I THOUGHT, REASSURING.
AND THAT MOST OF THEM, FIVE OF
THE EIGHT WON'T CONTRIBUTE TO
ANEMIA OR OTHER SICKLING ERRORS.
SO I'D LIKE TO FINISH WITH WHERE
WE ARE FOR THE FUTURE OF THIS
PARTICULAR GENE EDITING PROJECT.
AGAIN I EMPHASIZE WILL THE
BALANCE OF ON-TARGET
INSERTION-DELETIONS SHORT TERM
AND LONG-RANGE AND
HOMOLOGY-DIRECTED REPAIR SUPPORT
A CLINICAL BENEFIT AND OVERCOME
A THALASSEMIA PHENOTYPE?
SO THAT'S SAFETY QUESTION NUMBER
ONE THAT WILL BE FOREMOST IN OUR
MINDS.
WE'VE HEARD THIS MORNING ABOUT
THIS RISK, IS THERE RISK OF
CLONAL HEMATOPOIESIS OR
SELECTION OF PROLIFERATIVE
CLONES AFTER EX VIVO EXPANSION
AND REPOPULATION OF A LIMITED
NUMBER OF STEM CELLS?
WE LACK LONG TERM OUTCOME AND
WE'LL NEED THAT LONG TERM DATA
TO BE ABLE TO ANSWER THIS
QUESTION.
CERTAINLY WE KNOW THIS CAN
OCCUR, AND THIS WILL BE GERMANE
TO ALL OF THE GENOMIC EDITING
GENE THERAPY TRIALS.
AND FINALLY, MAYBE MOST
IMPORTANTLY, IS THAT -- SO THIS
IS A PROJECT THAT'S COMPLETELY
PUBLIC FUNDED.
WE HAVEN'T LICENSED TO ANY
COMPANY.
BUT STILL AT THE END OF THE
PROJECT, IF IT'S SUCCESSFUL,
WILLITY COST AND COMPLEXITY
RESTRICT ACCESS TO CARE?
SO THIS IS A POLICY QUESTION
THAT HAS TO BE DIRECTED
IMMEDIATELY.
WILL THERE BE BROAD VERSUS
LIMITED AVAILABILITY OF THIS
APPROACH, AND IF IT'S LIMITED,
WE NEED TO MOVE ON TO THE NEXT
THING.
SOONER RATHER THAN LATER.
THANKS VERY MUCH FOR YOUR
ATTENTION.
>>THANK YOU, MARK.
TIME FOR ONE QUICK QUESTION.
IS THERE ANYTHING IN THE CHAT?
NO?
OKAY.
IT WAS VERY CLEAR.
SO NEXT TALK IS DR. WILLIAMS,
DR. DAVID WILLIAMS FROM BOSTON
CHILDREN'S HOSPITAL.
POST TRANSCRIPTIONAL SILENCING
OF B CL11A USING A LENTIVIRUS
SHMIR VECTOR, THE PHASE 2 GRASP
TRIAL.
>>THANK YOU VERY MUCH.
I HOPE YOU CAN HEAR ME?
>>YES, WE CAN.
>>I APOLOGIZE I'M NOT THERE,
I'M ACTUALLY IN CLINIC TODAY, SO
I'M GOING TO TALK TO YOU IN
BETWEEN PATIENTS.
BUT I'D LIKE TO SHARE SOME OF
OUR EXCITING DATA FROM THE TRIAL
WE HAVE ONGOING AS WELL AS THE
PHASE 1 TRIAL THAT HAS BEEN
COMPLETED.
I'M SEEING MARK'S LAST SLIDE
STILL.
I'LL JUST MAKE THE POINT WE CALL
THIS POST TRANS KRIPTIONAL
SILENCING BECAUSE AS OPPOSED TO
SOME OF THE METHODOLOGIES YOU
HEARD THIS MORNING, THE PROCESS
OF INDUCING FETAL HEMOGLOBIN BY
REDUCTION OF BC L11A OCCURS NOT
AT THE DNA LEVEL BUT AT THE RNA
LEVEL.
SO THESE ARE MY DISCLOSURES.
I'LL POINT OUT A COUPLE THAT ARE
RELEVANT.
SO BLUEBIRD BIO PROVIDED GMP
VECTOR FOR THE PHASE ONE TRIAL
AND FOR THE PHASE TWO TRIAL AS
PART OF A LICENSING AGREEMENT
WHICH HAS NOW BEEN ENDED.
ALSO WE'LL JUST MAKE THE POINT
THAT WE HAVE A SPONSORED
RESEARCH AGREEMENT WITH EXCEL
THERAPY LOOKING AT DNA DAMAGE IN
SICKLE CELL PATIENTS.
SO WE CALL THIS FLIPPING THE
FETAL TO ADULT SWITCH.
I DON'T THINK I HAVE TO RE --
SPEND MUCH TIME ON THIS.
IF YOU CAN GO QUICKLY THROUGH
SOME ANIMATIONS, PLEASE.
SO QUICKLY AS YOU KNOW AFTER
BIRTH WE SHUT OFF FETAL
HEMOGLOBIN AND TURN ON BETA
ADULT HEMOGLOBIN, WHICH IN
PATIENTS WITH SICKLE CELL
DISEASE, OF COURSE, LEADS TO THE
CLINICAL SYMPTOMATOLOGY OF
SICKLE CELL.
AND SO OUR APPROACH IS TO
REVERSE THE SWITCH.
AS A THERAPEUTIC GOAL.
AND THE ADVANTAGE OF THIS IS
THAT WE SIMULTANEOUSLY INCREASE
HEMOGLOBIN F WHICH IS PROTECTIVE
AGAINST INTRACELLULAR
OXYGENATION OF -- AND REDUCE
HEMOGLOBIN IN THE CELL AND AS
YOU KNOW POLYMERIZATION OF
SICKLE IN DEOOXYGENATED STATE
IS -- OF THE CONCENTRATION OF
HEMOGLOBIN IN THE CELL.
SO WE'VE DONE THIS BY
ENGINEERING A SHMIR, AND THIS IS
A SH RNA TARGETING BCL11A THAT'S
EMBEDDED IN A MICRORNA SCAFFOLD.
AND THIS SHOWS YOU CONCEPTUALLY
WHAT THIS LOOKS LIKE.
WE'VE REMOVED PART OF THE
NATURALLY OCCURRING ENDOGENOUS
HAIRPIN OF THE MICRO RNA AND
REPLACED IT WITH THIS SH RNA
THAT TARGETS BCL11A.
THIS IS DESCRIBED IN THE
PUBLICATION SHOWN HERE.
THIS HAS ADVANTAGE BECAUSE IT
MIMICS INDIGENOUS MICRO RNA
LEVELS, LEADING TO MORE
PHYSIOLOGIC AND LOWER EXPRESSION
LEVELS THAT REDUCES NONSPECIFIC
TOXICITIES, AND BECAUSE OF THE
MICRORNA ARCHITECTURE, THIS
ALLOWS US TO EXPRESS THE SH RNA
IN A LIB YAJ-SPECIFIC FASHION.
TO ITS EXPRESSION IS ONLY IN
ERYTHROPRECURSORS, AND THAT
AVOIDS THE TOXICITIES OF BCL11A
KNOCKOUT OR KNOCK DOWN IN HSCs
AND THE LYMPHOCYTES.
SO THIS IS FROM OUR IND FOR THE
PHASE ONE TRIAL, AND YOU CAN SEE
ON THIS SLIDE THAT THREE
DIFFERENT PATIENTS WITH SICKLE
CELL WHO DONATED HEMATOPOIETIC
STEM CELLS FROM BONE MARROW DONE
IN TRIPLICATE.
THERE IS A VERY SIGNIFICANT
INDUCTION OF BOTH GAMMA
HEMOGLOBIN MRNA AND FETAL
HEMOGLOBIN PROTEIN BY HPLC.
AND AS WE WOULD THINK OF BY THE
FACT THAT WE'RE USING A
PHYSIOLOGIC SWITCH, THIS IS
ACCOMPANIED BY DRAMATIC DECREASE
IN THE CONCENTRATION OF
HEMOGLOBIN S IN EACH OF THOSE
PATIENTS.
SO YOU'RE BASICALLY GETTING A
TWO-FOR WITH THIS APPROACH:
REDUCTION IN S AND INCREASE IN
PROTECTIVE F.
SO THIS IS THE PROTOCOL WE USE
FOR THE PHASE 1 TRIAL WHICH HAS
COMPLETED ENROLLMENT WITH 10
PATIENTS.
WE USED PLERIXAFOR CELL
MOBILIZED STEM CELLS, CD34
SELECTION, AND THE TRANSDUCTION
THAT OCCURRED IN THE GMP
FACILITY, IN THIS CASE, THE C
MCF AT DANA FARBER CANCER
INSTITUTE.
AFTER RELEASE OF THE MEDICINAL
PRODUCT, THE PATIENTS WERE
ADMITTED FOR THE AGENT
CONDITIONING AND FOLLOWED FOR
TWO YEARS FOR HEMOGLOBIN F
LEVELS, THE PERCENT OF F CELLS,
BCL11A LEVELS AND SICKLE CELL
SYMPTOMS.
SO I WON'T BELABOR A LOT OF THE
DATA, BUT I'LL GIVE YOU SOME
SUMMARIES, AND PART OF THIS HAS
BEEN PUBLISHED IN THE NEW
ENGLAND JOURNAL OF MEDICINE IN
2020.
PREINFUSION, THE ONLY GRADE 3
AEs WERE CVL-RELATED.
WE HAD SEVERAL PATIENTS WHO
DEVELOPED CVL-ASSOCIATED
THROMBI, WE HAD ONE PATIENT THAT
DEVELOPED A PNEUMOTHORAX WITH
LINE PLACEMENT AND INFECTION.
THERE WERE NO GRADE III AEs
RELATED TO EITHER THE
MOBILIZATION OR COLLECTION
PROCEDURES.
THERE HAS BEEN NO ADVERSE EVENTS
ASSOCIATED WITH MEDICINAL
PRODUCT.
AND THERE'S BEEN NO CLONAL
DOMINANCE IN ANY SUBJECT.
ALL THE PATIENT HAS HAVE BEEN VY
POLYCLONAL, INCLUDING LOOKING AT
THESE PATIENTS USING SINGLE CELL
DNA IN A COLLABORATIVE EFFORT
WITH THE SANGER INSTITUTE IN THE
U.K.
THE LONGEST FOLLOW-UP IS NOW
APPROACHING FIVE YEARS.
SO THIS SHOWS YOU INDUCTION OF
BLOOD HEMOGLOBIN F AND THE
PATIENT IS INFUSED.
THERE'S ONE PATIENT, PATIENT
NUMBER 10 SHOWN WITH THE RED
ARROW, WHO WE CONSIDER A FAILURE
BECAUSE OF THE LACK OF
INDUCTION, AND THIS IS
ASSOCIATED WITH A LOW IN VIVO
VECTOR COPY NUMBER, THAT'S A
TERM THAT WE USE TO DESCRIBE THE
NUMBER OF STEM CELLS THAT HAVE
ENGRAFTED THAT CONTAIN THE SHMIR
THAT'S WITHIN THE LENTIVIRAL
VECTOR.
OTHERWISE THE PATIENTS HAVE HAD,
AS YOU CAN SEE, VERY LARGE
INCREASES IN THEIR BLOOD
HEMOGLOBIN F.
AND THIS IS ASSOCIATED WITH A
VERY BROADLY DISTRIBUTED
HEMOGLOBIN F.
YOU CAN SEE FOR MOST PATIENTS,
IT'S ABOVE 60%.
AGAIN, PATIENT 10, I MARK AS THE
PATIENT WHO FAILED BECAUSE OF A
LOW VCN IN VIVO.
NOW ONE OF THE INTERESTING
THINGS THAT WE HAVE STUDIED IS
TO COMPARE THE RELATIONSHIP OF
HEMOGLOBIN F INDUCTION WITH
HYDROXYUREA PATIENTS.
SO THIS IS A PAPER THAT'S IN
PRESS IN NATURE COMMUNICATION,
AND IT'S A LITTLE BIT
COMPLICATED BUT I'LL SHOW YOU ON
THE RIGHT-HAND SIDE WE COMPARED
THE NUMBER OF RED CELLS
CONTAINING MORE THAN 70%
HEMOGLOBIN S OF THE TOTAL
HEMOGLOBIN IN PATIENTS THAT HAD
HYDROXYUREA WITH LOW INDUCTION
OF HEMOGLOBIN F.
THOSE THAT HAD HIGH INDUCTION
WITH HYDROXYUREA AND THOSE IN
THE GENE THERAPY TRIALS.
TRIAL.
AND THE PATIENTS IN THE BLUE
PANEL ON THE RIGHT ARE PATIENTS
THAT HAD EQUIVALENT BLOOD
HEMOGLOBIN F WITH HYDROXYUREA AS
THE GENE THERAPY PATIENTS.
BUT YOU CAN SEE THAT THE
PATIENTS IN THE GENE THERAPY
TRIAL HAD SIGNIFICANTLY LOWER
NUMBER OF RED CELLS CONTAINING A
LOT OF HEMOGLOBIN S COMPARED TO
HOI DROOX EE UREA.
THIS SPEAKS TO THE MECHANISM BY
WHICH WE'RE ADDRESSING THE
INDUCTION OF HEMOGLOBIN F WHERE
WE'RE BASICALLY USING A
PHYSIOLOGIC SWITCH THAT'S
BINARY, SO THE AMOUNT OF S GOES
DOWN AS THE AMOUNT OF F GOES UP.
YOU CAN SEE AGAIN DOWN BELOW
THAT THE HYDROXYUREA F RANGE IN
BLUE WAS 27% COMPARED TO THE
BCL11A PATIENTS SHOWN ON THE
CHRONOLOGICAL AXIS ON THE LEFT.
THIS WAS ALSO SEEN HERE WHERE
WE'VE ASKED THE QUESTION UNDER
HYPOXIA CONDITIONS, WHAT HAPPENS
TO POLYMER FORMATION.
SO IN A, YOU CAN SEE A FLOW,
MICRO FLOW CHAMBER WITH RED
CELLS FLOWING AT 1.7% OXYGEN
TENSION, THAT'S THE OXYGEN
TENSION IN THE KIDNEY.
AND ON THE RIGHT, YOU CAN SEE
THE SAME FLOW AT 1.7% WITH
HEMOGLOBIN S POLYMER FORMATION
THAT YOU CAN SEE VISUALLY ON A
SINGLE CELL BASIS.
DOWN BELOW, AGAIN, IF YOU LOOK
AT THE GRAPHS, IT COMPARES THE
NUMBER OF RED CELLS WITH NO
DETECTABLE HEMOGLOBIN POLYMER
COULD BE TENT.
THAT'S IN C, AT 1.7%.
AGAIN, INSPITE OF THE FACT THAT
THE HEMOGLOBIN F LEVEL IN THE
PERIPHERAL BLOOD IS EQUIVALENT
IN THE HYDROXYUREA HIGH
RESPONDERS, THE NUMBER OF CELLS
CONTAINING POLYMER IS
SIGNIFICANTLY LESS IN THE GENE
THERAPY TREATED GROUP.
SO THIS AGAIN SUGGESTS THAT THE
NUMBER OF RED CELLS THAT HAVE
HIGH HEMOGLOBIN F ABOVE 8 OR
10PICOGRAMS IS HIGHER IN THE
GENE THERAPY TREATED PATIENTS
VERSUS THE HYDROXYUREA PATIENTS.
SO IN THIS INITIAL PILOT STUDY,
10 PATIENTS WERE TREATED.
WE WERE ABLE TO GENERATE A GMB
PRODUCT IN 11 PATIENTS, ONE
PATIENT WITHDREW FOR
CO-MORBIDITY REASONS BEFORE THE
INFUSION.
10 PATIENTS HAVE BEEN INFUSED.
THE SHMIR VECTOR IS SAFE WITH
FOLLOW-UP NOW ALMOST FIVE YEARS
IN THE LONGEST PATIENT.
THE VECTOR IS EXTREMELY
EFFICIENT IN TRANSDUCING HSCs.
THERE'S BEEN NO ADVERSE EVENTS
RELATED TO THE VECTOR.
EXPRESSION, I DIDN'T SHOW YOU
THE DATA, APPEARS
LINEAGE-SPECIFIC, AND GENE
MARKING IS STABLE.
HIGH HEMOGLOBIN F FOR F CELL
WITH REDUCED HEMOGLOBIN S PER
CELL AND THERE'S BEEN A
SIGNIFICANT ATTENUATION IN A
SICKLING PHENOTYPE IN THE
PATIENTS THAT WE'VE TREATED,
WITH THE EXCEPTION OF THE ONE
PATIENT WHO HAD A LOW VECTOR
COPY NUMBER IN VIVO.
OF THE 10 PATIENTS THAT WAVE
DONE THIS WITH, ONE OF THE 10
PATIENTS HAS A SOMATIC MUTATION
IN THE GENE ASSOCIATED WITH
CLONAL HEMATOPOE EE SES, DNMT3A.
IT'S INTERESTING THAT THIS
PATIENT HAD THIS DISCOVERED SIX
MONTHS POST INFUSION, AND THE
BASELINE ANALYSIS WAS NEGATIVE.
AND THAT WAS BECAUSE THE
MUTATION WAS PRESENT IN THE
BASELINE ANALYSIS, BUT THE
PRESAMPLE IN THE CLIA LAB WAS
BELOW THE LEVEL OF REPORT OUT AS
POSITIVE.
SO WE WERE QUITE INTERESTED IN
THIS PATIENT.
THE PATIENT WAS OFFERED GENETIC
COUNSELING AND HAS NOT TAKEN
THAT UP, BUT AS YOU CAN SEE,
WHAT'S INTERESTING IS THAT THIS
FRACTION OF THE DNMT3 ALLELE HAS
NOT INCREASED AFTER THE INITIAL
SIX MONTHS PERIOD.
YOU CAN SEE IT INCREASED
INITIALLY AFTER INFUSION AND
IT'S REMAINED RELATIVELY STABLE
OVER A LONG PERIOD OF TIME NOW,
2 1/2 YEARS IN PERIPHERAL BLOOD.
THE BONE MARROW OF THIS PATIENT
IS NORMAL EXCEPT FOR SOME EE RIT
RERYTHROID EXPANSION AND THE
PATIENT CONTINUES TO DO WELL.
I BRING THIS UP BECAUSE OF
COURSE IT IS AN ISSUE IN THE
FIELD AS TO WHETHER PATIENTS
WITH SICKLE CELL DISEASE HAVE AN
INCREASED RISK OF HEMATOLOGIC
MALIGNANCY.
WE ARE STUDYING THIS IN MORE
DETAIL, LOOKING AT THE
MANUFACTURING PROCESS, AS WELL
AS THE ENGRAFTMENT AT SINGLE
CELL DNA LEVELS, AND AS I
MENTIONED, THAT'S A
COLLABORATION WITH THE SANGER
INSTITUTE.
AND THOSE DATA FROM THE PILOT
STUDY ARE CURRENTLY UNDER REVIEW
AT NATURE MEDICINE AND HOPEFULLY
WILL BE ACCEPTED SHORTLY.
IN GENERAL, WE HAVEN'T SEEN ANY
SIGNATURE OF SICKLE CELL DISEASE
IN THOSE SINGLE CELL DNA
SEQUENCES THAT WE'VE DONE, AND
WE'RE CONTINUING THOSE STUDIES.
SO LET ME GO TO THE PHASE TWO
STUDY.
THIS IS CALLED THE GRASP STUDY,
GENE THERAPY TO REDUCE ALL
SICKLE PAIN.
IT'S CO-CHAIRED BY MARK AND
MYSELF AND IS FUNDED BY THE
NHLBI CURE SICKLE, AND BY CERM.
THE PRIMARY OBJECTIVE IS TO
DETERMINE IF A SINGLE INFUSION
OF AUTOLOGOUS HSCs TRANSDUCE
WITH THE SHMIR VECTOR CAN LEAD
TO THE COMPLETE ABSENCE OF
SEVERE VOEs DEFINED AS EITHER
ACS OR VOCs REQUIRING
PARENTERAL OPIOIDS IN THE PERIOD
OF 6 MONTHS TO 24 MONTHS AFTER
GENE THERAPY.
THIS TRIAL WAS HELD FOR A
SIGNIFICANT PERIOD OF TIME WHILE
WE WORKED OUT THE ISSUES OF THE
ANALYSIS OF CLONAL HEMATOPOIESIS
AND HOW THAT RELATED TO
INCLUSION IN THE TRIAL, BUT
OPENED IN JANUARY THIS YEAR.
AND SITES ARE SHOWN HERE,
MULTIPLE SITES IN CALIFORNIA AS
WELL AS THE REST OF THE COUNTRY.
ALL THESE SITES ARE NOW OPEN AND
ACCRUING, AND WE'VE NOW ACCRUED,
AS YOU CAN SEE, 13 PATIENTS
ALREADY INTO THE TRIAL, AND JUST
AS THE COMMENT FROM MY PREVIOUS
COMMENT ON CLONAL HEMATOPOIESIS,
12 OF THESE PATIENTS HAVE NOW
HAD THE ANALYSIS FOR CLONAL
HEMATOPOIESIS AND NONE OF THOSE
PATIENTS HAVE WE FOUND ANY
MUTATIONS IN GENES THAT WOULD
NOT ALLOW THEM TO CONTINUE INTO
THE TRIAL.
BECAUSE OF THE CHARACTERISTICS
OF THIS TRIAL AND THE RULES I'M
NOT ABLE TO PROVIDE MUCH IN THE
WAY OF CLINICAL OUTCOMES YET,
BUT I WOULD JUST SAY IN THE
PATIENTS THAT WE'VE ALREADY
COMPLETED COLLECTION ON, THOSE
HAVE ALL YIELDED EFFECTIVE
MEDICINAL PRODUCT AND THREE OF
THE PATIENTS HAVE ALREADY BEEN
INFUSED.
SO WE'VE GOT 15 PATIENTS
ENROLLED.
ONE WITHDREW FROM THE STUDY, AND
THE TARGET FOR THIS TRIAL IS 25
PATIENTS.
SO WE'RE OVER HALFWAY TO OUR
TARGET ACCRUAL IN THE FIRST AP
EIGHT MONTHS OF THE TRIAL.
SO FAR WE'VE HAD VERY EFFECTIVE
COLLECTION AND GMP PRODUCT
DEVELOPMENT FOR THE FIRST FOUR
PATIENTS AFTER THEIR TRANSFUSION
REQUIREMENT.
THREE OF THE FOUR ACTUALLY
ACQUIRED THEIR TARGET IN ONE
MOBILIZATION, THANKS A LOT TO
JOHN MANUS, WHO JUST HAD A
WORKSHOP ON THIS AT LUNCHTIME.
SO FAR THE HSCs HAVE BEEN
SUFFICIENTLY TRANSDUCED JUST AS
IN THE PILOT STUDY.
THREE PATIENTS HAVE BEEN
INFUSED.
THE LONGEST FOLLOW-UP IS THREE
MONTHS, AND THE INDUCTION OF THE
FIRST EVALUABLE PATIENT IS
COMPARABLE TO THE PILOT STUDY.
WE'RE OPENING A SECOND
MANUFACTURING SITE AT UCLA.
THE FIRST PRODUCT TO BE PRODUCED
THIS MONTH YET.
AND WE'RE TRANSITIONING OUR
VECTOR FROM A VECTOR THAT WAS
PRODUCED AS AN ADHERENT CULTURE
TO SUSPENSION CULTURE, WHICH IS
A MORE UP TO DATE MANUFACTURING
PROCESS, AND THE FIRST USAGE OF
THAT WILL BE IN AUGUST, WHICH IS
ACTUALLY WELL AHEAD OF THE
SCHEDULE THAT WE HAD PLANNED.
SO I'D JUST LIKE TO THANK
EVERYBODY THAT'S BEEN INVOLVED
FIRST AND FOREMOST, PATIENTS
WHO'VE BEEN WILLING TO ENROLL IN
A PHASE ONE AND NOW PHASE TWO
STUDY.
BOSTON CHILDREN'S SITE P.I. FOR
OUR STUDY, BOTH IN PHASE # AND D
THE PHASE 2 IS ERICA ESRICK.
WE'VE HAD GREAT SUPPORT FROM THE
TRANSLATIONAL LAB AT BOSTON
CHILDREN'S LED BY MYRI AM AMANT.
THE DANA FARBER, AND A NUMBER OF
OTHER COLLABORATIONS THAT HAVE
BEEN VERY FRUITFUL, INCLUDING
FOLKS AT BLUEBIRD BIO, WHO HAVE
BEEN GREAT COLLABORATORS,
ALTHOUGH THIS IS NOT THEIR TRIAL
OBVIOUSLY.
AND THEN I'VE MENTIONED ALREADY
THE FUNDING, WHICH IS BY NHLBI,
CURE SICKLE, AND WE HAVE
SEPARATE FUNDING FROM THE GATES
FOUNDATION TO TRANSITION OUR
TARGET INTO AN IN VIVO APPROACH,
WHICH WE'RE CARRYING OUT AT THIS
TIME.
I THINK THAT'S THE LAST SLIDE.
I'M HAPPY TO ANSWER QUESTIONS.
>>THANK YOU, DAVID.
QUESTIONS?
TIME FOR ONE QUICK QUESTION
MAYBE?
ANY QUESTIONS ONLINE?
NO QUESTIONS ONLINE.
THANK YOU, DAVID.
THANKS A LOT.
>>THANK YOU FOR INVITING ME.
>>SO OUR NEXT TALK IS GOING TO
BE A TAG TEAM BY MARK GLADWIN
AND KALEAB ABEBE FROM UNIVERSITY
OF PIT BURG AND UNIVERSITY OF
MARYLAND.
THIS IS GOING TO BE THE PRIMARY
RESULTS OF THE STEREO SICKLE
CELL DISEASE TRIAL.
MARK, CAN YOU HEAR ME?
>>I CAN HEAR YOU.
CAN YOU HEAR ME OKAY?
>>YES.
GO AHEAD.
>>DO YOU THINK I COULD SHARE MY
SLIDES?
THAT MAY HELP WITH THE
ANIMATION.
OR IS IT BETTER TO USE THEM
THROUGH YOU?
>>I THINK THEY ARE DOING ALL OF
THEM THROUGH HERE.
>>OKAY.
I'LL JUST GO THROUGH.
THIS WILL BE A PRESENTATION BY
BOTH ME AND KALEAB ABEBE, WHO IS
THE P.I. OF OUR DATA RECORDING
CENTER AT THE UNIVERSITY OF
PITTSBURGH.
AT THE END, I'LL RECOGNIZE ALL
THE SITES AND PIs THAT HAVE
PARTICIPATED.
BUT THIS IS A PHASE IIB
RANDOMIZED DOUBLE BLIND PLACEBO
CONTROLLED TRIAL TO STUDY THE
SAFETY, TOLERABILITY AND
EFFICACY OF RIOCIGUAT IN
PATIENTS WITH SICKLE CELL.
SO WE'LL JUST QUICKLY GO THROUGH
THESE BULLETS.
SO HEMOLYSIS THROUGH A VARIETY
OF MECHANISMS REDUCES ANO
BIOAVAILABILITY AND DAMAGES
BLOOD VESSELS LEADING TO A
NUMBER OF CLINICAL COMPLICATIONS
SHOWN HERE.
THESE COMPLICATIONS HAVE BEEN
ASSOCIATED WITH A NUMBER OF
OBJECTIVE FINDINGS LIKE SYSTEMIC
SYSTOLIC HYPERTENSION, PULMONARY
HYPERTENSION, AS ESTIMATED BY
THE HIGH TRICUSPID VELOCITY AND
PROTEINURIA WITH THE DEVELOPMENT
OF CHRONIC KIDNEY DISEASE.
IF YOU JUST WANT TO CLICK
THROUGH SOME OF THESE
ANIMATIONS.
SO THESE THREE THINGS ARE ALL
ASSOCIATED WITH INCREASED RISK
OF STROKE, CHRONIC KIDNEY
DISEASE, PULMONARY HYPERTENSION
AND DEATH.
A NUMBER OF STUDIES OVER THE
YEARS HAVE SHOWN THAT EVEN
RELATIVE SYSTOLIC HYPERTENSION
OR A HIGH PULSE PRESSURE IN
PATIENT WITH SICKLE CELL DISEASE
IS ASSOCIATED WITH RISK OF
STROKE, AS SHOWN HERE WITH
HAZARD RATIOS OF ABOUT 10 FOR
THE ASSOCIATION OF SYSTOLIC
HYPERTENSION WITH STROKE.
AND RELATIVE HYPERTENSION, AND
WHAT I MEAN BY RELATIVE IS
HYPERTENSION WITHIN POPULATIONS
OF SICKLE CELL PATIENTS AS
OPPOSED TO TRADITIONAL MEASURES
OF HYPERTENSION ARE ASSOCIATED
WITH A WORSE SURVIVAL.
AND IN THIS STUDY BY
DR. DORDEUK, HE SHOWED
INDIVIDUALS WITH SICKLE CELL
DISEASE, AS THE SYSTOLIC
PRESSURE RISES ABOVE 120 AND
PARTICULARLY ABOVE 140, THERE'S
AN INCREASED RISK OF HIGH --
VELOCITY, SO AGAIN SYSTOLIC --
AND INCREASED CREATININE VALUES
OVER TIME.
AND YOU CAN CLICK THROUGH THE
ANIMATION ON THIS SLIDE.
A NUMBER OF STUDIES THAT ALL OF
YOU ARE AWARE OF HAVE CLEARLY
ASSOCIATED THE NONINVASIVE
ESTIMATE OF PULMONARY ARTERY
SYSTOLIC PRESSURE WITH DEATH,
AND THIS AS YOU LOOK IN THE
LOWER LEFT, THERE IS A LINEAR OR
EXPONENTIAL INCREASE IN THE RISK
OF DEATH AS THE PRESSURE RISES
AND EVEN IF WE USE RIGHT HEART
CATH MEASURES, INVASIVE MEASURES
OF PULMONARY HYPERTENSION,
CLEARLY PREDICT INCREASED RISK
OF DEATH.
AND WE SEE THE SAME THING FOR
PROTEINURIA AND MEASURES OF
EARLY CHRONIC KIDNEY DISEASE.
AND THIS STUDY BY MARILYN
TELEN'S GROUP WAS ONE OF THE
FIRST TO SHOW A HIGH HAZARD
RATIO FOR PROTEINURIA BEING
ASSOCIATED WITH POOR SURVIVAL.
SO IN TERMS OF MECHANISM, AND
YOU CAN GO THROUGH THE
ANIMATION, CELL-FREE HEMOGLOBIN
AS WE KNOW CAN POTENTLY REACT
WITH AND SCAVENGE NITRIC OXIDE,
RECUSE DUESINREDUCING THE SIGNAT
NORMAL BINDING ACTIVATES THAT
ENZYME IN SMOOTH MUSCLE TO
INCREASE THE PRODUCTION OF
CYCLIC GMP WHICH INCREASES BLOOD
FLOW.
WE BECAME INTERESTED IN THE
DEVELOPMENT OF A SMALL MOLECULE
CALLED RIOCIGUAT, AND THIS IS A
SMALL MOLECULE THAT DIRECTLY
BINDS TO THE RECEPTOR FOR NITRIC
OXIDE, SOLUBLE CYCLASE, AND CAN
STIMULATE OR ACTIVATE THAT
ENZYME.
AND THIS MIGHT PROVIDE A
MECHANISM TO BYPASS THE
SCAVENGING REACTIONS OF NITRIC
OXIDE.
SO ONE OF THE FORMS OF COURSE IS
IF WE GIVE ARGININE OR --
DONORS, THAT NITRIC OXIDE THAT'S
PRODUCED CAN BE SCAVENGED BY A
VARIETY OF THINGS, AND THE
RIOCIGUAT, WE HYPOTHESIZE, COULD
BYPASS THIS NO SCAVENGING.
SO THIS IS SORT OF LIKE NITRIC
OXIDE IN A PILL.
YOU CAN HIT THE ANIMATION.
AND THIS IS AN EXAMPLE OF
RIOCIGUAT, WHICH HAS BEEN FDA
HFDA-APPROVED FOR BOTH PULMONARY
ARTERIAL HYPERTENSION AND THROMT
NEVER TESTED IN THE SEGHT OF
SICKLE CELL.
SETTING OF
SICKLE CELL.
SO THIS IS A SMALL MOLECULE THAT
BINDS TO THE HEME SITE OF THE
ENZYME AND STIMULATES IT.
IT WILL ACTUALLY INCREASE THE
POTENCY OF NITRIC OXIDE AND ALSO
TURN THE ENZYME ON TO INCREASE
THE PRODUCTION OF CYCLIC GMP.
SO AGAIN OUR HYPOTHESIS IS WE
COULD DO AN ENRICHMENT PROCESS
IN THE STUDY WHERE WE COULD
SCREEN FOR PATIENTS THAT EITHER
HAD SYSTEMIC HYPERTENSION,
PROTEINURIA OR HIGH TRV.
AND THAT WOULD IDENTIFY AS A
SURROGATE PATIENTS AT HIGHER
RISK FOR STROKE, CONGRESS KIDNEY
DISEASE, HYPERTENSION AND RISK
OF DEATH.
AND THAT WE COULD TEST THIS
HYPOTHESIS, COULD RIOCIGUAT
SAFELY REDUCE THE HYPERTENSION,
THE TR JET PROTEINURIA WITHOUT
CAUSING PAIN.
SO THAT WAS OUR PRIMARY
HYPOTHESIS IN THIS VERY EARLY
STUDY.
SO ONE OF THE REASONS THIS WAS A
NECESSARY STUDY WAS BECAUSE IN
THE WALK-PHASST STUDY OF
PULMONARY HYPERTENSION, WE HAD
USED SILDENAFIL, ANOTHER WAY OF
INCREASING CYCLIC GLP.
SO IT ESSENTIALLY INHIBITS THE
ENZYME THAT BREAKS DOWN CYCLIC
GMP.
SO BOTH THIS DRUG, RIOCIGUAT,
AND SILDENAFIL, WOULD INCREASE
THE LEVELS OF CYCLIC GMP.
HOWEVER, IN THE WALK-PHA STST
STUDY, THAT STUDY WAS STOPPED
EARLY, RAISING CONCERNS THAT
THERAPIES THAT ENHANCE GMP
SIGNALING IN PATIENTS WITH
SICKLE CELL COULD HAVE A SIMILAR
EFFECT.
HOWEVER, OVER TIME, A HYPOTHESIS
HAS EMERGED THAT THIS
OBSERVATION FROM WALK-PHASST WAS
REALLY A CLASS EFFECT OF THE
PDE5 INHIBITORS.
IN MANY OF THE STUDIES -- THE
PDE5 INHIBITORS ALSO CAUSED
PAIN.
TYPICALLY THEY WOULD CAUSE LIMB
PAIN OR LOWER BACK PAIN OR
MUSCLE ACHES, AND IN FACT, OFTEN
IN PATIENTS WITH PULMONARY
ARTERIAL HYPERTENSION WHO DO NOT
HAVE SICKLE CELL WHEN THEY
RECEIVE PDE5 INHIBITORS, THEY'LL
DEVELOP SIGNIFICANT ACHES.
SO WE HAD HYPOTHESIZED THAT THIS
WASN'T A DIRECT EFFECT OF CYCLIC
GMP BUT MIGHT HAVE BEEN A CLASS
EFFECT OF THE PDE5 INHIBITORS,
AND PERHAPS WOULD NOT BE
OBSERVED WITH RIOCIGUAT, AND IN
FACT, IN THE PAH TRIALS AND CTEF
TRIALS WITH RIOCIGUAT, THERE WAS
NO OBSERVED LIMB PAIN OR BACK
PAIN IN PATIENTS THAT RECEIVED
THOSE DRUGS.
SO THIS PRIMARY DESIGN OF THIS
STUDY WAS TO TEST WHETHER
RIOCIGUAT WAS SAFE, AND WE
ACTUALLY POWERED TO 100
PATIENTS, WHICH WOULD HAVE
SUFFICIENT POWER WITH 50 PLACEBO
AND 50 RIOCIGUAT TO DETERMINE IF
THERE WAS A SIMILAR PAIN EFFECT
AS OBSERVED WITH SILDENAFIL.
WE WEREN'T EXPECTING RIOCIGUAT
TO HELP WITH PAIN BUT RATHER
THAT IT WOULD TARGET THE
CARDIOVASCULAR END POINTS THAT I
MENTIONED BUT THAT IT WOULD NOT
CAUSE PAIN.
SO IF WE GOT THROUGH THIS
100-PATIENT PHASE 12A TRIAL WE
WOULD KNOW WHETHER THIS DRUG
WOULD BE SAFE TO MOVE FORWARD
WITH.
SO THE STUDY HYPOTHESES ARE
SHOWN HERE.
SO WE ARE GOING TO TEST THE
SAFETY, THE TOLERABILITY, AND
PRELIMINARY EFFICACY IN PATIENTS
WITH SICKLE CELL DISEASE.
AND AGAIN, SAFETY THAT THIS
WOULD -- THAT THERE WOULD BE NO
INCREASE IN THE RATES OF
TREATMENT EMERGENT SAEs WITH
THIS DRUG, AND AGAIN, POWERED TO
HAVE THE SAME -- TO BE ABLE TO
SEE AN EFFECT THAT WOULD BE LAKE
THE WALK-PHASST TRIAL.
AND TOLERABILITY, AGAIN WE ALSO
LOOKED AT OTHER PAIN SIGNALS.
AND THEN WE LOOKED AT
PRELIMINARY EFFICACY.
NOW WE WERE POWERED TO SEE
CHANGES IN MEAN ARTERIAL
PRESSURE, AND WE WERE REALLY
UNDERPOWERED FOR TR JET,
6-MINUTE WALK, ET CETERA -- TO
LOOK AT EXPLORATORY END POINT
THERE.
I'LL TURN THIS OVER TO KALEAB
FOR THE NEXT PART OF THE
PRESENTATION.
NOT TO REPEAT TOO MUCH, THIS IS
REALLY AN EARLY PHASE
MULTICENTERRED RAN DOSMIZED
DOUBLE BLIND PLACEBO CONTROLLED
PARALLEL GROUP STUDY.
WE HAD RANDOMIZATION FROM THE
COORDINATING CENTER HERE AT THE
UNIVERSITY OF PITTSBURGH, THIS
WAS A DOUBLE-BLIND PLACEBO
CONTROLLED TRIAL SO THAT WE HAD
NECESSARY BLINDING ON THE
PARTICIPANT AND STUDY
INVESTIGATOR SIDE.
AND THEN WE OBVIOUSLY HAD
UNBLINDING PROCEDURES IN CASE
NEEDED.
THIS WAS A GROUP-SEQUENTIAL
DESIGN, SO THE WAY WE DID THIS
WAS UTILIZING THE
O'BRIEN-FLEMING ALPHA SPENDING
FUNCTION, TO SEE IF THERE WAS
ANY SORT OF SAFETY SIGNAL DURING
THE FIRST HALF OF THE RANDOMIZED
PARTICIPANTS.
AND AS MARK MENTIONED BEFORE,
PART OF THIS -- THE INCLUSION
CRITERIA YOU CAN SEE HERE BUT
REALLY HONING IN ON THE ORIGIN
PIECE OF THIS.
ONE OF THE KEY CRITERIA, THERE'S
REALLY FIVE THAT THEY COULD GET
THE STUDY BASED OFF OF, BLOOD
PRESSURE GREATER THAN 130, ALSO
MACROALBUMINU RI A, TRV VALUES
GREATER THAN 2.9 AND NT-PRO BNP
GREATER THAN 160 AND URINALYSIS
PROTEIN 1 PLUS OR HIGHER.
THESE ARE THE MAIN INCLUSION TIE
TIER YA FOR STERIO.
AND AS PART OF THIS BEING A
DOUBLE BLIND STUDY, WE RANDOMIZE
OBVIOUSLY TO THE RIOCIGUAT
PLACEBO, WE USED THE
INVESTIGATIONAL DRUG SERVICE
HERE, CENTRAL PHARMACY, NEARLY
ALL PARTICIPANTS WERE STARTED ON
A STARTING DOSE OF 1 MG THREE
TIMES A DAY AND THEY WERE
UPTITRATED ALL THE WAY TO 2.5 3
TIMES A DAY.
WE'LL SHOW A LITTLE LATER IN
TERMS OF HOW THAT LAID OUT
ACROSS THE 100 OR SO
PARTICIPANTS.
AND AGAIN, THE EXACT SAME
TITRATION PHASE WAS DONE ON THE
PLACEBO ARM.
SO THE PRIMARY OUT COME IS THAT
THE PRIMARY PROPORTION OF
PARTICIPANTS EXPERIENCING
GREATER THAN 1SAE.
SECONDARY, SPECIFICALLY RELATED
TO SICKLE CELLs, AS EVERYONE
KNOWS, VASOOCCLUSIVE CRISES WERE
THE KEY ONES.
IN GENERAL, TREATMENT EMERGENT
ADVERSE EVENTS, AND CHANGES IN
PAIN SEVERITY AND INTERFERENCE
FROM BASELINE OUT TO WEEK 12.
AND THEN I WON'T WALK THROUGH
THIS TOO MUCH, BUT JUST IN
GENERAL AS MARK WENT THROUGH
SOME OF THE PRELIM EFFICACY,
MAP, 6-MINUTE WALK BUT WE HAD A
FEW OTHER LAB MEASURES TO SEE IF
THERE WAS ANY PREHIM EFFICACY
SIGNAL.
WE WERE REALLY BASED ON OUR
NUMBERS POWERED FOR MAP AS A
PRELIMINARY EFFICACY OUTCOME.
OUR SAMPLE SIZE AND POWER, WE
NEEDED 100 COMPLETERS TO FINISH
THE 12-WEEK TO YIELD
APPROXIMATELY 82% POWER TO SEE
DIFFERENCES IN HOSPITALIZATIONS,
SIMILAR TO WHAT WE SAW IN
WALK-PHASST.
THEN FOR PRELIM EFFICACY, WE
WERE WELL POWERED AS I MENTIONED
BEFORE AND WE ALSO HAD A LITTLE
BIT LOWER POWER BUT THAT WASN'T
THE PRIMARY PURPOSE OF THAT FOR
THE 6-MINUTE WALK AND OTHER
PRELIM EFFICACY OUTCOMES.
OVERALL ANALYSIS, WE GUARDED
AGAINST A 10% ERROR RATE,
INCLUDED AN INTERIM ANALYSIS, WE
ALSO LOOK AT SAFETY AND
TOLERABILITY IN A PRETTY
STRAIGHTFORWARD WAY, UTILIZING
ANCOVA OR LINEAR MIXED MODELS
FOR LONGITUDINAL OUTCOMES.
THEN WE LOOKED AT A HANDFUL OF
EXPLORATORY ANALYSES.
EGFR, LOOKING TO SEE WHETHER OR
NOT THE CHANGES -- IN 12 WEEKS
ACROSS THESE LOOK DIFFERENT
ACROSS SOME OF THESE HIGH RISK
SUBGROUP CATEGORIES, AND WE ALSO
LOOKED AT MEDIAN AGE AND USE OF
HYDROXYUREA AT BASELINE.
SO AS WE GO THROUGH THE RESULTS
TO WALK THROUGH THE CONSORT, WE
HAVE AS MENTIONED BEFORE
SCREENED A NUMBER TO GET TO OUR
100 THAT COMPLETED THE PROTOCOL,
WE HAD 130 THAT WERE RANDOMIZED
AND THEY WERE EQUALLY BALANCED
INTO THE TWO ARMS IN RIO AND
PLACEBO ARM.
AND THEN IN TERMS OF REASONS FOR
DROPPING OUT, WE HAD ABOUT EQUAL
NUMBERS IN BOTH ARMS THAT
WITHDREW FROM THE STUDY PRIOR TO
THEIR LAST ON-PROTOCOL VISIT.
AND ONLY A HANDFUL OF THOSE
WITHDREW AFTER THAT.
BUT YOU CAN SEE THE REASONS,
PRIMARILY DUE TO SAFETY, ADVERSE
EVENTS, I SHOULD SAY, TREATMENT
INTERRUPTIONS BUT FAIRLY SIMILAR
BETWEEN ARMS WHICH WAS A GOOD
SIGN, AND OVERALL, WE HAD NEARLY
EVERYONE WAS INCLUDED IN THE
PRIMARY ANALYSES BASED ON WHAT
THEY WERE CONTRIBUTING OVER THE
12 WEEKS OF BEING ON PROTOCOL
AND SAFETY.
BASELINE CHARACTERISTICS, I JUST
WANT TO WALK THROUGH THIS JUST
BRIEFLY.
IN GENERAL, THE SHORT STORY IS
THAT IT WAS FAIRLY SIMILAR
ACROSS THE BOARD IN TERMS OF
BASELINE AND DEMOGRAPHIC
CHARACTERISTICS, SO AS YOU CAN
IMAGINE, MAJORITY BLACK, AFRICAN
AMERICAN, NON-HISPANIC, BUT YOU
CAN SEE IN TERMS OF SICKLE CELL
PHENOTYPE, THE MAJORITY, 75%,
THREE FOURTHS OF THE COHORT WAS
HBSS SICKLE CELL PHENOTYPE.
AND THEN IN TERMS OF THE BLOOD
PRESSURE, AROUND 125 TO
128/75 IN TERMS OF SYSTOLIC, AND
DIASTOLIC BLOOD PRESSURE.
THERE WAS A BIT MORE THAN 50%
HAD STAGE I HYPERTENSION BASED
ON THE BLOOD PRESSURE, AND HEART
RATE VALUES, YOU CAN SEE THERE
RIGHT AROUND IN THE LOW TO MID
80s.
AND THEN FOLLOWING THROUGH SOME
OF OUR CHARACTERISTICS FOR MAP,
91 TO 94 FOR MAP, AND THEN PAIN
SCORES WERE FAIRLY SIMILAR AFTER
BOTH THE SEVERITY INTERFERENCE
SCORES AND THE BPI, AND WALK
DISTANCE WAR ANYWHERE BETWEEN
375 TO 416 FOR THE 6-MINUTE WALK
TEST.
THEN JUST A FEW OTHER WITH THE
TR JET HOVERED AROUND JUST SHY
OF THE 2 1/2 MARK AUTOIMMUNE
ACROSS BOTHARMS AND THEN OTHER
CHARACTERISTICS WITH RESPECT TO
THE EJECTION FRACTION MACRO AND
THE ACR VALUES AS WELL.
BUT AGAIN, FAIRLY CONSISTENT
BETWEEN THE TWO COHORTS OR THE
TWO RANDOMIZED ARMS.
GO AHEAD.
>>I WOULD JUST POINT OUT IN
TERMS OF THE ENRICHMENT, ALMOST
44% OF THE PATIENTS IN THE TRIAL
HAD A TR JET OVER 2.5.
AND 40% HAD MACRO ALBUMINURIA.
SO WE DID ATTEMPT TO ENRICH FOR
THOSE GROUPS HOPING TO HAVE
ENOUGH GROUPS WITHIN THIS WHERE
WE COULD HAVE AT LEAST AN
EXPLORATORY LOOK AT EFFICACY.
>>NEXT SLIDE, PLEASE.
AND THEN JUST FINISHING OUT
BASELINE IN TERMS OF THE GFR, IN
TERMS OF RENAL FUNCTION AS WELL
AS SOME KEY CHARACTERISTICS
AROUND CIGARETTE SMOKING AND
BLOOD TRANSFUSION, AS YOU CAN
SEE THOSE VALUES THERE.
SO JUST WRAPPING THIS UP BEFORE
WE GET TO THE PRIMARY RESULTS
AND MARK WILL TAKE OVER, AROUND
AS I MENTIONED TH THE TITRATION,
THIS IS WHERE THE HIGHEST -- THE
MAJORITY, 60% ACROSS BOTH ARMS
AT LEAST REACHED OUR 2 1/2 HIGH
TITRATION, 2 1/2, 3 TIMES A DAY,
WHICH IS GREAT, BUT NOT ONLY
THAT, IT'S GREAT TO SEE THAT
CONSISTENCY BETWEEN ARMS.
AND THEN WE DID HAVE SOME
PREMATURE DISCONTINUATION, BUT
IT WAS ABOUT A QUARTER OF THE
COHORT, AND AGAIN, CONSISTENT --
WAS NOT DIFFERENTIAL BETWEEN THE
TWO ARMS.
SO MARK WILL TAKE OVER HERE AND
WE'LL WALK THROUGH THE PRIMARY
END POINT, SAFETY, AS WELL AS
THE ADJUDICATED SAEs.
>>THANK YOU, KALEAB.
SO IN TERMS OF THE PRIMARY
SAFETY END POINT, AND REMEMBER
THE HYPOTHESIS WAS THAT WE WOULD
NOT SEE AN INCREASE IN PAIN WITH
TREATMENT CONSISTENT WITH WHAT
WAS OBSERVED WITH THE
PDE5 INHIBITORS, AND THAT WAS
THE TREATMENT EMERGENT
ADJUDICATED SAEs, WE SAW THAT
THERE'S 22% OF THESE EVENTS IN
THE RIOCIGUAT GROUP VERSUS 31%
IN THE PLACEBO.
THIS WAS NOT SIGNIFICANT IN
TERMS OF AN IMPROVEMENT WITH
RIO, BUT PRETTY REASSURING THAT
THIS DRUG WAS NOT CAUSING AN
INCREASE IN HOSPITALIZATION FOR
PAIN THAT WE DID SEE WITH
SILDENAFIL.
IN TERMS OF VOE EVENTS, IT WAS
16.7% WITH REY RIO VERSUS 29% WH
PLACEBO, AGAIN, NOT SIGNIFICANT.
WHEN WE LOOKED AT ALL TREATMENT
EMERGENT -- ADVERSE EVENT KNOWN
TO OCCUR WITH IT DRUG, LIKE SOME
REFLUX, SOME ESOPHAGEAL SPASM
PAIN, SOME HEADACHE, SOME
LIGHT-HEADEDNESS, THINGS KNOWN
TO HAVE BEEN OBSERVED BEFORE
WITH RIOCIGUAT, WHICH
INHIBITS -- OR ACTIVATES, EXCUSE
ME -- AND PRESSURE.
WE ALSO SO NO EFFECT OF PAIN
SEVERITY SCORES OR -- AND THIS
JUST SHOWS IN RED THE TREATMENT
EMERGENT SAEs AND BOTH
ADJUDICATED AND THE ADJUDICATED
VOE EVENTS WITH RIOCIGUAT IN RED
COMPARED TO THE PLACEBO IN BLUE.
THESE ARE SOME OF OUR EFFECTS.
WHILE AGAIN WE WERE
UNDERPOWERED, WE REALLY WOULD
HAVE NEED TO SEE AN IMPACT ON
#-MINUTE WALK, WE SAW NO
SIGNIFICANT IMPACT OF THE DRUG
ON 6-MINUTE WALK, AND FOR THE
SORT OF ADJUSTED RESPONSE, THERE
WAS ACTUALLY A DROP IN WALK WITH
REYRIO COMPARED TO PLACEBO.
IN TERMS OF BLOOD PRESSURE --
LOWERING SYSTEMIC, DIASTOLIC AND
MEAN PRESSURE, HIGHLY
SIGNIFICANT WITH P VALUES LESS
THAN .001.
TR JET VELOCITY, THE ADJUSTED
CHANGE IN TR JET VELOCITY, THERE
WAS A TREND TOWARDS LOWER TR JET
VELOCITY IN THE RIOCIGUAT GROUP
WITH A P VALUE OF .12.
INTERESTINGLY, WE SAW
SIGNIFICANT REDUCTIONS IN LEFT
VENTRICULAR AND SYSTOLIC VOLUMES
WITH RIOCIGUAT, AND SIGNIFICANT
INCREASES IN EJECTION FRACTION
WITH RIOCIGUAT, AND VERY
SIGNIFICANT CHANGES THAT WERE
OBSERVED, THAT WAS A LITTLE BIT
UNEXPECTED, AND WE DIDN'T SEE
ANY CHANGE IN THE END TERMINAL
PRO BNP WITH RIOCIGUAT IN THIS
STUDY.
WE SAW NO CHANGE IN THE
BORROWBORGDYSPNEA SCALES.
WE DID SEE A REDUCTION -- WE
ALSO SAW CONSISTENT WITH THAT
REDUCTION IN THE DP. FR GFR, COT
WITH THE KNOWN EFFECTS OF
RIOCIGUAT IN LOWERING GFR,
LOWERING BLOOD PRESSURE AND
POTENTIALLY REDUCING
PROTEINURIA.
WE DIDN'T SEE ANY SIGNIFICANT
CHANGES IN HEMOGLOBIN OR LDH OR
ANY OTHER LAB PARAMETERS.
THIS JUST SHOWS THE MEAN
ARTERIAL PRESSURE, AND IN THE
STUDY, WHICH AGAIN REFLECTS THE
INCREASING DOSE BY DESIGN VERSUS
PLACEBO DOSE INCREASES.
AND SO THE MAP WAS VERY
SIGNIFICANT BY 12 WEEKS OF
STUDY.
AGAIN THIS SHOWS THE SAME THING
FOR BOTH SYSTOLIC AND DIASTOLIC
BLOOD PRESSURE.
THIS JUST SHOWS THE 6-MINUTE
WALK TEST.
THIS IS UNAJESTED PRE AND POST,
AND WITH RIOCIGUAT, WE SAW NO
CHANGE IN THE 6-MINUTE WALK
DISTANCE IN THIS GROUP.
ALTHOUGH AGAIN, ONLY ABOUT 40%
HAD ELEVATED TR JET IN THIS
PHASE 12A STUDY.
IF WE LOOKED AT THE SUBGROUP
THAT HAD A 6-MINUTE WALK LESS
THAN 450-METER, WHICH WOULD
TYPICALLY BE AN ENROLLMENT
CRITERIA, WE ALSO SAW NO CHANGE
IN WALK.
AND YOU CAN SEE OUR NUMBERS HERE
ABOUT BY THE END OF THE STUDY,
35 VERSUS 36 INDIVIDUALS.
AGAIN, VERY LOW PA WE ARED BUT
WE DID NOT SEE EFFECT IN THIS.
THIS IS THE N SYSTOLIC VOLUME,
AGAIN THIS WAS A HIGHLY
SIGNIFICANT DROP.
THESE ARE, BY THE WAY,
CONFIDENCE INTERVALS, THESE
AREN'T STANDARD ERRORS, THESE
ARE REALLY THE 90TH% CONFIDENCE
INTERVALS AROUND THE MEANS.
THIS IS THE EJECTION FRACTION
AGAIN SHOWING THE CONFIDENCE
INTERVALS WITH THE SIGNIFICANT
INCREASE IN EJECTION FRACTION
WITH RIOCIGUAT.
AND IN THE SUBGROUP, WE SAW A TR
JET GROUP LESS THAN 3 AND A
GROUP GREATER THAN 3.
THIS WAS JUST EXPLORATORY BUT WE
SAW AN INCREASE IN EJECTION
FRACTION WITHIN BOTH GROUPS THAT
WAS EVEN GREATER FOR THE GREATER
THAN 3.
YOU CAN SEE THE P VALUE WAS
HIGHLY SIGNIFICANT EVEN WITH
SMALL SAMPLE SIZES WITHIN THIS.
THIS IS THE GFR, AND AGAIN AS
I'VE TOLD YOU, THE GFR DID DROP
WITH THE P VALUE OF .06 AND
SHOWN FOR PLACEBO IN RED AND
RIOCIGUAT IN BLUE.
THIS IS JUST SOME OF THE SAEs,
JUST SHOWING YOU THE SAEs.
OUTSIDE OF THE OVERALL TREATMENT
EMERGENT ADJUDICATED -- AND THE
SPECIFIC VOEs, BUT WHEN WE
LOOK AT OTHER SIDE EFFECTS, WE
REALLY DIDN'T SEE SIGNIFICANT
DIFFERENCE.
THERE WAS SOME CONCERN DURING
THE STUDY, YOU KNOW, THERE WERE
A FEW PATIENTS WHERE
INVESTIGATORS TOOK PATIENTS OFF
THE TRIAL, CONCERNED ABOUT A
POTENTIAL FOR AN SAE, BUT WE
REALLY DIDN'T SEE A DIFFERENCE
WITHIN THESE SAEs BETWEEN
RICHARD CAPRIOLI AND PL PLACEBO.
THE ONLY ONE THAT WAS NOTABLE IS
WE DID HAVE 3EOPISM EVENTS,
WHICH IS INTERESTING -- COMPARED
TO ELEVATED CYCLIC GMP
SIGNALING.
SO I'LL LET KALEAB CONCLUDE THE
FINDINGS FROM THIS EARLY FIRST
IN SICKLE CELL TRIAL COLLAB.
>>SO WHAT SEEING HERE IS
POINTING TO THE FACT THAT RIO
DOES NOT SHOW ANYTHING TO
INCREASE WITH RESPECT TO THAT.
THERE'S POTENTIAL OF OPENING THE
DOOR TO SAFE USE OF RIO FOR
PULMONARY HYPERTENSION AND CTEPH
IN SICKLE CELL, AND THERE IS THE
SUGGESTION THAT MAYBE -- AND I
THINK THIS MAKES SENSE, BUT
HAVING A LARGER TRIAL IN THE
LARGER PATIENT POPULATION IS
KIND OF THE NEXT STEP.
WHAT WE SAW WAS TRENDS TOWARDS
REDUCED TREATMENT EMERGENT
SAEs BUT VOEs THAT WE SAW
WERE JUST FAR LESS THAN THE
REYOE ARM, WHAT WE'RE SEEING IS
THAT TOO MUCH IN TERMS OF DATA
THAT SUGGESTS THAT SGG SIGNALING
REDUCES PAIN BASED ON THE
RESULTS.
KIND OF GOING BACK TO THE
ENRICHMENT STRATEGY, KIND OF
WHAT MARK HAD POINTED OUT
BEFORE, WHAT WE'RE SEEING BASED
ON THESE FIVE KEY STRATEGY
POINTS HERE, THAT ROUGHLY ABOUT
45% THAT WE SAW SYSTOLIC BLOOD
PRESSURE GREATER THAN 130, 35%
WITH MACRO, ALMOST HALF HAD TRV
GREATER THAN 2 1/2 AND ABOUT 15%
HAD TRV GREATER THAN 2.9, AND
ABOUT 6%.
SO YOU'RE GETTING A SENSE OF
WHERE PEOPLE HIT IN TERMS OF THE
ENRICHMENT CRITERIA COMING INTO
THE STUDY, BUT IT'S FAIRLY
SUCCESSFUL IN TERMS OF
IDENTIFYING THIS COHORT.
SO IT'S WELL TOLERATED AND WE'RE
SEEING OBVIOUSLY A SIGNIFICANT
HEMODYNAMIC EFFECT ON BLOOD
PRESSURE, BUT OBVIOUSLY GIVEN
WHERE WE'RE AT AT THIS EARLY
STAGE, PHASE 1/2-ISH AREA, WE
SEE LARGER TRIALS TO SEE IF RIO
IMPROVES MEASURES OF END-ORGAN
FUNCTIONS.
AND THIS JUST COVERING THE --
NOT ONLY THE STEERING COMMITTEE
AND SITES THAT MAKE UP THE STEER
YOE COMMITTEE AS WELL AS THE
MANY OTHER SITES AS MARK HAD
MENTIONED BEFORE, HE AND I ALONG
WITH OTHERS LED THE CLINICAL AND
DATA COORDINATING CENTERS, JUST
WANTED TO SHOW THE BREADTH OF
WORK THAT WENT INTO THIS AND THE
SITES THAT WERE INVOLVED AS
WELL.
MARK, DO YOU WANT TO SAY
ANYTHING ELSE?
>>NO, I JUST DO WANT TO
RECOGNIZE GREG KATO, WHO REALLY
HELPED DESIGN AND LEAD THIS
STUDY BEFORE MOVING FROM
PITTSBURGH INTO INDUSTRY, SO HE
WAS KEY TO THIS.
AND JUST RECOGNIZING THE
STEERING COMMITTEE MEMBERS WHO
PUT A LOT OF EFFORT INTO THIS
WORK, AND ALL THE SITE PIs WHO
HAVE CONTRIBUTED A LOT TO THIS
EFFORT.
>>I THINK THAT'S THE LAST SLIDE
WE HAVE.
>>GREAT.
THANK YOU SO MUCH.
GREAT TALK.
QUESTIONS?
>>THERE'S ONE IN THE CHAT.
>>WE HAVE A CHAT QUESTION?
>>YES.
ONE QUESTION IN THIS CHAT.
WERE P VALUES ADJUSTED FOR
MULTIPLE TESTING?
>>THAT'S A GREAT QUESTION.
SO OUR PRIMARY HYPOTHESIS HERE
WAS REALLY FOCUSED ON THE SAFETY
AND TOLERABILITY PIECE.
SO OUR OVERALL TYPE 1 WAS
STARTED AGAINST THAT 10% OF
THAT.
EVERYTHING ELSE WAS SECONDARY
AND EXPLORATORY.
SO FOR A CLINICAL TRIAL LIKE
THIS, WE DID NOT ADJUST FOR
MULTIPLE TESTING BECAUSE WE
NEVER ELEVATED THOSE TO ANY SORT
OF PRIMARY STATUS.
WE COULD HAVE LOOKED AT THAT,
BUT AGAIN, THAT WAS NOT THE GOAL
OF THOSE OTHER OUTCOMES.
THEY WERE REALLY FOCUSED ON
EXPLORATORY SECONDARY OUTCOMES.
THAT'S A GREAT QUESTION.
>>ONE MORE QUESTION HERE FROM
THE AUDIENCE.
>>REGINA CRAWFORD FROM THE OHIO
STATE UNIVERSITY.
REALLY NICE WORK.
HAD A QUESTION IN REGARDS TO THE
ENTRY CRITERIA IN TERMS OF THE
TR JET VELOCITY.
ARE YOU BASING IT ON WHEN
THEY'RE AT STEADY STATE OR JUST
ANY TR JET THAT MET THE
CRITERIA?
>>SO THE TR -- MARK, DID YOU
WANT TO --
>>SORRY.
YES, GREAT QUESTION.
THE TR JET VELOCITY IS IN STEADY
STATE.
SO IT HAD TO BE WITHIN, YOU
KNOW, TWO WEEKS AWAY FROM A
HOSPITALIZATION FOR VOE.
SO THE IDEA OF THE TR JET, THE
PROTEINURIA, THE SYSTOLIC BLOOD
PRESSURE, THESE WERE REALLY
DESIGNED AS INCLUSION CRITERIA
TO ATTEMPT TO ENRICH THE STUDY
COHORT FOR CARDIOVASCULAR
COMPLICATIONS SO THAT WE MIGHT
HAVE MORE POWER FOR A
PRELIMINARY LOOK AT WHETHER
RIOCIGUAT HAD EFFICACY FOR SOME
OF THESE END POINTS, LIKE
PROTEINURIA, LIKE TR JET
VELOCITY.
THAT WAS THE REASON FOR THAT
DESIGN.
BUT IT WAS ALL STEADY STATE
MEASUREMENTS.
>>THANK YOU.
>>ONE MORE QUESTION.
>>HI.
ILA FROM EMORY.
DID YOU GUYS CHECK ORTHO
STATICS?
BECAUSE I FIND IT INTERESTING
THAT THE BLOOD PRESSURES WERE
RETUESDAYEDREDUCED, AND THAT COE
IMPACTED WHAT YOU SAW IN THE
WALK-PHASST EVALUATION.
>>SO WE DID NOT DO ORTHOSTATIC
BLOOD PRESSURE MEASUREMENTS.
WE WERE VERY CONCERNED THAT THIS
MEDICINE COULD LOWER BLOOD
PRESSURE TOO MUCH, AND WE IN
FACT, AS I SAID, WE HAD ABOUT
80% POWER TO DETECT A
6-MILLIMETER MERCURY DROP IN
MEAN ARTERIAL PRESSURE BASED ON
THE DATA FROM THE PULMONARY
HYPERTENSION TRIALS AND THE CTEF
TRIALS IN PATIENTS WITHOUT
SICKLE CELL.
THE OTHER THING IS SMOKING
CIGARETTES, FOR EXAMPLE, WILL
REDUCE -- LEAD TO A METABOLIC
EFFECT THAT REDUCES THE
METABOLISM OF RIOCIGUAT SO WE
WERE SOMEWHAT WORRIED ABOUT
SMOKERS AND SO WE WERE WATCHING
CAREFULLY BLOOD PRESSURE WITH
EVERY DOSE ESCALATION.
WE ALSO DID NOT KNOW, SINCE THIS
DRUG CAN SENSITIZE -- CYCLASE TO
NO AND HYDROXYUREA CAN BE
METABOLIZED TO NITRIC OXIDE, WE
DID NOT KNOW WHETHER THERE MIGHT
BE AN INTERACTION BETWEEN
HYDROXYUREA AND THIS DRUG ON
BLOOD PRESSURE.
WE DID NOT SEE A POTENTIATION OF
THE BLOOD PRESSURE EFFECT WITH
EITHER SMOKING OR HYDROXYUREA.
SO IT DOES APPEAR THAT THIS DRUG
IS SAFE AND TOLERABLE IN
PATIENTS WITH HYDROXYUREA AND
SMOKING.
WE DID HAVE PATIENTS THAT DID
GET LIGHT-HEADED OR COULD NOT
DOSE-ESCALATE.
SO AS YOU SEE BY THE END OF THE
STUDY, I THINK ABOUT 62% OF THE
PATIENTS TOLERATED THE FULL
2.5 MILLIGRAMS, AND THAT COULD
REFLECT THE FACT THAT SOME
PEOPLE JUST COULDN'T GO UP ON
DOSE, SO THERE WAS THIS DOSE
ESCALATION PART OF THE STUDY,
AND THE PLACEBO ALSO HAD A SHAM
DOSE ESCALATION WITH PLACEBO,
PILL DOSE ESCALATIONS.
BUT IT DOES APPEAR THAT IF YOU
FOLLOW THE FDA-APPROVED
ALGORITHM FOR DOSE ESCALATION
THAT'S APPROVED FOR PAH AND
CTEF, THAT THIS DRUG APPEARS TO
BE AS TOLERATED AS PLACEBO.
I HOPE THAT ANSWERS YOUR
QUESTION.
>>IT DOES.
THANK YOU.
>>SO YOU KNOW, A LOT OF PEOPLE
ARE USING THIS DRUG OFF LABEL
FOR PULMONARY HYPERTENSION AND
SICKLE CELL.
A LOT OF PEOPLE CONTACT ME, LIZ
AND OTHERS IN THE FIELD, WHAT'S
THE RIGHT DRUG TO USE IN A
PATIENT THAT HAS CTEF AND A
PATIENT THAT HAS SICKLE CELL
THAT HAS PULL KNOW NEAR O.A.R.
TIER YAL HYPERTENSION BY RIGHT
HEART CATH.
WE DON'T RECOMMEND USING SILL 15
FILL AND MANY PEOPLE USE AN ENDO
FI LIN RECEPTOR BLOCKER OR
INCREASINGLY PEOPLE ARE USING
RIOCIGUAT, AND LIZ PUBLISHED A
CASE SERIES OF THE SUCCESS WITH
RIOCIGUAT IN SMALL NUMBERS OF
PATIENTS, AND THIS STUDY AT
LEAST TELLS US THAT THE DOSE
ESCALATION PROTOCOL FOR RIO IS
SAFE IN PATIENTS WITH SICKLE
CELL DISEASE AND THAT THE DRUG
IS WELL TOLERATED.
THE OTHER THING -- THE ONLY
THING TO WATCH FOR IS PRIOPISM.
WE DID HAVE THREE CASE IS VERSUS
ZERO SO THERE IS A CONCERN AND
THAT'S GOING TO REQUIRE SOME
OBSERVATION IF PATIENTS ARE
STARTED ON THIS FOR PAH OR CTEF.
>>OKAY.
ONE LAST QUESTION FROM MARK HERE
IN THE AUDIENCE.
>>MARK WALTERS.
SHORT QUESTION.
DO YOU THINK WE GE THE EJECTION
FRACTION IMPROVEMENT WAS RELATED
TO AFTER LOAD OR --
>>MARK, THAT'S A GREAT
QUESTION.
WE DON'T KNOW.
I WOULD PRESUME THAT IT IS AN
EFFECT AFTER LOAD.
IN FACT IN SOME DISCUSSIONS WITH
OUR COLLEAGUES IN FRANCE, THIS
STUDY REALLY ENROLLED ALL-COMERS
BECAUSE WE WANTED TO SEE IF THE
DRUG WAS SAFE, BUT THERE IS
CONCERN THAT THIS COULD ENHANCE
A HIGH CARDIAC OUTPUT STATE,
BECAUSE WE SAW THE TR JET DROP,
WE SAW THE BLOOD PRESSURE DROP,
WE SAW THE GFR DROP, BUT WE DID
NOT SEE AN IMPROVEMENT IN WALK
AND WE DID NOT SEE AN
IMPROVEMENT IN NT PRO BNP.
SO THIS IS POSSIBLE IF IT'S USED
IN PATIENTS WITHOUT PULMONARY
ARTERIAL HYPERTENSION WITHOUT RV
DYSFUNCTION, THAT WE COULD BE
DRIVING INCREASING EF AND
INCREASING STROKE VOLUME, AND
THAT THAT MAY BE MALADAPTIVE
OVER TIME.
SO I THINK THIS STUDY SORT OF
TELLS US THAT IT'S SAFE FOR
THREE MONTHS OF THERAPY AND IT
MAY HAVE EFFECTS ON LIMITING
PROTEINURIA, BUT IT DOESN'T
REALLY ANSWER THE QUESTION
WHETHER THIS WOULD BE EFFECTIVE
FOR A PATIENT WITH SICKLE CELL
THAT HAS PULMONARY HYPERTENSION
BECAUSE WE WERE JUST TOO
UNDERPOWERED TO REALLY STATE
THAT.
>>THANK YOU SO MUCH, MARK.
SO FOR US TO BE ON SCHEDULE,
WE'LL TAKE A QUICK BREAK.
WE CAN BE BACK HERE, A QUICK
BIOBREAK, WE CAN BE BACK HERE
5 AFTER 3:00.
PROMPTLY SO WE CAN START OUR
NEXT TALK.
THERE ARE SOME COMMENTS ON THE
CHAT.
AND I WOULD RECOMMEND THE
SPEAKERS TO PLEASE LOOK UP THE
CHATS AND TRY TO ANSWER THE
QUESTIONS.
THANK YOU.
THANK YOU, MARK, AND ABEBE, FOR
GREAT TALKS.
>>THANK YOU VERY MUCH.
APPRECIATE IT.
THANK YOU VERY MUCH.
MY NAME IS DAVID BROUSSEAU,
CHAIR OF THE PEDIATRICS IN
DELAWARE, PEDIATRIC EMERGENCY
MEDICINE BY TRAINING, SO I DON'T
KNOW HOW MANY PEDIATRIC
EMERGENCY MEDICINE PEOPLE ARE
SPEAKING HERE, BUT I'M GOING TO
TALK A LITTLE BIT ABOUT SICKLE
CELL CARE IN THE EMERGENCY
DEPARTMENT.
I AM CURRENTLY MPI WITH AMANDA
BRANDOW FUNDED BY NHLBI TO DO
THIS WORK.
WE'RE GOING TO TALK A LITTLE
ABOUT SICKLE CELL DISEASE AND
TIMELINESS OF EMERGENCY
DEPARTMENT CARE IN SICKLE CELL
DISEASE AND TYPE TWO
EFFECTIVENESS IMPLEMENTATION
TRIAL.
THERE'S ABOUT 100,000 PEOPLE
WITH SICKLE CELL DISEASE IN THE
UNITED STATES, ABOUT 36,000 OF
THOSE ARE CHILDREN.
THEY HAVE RECURRENT PAIN THAT'S
ALL THE BACKGROUND YOU GET.
I HOPE THAT'S PROBABLY MORE THAN
MOST OF YOU NEED.
SO, THE NHLBI DOES HAVE SICKLE
CELL ACUTE PAIN TREATMENT
GUIDELINES.
TO ADMINISTER OUR FIRST DOSE OF
OPIOIDS WITHIN 60 MINUTES OF
REGISTRATION OR 30 MINUTES OF
TRIAGE THAT IS TYPICALLY
OPERATIONALIZED AS WITHIN 60
MINUTES OF ARRIVAL FOR EMERGENCY
DEPARTMENT CARE WITH REPEAT
DOSES EVERY 15 TO 30 MINUTES
UNTIL THE PAIN IS MANAGED.
USUALLY AFTER THREE OR FOUR
DOSES, A PATIENT IS EITHER
DISCHARGED TO HOME OR ADMITTED
TO THE HOSPITAL.
SO IN ORDER TO STUDY THIS, WE
NEED TO DO A COUPLE OF THINGS.
WE NEED TO DEFINE AN
UNCOMPLICATED PAIN CRISIS THAT
WE COULD LOOK AT ACROSS MULTIPLE
INSTITUTIONS AND FOR A
REASONABLE COST.
LIKE I SAID, WE WANTED TO LOOK
AT MULTISITE DATA.
SO WE LEVERAGED DATA FROM THE
PEDIATRIC EMERGENCY CARE APLAYED
RESEARCH NETWORK, OR PECARN.
THE PECARN REGISTRY WAS
ESTABLISHED BY LAURIE
CHILDREN'S.
IT'S AN EMERGENCY CARE REGISTRY
THAT LITERALLY FOR THE SITES
LISTED DUMPS EVERY EMERGENCY
DEPARTMENT VISIT, EVERY
EMERGENCY DEPARTMENT VISIT, THAT
COMES TO THAT FACILITY TO A
CENTRAL DATA REPOSITORY.
IT WAS DEVELOPED TO DETERMINE
BENCHMARKS FOR ED PERFORMANCE
FOR SOME ALREADY ACCEPTED
STANDARDS OF CARE.
WE HAVE ELEVATED SICKLE CELL
TIMELINESS NOW TO BE ONE OF
THOSE QUALITY METRICS THAT IT
LOOKS AT WITHIN OUR DATABASE.
SO IN ORDER TO INITIALLY
CATEGORIZE VISITS AS
UNCOMPLICATED BASED ON
ICD-9/WHATEVER INFORMATION IS
AVAILABLE IN AN EMERGENCY
DEPARTMENT RECORD, WE DID A
ONE-SITE CHART REVIEW, WE LOOKED
AT ABOUT 1200 VISITS, WE
DETERMINED ABOUT 25% OF THEM
WERE COMPLICATED, THE OTHER 75%
OR 902 VISITS WERE
UNCOMPLICATED.
THESE ARE THE PATIENTS THAT WE
THINK THAT THE SICKLE CELL
GUIDELINE WAS MEANT TO APPLY TO,
ABOUT 40% OF THOSE ENDED UP
HOSPITALIZED.
WHEN TRYING TO IDENTIFY THESE BY
THINGS ALREADY ESTABLISHED IN AN
EHR, IF YOU LACK AT RECEIPT OF
AT LEAST ONE OPIOID, A CLINICAL
IMPRESSION OR ICD-9 CODE OF
CRISIS AND THEN EXCLUDE PATIENTS
WITH ACUTE CHEST, PRIAPISM,
CONSTIPATION OR SPLENIC
SEQUESTRATION AND EXCLUDE
ANYBODY WITH A FEVER GREATER
THAN 38.5 IN THE EMERGENCY
DEPARTMENT, THE RESULTING
POPULATION, 92% OF THOSE HAVE AN
UNCOMPLICATED PAIN CRISIS.
WE FIGURED FOR THE POINT OF THIS
STUDY, IF WE WERE 92% ACCURATE,
WE WERE PROBABLY GOOD ENOUGH TO
SHOW IF WE WERE MAKING
SIGNIFICANT CHANGE.
SO THESE ARE THE SITES CURRENTLY
CONTRIBUTED TO THE PECARN
REGISTRY.
OUR STUDY TAKES PLACE AFTER
2016, BUT JUST FOR HISTORICAL
PURPOSE, THE CHILDREN'S HOSPITAL
OF COLORADO, CHILDREN'S -- OR
CH -- LATER LURIE CHILDREN'S
HOSPITAL OF CHICAGO, CHILDREN'S
HOSPITAL OF WISCONSIN -- THEY
VARY IN SIZE CONSIDERABLY WITH
CHILDREN'S HOSPITAL OF COLORADO
HAVING THE SMALLEST SICKLE CELL
POPULATION IN CHILDREN'S
NATIONAL MEDICAL CENTER OF THESE
HAVING THE LARGEST.
SO WE LOOKED AT 2016 TO 2018
BASE LANE DATA AS PART OF A
PRELIMINARY GRANT, AND WHAT
WE'VE FOUND WAS ACROSS THESE
SEVEN MAJOR CHILDREN'S
HOSPITALS, THE TIME TO FIRST
OPIOID IN LESS THAN 60 MINUTES
WAS 48%.
IT'S ACTUALLY BETTER THAN WE
THOUGHT.
THAT'S BASED ON 4,578 VISITS,
NOW THERE WAS A SIGNIFICANT
RANGE IN THERE.
WITH SOME SITES AS LOW AS 22%
GETTING THE FIRST OPIOID WITHIN
60 MINUTES AND ONE SITE AS HIGH
AS 70.
I WILL SHOW YOU SOME DATA WHEN
WE PULL THAT 70 OUT AND WHY THAT
70 IS A BIT OF AN OUTLIER.
WE THEN LOOKED AT TIME BETWEEN
FIRST AND SECOND OPIOID LESS
THAN 30 MINUTES, AND THAT WAS
15%.
THAT WAS BASED ON 3,538 OF THOSE
INITIAL 4500 VISITS WITH A
RAPINGA RANGEOF 2% TO 36%, A LIN
OUTLIER BASED ON SOME PRELIM
DATA.
SO THIS WAS DATA FROM ONE SITE.
THIS WAS THE CHILDREN'S HOSPITAL
OF WISCONSIN.
IT WAS THE FIRST SITE TO GET
SOME PRELIMINARY DATA AND SOME
PILOT FUNDING TO TRY TO IMPROVE
TIME TO OPIOID ADMINISTRATION.
SO YOU CAN SEE ALONG THE BOTTOM,
THAT INITIAL STUDY THAT WE JUST
SHOWED WITH THE 48 AND 15% WAS
2,016 TO 2018, YOU CAN SEE
CHILDREN'S WISCONSIN MADE SOME
SIGNIFICANT PROGRESS BETWEEN
2016 AND 2018.
AND BOTH TIME TO FIRST WHICH IS
THE KIND OF LIGHTER BLUE UP TOP
WHERE OVER THE COURSE OF THE
FOUR YEARS OF PRELIM DATA,
CHILDREN'S HOSPITAL OF WISCONSIN
WENT FROM ABOUT 45 TO 50% TO
JUST UNDER 90% GUIDELINE
ADHERENT.
AND THEN FOR TIME BETWEEN FIRST
AND SECOND, THE BLACK LINE
WITHIN 30 MINUTE OF THE FIRST,
CHILDREN'S HOSPITAL OF WISCONSIN
IMPROVED FROM 20% TO 40%.
SO THIS WAS SOME NICE PRELIM
DATA.
REALLY IMPORTANT BECAUSE THERE
IS NOW MULTIPLE STUDIES THAT
SHOW TIME TO FIRST WITHIN 60
MINUTES SIGNIFICANTLY REDUCES
PAIN SCORES.
TIME TO SECOND LESS THAN 30
MINUTES IS MORE ASSOCIATED WITH
DISPOSITION HOME.
SO ENOUGH IMPROVEMENT IN PAIN
THAT YOU MIGHT BE ABLE TO
DISCHARGE PATIENTS TO HOME.
SO IT'S NOT JUST GETTING THERE
TIMELY IS GOOD, GETTING THE
FIRST DOSE IS GOOD, IT'S THE
RIGHT THING TO DO.
BUT THERE IS SOME MOUNTING
EVIDENCE THAT THAT TIME BETWEEN
FIRST AND SECOND MIGHT ACTUALLY
SIGNIFICANTLY ALTER THE
DISPOSITION, STOP HAVING SO MANY
PATIENTS HAVING TO SPEND THE
NIGHT IN THE HOSPITAL, MORE
GOING HOME.
SO WE WERE A LITTLE WORRIED,
RIGHT, THIS IS JUST TRENDS OVER
TIME.
SO CERTAINLY MAYBE EVERYBODY WAS
IMPROVING OVER TIME.
IT WASN'T JUST THAT CHILDREN'S
OF WISCONSIN WAS DOING SOME
THINGS -- PART OF THE PILOT
STUDY, SO WE REMOVED THAT DATA
AND JUST LOOKED AT THE OTHER SIX
SITES.
THIS IS THE OTHER SIX SITES.
SO IN THE LAST TWO YEARS OF THE
STUDY, YOU CAN SEE REALLY NO
IMPROVEMENT IN TIME TO FIRST
OPIOID WITHIN AN HOUR, WITH
BARELY GETTING OVER 40% BY THE
END OF THE STUDY.
AND THE TIME BETWEEN FIRST AND
SECOND ALSO SHOWING NO
IMPROVEMENT AND INABILITY TO GET
OVER 20%.
THIS IS DESPITE A LOT OF
INFORMATION, A LOT OF PRESS,
ABOUT RACIAL UNCONSCIOUS BIAS,
THE GEORGE FLOYD STUFF WAS
HAPPENING.
WE REALLY THOUGHT THERE MIGHT BE
SOME UNDERLYING IMPROVEMENT THAT
WE JUST DID NOT SEE.
SO AGAIN, LED A WHOLE BUNCH OF
CREDIBILITY TO THAT WE REALLY
NEED A DEDICATED EFFORT IN ORDER
TO IMPROVE TIMELINESS OF OPIOID
ADMINISTRATION AND REALLY SHOW
THAT THESE NHLBI GUIDELINES
WOULD AFFECT CARE IN A
DEMONSTRABLE WAY.
SO THE AIMS FOR OUR NOW-FUNDED
STUDY ARE FOR THE TREATMENT OF
CHILDREN WITH ACUTE PAINFUL
VASOOCCLUSIVE CRISES IN THE
EMERGENCY DEPARTED, AGAIN,
UNCOMPLICATED PAIN CRISES, TO
COMPARE THE PRIMARY
IMPLEMENTATION OUTCOMES OF
REACH, ADOPTION, AND
IMPLEMENTATION.
WE'LL GO OVER THESE IN A LITTLE
BIT, BETWEEN THE INTERVENTION
AND THE CONTROL GROUPS.
AND THEN TO COMPARE THE PRIMARY
CLINICAL OUTCOMES OF
GUIDELINE-ADHERENT TIMELINESS,
HOSPITALIZATION RATES, PAIN
SCORES BETWEEN THE INTERVENTION
AND CONTROL GROUPS.
SO IN OUR PRELIMINARY WORK, WE
DID SOME QUALITATIVE ANALYSES
LOOKING AT KIND OF THE
COMPONENTS OF ED TREATMENT AND
HOW WE COULD REALLY BREAK THOSE
DOWN TO HELP SITES IMPROVE IN
OUR IMPLEMENTATION EFFECTIVENESS
TRIAL.
IF YOU LOOK AT THE TARGET
BEHAVIORS, WE REALLY BROKE THE
STEPS IN EMERGENCY DEPARTMENT
CARE DOWN INTO FOUR STEPS.
RAPID ROOM PLACEMENT, INITIAL
TREAT M OF PAIN, PAIN
RE-ASSESSMENT AND THEN RE-DOSING
OF PAIN MEDICATION.
YOU BREAK DOWN EACH ONE OF THOSE
INTOITY STEPS.
INTO ITS STEPS.
HOW DO YOU GET INTO A ROOM
QUICKLY, YOU GET ESI LEVEL 2 OR
THE SECOND HIGHEST LEVEL OF
TRIAGE CATEGORY AND THEN YOU GET
DIRECT BEDDED OR PLACED INTO A
BED IMMEDIATELY ON ARRIVAL.
HOW DO YOU START PAIN TREATMENT
QUICKLY?
FIRST YOU DON'T LET THE MED
STUDENT GO IN AND THEN PRESENT
TO A RESIDENT AND THEN PRESENT
TO AN ATTENDING BEFORE YOU
FINALLY GET A PAIN MEDICATION
ORDERED.
YOU HAVE A TARGETED ASSESSMENT,
RULE OUT OTHER SEVERE
COMPLICATIONS AND IMMEDIATELY
GET PAIN MEDICATION ORDERED.
THEN THERE'S INTRANASAL
FENTANYL, IV OPIOIDS WITH THE
INITIAL ORDER, IV PLACEMENT
IMMEDIATELY AFTER NASAL FENTANYL
AND AS YOU MOVE DOWN,
RE-ASSESSING OF PAIN, REDOING OF
PAIN MEDICATIONS AND THEN KIND
OF THIS CONTINUOUS PATTERN.
HOW DO YOU DO THIS?
WELL, YOU NEED EVERYBODY'S
BUY-IN, BOTH IN THE DEPARTMENT
AND OUT OF THE EMERGENCY
DEPARTMENT.
THIS HEAVILY RELIES ON NURSES,
IT RELIES ON PATIENT' FAMILIES
ADVOCATING FOR THEMSELVES.
IT RELIES ON ED NURSE, ED
PROVIDERS, ED PHARMACIST, THE
SICKLE CELL PROVIDER IN THE
CLINIC REMINDING PATIENTS THAT
THIS IS WHAT HAPPENS IN THE
EMERGENCY DEPARTMENT, NOT TO
REFUSE INTRANASAL FENTANYL, THAT
THIS IS PART OF THE SAME CARE
CONTINUUM THAT WE WOULD DELIVER
IN AN OUTPATIENT HEME CLINIC NOW
BEING DELIVERED IN THE EMERGENCY
DEPARTMENT, AND THEN YOU CAN SEE
THAT THAT SORT OF COMBINED
STAKEHOLDER BUY-IN IS NECESSARY
THROUGHOUT THE PROCESS.
SO WE USE THE RE-AIM
IMPLEMENTATION FRAMEWORK LOOKING
AT REACH, THE PERCENT OF PEOPLE
WHO GET THE DESIRED TREATMENT.
EFFECTIVENESS IS REALLY THE
CLINICAL OUTCOMES, ADOPTION WAS
SOMEBODY ACTUALLY WILLING TO SAY
THEY WERE GOING TO DO THINGS,
IMPLEMENTATION, WHICH COMPONENTS
OF THIS PATHWAY DID THEY DO, AND
THEN MAINTENANCE, AFTER WE MADE
THE SWITCH, WERE WE ABLE TO
MAINTAIN THE IMPROVEMENT.
SO FOR OUR IMPLEMENTATIONS, WE
HAD LOCAL CHAMPIONS.
WE HAD AN ED AND HEMATOLOGY
PROVIDER AT EACH SITE FUNDED.
WE GAVE EACH SITE A REPORT CARD
ONCE THEY ENTERED THE TRANSITION
PHASE.
THEY THEN WERE ABLE TO USE ALL
OF THESE IMPLEMENTATION STEPS TO
TAILOR WHAT WOULD WORK AT THEIR
SITE.
THEY CONDUCTED MULTIDISCIPLINARY
WORKSHOPS, CHANGE, EPIC,
WHATEVER EHR THEY HAD TO
FACILITATE THESE THINGS, AND
REALLY FACILITATE PATIENT
CAREGIVERS AND HEMATOLOGISTS IN
THE PROCESS.
SO WE DID A FAIRLY STANDARD STEP
WEDGED DESIGN.
IF YOU'RE NOT FAMILIAR WITH A
STEP WEDGE DESIGN, YOU HAVE
SITES THAT TRANSITION SOCIETY
ONE TRANSITIONS IN QUARTER THREE
OF YEAR ONE.
THEY THEN STARTED THE CARE
PATHWAY OR IMPLEMENTATION PHASE
AND WHAT THAT ALLOWS IS ALL THE
OTHER SITES TO ACT AS STANDARD
SAN FRANCISCO CARE OR REALTIME
CONTROLS.
AS YOU STEP OTHER SITES, THE
OTHER SITES REMAIN AS REALTIME
CONTROL SO YOU GET AN EVALUATION
OF SITES PRE AND POST
TRANSITION, AND THEN TRANSITION
COMPARED TO NOT YET TRANSITION
AND -- ALREADY IMPROVED CARE.
SO THESE ARE THE STEPS IN OUR
IMPLEMENTATION OUTCOMES THAT WE
SHOW ALL THE SITES ONCE THEY
HAVE TRANSITIONED.
WE GIVE THEM REPORTS ON THEIR
DIRECT BEDDING, THE NUMBER THAT
ARE DIRECTORIAGE LEVEL 2,
WHETHER THEY HAVE A RAP PID
TARGETED ASSESSMENT BY PROVIDER
PRIOR TO INITIAL.
YOU CAN SEE UNDER THE REACH OUT
KS COUTCOME FOR THAT ONE, THAT'S
DEFINED FROM OUR ELECTRONIC
HEALTH RECORD FROM THE FIRST
TIME A PROVIDER SIGNS UP TO SEE
THE PATIENT TO THE FIRST OPIOID
ORDER.
IF THAT TAKES MORE THAN 15
MINUTES, THEY ARE NOT DOING A
RAPID ASSESSMENT FOLLOWING BY
ORDERING OF IV PAIN MEDICATION,
SO WE GIVE THEM FEEDBACK ON
THAT.
ORDER SETS FOR PAIN, WHETHER A
LAB ORDER AND AN OPIOID ORDER
ARE ORDERED WITHIN ONE MINUTE OF
EACH OTHER, USUALLY THAT MEANS
THEY'RE PART OF AN ORDER SET.
MOST PEOPLE DON'T GO IN AND
INDIVIDUALLY ORDER THINGS BUT
REPEATEDLY WITHIN ONE MINUTE,
AND THEN USE OF INTRANASAL
FENTANYL.
SO THE TIME BETWEEN SUBSEQUENT
OPIOID, AND THEN THE OUTCOMES
THAT MAY MATTER MORE TO PATIENT'
DISPOSITION, DID IT AFFECT THEIR
PAIN SCORES, MAYBE PROVIDERS,
DID IT AFFECT THE ED LENGTH OF
STAY, AND THEN SOME ADVERSE
OUTCOMES, IF WE SEND PEOPLE HOME
AND THEY ALL BOUNCE BACK, THAT'S
NOT NECESSARILY IDEAL, AND THEN
ADVERSE EVENT, WHAT PERCENT
NEEDED NALOXONE OR SUPPLEMENTAL
OXYGEN IF THERE'S A CONCERN THAT
YOU'RE ACTUALLY FIFING GIVING
MEDICATION SO FAST THAT MAYBE
YOU'RE SEDATING THEM AND THEY
HAVE SOME ADVERSE EVENT.
S.
SO THIS IS A SAMPLE REPORT CARD
FOR ONE SITE.
YOU CAN SEE WE JUST GIVE THEM
ALL OF THOSE NUMBERS, COMPARE TO
THE THREE MONTHS BEFORE, AND
THEN WE HAVE DATA FOR AS MANY
MONTHS AS THEY ARE IN THE STUDY.
SO HERE'S SOME DATA THAT YOU CAN
SEE.
SO THE FIRST SITE TO TRANSITION
IS THE FIRST, YOU CAN SEE THEIR
NUMBERS.
THE GREEN LINE WITH THE
TRIANGLES IS ALL THE SITES NOW
ON THE CARE PATHWAY, AND THE
GREEN LINE WITH THE CIRCLES ARE
ALL SITES THAT HAVE YET TO
TRANSITION.
SO THIS IS STILL ALL BLINDED,
THE DSMV IS AWARE -- BLINDED TO
THE SITES.
ONCE YOU TRANSITION, YOU GET TO
SEE ALL THIS.
SO THROUGH JUNE OF 2023, WE ARE
ONLY, AS I SHOWED YOU, YEAR TWO
OF THE STUDY.
USING OUR METHODS, WE HAVE
ALREADY ENROLLED 2,652 CHILDREN
IN THIS.
AND THIS IS THEIR TIMELINESS TO
DATE.
SOME EVIDENCE THAT MAYBE THINGS
ARE HELPFUL, BUT AGAIN, WE
HAVEN'T LOOKED AT MAINTENANCE,
WE HAVEN'T DONE ENOUGH ANALYSIS
OR HAD ENOUGH TIME.
OF TO LOOK AT ALL THE DATA TO
DEFINITIVELY SAY WHERE THESE
THINGS ARE GOING.
SO WE HAVE HAD A LOT OF SUCCESS
SO FAR TO DATE.
A LOT OF ENTHUSIASM FROM THE
LOCAL CHAMPIONS.
AGAIN, LET ME GO BACK AND SHOW
THAT DESPITE THE ENTHUSIASM,
DESPITE PEOPLE'S WILLINGNESS,
WE'RE STILL HAVING REALLY NO
IMPROVEMENT IN THE SITES THAT
HAVEN'T TRANSITIONED.
THERE'S A LOT OF THINGS GOING ON
IN THE WORLD AND WE ARE SEEING
ZERO CHANGE.
CHANGE IN THE EMERGENCY
DEPARTMENT IS HARD, ALL OF YOU
WHO TAKE CARE OF PATIENTS WITH
SICKLE CELL KNOW SOME OF THE
MOST FRUSTRATING TAIMS ARE WITH
THEY GO TO THE EMERGENCY
DEPARTMENT BUT WE ARE NOT SEEING
SIGNIFICANT IMPROVEMENT IN OUR
BASELINE GROUP.
BAD FOR THE PATIENTS, I GUESS,
GOOD FOR THE STUDY DESIGN.
SO OUR LOCAL CHAMPIONS HAVE BEEN
VERY ENGAGED.
OUR DSMV AND OTHER SICKLE CELL
EXPERTS HAVE BEEN EXTREMELY
HELPFUL.
WE DID FIND ONE SITE HAD A HIGH
NALOXONE RATE WHICH WHEN WE
FURTHER INVESTIGATED WAS ALL DUE
TO ITCHING, SO WE'VE BEEN ABLE
TO SEPARATE THAT OUT, HAD
NOTHING TO DO WITH UR OH OUR
TRANSITION PHASE.
THINGS WE'VE LEARNED ALREADY.
IF YOU GO BACK TO OUR STEP
WEDGE, WE ALLOWED A THREE-MONTH
TRAN CIRCLES WHICH WAS NICE
BECAUSE I THINK WE KIND OF
THOUGHT PEOPLE WOULD BE ALL
GEARED UP TO GO.
THAT IS CLEARLY TOO SHORT A
TRANSITION TIME TO IMPLEMENT ALL
THE THINGS WE NEED TO DO.
IT'S A MINIMUM OF SIX MONTHS,
PROBABLY NINE, AND WE'VE ALREADY
TALKED TO THE DATA COORDINATING
CENTER AT THE UNIVERSITY OF
UTAH.
THE PARTNERSHIP BETWEEN THE HEME
AND ED TEAMS ARE VITAL, AND THAT
MEANS THAT A LOT OF EDUCATION IN
THE HEMATOLOGY CLINIC BECAUSE
IT'S A LOT EASIER FOR PATIENTS
TO TAKE INTRANASAL FENTANYL IF
THEY'VE PREPPED THEM.
WE HAVE QR CODES AND PICTURES
THAT WE GIVE FAMILIES.
THE TRIPLEDEMIC, IF YOU REMEMBER
THAT THE NATIONAL PRESS WAS
COVERED WITH THE FACT THAT RSV,
FLU AND -- IS BAD FOR
EVERYBODY'S CARE ALTHOUGH I WILL
SAY THE TIMELINESS WAS
MAINTAINED IN THOSE SITES THAT
ALREADY TRANSITIONED, AND THEN
LOOKING AT REALLY IS ANY -- IS
THERE SOME SIGNAL HAVING A
DIVISION CHIEF OR SECTION LEADER
OR QUALITY CHAMPION ALREADY IN
THAT ROLE MIGHT BE MORE HELPFUL.
BUT THAT'S WHERE WE ARE IN THE
STUDY.
WE'RE ABOUT HALFWAY DONE.
WE'VE TRANSITIONED JUST OVER
HALF THE SITE WITH THE NEXT ONE
TRANSITION BUT WE ARE VERY
ENTHUSIASTIC ABOUT SOME OF THE
EARLY RESULTS AND HOPEFUL THAT
WE CAN MAKE A DIFFERENCE IN THE
LIVES OF CHILDREN WITH SICKLE
CELL DISEASE.
THANK YOU.
>>THANK YOU, DAVID.
QUESTIONS.
ARE THERE ANY QUESTIONS ONLINE?
>>YES.
>>OKAY.
>>HI.
SO THE QUESTION I HAVE IS, IN
TERMS OF TO THE -- GIVING PAIN
OPIOIDS WITHIN 60 MINUTES, I
THINK IT ALSO -- COMING FROM THE
ADULT POPULATION, IT ALSO
DEPENDS ON HOW MUCH THEY'RE
GIVING.
SO FOR THE ADULTS, THEIR
COMPLAINT IS THAT THEY KNOW WHAT
NORMALLY WORKS, BUT YET THEY'RE
GETTING ABOUT 25%, A QUARTER OF
WHAT NORMALLY WORKS.
SO IS THAT STILL PART OF YOUR
PROTOCOL?
IS THAT SOMETHING YOU STILL
ADVISE, OR YOU'RE WANTING THE
PATIENTS TO RECEIVE WHAT THEY
SHOULD RECEIVE, WHAT NORMALLY
WORKS FOR THEM, IN ORDER TO BE
EFFECTIVE?
>>YEAH, SO THE QUESTION IS A
LITTLE BIT INDIVIDUALIZED PAIN
PLANS.
WE ALLOW SITES TO USE INDIVIDUAL
PAIN PLANS, WHATEVER THEY ARE
ALREADY DOING AT THEIR SITE, WE
ARE NOT CHANGING.
WE WILL SAY IT WAS VERY CLEAR
FROM THE QUALITATIVE WORK AND
FROM THE WORK WE'RE DOING NOW
THAT SITES THAT USE
INDIVIDUALIZED PAIN PLANS, EVEN
IF IT'S THE RIGHT DOSE, GET
DRAMATICALLY SLOWER CARE IN THE
EMERGENCY DEPARTMENT BECAUSE YOU
CAN'T AUTO-POPULATE THAT.
IT TAKES TIME TO LOOK IT UP.
WHAT WE HAVE TALKED WITH THOSE
SITES IS, ARE THEY WILLING TO
LET AN INITIAL WEIGHT-BASED DOSE
GO, THEN WE GET THE INITIAL PAIN
MEDICATION IN, AND THEN YOU HAVE
TIME TO LOOK UP THE
INDIVIDUALIZED DOSE.
SO AGAIN, SOME OF THE
HEMATOLOGISTS ARE MORE
COMFORTABLE WITH THAT THAN
OTHERS.
WE'RE JUST TRYING TO GET THAT
FIRST DOSE IN AND THEN THE
SECOND.
BUT AGAIN, IF SITES WANT
INDIVIDUALIZED PAP PAIN PLANS OR
THAN WEIGHT BASED, EVERYTHING IN
PEDIATRIC IS WEIGHT-BASED, WE
ARE CERTAINLY WILLING TO LET
THEM USE INDIVIDUALIZED DOSING.
>>SO ON THE DOSES QUESTION, WE
HAVE A BUNCH OF QUESTIONS IN THE
CHAT.
THE FIRST ONE IS, WHAT IS THE
MORPHINE AND FENTANYL DOSAGE
THAT YOU USE IN YOUR PED AND MAX
DOSAGE?
>>SO AGAIN WE'RE NOT MANDATING
A CERTAIN DOSE.
WHAT MOST PEOPLE USE OF
INTRANASAL FENTANYL -- WHAT MOST
PEOPLE USE FOR MORPHINE IS
.1 PER KILO OF IV MORPHINE, MAX
OF 6 OR 8.
SOME PEOPLE KEEP THAT SECOND
DOSE THE SAME.
SOME SITES CUT IT IN HALF.
AGAIN, WE WERE NOT TRYING TO
NECESSARILY CHANGE THAT PROCESS.
WE HAVE SHARED WHAT ALL THE
SITES DO AMONG THE SITES BUT
HAVE NOT MANDATED THAT THEY
CHANGE.
THE NHLBI GUIDELINES DON'T
RECOMMEND THAT DECREASE IN DOSE
BUT IF A SITE IS COMFORTABLE
DOING THAT, THAT'S A BIGGER
HURDLE TO CLIMB THAN ACTUALLY
GIVE THEM TIMELY MEDICATION.
>>HI, DAVID.
MONICA HULBERT, ST. LOUIS.
THIS IS SUCH A PERSISTENT AND
COMMON PROBLEM AMONGST ALL OUR
CENTERS.
I THINK ONE OF THE THINGS THAT I
FIND MOST FRUSTRATING IS THAT
THESE INTERVENTIONS OFTENTIMES
LOOK REALLY GOOD WHEN THERE'S
FUNDING TO SUPPORT THE
INTERVENTION, BUT AS YOU KNOW,
LIKE OUR -- THE MEDICAL STAFF,
LIKE THE NURSING STAFF TURNS
OVER, YOU KNOW, ATTENDING
PHYSICIANS COME AND GO AND WE
HAVE LITERALLY NEW TRAINEES IN
THE EMERGENCY DEPARTMENT EVERY
SINGLE MONTH.
SO MAINTAINING THIS KIND OF
EFFORT OVER THE LONG TERM SEEMS
EVEN MORE DIFFICULT THAN
STARTING IT THE FIRST TIME,
BECAUSE WHEN YOU'RE JUST IN THE
MAINTENANCE PHASE, IT'S LIKE OH,
THIS IS BORING, WE'VE ALREADY
DONE THAT.
SO WHAT DO YOU THINK ARE WAYS
THAT IMPROVEMENTS CAN BE
SUSTAINED OVER TIME WHEN THERE'S
NO MORE GRAFNT FUNDING?
GRAND FUNDING?
>>THANK YOU, MONICA.
SO FIRST WE HAVE TO MAKE SURE
IT'S EVEN MAINTAINED DURING A
FUNDING PEER.
THAT'S WHY IT'S NICE IN THIS
STEP WEDGE DESIGN, WE WILL HAVE
THREE YEARS OF FUNDING AT SOME
SITES.
THE OTHER NICE THING ABOUT THE
WAY THIS STUDY IS DESIGNED, WE
HAVE NO REALTIME DATA COLLECTION
IN THE EMERGENCY DEPARTMENT,
RIGHT?
ALL OF THE DATA IS COLLECTED VIA
THE REGISTRY AS A DATA DUMP.
SO NOBODY IS THERE EVERY DAY
CONSENTING A FAMILY, REMINDING
PEOPLE THE STUDY IS ONGOING.
LIKE YOU SEE IN MANY
INTERVENTIONAL TRIALS WHERE THE
RESEARCH TEAM APPEARS AND
EVERYBODY SUDDENLY IS AWARE.
THIS IS REALLY ABOUT A CHANGE IN
CULTURE.
IT'S PRIORITIZING A PATIENT
POPULATION THAT WAS
UNFORTUNATELY NOT PRIORITIZED,
AND A LOT OF THE CHANGES WE'RE
DOING HAVE REALLY BECOME NEW
STANDARDS AT THOSE PLACES.
SOMETIMES PLACES ALREADY HAVE A
SPECIFIC -- WITH FEVER, SICKLE
CELL WITH FEVER THAT THEY DO
REALLY WELL WITH, THEY'RE JUST
THROWING PAIN INTO THAT METRIC
NOW.
SO I'M A LITTLE BIT MORE
OPTIMISTIC BECAUSE THIS STUDY
DOESN'T RELY ON BOOTS ON THE
GROUND FUNDING REALTIME TO
EFFECT CHANGE.
WHAT WE SEE OVER TIME IS ANY
IMPROVEMENT IS BETTER THAN WE
HAVE NOW.
>>THANK YOU.
I THINK WE NEED TO MOVE ON.
OUR NEXT TALK IS MAKING CASE OF
PALLIATIVE CARE IN SICKLE CELL
DISEASE.
WE HAVE A TAG TEAM OF THREE
DIFFERENT SPEAKERS.
DR. NKILE, DR. KISER AND
DR. ALLEN.
>>WE'RE GOING TO DO SOMETHING
DIFFERENT HERE.
WE HAVE TO SHARE OUR SCREEN.
>>KE WITH MO
>>WE'RE ACTUALLY USING OUR
SLIDES.
>>IS THAT YOURS?
>>CAN EVERYONE SEE OUR SLIDE?
HELLO, MY NAME IS ASHLEY ALLEN.
I'LL BE SPEAKING FIRST.
APPRECIATE EVERYONE HAVING US
HERE TODAY.
THIS IS A TOPIC WE'RE ALL
EXTREMELY PASSIONATE ABOUT, AND
HOPE YOU FIND INTERESTING.
SO THE TOPIC OF OUR PRESENTATION
TODAY IS MAKING THE CASE FOR
PALLIATIVE CARE IN SICKLE CELL
DISEASE.
A LITTLE INTERACTIVE, IF YOU
GUYS COULD USE -- BRING YOUR
SMARTPHONES OUT AND GO TO THIS
WEBSITE OR USE THE QR CODE AND
TYPE IN THIS SURVEY CODE.
THAT WOULD BE EXCELLENT.
WE HAVE A FEW QUESTIONS FOR YOU
AND I'LL GIVE EVERYONE A
FEW SECONDS TO SORT THAT OUT.
THOSE OF YOU WHO ARE VIRTUAL,
PLEASE DO THIS AS WELL.
SO HOPEFULLY THIS WORKS.
WE'RE GOING TO GO TO THE NEXT
SLIDE, AND IF YOU'RE HAVING A
HARD TIME GETTING TO THIS, THERE
WILL BE -- THE NUMBERS WILL BE
ON THE NEXT SLIDES AS WELL.
SO HERE WE GO.
THE FIRST QUESTION FOR THE POLL
IS, WHAT WORDS COME TO MIND WHEN
YOU HEAR "PALLIATIVE CARE"?
AND THEY SHOULD BE POPPING UP AS
YOU ALL ARE PUTTING THEM IN.
SO THE BIGGER WORDS ARE ONES
THAT MORE PEOPLE HAVE BEEN
PUTTING IN THE SURVEY.
SO END OF LIFE, TO COMFORT,
DEATH AND DYING, PAIN
MANAGEMENT.
SO A LOT OF PAIN AND SYMPTOM
MANAGEMENT I'M SEEING, COMFORT,
END OF LIFE.
VERY INTERESTING.
LAST RESORT, I'M SEEING
SOMEONE -- OH.
WE'LL TALK A LITTLE BIT MORE
ABOUT SOME OF THESE THINGS AS WE
GO, BUT THIS IS REALLY
INTERESTING.
NEXT QUESTION.
DO YOU THINK THERE IS A ROLE FOR
PALLIATIVE CARE IN THE CARE OF
PATIENTS WITH SICKLE CELL
DISEASE?
SO YES, NO, OR NOT SURE.
PLEASE CONVINCE ME.
WE'LL GIVE EVERYONE A FEW
MORE SECONDS.
SO THIS IS GOOD.
MORE THAN 80% OF YOU THINK THAT
THERE IS A ROLE.
AND WE HAVE A SOLID PERCENTAGE
OF PEOPLE WHO I THINK HOPEFULLY
WE CAN CONVINCE TODAY OR MAKE
YOU A LITTLE BIT MORE TOWARDS
YES.
AND THEN THE FINAL QUESTION IS,
WHAT ROLE OR ROLES DO YOU SEE
FOR PALLIATIVE CARE IN SICKLE
CELL DISEASE?
SO PAIN MANAGEMENT, A BIG ONE.
ONE THAT WE SEE OFTEN WHEN WE
ASK THESE QUESTIONS.
COMFORT.
SYMPTOM MANAGEMENT, QUALITY OF
LIFE.
AND WE'LL TALK ABOUT SEVERAL OF
THESE THINGS OVER THE COURSE OF
THE PRESENTATION, BUT I THINK
THIS IS GREAT.
I'M GLAD TO SEE QUALITY OF LIFE
GETTING BIGGER.
THAT'S GREAT.
SO A LITTLE BIT ABOUT WHAT WE'RE
GOING TO TALK ABOUT TODAY.
I'M GOING TO LEAD US OFF IN JUST
REVIEWING THE LITERATURE IN
SICKLE CELL DISEASE AND
PALLIATIVE CARE.
WE'LL THEN KIND OF TRANSITION TO
ASPECTS OF QUALITY OF LIFE AND
PSYCHOSOCIAL ASPECTS OF SICKLE
CELL DISEASE, WHICH I'M SURE
MANY OF YOU ARE ALREADY AWARE.
THEN WE'LL GO INTO THE RULES FOR
PALLIATIVE CARE AS WE SEE THEM,
EBERECHI WILL TALK ABOUT A STUDY
SHE RECENTLY COMPLETED, AND OUR
FIELDS IN PALLIATIVE CARE.
SO I CAN TELL YOU PRETTY
CONFIDENTLY THAT THE LITERATURE
IS EXTREMELY LIMITED WHEN IT
COMES TO SICKLE CELL DISEASE AND
PALLIATIVE CARE.
I INITIALLY DID THIS TALK FOR MY
PALLIATIVE CARE TBRAND RO GRANDN
2020 AND JUST SEARCHED -- THIS
WASN'T AN EXTENSIVE LITERATURE
REVIEW BUT I SEARCHED THE TERMS
PALLIATIVE CARE AND SICKLE CELL
DISEASE AND I CAME UP WITH SIX
ARTICLES, MOST OF WHICH WERE
OPINION PIECES, A CASE REPORT,
VERY MINIMAL LITERATURE ON THE
SUBJECT, AND THEN DID IT AGAIN
PRIOR TO THIS PRESENTATION, GOT
SEVEN ARTICLES.
NOW, AGAIN, THOSE ARE USING
THOSE SPECIFIC TERMS, SO THERE
IS RELATED LITERATURE THAT ISN'T
NECESSARILY THOSE TWO TERMS, BUT
I THINK IN GENERAL, KIND OF AN
INTERESTING FINDING.
SO VERY LIMITED.
BY COMPARISON, YOU DO THE SAME
SEARCH DO BE CF AND PALLIATIVE
CARE AND YOU GET 17 17 175 ARTI,
SO THIS IS ONE STUDY THAT'S
LOOKED AT ACUTE CARE UTILIZATION
AT THE END OF LIFE IN SICKLE
CELL DISEASE.
THEY LOOKED AT ALMOST A TOTAL OF
500 DEATHS WHERE THE MEDIAN AGE
WAS 45 YEARS, AND THE REALLY BIG
TAKEAWAY FROM THIS STUDY WAS
THAT 78% OF PATIENTS WERE DYING
EITHER IN THE HOSPITAL OR IN THE
EMERGENCY DEPARTMENT.
AND THAT WE SEE AN OPPORTUNITY
IN THIS STUDY THAT CAME ABOUT AS
WELL, IS THAT PATIENTS WERE
HOSPITALIZED FOR A TOTAL OF 42
DAYS IN THE LAST YEAR OF THEIR
LIFE, AND THIS WAS SPREAD OUT
OVER FIVE ADMISSIONS, AND SO WE
SEE THIS VERY MUCH AS AN
OPPORTUNITY FOR ADVANCED CARE
PLANNING, AND THEN AGAIN KIND OF
THAT LAST MONTH OF LIFE, THE
ACUTE CARE UTILIZATION REALLY
SPIKED.
SO VERY, VERY INTERESTING
COMPARED TO THE GENERAL
POPULATION IN TERMS OF LOCATION
OF DEATH.
THIS IS A STUDY EBERECHI DID
THAT LOOKED AT INPATIENT
PALLIATIVE CARE UTILIZATION IN
PATIENTS WITH SICKLE CELL
DISEASE.
SO THE ORANGE LINE IS THE KIND
OF RAY OF INPATIENT PALLIATIVE
CARE UTILIZATION IN TERMINAL
HOSPITALIZATION, SO YOU CAN SEE
INCREASED USE BUT ALSO AN
INCREASED RATE OF RISE OVER THE
COURSE OF THE STUDY.
HOWEVER, THE TOTAL NUMBER OF
HOSPITALIZATIONS WHERE PATIENTS
WERE RECEIVING PALLIATIVE CARE
SERVICE WAS ONLY .45%, SO VERY,
VERY LOW UTILIZATION.
BUT DID INCREASE OVER THE COURSE
OF THE STUDY.
AND THE USE OF PALLIATIVE CARE
WAS HIGHER IN PATIENTS WHO WERE
OLDER, MALE, HIGHER INCOME,
SICKER PATIENTS, WHICH MAKES
SENSE, AND THOSE IN URBAN
HOSPITALS.
THERE IS SOME DATA, AGAIN
LIMITED IN ADVANCED CARE
PLANNING IN SICKLE CELL DISEASE.
IT HAS SHOWN THAT ADVANCED CARE
PLANNING AND THESE CONVERSATIONS
ARE LIMITED BY MISTRUST, BOTH BY
KIND OF THE SYSTEM IN GENERAL AS
WELL AS HEALTHCARE PROVIDERS.
DESIRE NOT TO HAVE THESE
CONVERSATIONS DOCUMENTED AND A
RELUCTANCE GENERALLY TO TALK
ABOUT DYING.
THERE'S ALSO SOME DATA THAT
SUGGESTS IT'S NOT REALLY
HAPPENING, SO THEY LOOKED --
THERE WAS A STUDY THAT LOOKED AT
ABOUT 70 PATIENT THAT MOST OF
WHICH DID NOT HAVE ANY KIND OF
WRITTEN DECISIONS FOR KIND OF IN
TERMS OF ADVANCED CARE PLANNING
IN TERMS OF THEIR DESIRES FOR
END OF LIFE MEDICAL TREATMENT.
IF THEY DID HAVE DOCUMENTATION,
THEY TENDED TO BE OLDER, SO
GREATER THAN 50.
AT THE SAME TIME, 90% WANTED TO
HAVE THESE CONVERSATIONS.
LOOKING A LITTLE BIT MORE INTO
THAT, THIS IS ACTUALLY A STUDY
OUT OF MY INSTITUTION, DUKE.
THIS IS A QUALITATIVE STUDY THAT
LOOKED AT KIND OF ATTITUDES AND
EXPERIENCES OF PREPARING FOR
DEATH IN OLDER ADULTS WITH
SICKLE CELL DISEASE, AND THEY
LOOKED AT -- THEY IDENTIFIED
FOUR DIFFERENT MAJOR THEMES.
THE FIRST BEING KIND OF
ANTICIPATION OF AN EARLY DEATH.
BEING ABLE TO KIND OF MAKE PLANS
FOR THIS AND BEING INFORMED OF
THAT.
MANY OF THE PATIENTS HAD ALREADY
EXPERIENCED NEAR-DEATH
EXPERIENCES.
AND REALLY THE THIRD THEME AS
BEING KIND OF DIFFERENCES IN
COMFORT LEVEL TALKING ABOUT
THIS.
FOR SOME PATIENTS THIS WAS DEATH
AS BEING KIND OF A PART OF LIFE.
AND FOR OTHERS, THIS WAS NOT
SOMETHING THAT THEY FELT
COMFORTABLE TALKING ABOUT.
AND THEN THE INFLAWNS OF INFLUEF
SPIRITUALITY.
GOD CONTROLS THE TIMING OF OUR
DEATH AND BELIEF IN AFTERLIFE
BEING A SUBTHEME IN THAT GROUP.
THIS IS ANOTHER STUDY BY THE
SAME GROUP THAT LOOKED AT
FACILITATORS AND BARRIERS OF
HAVING THESE CONVERSATIONS.
I WON'T GO OVER THIS, BUT I
THINK IT'S REALLY, REALLY
IMPORTANT TO UNDERSTAND
GENERALLY WHAT THESE ARE.
SO IN TERMS OF FACILITATORS, THE
BIG KEY POINT IS TO UNDERSTAND
THIS NEEDS TO BE IN THE RIGHT
PLACE, NOT IN THE HOSPITAL, NOT
HAD SOMEONE IS SICK.
IT NEEDS TO BE WITH A RESPECTED
AND TRUSTED PROVIDER, OFTENTIMES
AT THEIR PRIMARY HEMATOLOGIST.
HAVING FAMILY PRESENT IS A HUGE
FACILITATOR FOR THESE PATIENTS.
AND I THINK OPEN AND HONEST
COMMUNICATION IS A BIG
FACILITATOR.
IN TERMS OF BARRIERS, IT SORT OF
THE OPPOSITE OF THAT, BEING IN
THE HOSPITAL, BEING ACUTELY ILL,
NOT WITH A TRUSTED PROVIDER.
SPIRITUALITY DID SEEM TO BE A
BARRIER TO THESE CONVERSATIONS,
SO THINKING ABOUT PLANNING FOR
DEATH AS NOT BEING CONSISTENT
WITH ONE'S RELIGIOUS BELIEFS OR
THAT UNDERPINNING OF GOD
CONTROLS THE TIMING OF THIS, SO
I'M NOT GOING TO TALK ABOUT IT.
AND THEN PATIENTS' OWN NEGATIVE
EXPERIENCES OF END OF LIFE,
WHETHER IT'S WITH THEIR FAMILY
MEMBERS AND WHATNOT, AND PART OF
THAT IS THE MISTRUST OF MAYBE
THE PROVIDER THAT'S BRINGING
THIS UP BUT ALSO MISTRUST OF THE
SYSTEM.
SO NOW A TRANSITION TO SOME OF
THE BIG QUALITY OF LIFE AND
PSYCHOSOCIAL ASPECTS OF SICKLE
CELL DISEASE THAT UNDERPIN WHY
WE FEEL LIKE PALLIATIVE CARE HAS
A BIG ROLE.
AND ALL OF YOU KNOW THIS, BUT
ALWAYS GOOD TO REMEMBER SICKLE
CELL DISEASE IS MULTIORGAN,
AFFECTS EVERY BODY SYSTEM AND
ORGAN SYSTEM.
THERE'S BOTH ACUTE AND CHRONIC
COMPLICATIONS.
WHEN WE LOOK AT QUALITY OF LIFE
IN SICKLE CELL DISEASE, CHILDREN
ARE KIND OF IN THE GREEN AND
ADULTS IN YELLOW, THAT SICKLE
CELL DISEASE, THE HEALTH-RELATED
QUALITY OF LIFE IS EQUIVALENT IN
CHILDREN TO CHILDREN ON ACTIVE
CANCER TREATMENT.
AND FOR ADULTS WITH SICKLE CELL
DISEASE, THEIR HEALTH-RELATED
QUALITY OF LIFE IS ACTUALLY
WORSE THAN PATIENTS ON ACTIVE
CANCER TREATMENT, AS WELL AS
CYSTIC FIBROSIS AND MORE ON PAR
WITH ADULT ASTHMA.
SO PRETTY POWERFUL IMAGE IS THIS
ONE I GO TO A LOT WHEN I'M
TALKING TO PEOPLE WHO DON'T HAVE
A LOT OF KNOWLEDGE ABOUT SICKLE
CELL DISEASE AND PALLIATIVE
CARE.
THIS IS A SIMILAR KIND OF LOOK
AT QUALITY OF LIFE SO THE SICKLE
CELL DISEASE COHORT, THERE'S
BOTH THE UNAGISTED LIVE
EXPECTANCY AND -- YOU CAN SEE
UNADJUSTED IS AROUND 54, SO MUCH
LOWER THAN THE LIFE EXPECTANCY
OF THE U.S. GENERAL POPULATION
BUT THEN THE NON-SCD POPULATION
AS WELL.
THEN WHEN YOU ADJUST FOR
QUALITY -- QUALITY OF LIFE IS
DEEPLY AFFECTED BY THIS DISEASE.
THE PISCES STUDY IS ONE OF THE
KIND OF -- IS ONE OF THE BIG
STUDIES LOOKING AT
HEALTH-RELATED QUALITY OF LIFE.
THEY LOOKED AT EIGHT DIFFERENT
DOMAINS INCLUDING PHYSICAL
FUNCTION, EMOTIONAL BODILY PAIN,
VITALITY, ET CETERA, AND WAS A
LONGITUDINAL STUDY WHERE THEY
HAD PATIENTS DO DAILY PAIN
DIARIES THAT ALLOWED THEM TO
CALCULATE VARIOUS VARIABLES.
FOR PAIN, ABOUT 55% OF TOTAL
PAIN DAYS -- TOTAL DAYS WERE
SPENT WITH PATIENTS IN PAIN.
29% OF PATIENTS REPORTED DAILY
PAIN.
AND FOR MAJORITY OF THOSE
PATIENTS, THEY WERE MANAGING
THIS AT HOME.
TYPICALLY WITH THE USE OF
OPIOIDS, AND ONLY 3.5% OF DAYS
WAS PAIN REQUIRING SOME SORT OF
MEDICAL ATTENTION.
SO REALLY THE KEY HERE IS THAT
PAIN IS THE RULE AND NOT THE
EXCEPTION.
THIS WAS JUST HIGHLIGHTED IN THE
LAST PRESENTATION, BUT PAIN
MANAGEMENT ESPECIALLY IN THE
EMERGENCY DEPARTMENT IS
FREQUENTLY DELAYED, THOUGH LOTS
OF EFFORTS HAVE BEEN ONGOING.
THIS CAN OFTEN LEAD TO
UNDERTREATED AND INAPPROPRIATELY
MANAGED PAIN, AND CAN LEAD TO
THIS IDEA OF PSEUDOADDICTION
WHERE SOMEONE IS SHOWING RED
FLAG BEHAVIOR BUT ACTUALLY THEIR
BEHAVIOR IS A RESULT OF
UNDERTREATED INAPPROPRIATELY
MANAGED PAIN.
FOR ABOUT A THIRD OF THE
PATIENTS, THEY DON'T HAVE A
VASOOCCLUSIVE CRISIS OVER THE
COURSE OF THE YEAR, BUT ALMOST
20% HAVE GREATER THAN THREE
HOSPITALIZATION RATES.
SO ABOUT HALF THE TIME FOR PEDS
COMPARED TO ADULTS.
AND AGAIN, PHYSICAL EXAM
FINDINGS ARE OFTEN ABSENT.
SO A PATIENT-REPORTED PAIN IS
THE GOLD STANDARD.
IN ADDITION TO KIND OF THE
DETAILS ABOUT THE PAIN ITSELF,
THERE'S A LOT OF MISPERCEPTIONS
ABOUT SICKLE CELL DISEASE
PATIENTS AND THE PAIN THAT THEY
EXPERIENCE.
SO A LOT OF MISPERCEPTIONS FROM
ED PHYSICIANS, HEMATOLOGISTS,
FEELING LIKE PATIENTS ARE
ADDICTED TO OPIOIDS DESPITE THE
FACT THAT THE LITERATURE HAS
SHOWN THAT THEY ARE NOT, AND
THAT THEY HAVE EITHER EQUIVALENT
OR LESS OPIOID ADDICTION
COMPARED TO THE GENERAL
POPULATION.
AND THAT A 2005 SURVEY SHOWED
THAT HOSPITAL PHYSICIANS DID NOT
BELIEVE THAT A PATIENT'S OWN
SELF-REPORT WAS THE BEST
INDICATOR OF THEIR ACTUAL PAIN.
AND US IN PALLIATIVE CARE, WE
BELIEVE VERY STRONGLY THAT WORDS
MATTER, AND SO THE UNDERPINNINGS
OF SOME OF THESE WORD THAT WE
HEAR ALL THE TIME IN PRACTICE
REALLY VL RAC HAVE RACIAL UNDERS
THAT AFFECT THE CARE ULTIMATELY
THAT PATIENTS RECEIVE.
THE PSYCHOSOCIAL BURDEN IS ALSO
HUGE, AND WE'LL TALK A LITTLE
BIT MORE ABOUT THE PISCES STUDY
RESULTS OF MENTAL HEALTH BUT
HIGH LEVELS OF CO-MORBID
DEPRESSION AND ANXIETY, WHICH WE
KNOW IS IN SICKLE CELL DISEASE
BUT ALSO IN OTHER PAIN SI SYNDRS
THAT THIS LEADS TO HIGHER
SENSITIVITY TO PAIN, HIGHER
UTILIZATION, OTHER SOMATIC
SYMPTOMS, SLEEP DISTURBANCE, AND
ALSO IS ASSOCIATED WITH
DECREASED PRODUCTIVITY, SCHOOL
WORK PERFORMANCE, HIGHER LEVELS
OF STIGMA.
SO GOING INTO THE KIND OF
RESULTS OF THE PISCES STUDY,
ABOUT 28% OF PATIENTS WERE --
HAD CO-MORBID DEPRESSION AND
THEN ABOUT 6.5% HAD CO-MORBID
ANXIETY.
THE DEPRESSED PATIENTS TENDED TO
HAVE PAIN ON MORE DAYS AND HAD
HIGHER MEAN PAIN, AND
INTERFERENCE ON PAIN ON
NON-CRISIS DAYS.
SIMILAR RESULTS WITH ANXIOUS
PATIENTS, IN ADDITION, THEY
TENDED TO HAVE MORE OPIOID USE.
AND WE WOULD BE REMISS WITHOUT
TALKING ABOUT THE EFFECT OF
INEQUITY AND RACISM ON THE
QUALITY OF LIFE THAT THESE
PATIENTS EXPERIENCE, SO THIS IS
OLD INFORMATION, A FEW YEARS
OLD, BUT I THINK IT'S REALLY
INTERESTING TO SEE THAT DESPITE
THE FACT THAT THE PREVALENCE OF
SICKLE CELL DISEASE IS HIGHER IN
THE U.S. POPULATION, THESE
PATIENTS RECEIVE LESS NIH
FUNDING PER PERSON, LESS
PHILANTHROPIC SUPPORT, FEWER
PUBLICATIONS, FEWER TRIALS,
FEWER DISEASE-SPECIFIC DRUGS.
SO VERY KIND OF HARD TO IGNORE
THE SCIEBD R KIND OF EFFECT OF
RACISM IN SICKLE CELL DISEASE.
THIS IS A BOOK IN MEDICAL SCHOOL
THAT I'M EXTREMELY PASSIONATE
ABOUT THIS SUBJECT.
THIS PERSPECTIVE PIECE ON THE
BOTTOM, I'M SURE 19 OF YOU HAVE
READ IT BUT IF YOU'RE NOT, IT'S
A NEW ENGLAND JOURNAL PIECE
ABOUT SORT OF THE UNDERPINNINGS
OF RACE IN SICKLE CELL DISEASE
AND HOW THAT'S AFFECTED THE
HISTORY, AND THEN IT MAKES VERY
SPECIFIC RECOMMENDATIONS FOR
PROPOSED CHANGES OF HOW WE CAN
CHANGE THE TRAJECTORY OF THEIR
CARE.
AND SO I ALSO WANTED TO POINT
OUT THAT WORDS LIKE SICKLIERS,
WHAT THEY DO IS THEY
DEPERSONALIZE THE PERSON AT THE
CENTER OF ALL OF THIS.
SO I THINK TO IGNORE THAT
EXPERIENCE IS ONE THAT IS HARD
TO DO.
SO NOW I'M GOING TO TRANSITION
TO STEPHANIE, WHO'S GOING TO
TALK ABOUT THE ROLE FOR
PALLIATIVE CARE.
>>THANK YOU, ASHLEY.
SO AS ASHLEY SAID, I'M GOING TO
SPEND A FEW MINUTES SORT OF
ZOOMING OUT WITH ALL OF THAT
BACKGROUND TO TALK ABOUT THE
PHILOSOPHY OF PALLIATIVE CARE
AND ALSO WHAT WE SEE AS THE
OPPORTUNITIES FOR RESEARCH AND
CLINICAL CARE IN THE FUTURE.
SO PALLIATIVE CARE IS REALLY A
PHILOSOPHY OF CARE FOR ANYONE
WITH A SERIOUS ILLNESS THAT
AIMED AS AN EXTRA LAYER OF
SUPPORT AND ALL OF THE OTHER
MEDICAL CARE THAT THEY'RE
ALREADY GETTING.
AND AS PALLIATIVE CARE
PHYSICIANS, WE FOCUS A LOT ON
QUALITY OF LIFE AND NOT ONLY
QUALITY OF LIFE FOR THE
INDIVIDUAL PATIENT BUT ALSO FOR
THE FAMILY AND OTHER SUPPORT
SYSTEMS AROUND THE PATIENT.
PALLIATIVE CARE REALLY FOCUSES
ON NOT ONLY WHAT WE CAN PROVIDE
ON PHYSICIANS, ALL THREE OF US
ARE PHYSICIAN, BUT WE ALSO WORK
IN INTERDISCIPLINARY TEAMS AND
RECOGNIZE THAT PROVIDERS FROM A
VARIETY OF TRAINING BACKGROUNDS
REALLY ENHANCE THE CARE OF THESE
PATIENTS SO THAT CAN INCLUDE
NURSES, SOCIAL WORKERS, AND
OTHER SUPPORT PEOPLE ON OUR
HEALTHCARE TEAMS.
AND THEN PALLIATIVE CARE IS
REALLY BASED ON THE NEEDS OF THE
PATIENT, NOT ON THE PATIENT'S
PROGNOSIS, SO IT'S APPROPRIATE
AT ANY AGE AND I STAGE IN A
SERIOUS ILLNESS, AND IT CAN --
AND THIS IS REALLY IMPORTANT TO
US TO EMPHASIZE, IT CAN BE
REPORTED ALONG WITH CURATIVE
TREATMENT.
I THINK THAT'S TO SAY THAT'S ONE
OF THE BIGGEST MISCONCEPTIONS
THAT WE STILL IS HEAR A LOT WHE
BRING UP PALLIATIVE CARE NOT
ONLY IN THIS SPACE BUT OTHER
PATIENT POPULATIONS.
OFTENTIMES WHAT WE HEAR THE MAIN
FOCUS BEING ON IS END OF LIFE
AND SORT OF HOSPICE CARE AT THE
END OF SOMEONE'S CLINICAL
DISEASE COURSE.
AND WHILE THAT'S CERTAINLY AN
IMPORTANT PART OF PALLIATIVE
CARE, WHAT WE WANT TO EMPHASIZE
IS THAT PALLIATIVE CARE IS
REALLY APPROPRIATE FROM THE TIME
OF DIAGNOSIS.
SO IT IS REALLY IMPORTANT FOR US
TO FOCUS ON SYMPTOM MANAGEMENT
AND QUALITY OF LIFE FROM THE
TIME OF DIAGNOSIS ACROSS
SOMEONE'S DISEASE AND ILLNESS
COURSE.
WHEN WHICH THINK WE THINK ABOUE
APPROACH THINGS AS PALLIATIVE
CARE PROVIDERS, WE SEE THIS
WEDGE THAT REPRESENTS THIS TOTAL
OR HOLISTIC APPROACH.
STARTING AT THE TOP RIGHT, THE
PHYSICAL SYMPTOMS ARE SOME OF MT
COMMON THINGS PEOPLE THINK OF US
IN PALLIATIVE CARE AS BEING
HELPFUL WITH, AND FOR WHICH WE
OFTEN GET REFERRALS.
SO TREATING THINGS LIKE PAIN,
FATIGUE, DYSPNEA, WHICH ARE ALL
CERTAINLY IMPORTANT, BUT I JUST
WANT TO ALSO EMPHASIZE THAT WE
TRY TO TAKE A WHOLE APPROACH,
AGAIN, IN OUR INTERDISCIPLINARY
TEAMS TO ALSO THINK ABOUT ALL
THE OTHER WAYS IN WHICH SOMEONE
WITH A SERIOUS ILLNESS LIKE
SICKLE CELL DISEASE IS IMPACTED
BY THEIR ILLNESS.
SO THAT INCLUDES THINGS LIKE
EMOTIONAL ASPECTS, ASHLEY
POINTED OUT THAT THERE ARE HIGH
RATES OF ANXIETY AND DEPRESSION
AND THINKING ABOUT HOW YOU'RE
COPING WITH A SERIOUS ILLNESS.
SOCIAL SUPPORT, AND WE ALL KNOW
THAT MANY OF THE PATIENTS WITH
SICKLE CELL DISEASE HAVE
CHALLENGES WITH THEIR
RELATIONSHIP, THEIR LIVING
SITUATION AND FINANCIAL ISSUES
THAT IMPACT THEIR DISEASE.
SPIRITUALITY IF THAT IS
IMPORTANT TO THE PATIENT, WHERE
THEY FIND HOPE AND MEANING, AND
THEN AN OVERALL VIEW OF WHERE
THEY ARE IN THEIR ILLNESS,
THINKING ABOUT PROGNOSIS, THEIR
ILLNESS UNDERSTANDING, ADVANCED
CARE PLANNING, AND HOW TO REALLY
TAYLOR THEIR TREATMENT TO THEIR
OWN GOALS.
WHEN WE THINK ABOUT THE BENEFITS
OF PALLIATIVE CARE, I WILL SAY
AND AS ASHLEY POINTED OUT,
THERE'S VERY LIMITED DATA AND
EVIDENCE IN TERMS OF THE
INTEGRATION OF PALLIATIVE CARE
IN PATIENTS WITH SICKLE CELL
DISEASE. IN FACT, MUCH OF THE
EVIDENCE FOR PALLIATIVE CARE TO
DATE HAS BEEN INITIALLY STARTED
IN THE CANCER POPULATION, SO ONE
OF THE HALLMARK STUDIES WITHIN
OUR FIELD WAS ACTUALLY DONE WITH
THE GROUP AT THE HOSPITAL THAT I
WORK AT LOOKING AT PALLIATIVE
CARE INTEGRATION EARLY IN THE
DISEASE COURSE FOR THOSE WITH
METASTATIC NON-SMALL SELL LUNG
CANCER, AND WHAT THEY ACTUALLY
FOUND IN THAT STUDY WAS THAT
PATIENTS WHO HAD EARLY
PALLIATIVE CARE AS PART OF THEIR
DISEASE COURSE HAD NOT ONLY A
BETTER QUALITY OF LIFE BUT LOWER
RATES OF DEPRESSION AND ALSO A
LONGER SURVIVAL PERIOD WITH
THEIR DISEASE.
THIS HAS ALSO EXPANDED INTO
OTHER DISEASE STATES BEYOND
CANCER, SO THERE'S BEEN A LOT OF
EVIDENCE IN THE LAST FIVE TO 10
YEARS IN DISEASE STATES LIKE
HEART FAILURE, RECENTLY IN
CIRRHOSIS, AND AGAIN, NOT A LOT
OF EVIDENCE IN THE SICKLE CELL
POPULATION, BUT WE THINK THAT
THERE'S INCREDIBLE OPPORTUNITY
HERE.
A LOT OF THE INTEGRATION OF
PALLIATIVE CARE STUDIES HAVE
ALSO SHOWN IMPROVED CA CAREGIVER
AND FAMILY OUTCOMES AND THINGS
WHEN WE THINK THE HEALTHCARE
SYSTEM ARE ALSO BENEFICIAL, LIKE
COST SAVINGS, SHORTENED HOSPITAL
STAYS AND IMPROVED END OF LIFE
OUTCOMES AT THE END OF LIFE FOR
PATIENTS.
NOW TO SORT OF PUT THAT CONTEXT
AND HOW WE THINK ABOUT
PALLIATIVE CARE AND ITS EVIDENCE
BASE BACK INTO THE SICKLE CELL
DISEASE POPULATION.
AS ASHLEY POINTED OUT, YOU KNOW,
ONE OF THE FIRST THINGS WE WANT
TO MAKE A CASE FOR WHICH I DON'T
THINK WE HAVE TO CONVINCE ANY OF
YOU GUYS OF, IS THAT THIS
PATIENT POPULATION HAS SOME OF
THE HIGHEST NEED IN TERMS OF
PALLIATIVE CARE SUPPORT.
PARTICULARLY FROM A PROGNOSTIC
SENSE.
SO ASHLEY POINTED OUT THAT
RECENTLY THE AVERAGE LIFE
EXPECTANCY FOR SOMEONE WITH
SICKLE CELL DISEASE IS AROUND 50
YEARS OLD.
IT'S ALWAYS INCREDIBLE FOR ME TO
NOTE THAT AS RECENTLY AS 1970,
THAT WAS AS YOUNG AS 20 YEARS,
WE'VE MADE INCREDIBLE
IMPROVEMENT IN HOW LONG PEOPLE
ARE LIVING WITH THIS DISEASE,
BUT AS ASH LEA STATED, 50 YEARS
IS SO MUCH LOWER THAN THE
GENERATHAN THE LIFEEXPECTANCY OL
POPULATION.
THE MAIN CAUSES OF DEATH FOR
PATIENTS WITH SICKLE CELL
DISEASE, AS YOU GUYS WELL KNOW,
CVA, ACUTE CHEST, INFECTION,
MULTIORGAN FAILURE AND SUDDEN
CARDIAC DEATH.
AND WE ALSO KNOW THAT THERE IS
INEQUITY ACROSS THE SICKLE CELL
DISEASE POPULATION, AND THAT
SOME PATIENTS HAVE MORE SEVERE
DISEASE SUBTYPE AND THEY OFTEN
HAVE MORE CO-MORBIDITY WHEN WE
LOOK AT THINGS ACROSS THE
SPECTRUM.
SO THERE'S CERTAINLY INCREDIBLE
NEED FROM A PROGNOSTIC SENSE,
AND WE WOULD ALSO ARGUE THAT
WITH THIS INCREASING LIFE
EXPECTANCY COMES INCREASING RATE
OF MORBIDITY, SO ONE
OBSERVATIONAL STUDY SAW THAT 73%
OF SICKLE CELL DISEASE HAD
GREATER THAN ONE FORM OF
IRREVERSIBLE ORGAN DAMAGE, WHICH
WILL OFTEN COME WITH A VARIETY
OF SYMPTOMS.
SO THERE'S HIGHER SYMPTOM NEEDS,
AND THESE PATIENTS'
PSYCHOLOGICAL AND SOCIAL
STRESSORS, AND THEN AGAIN
THERE'S A PAUCITY OF ADVANCED
CARE PLANNING THAT'S OFTEN
HAPPENING.
SO WE SEE A REAL OPPORTUNITY
THERE TO THINK ABOUT MID CAL
MEDICALCARE PLANS, DECISION-MAKD
PLANNING FOR END OF LIFE WHICH
IS NOT REALLY HAPPENING RIGHT
NOW.
THERE'S A TON OF OPPORTUNITY,
AND I'LL JUST NAME SOME OF THE
WAYS IN WHICH WE FEEL LIKE WE
COULD MAKE A BETTER EVIDENCE
BASE AND HAVE A STRONGER
INTERVENTION FROM A PA PALLIATIE
CARE STANDPOINT.
SO I THINK ONE OF THE BIGGEST
NEEDS THAT YOU GUYS IDENTIFIED
WHEN WE STARTED OUT WITH THE
WORD CLOUD WAS IN PAIN AND
SYMPTOM MANAGEMENT.
ALSO ADVANCED CARE PLANNING,
THINKING ABOUT TRANSITIONS OF
CARE.
I KNOW THERE'S A VARIETY OF
PEOPLE HERE INTERESTED IN THAT
SPACE SPECIFICALLY, AND WE KNOW
THAT SOME OF THE OUTCOMES
WORSENED DURING THAT TIME IN
PARTICULAR.
THINKING ABOUT COMMUNICATION AND
CARE COORDINATION, IMPROVING
CAQUALITY OF LIFE AND FUNCTIONI,
A FOCUS ON TOTAL PAIN WHICH I'LL
TALK ABOUT IN A COUPLE OF
SLIDES, COMPLEX MEDICAL
DECISION-MAKING.
WE SEE AN INCREDIBLE ROLE FOR
SOCIAL JUSTICE AND ADVOCACY, AND
THEN THINKING ABOUT AGAIN
INTEGRATED AND MULTIDISCIPLINARY
CARE MODELS.
SO THIS IS JUST A SLIDE TO
HIGHLIGHT SORT OF THE
INTERDISCIPLINARY PALLIATIVE
CARE APPROACH THAT WE THINK HAS
INNATE VALUE AND REALLY ENHANCES
THE CARE OF THIS PATIENT
POPULATION.
THIS WAS A FIVE-YEAR STUDY AT
YALE CHILDREN'S THAT
DEMONSTRATED THE POWER OF JUST A
MULTIDISCIPLINARY APPROACH, SO
THEY WERE LOOKING AT PAIN AS AN
OUTCOME, AND THEY SAW THAT WHEN
THEY APPROACH IT FROM A
MULTIDISCIPLINARY STANDPOINT,
THEY ACTUALLY HAD A 61% OF
HOSPITALIZATIONS, DECREASED
LENGTH OF STAY AND REDUCED
READMISSION RATES BY ALMOST
HALF.
WHEN WE THINK ABOUT THE
OPPORTUNITY AGAIN JUST TO SORT
OF HIGHLIGHT SOME OF THE THINGS
THAT WE'VE NOTED IN THE DATA
THAT WE HAVE, PATIENTS WITH
SICKLE CELL DISEASE HAVE HIGHER
RATES OF DEPRESSION AND ANXIETY,
AND A LOT OF THIS IS WRAPPED
INTO THE COPING WITH THEIR
ILLNESS AND SPECIFICALLY HOW
THEY LEARN TO COPE OVER TIME
FROM BEING DIAGNOSED AND DEALING
WITH THIS THROUGHOUT THEIR LIFE.
AND SO PALLIATIVE CARE, I THINK
HAS A UNIQUE PERSPECTIVE IN THAT
SENSE AND CAN HELP WITH THAT IN
A WAY THAT MAYBE SOME OTHER
PROVIDERS WHO JUST APPROACH
DEPRESSION AND ANXIETY CAN'T.
AND THEN WHEN WE THINK ABOUT ARE
THERE SORT OF OPPORTUNITIES,
PATIENTS WITH -- OFTEN WILL HAVE
SOCIAL AND EMOTIONAL ISOLATION.
I CAN TELL YOU THAT I WORK IN A
COMPREHENSIVE ADULT SICKLE CELL
CLINIC AND IT'S MORE TIMES THAN
NOT THAT WHEN I ASK A PATIENT DO
YOU KNOW ANYONE ELSE IN YOUR
LIFE OR YOUR FAMILY WITH THIS
DISORDER, AND DESPITE IT BEING
VERY PREVALENT, THE ANSWER IS
OFTEN NO, AND THEY'VE OFTEN
SPENT THEIR WHOLE LIFE BEING THE
ONLY PERSON.
MANY OF MY ADULT PATIENTS ARE
FREQUENTLY NEEDING TO BE OUT OF
WORK OR GO OUT ON DISABILITY
BECAUSE OF THEIR PAIN CRISES AND
THEN HAVE GENERAL FRUSTRATION
WITH THE HEALTHCARE SYSTEM AND
HOW TO NAVIGATE THAT, AND
SUPPORT THEIR NEEDS WITH ALL OF
THE STABILITY.
AND THEN AS YOU GUYS KNOW,
THERE'S BEEN A TON OF RESEARCH
PRESENTED TODAY ON ADVANCED
THERAPIES, AND THINGS LIKE BONE
MARROW TRANSPLANTS, STEM CELL
TRANSPLANT, AND PATIENTS WITH
SICKLE CELL DISEASE ARE OFTEN
FACING THESE TREATMENT DECISIONS
AND I THINK THERE'S A NEED
OPPORTUNITY FOR US TO ASSIST
THEM IN THE DECISION-MAKING
THERE.
AND THEN FINALLY, AS WE THINK
ABOUT THEIR RISK FOR RECURRENT
HOSPITALIZATIONS AND ED VISITS
FROM COMPLICATIONS OF THE
DISEASE OVER TIME, ASH LEGAL
HIGHLIGHTED THAT MOST PEOPLE
WITH SICKLE CELL DISEASE DIE IN
THE HOSPITAL OR THE EMERGENCY
DEPARTMENT AND ALSO THEY OFTEN
SPEND THE LAST YEAR OF THEIR
LIFE MORE IN THE HOSPITAL THAN
NOT.
I THINK WHAT WE DON'T KNOW HERE
IS WE DON'T WANT TO PLACE ANY
VALUE ON WHERE WE THINK PATIENTS
WOULD WANT TO DIE.
WE CERTAINLY DON'T HAVE THAT
DATA.
BUT I THINK THIS SAYS A LOT
ABOUT WHAT'S HAPPENING AND HOW
LITTLE CONVERSATION IS HAPPENING
OVER TIME AND THE REAL
OPPORTUNITY THERE.
SO WHEN WE THINK ABOUT TOTAL
PAIN, THE THING THAT WE WANTED
TO EMPHASIZE FROM A PALLIATIVE
CARE LENS IS THAT -- IS PRIDE OF
CARE -- PAIN AS A TOTAL PAIN
EXPERIENCE.
WHAT WE KNOW IS THERE ARE
CERTAINLY BIOLOGICAL FACTORS.
THE BIOLOGY WE KNOW THAT'S
BEHIND SICKLE CELL DISEASE
THAT'S CAUSING PAIN EPISODES.
IN ADDITION TO THAT, ALL THE
OTHER THINGS WE MENTIONED, THE
PSYCHOLOGICAL DISTRESS THAT
THESE PATIENTS EXPERIENCE OVER
TIME AND ALSO THE SOCIAL FACTORS
REALLY CONTRIBUTE TO THIS TOTAL
PAIN EXPERIENCE, AND I KNOW THAT
MANY OF YOU WHO TAKE CARE OF
PATIENTS -- SOMETIMES PATIENTS
COME IN WITH WORSENING PAIN WHEN
THEY'RE HAVING PSYCHOLOGICAL
DISTRESS AND SOCIAL FACTORS THAT
ARE REALLY EXACERBATED IN THEIR
LIFE.
SO AS PALLIATIVE CARE DOCTORS,
WE REALLY ARE THINKING ABOUT
THAT, HOW TO TREAT TOTAL PAIN
AND ALSO HOW TO NOT ONLY TREAT
WITH OPIOIDS BUT ALSO THINK
ABOUT OTHER PAIN MANAGEMENT
INTERVENTIONS.
AND THEN AS WE THINK ABOUT, YOU
KNOW, SORT OF THE OPPORTUNITY
FOR ADVANCED CARE PLANNING AND
GOALS OF CARE DISCUSSIONS, THESE
PATIENTS REALLY HAVE TO NAVIGATE
THE MEDICAL SYSTEM THAT'S
BECOMING MORE AND MORE COMPLEX
OVER TIME.
WE'VE TALKED ABOUT THE INEQUITY
THAT THEY'VE ALL EXPERIENCED,
NOT ONLY IN INDIVIDUAL
ENCOUNTERS BUT SORT OF OVER THE
COURSE OF THEIR DISEASE OVER
TIME, AND THERE'S REALLY AN
OPPORTUNITY THERE TO FIF THEM GM
MORE SUPPORT AND
DECISION-MAKING.
AND THEN FINALLY, THEIR
PSYCHOLOGICAL AND SPIRITUAL
SUPPORT, A NEED FOR MENTAL
HEALTH SUPPORT AND ALSO SOCIAL
WORK CONGLOMERATE WHICH IS OFTEN
A PART OF OUR PALLIATIVE CARE
TEAMS.
SO JUST IN SUMMARY, I THINK WE
ALL AGREE THERE'S -- WE
DEFINITELY NEED TO DEVELOP MORE
EVIDENCE FOR THAT.
PATIENTS WITH SICKLE CELL
DISEASE OFTEN HAVE INCREDIBLE
MORBIDITY AND CONTINUE TO HAVE
HIGHER MORTALITY AT A YOUNGER
AGE THAT REALLY IS AN
OPPORTUNITY FOR PALLIATIVE CARE
SUPPORT.
I'M GOING TO TRANSITION TO
EBERECHI, WHO'S GOING TO TALK A
LITTLE BIT ABOUT THE DATA SHE
HAS COLLECTED FROM HER
CROSS-SECTIONAL STUDY.
>>THANK YOU SO MUCH, STEPH.
SO I HOPE OVER THE PAST FEW
MINUTES WE'VE BEEN HERE THAT
STEPH AND ASHLEY HAVE GIVEN YOU
A STRONG CASE FOR PALLIATIVE
CARE IN SICKLE CELL DISEASE.
SO THE BIG QUESTION THAT I ASK
IS YES, I KNOW HOW I FEEL ABOUT
PALLIATIVE CARE AND SICKLE CELL
DISEASE, BUT WHAT DO SICKLE CELL
DISEASE PROVIDERS THINK ABOUT
PALLIATIVE CARE?
SO TO ANSWER THIS QUESTION, WE
CONDUCTED A CROSS-SECTIONAL
STUDY OF SICKLE CELL PROVIDERS.
WHAT WE DID WAS WE CREATED A
47-ITEM CONFIDENTIAL LINE-BASED
STUDY THAT ADDRESSED FIVE NAMES
THAT LOOKED AT PALLIATIVE CARE
AND SICKLE CELL DISEASE.
THIS SURVEY WAS REVIEWED BY
THREE HEMATOLOGISTS AND ONE
PALLIATIVE CARE PHYSICIAN, AND
THEY WENT THROUGH MULTIPLE
ITERATIONS PRIOR TO LAUNCH.
WE TARGETED SICKLE CELL PROVIDER
GROUPS AND ALSO SENT INDIVIDUAL
EMAILS TO PROVIDERS, USING THE
SCAPN METHOD TO GET AS MANY
PARTICIPANTS AS POSSIBLE.
SO IN TERMS OF THIS STUDY, I
WOULD SAY OUR EXCLUSION CRITERIA
WAS ESSENTIALLY ANY PROVIDER WHO
DID NOT HAVE PROVIDER PRACTICE
WITH PATIENTS WITH SICKLE CELL
DISEASE.
THE SURVEY WAS COMPLETED OVER A
FOUR-MONTH PERIOD, SO I WILL
SPENT SOME -- WHAT WE DID WAS WE
PERFORMED EXPLORATORY FACTOR AND
THIS ANALYSIS YIELDED SEVEN
INDIVIDUAL FACTORS.
WE USED THESE SEVEN FACTORS TO
BE THE NEW DOMAINS FOR THE
SURVEY.
THIS WAS A NEW SURVEY FOR US.
WE ALSO DID INTERNAL CONSISTENCY
RELIABILITY OF EACH DOMAIN MAIN
USING CRONBACH'S ALPHA.
WE DID COMPOSITE SCORES THAT
WERE CALCULATED FOR THE DOMAINS.
WE DID A ZERO ORDER CORRELATION
SO I WILL GO OVER THE MAZE THAT
WE IDENTIFIED.
FIRST LET'S TALK ABOUT THE
PARTICIPANTS.
SO THE M MAJORITY OF PHYSICIANS
WERE FAIL MAIL, THERE WAS A NICE
MIX OF EARLY, YEAR AND MID
PROVIDERS.
THE MAJORITY WITH -- PEDIATRIC
HEMATOLOGIST?
IN TERMS OF PRACTICE TYPE, MOTH
WORK FROM TEACHING HOSPITALS AND
COMPREHENSIVE SICKLE CELL
CENTERS.
MOST HAD A MIXED -- IN
OUTPATIENT PRACTICE.
63% SAID THEY HAD A PRACTICE
THAT INCLUDED GREATER THAN 50%
OF CARE FOR PATIENTS WITH SICKLE
CELL DISEASE.
AND THEN THE MAJORITY OF OUR
PARTICIPANTS DID NOT HAVE PRIOR
PALLIATIVE CARE TRAINING.
ONLY 27% REPORTED TAKING COURSES
IN PALLIATIVE CARE OR ATTENDED A
LECTURE IN PALLIATIVE CARE, AND
THEN 13% SAID THEY HAD SOME SORT
OF FORMAL PALLIATIVE CARE
ROTATION DURING TRAINING,
WHETHER IT WAS A RESIDENCY OR IN
FELLOWSHIP.
AND THEN OF THE PROVIDERS, 40%
REPORTED THAT THEY HAVE NEVER
REFERRED A PATIENT TO PALLIATIVE
CARE.
THE FIRST DOMAIN WE LOOKED AT
LOOKED AT PROVIDERS' FREQUENCY
WITH PALLIATIVE CARE
COLLABORATION.
SO TO ADDRESS THIS, WE ASKED IN
YOUR DEALINGS WITH PATIENTS WITH
SICKLE CELL DISEASE, HOW OFTEN
DO YOU COLLABORATE WITH.
AND TO ORIENT YOU GUYS HERE, THE
OPTIONS FOR RESPONSE IS OFTEN,
WHICH IS GREEN, OCCASIONAL WHICH
IS BLUE, AND NEVER.
WHAT WE SEE HERE IS THAT 60% OF
THE PARTICIPANTS REPORT THAT
THEY OFTEN OR OCCASIONALLY
COLLABORATE WITH INPATIENT
PALLIATIVE CARE TEAMS.
37% REPORTS THAT THEY
COLLABORATE WITH OUTPATIENT
PALLIATIVE CARE TEAMS, BUT WHEN
IT CAME TO HOSPICE, WHETHER
INPATIENT OR OUTPATIENT, THAT
NUMBER DROPPED TO 20%.
THE NEXT DOUGH MAYBE DOMAIN WE S
PROVIDERS' DIRECT INVOLVEMENT IN
SYMPTOM MANAGEMENT.
AGAIN TO ORIENT YOU GUYS TO THIS
GRAPH, IT'S A LITTLE BUSY, SO WE
ASKED THEM, IN YOUR DEALINGS
WITH PATIENTS WITH SICKLE CELL
DISEASE, HOW OFTEN ARE YOU
INVOLVED WITH: AND WE HAVE
THOSE ITEMS THERE.
AND THE RESPONSE, THEY COULD
RESPOND TO US OFTEN, WHICH IS
GREEN, OCCASIONAL, WHICH IS
YELL, AND RARELY, WHICH IS
YELLOW.
TO KIND OF WRAP THIS UP NICELY
FOR YOU, WHAT I WOULD SUMMARIZE
FROM THIS IS THAT PROVIDERS
SPENT A GREAT DEAL MANAGING
SICKLE CELL SYMPTOMS AND
DISEASE.
SO FOR INSTANCE, WE HAVE --
PERCENT REPORT THEY ARE OCCASION
OCCASIONALLY OR OFTEN INVOLVED
IN MANAGING CHRONIC PAIN.
80%, GNAW YA AND VOMITING, A
GOOD -- THEY ARE OCCASIONALLY
INVOLVED IN THIS SYMPTOM.
THE NEXT DOMAIN LOOKED AT DIRECT
INVOLVEMENT IN END OF LIFE CARE.
OFTEN, OCCASIONAL OR RARELY.
I THINK THE KEY POINT HERE TO
NOTE IS THAT UNLIKE THE LAST
DOMAIN, PROVIDERS REPORT THAT
THEY ARE RARELY INVOLVED IN
DISCUSSING END OF LIFE
PREFERENCES WITH THEIR PATIENTS.
SO WE HAVE 64%.
AND 77% SAID THEY ARE RARELY
INVOLVED IN RECOMMENDING HOSPICE
FOR PATIENTS.
SO I WOULD SAY FROM THE LAST TWO
DOMAINS TWO AND -- THIS IS
REALLY I THINK POTENTIAL FEUNTS
FOR US AS CHILD CARE PROVIDERS
TO WORK AND COLLABORATE AND WORK
HAND IN HAND WITH SICKLE CELL
PROVIDERS, AND THAT WE'RE ALSO
HAVING THESE CONVERSATIONS
REGARDING PREFERENCES, AND AS WE
TALK ABOUT IN ADVANCED CARE
PLANNING AS WELL.
SO THE NEXT DOMAIN WAS THAT
PROVIDERS ATTITUDE ABOUT
PALLIATIVE CARE.
AND THE QUESTION SAID DO YOU
AGREE WITH THE FOLLOWING
STATEMENTS ABOUT THE MANAGEMENT
OF PATIENTS WITH SICKLE CELL
DISEASE?
TO ORIENT YOU, THE RESPONSES
THEY GIVE STRONGLY AGREE, WHICH
GREEN, STRONGLY DISAGREE IS THE
DARK GREEN.
WHAT WE SEE HERE IS THAT 88% OF
PROVIDERS AGREED THAT PATIENTS
WITH SICKLE CELL WOULD BENEFIT
FROM PALLIATIVE CARE.
WHAT I FOUND EVEN MORE
INTERESTING WAS THAT 79% AGREED
THAT PATIENTS WITH SICKLE CELL
DISEASE WOULD BENEFIT FROM EARLY
INITIATION OF PALLIATIVE CARE,
AND THEN 99% DISAGREED THAT
PALLIATIVE CARE IS ONLY FOR
DYING PATIENTS.
THEN WE LOOKED AT ATTITUDES
ABOUT PALLIATIVE CARE PROVIDER,
AND I WOULD JUST SUMMARIZE AND
SAY WHICH IS THAT 40% OF
PROVIDERS FELT THAT OR AGREED
THAT PALLIATIVE CARE PROVIDERS,
WE, DO NOT HAVE ENOUGH
UNDERSTANDING OF SICKLE CELL TO
MANAGE THE PSYCHOLOGICAL
SYMPTOMS OF SICKLE CELL.
OVER 5 50% AGREED PALLIATIVE CAE
PROVIDERS DO NOT HAVE ENOUGH
KNOWLEDGE OF SICKLE CELL TO
MANAGE PHYSICAL SYMPTOMS OF
SICKLE CELL DISEASE.
THE NEXT DOMAIN LOOKED AT
PROVIDER SENSE OF OWNERSHIP OF
PALLIATIVE CARE INTERVENTIONS.
I WILL SAY AGAIN TO SUMMARIZE
THIS QUITE BUSY RESULTS HERE,
OVER 90% OF THE PROVIDERS AGREED
THAT THE SICKLE CELL PROVIDER
SHOULD BE AN EXPERT IN MANAGING
THE PHYSICAL SYMPTOM OF SICKLE
CELL DISEASE.
AND THEN 70% AGREE THAT THE
SICKLE CELL PROVIDER SHOULD BE
AN EXPERT IN THE MANAGEMENT --
SICKLE CELL DISEASE.
BUT INTERESTING ENOUGH AS WELL,
80% DISAGREED THAT SICKLE CELL
PROVIDERS ARE THE BEST PEOPLE OR
THE BEST PERSON TO PROVIDE
PALLIATIVE CARE TO THEIR
PATIENTS.
AGAIN, I THINK THIS HIGHLIGHTS
THE OPPORTUNITY TO COLLABORATE
WITH EACH OTHER TO ENSURE THAT
THE SYMPTOMS OF OUR PATIENTS ARE
ADDRESSED.
AND THEN THE LAST DOMAIN IS
PROVIDERS' PERCEPTION OF
PATIENTS AB REACTION TO
PALLIATIVE CARE.
SO THE QUESTION IF A PALLIATIVE
CARE REFERRAL WAS SUGGESTED TO
MY PATIENT WITH SICKLE CELL
DISEASE, THEY MIGHT, AND THE
RESPONSES ARE AGREE, HIGHLY
AGREE, DISAGREE AND STRONGLY
DISAGREE.
PROVIDERS FELT THAT A GOOD CHUNK
OF PATIENTS -- NOTHING CAN BE
DONE FOR HAIR -- WILL TALK TO
THEM ABOUT DYING.
THESE RESPONSES, I WILL SAY OVER
70% OF RESPONSES THAT SAID
HIGHLLY AGREEABLE, AGREE.
ON THE OTHER HAND AS WELL, IF
YOU LOOK AT THE BOTTOM OF THIS
CHART, OF THIS GRAPH, IT ALSO --
THE PROVIDERS REPORT THEY FELT
IF THEY REFERRED THEIR PATIENTS
TO PALLIATIVE CARE, THAT THEY
MIGHT THINK THE MORE SUPPORT
THEY GOT, THE BETTER THEY WILL
FEEL, AND ALSO THE PATIENT MIGHT
FEEL THAT THEY'RE MORE IN
CONTROL OF THEIR SITUATION.
SO HOW HOW PATIENTS RESPOND TO
PALLIATIVE CARE.
I WILL STIP THE SLIDE.
SO JUST TO GIVE A BIRD'S EYE
OVERVIEW OF THE DOMAINS, WE HAVE
THE MEAN OF THE COMPOSITE
SCORES, THE STANDARD DEVIATION
AND RANGE, AND THEN LIKE I
MENTIONED, WE DID THE
CORRELATION ANALYSIS TO SEE IF
THERE WAS ANY RELATIONSHIP
BETWEEN THE DIFFERENT DOMAINS.
WE HAVE SOME STATISTIC LITTLE
SIGNIFICANT FINDINGS, WHAT THE
CORRELATIONS WERE WEAK OR
NEGLIGIBLE.
SO AT THIS TIME WHAT WE LOOK
FORWARD TO DOING IS A SEEING
THAT THERE'S A RELATIONSHIP
BETWEEN THOSE AND THE DOMAINS
THAT WE HAVE THERE FOR THE
SURVEY.
SO IN CONCLUSION, SICKLE CELL
PROVIDERS REPORT FREQUENT
INVOLVEMENT IN SYMPTOM
MANAGEMENT.
THEY ALSO REPORT LESS
INVOLVEMENT IN END OF LIFE
DISCUSSION AND CARE.
AND MOST SICKLE CELL PROVIDERS
THINK THAT THEIR PATIENTS WOULD
BENEFIT TO EARLY INTRODUCTION TO
PALLIATIVE CARE.
HOWEVER, PROVIDERS ALSO STAY
CONCERNED THAT THEIR SO --
>>LEAKING, SO --
>>SO MORE STUDIES ARE NEEDED
TO -- I WILL SAY WE DID A FOCUS
GROUP STUDY THAT RAN PARALLEL TO
THIS SURVEY STUDY AND WE DO
HOPE -- ON BARRIERS, AND WE HOPE
TO SHARE THE RESULTS OF THAT
QUALITATIVE STUDY IN THE NEAR
FUTURE.
LASTLY DISCUSSIONS ARE NEEDED
BETWEEN PALLIATIVE CARE
PROVIDERS AND -- TO IDENTIFY
WAYS IN WHICH PALLIATIVE CARE
CAN BENEFIT INDIVIDUALS WITH
SICKLE CELL DISEASE.
AND WITH THAT SAID, I WOULD LIKE
TO ACKNOWLEDGE THE PRIDE-FTG
PROGRAM WHICH FUNDED THIS STUDY.
DR. BETTY PACE, DIRECTOR OF THAT
PROGRAM, DR. IFY OSUNKWO, MY
MENTOR, AND I THINK A LOT OF
WHAT WE'RE HOPING TO DO IS TO
INCREASE EX-PE SURE OF CALTIVE
CARE AND SICKLE CELL DISEASE
THROUGH SICKLE CELL
PRESENTATION.
WE LAUNCHED A PALLIATIVE CARE
AND SICKLE CELL WORKING GROUP
WHERE A LOT OF PROVIDERS IN
PALLIATIVE CARE WERE INTERESTED
IN THIS AREA OR WORKING TOGETHER
TO SEE HOW WE CAN BRING
INCREASED EXPOSURE TO THIS AREA
IN OUR FIELD.
AND THEN WE'LL ALSO LOOK INTO
ONE DEFINE THE ROLE OF
PALLIATIVE CARE IN SICKLE CELL,
TO BETTER DEFINE WHAT IS OUR
ROLE IN THIS DISEASE MANAGEMENT.
AND THEN LASTLY, KREE HEN SIEVE
SICKLE CELL CLINICS, WE'RE
HOPING TO DEVELOP MORE HOW-TO
GUIDES TO GUIDE OUR CLINICAL
MANAGEMENT AND SYMPTOM
MANAGEMENT OF THIS POPULATION.
SO AGAIN, THANK YOU ALL SO MUCH
FOR YOUR ATTENTION, AND WE
REALLY DO APPRECIATE THIS
PLATFORM TO TALK ABOUT THIS.
>>THANK YOU.
ANY QUESTIONS FROM THE AUDIENCE?
OKAY.
>>HI, THAT WAS A GREAT
QUESTION.
I'M FROM UCSF-OAKLAND.
I WANTED TO KNOW FROM YOU -- WE
HAVE PSYCHOLOGY IN OUR CLINIC.
WE ALSO HAVE AN INTEGRATIVE PAIN
LINK.
SO WE UTILIZE THAT ARE MORE THAN
OUR PALLIATIVE TEAM, SO I WANTED
TO HEAR FROM YOU, WHERE DO YOU
SEE THOSE TEAMS COLLABORATING
MAYBE TOGETHER?
BECAUSE IT SEEMS LIKE A LOT OF
THINGS THAT YOU WERE ADDRESSING
ARE ADDRESSED BY OUR PSYCHOLOGY
TEAM AND PAIN TEAM.
>>DEFINITELY, THERE'S AN
OVERLAP BETWEEN THOSE
DISCIPLINES, WHICH IS WHY WE SAY
PALLIATIVE CARE IS A
MULTIDISCIPLINARY FIELD N A
PALLIATIVE CARE TEAM, YOU COULD
HAVE A PSYCHOLOGIST PART OF OUR
TEAM.
WE COULD HAVE PHARMACISTS AS
PART OF OUR TEAM OR A NURSE.
SO HAVING THOSE MEMBERS OF THE
TEAM IN YOUR INSTITUTION, THEY
ARE FILLING THE ROLE THAT WE
COULD FILL BUT ADDING ADDITIONAL
PALLIATIVE CARE PROVIDERS TO
TALK ABOUT OTHER ASPECTS OF
THEIR CARE WILL BE
COMPLEMENTARY.
IT DOESN'T DISTRACT, IT JUST
ADDS TO THE LAYER OF SUPPORT
THAT THE PATIENT GETS.
IT'S A LAYER OF SUPPORT THAT WE
WOULD PROVIDE TO OUR PATIENT.
THAT'S HOW I WOULD LOOK AT THAT.
>>ONE --
>>THANK YOU SO MUCH.
THIS WAS REALLY GREAT AND I'M SO
GLAD THAT WILL YOU FIND THAT
PALLIATIVE CARE AT THE VERY
BEGINNING IS WHERE WE NEED TO
BE.
ONE OF THE THINGS THAT WE'VE
FOUND IN ALL OUR ADVOCATING WORK
OF WELL OVER, I DON'T KNOW,
2,000 HOURS AT POINT OF CARE, IS
THAT WHEN WE HAVE A PALLIATIVE
CARE TEAM INVOLVED, IT PROVIDES
PROTECTION FOR PARTICULARLY OUR
ADULTS, AND BY THAT, I MEAN
ANYBODY THAT COMES IN CAN EFFECT
THE CARE.
IF THEY HAVE A PALLIATIVE CARE
TEAM, THEN HE ARE AVOID ALL THAT
INTERFERENCE AND HAVE THAT
CONNECTIVITY AND CARE, SO I
THINK THAT'S SOMETHING THAT YOU
NEED TO REALLY SERIOUSLY --, YOU
KNOW, LOOK AT.
THE OTHER IS, A CLEARER
DEFINITION OF PALLIATIVE CARE,
HOSPICE, AND I SUE YOU USE SAW E
CURATIVE, WE USE CHRONIC CARE.
SOMETHING LIKE THAT THAT'S
REALLY CLEAR WILL HELP EDUCATE
BOTH THE PATIENTS AND THE DOCS.
THANK YOU.
>>THANK YOU FOR THOSE POINTS.
>>THANK YOU.
THANK YOU, EVERYBODY.
OKAY.
SO WE'RE MOVE ON TO THE NEXT
TALK.
WE'RE GOING TO CHANGE A LITTLE
GEARS HERE.
SO THE NEXT TALK IS FROM
DR. SERGEI NEKHAI FROM HOWARD
UNIVERSITY, HIV INFECTION IN
SICKLE CELL DISEASE.
CAN WE GO TO THE NEXT SLIDE SET?
>>I'D LIKE TO THANK THE
ORGANIZERS, EVERYBODY WHO STAYED
TO THE END OF THE SESSIONS, IT'S
MY PLEASURE TO TALK HERE ABOUT
THE --
[ZOOM INTERRUPTION]
>>CAN YOU MUTE YOUR PHONE,
PLEASE?
GREAT YOU THOO. YOU LET ME
THANK YOU.
I THOUGHT IT WAS SOMETHING ABOUT
ME.
I'M GOING TO TALK TO YOU ABOUT
THE HIV INFECTION IN PATIENTS
WITH SICKLE CELL DISEASE.
I DON'T HAVE CONFLICTS OF
INTEREST.
SO THE STORY GOES WHA BACK TO TE
LATE 80s AND EARLY 90s WHEN
DR. CASTRO, DIRECTOR OF THE
SICKLE CELL CENTER NOTICED THAT
PATIENTS WITH SICKLE CELL
DISEASE HAD LOWER LEVELS OF
ANTIBODIES AGAINST HIV AS
OPPOSED TO THE HIGH LEVELS OF
ANTIBODIES AGAINST --.
STUDY WAS CONDUCTED WITH THE
PATIENTS, SEVERAL PATIENTS WERE
IDENTIFIED WITH HIV INFECTION
AND SICKLE CELL DISEASE AND
THOSE PATIENTS SEEM TO PROGRESS
SLOWER TO THE AIDS, BASICALLY TO
BE NON-PROGRESSERS COMPARED TO
THE CONTROL PARTICIPANTS WITH
JUST HIV INFECTION.
SO WE LATER ANALYZED THESE
CHALLENGES FROM THE HOSPITALS
WHERE WE LOOKED AT THE CHANCES
OF HAVING SICKLE CELL DISEASE
AND HIV AND THE ODDS WERE LOWER
FOR THE HIV AND SICKLE CELL
DISEASE COMPARED TO THE --
INFECTION.
THERE WAS A RECENT STUDY FROM
SHAWN KELLY AT UCSF-OAKLAND
WHERE THEY FOUND SICKLE CELL
PATIENTS HAVE AGAIN LOWER RISK
OF INFECTION COMPARED TO THE
OTHER GROUPS OF PEOPLE WHERE WE
WERE RECEIVING MUCH BLOOD
TRANSFUSIONS.
ALSO A COUPLE REPORTS FROM
AFRICA WHERE SICKLE CELL
PATIENTS WERE FOUND TO HAVE LOW
RISK OF INFECTION SO THIS WAS IN
THE DEMOCRATIC REPUBLIC OF CONGO
AND ALSO NIGERIA.
SO A FEW YEARS AGO WE ANALYZED
EX VIVO HIV INFECTION, SO WE
USED HIV VIRUS WHICH HAS
MUTATION -- PART OF GENOME, AND
ALSO IN CONTRAST TO THE STUDY BY
SHAWN KELLY ACTUATED PBMCs --
INFECTION ONLY -- ACTIVATE
PBMCs.
SO WE SEE DECREASE IN THE
HA1 ROUND INFECTION AND ALSO CAN
DETECT ALL OF THE HIV -- LOWER
RATE OF TRANSCRIPTION AND WE
COULD ALSO DETECT LESS HIV
ADVERSE TRANSCRIPTION INDICATING
THAT THE EARLY POST INFECTIOUS
STEP OF HIV INFECTION.
SO INITIALLY WE FOCUSED ON THE
ROLE OF IRON, SO WE USED CALLS
YUM, WHICH -- FOR IRON INSIDE
THE CELLS, SO WE SEE FRACTION,
WE HAVE LESS INTA -- SUPPORTED
BY THE INCREASED LEVEL OF --
MARKER OF THE INTRACELLULAR IRON
TO THE ROLE OF IRON IN CELLS.
THIS WAS ALL SUPPORTED BY THE --
NO CHANGE IN DECREASE -- IN THE
PATIENTS.
SO OUR PREVIOUS STUDIES SHOW IF
YOU BLOCK IRON IN CELLS USING
IRON -- ONE OF THE CELL CYCLE
KINASES AND WE LOOKED WHAT
HAPPENED IN SICKLE CELL
PATIENTS, WE SEE DECREASE IN THE
CDK2 ACTIVITY, SO THE SELL
CYCLES IS INVOLVED IN THE --
WHICH IS ONE OF THE -- FACTORS.
DECREASED IN SICKLE CELL
PATIENTS -- SO HERE WE SEE --
ONE ACTIVITY GOES UP, IT REDUCES
NUCLEOTIDES IN CELLS AND CAN
BLOCK REVERSE TRANSCRIPTIONS.
SO WE WANTED TO CONTINUE THE
STUDY WITH FULLY -- EFFECT
AGAINST SICKLE CELL DISEASE
DERIVED PBMCs TO CONTROL WE
SEE -- WHICH WE CAN DETECT --
MRNA AND WE CAN ALSO DETECT P24
IN PBMCS AND WE CAN ALSO
DETECT -- INCLUDING --
TRANSCRIPTION, CIRCLES AND
INTEGRATION OF -- DNA.
SO WE WANTED TO DIG INTO THE --
FACTORS.
THIS IS THE RNA SEQ.
PBMCs WHICH ARE ACTIVATED SO
MY SICKLE CELL PATIENT DERIVED
SAMPLES.
SO WE DETECTED AROUND 2,000
GENES WHICH WERE UP AND DOWN
REGULATED, 1900 GENES WERE
UPREGULATED, ABOUT 200 GENES
WERE DOWNREGULATED.
SO THE TOP WE DETECT WAS --
WHICH IS KNOWN FOR ITS ANTIVIRAL
ACTIVITY AGAINST PARVO VIRUSES,
AND THE HAV, ACTUALLY IT LEADS
TO -- SOME OTHER FACTORS --
RECEPTORS IN DIFFERENT FACTORS,
WE'LL ALSO SEE CONSISTENTLY
HIGHER LEVELS OF P21.
SO WE CHOSE -- THEN WE ALSO DID
THE ANALYSIS WHICH BASICALLY WAS
ALSO KIND OF CLOSE LOOK AT THE
DIFFERENT FACTORS IN SICKLE
CELL.
SO WE PUT TOGETHER CLOSE TO 50
KNOWN RESTRICTION -- FACTORS
INVOLVED IN -- AND SEE THOSE
FACTORS ARE HIGHLY -- PBMCs TO
CONTROLS WITH HIGH NORMALIZED
ENRICHMENT, ADDITIONAL -- ON THE
TOP OF THE LIST, I SEE NOT ONE
WHICH IS NOT ACTUALLY THE ISSUE
HERE, IT'S A SENSOR -- DURING
BACTERIAL INFECTION, WE SEE P21,
CH25H AND THEN NUMBER OF
INDUCIBLE FACTORS.
WE CHOSE SEVERAL FACTORS
INCLUDING APOBEC3A, HO-1, CH25H
AND P21 AND WE VALIDATED -- WE
CAN ALSO SEE -- ANALYSIS AT THE
PROTEIN LEVEL.
SO THE PATIENT WAS -- WHAT DOES
IT COST FOR THESE FACTORS?
SO WE LOOKED AT THE INTERFERON
PRODUCTION, SO WE CAN SEE
INTERFERON CIRCULATION, BUT WE
DIDN'T SEE INTERFERON -- PBMCs
WAS THE -- LEVEL OR THE GENE
EXPRESSION LEVEL.
SO WE HYPOTHESIZED THAT
INTERFERE ON MIGHT BE PRODUCED
BY MACROPHAGES WHICH SENSE
HEMOGLOBIN SO THEY USE --
DERIVED MACROPHAGES, TREATED
THEM WITH -- S, RNA SEQ ANALYSIS
AND LOOK AT THE DIFFERENT
FACTORS IN THE STATION, SO WE
SEE A NUMBER OF FACTORS.
IF WE PLUG THOSE FACTORS INTO
THE ANALYSIS, WE CAN ACTUALLY
SEE NICELY THAT THEY POINT TO
THE INTERFERON INDUCTION, RF7,
F1, SOME OTHER FACTORS WHICH
LEAD TO THE INTERFERON
INDUCTION.
WE CAN ALSO DO JUST ENRICHMENT
ANALYSIS USING HALLMARK
INTERFERON GEN SET AND WE CAN
SEE AGAIN THOSE ARE ENRICHED IN
THE MACROPHAGES WHICH WE WOULD
TREAT WITH HEMOGLOBIN S BUT NOT
HEMOGLOBIN A AND WE CAN SEE --
FACTORS.
SORE WE NEXT LOOKED IN THE MOUSE
MODEL, SICKLE CELL DISEASE MOUSE
MODEL, AND SO THIS MODEL CAN BE
INFECTED WITH MOUSE ABDUCTED
VIRUS, ECOTROPIC VIRUS ENVELOPE
INSTEAD OF HIV ENVELOPE, WE CAN
SEE INFECTION OF SPLEEN, BUT WE
DON'T SEE ANY INFECTION IN THE
SICKLE CELL MICE SPLEAN.
AND WE COMPANY ANALYZE THIS --
THE LEVEL OF GENE EXPRESSION
DURING THE DECREASE IN
EXPRESSION, WE CAN SEE ALSO
DECREASE IN P24 AND WE CAN SEE
BLOCK IN THE -- REVERSE
TRANSCRIPTION AND INTEGRATION.
WE CAN ALSO KIND OF SEE IN
PARALLEL WITH WHAT WE HAVE SEEN
IN PATIENTS, WE CAN SEE --
RECEPTOR IN SPLEEN OF SICKLE
CELL MICE, REGULATION OF CH25H,
P21, AND THEN --.
AND WE SEE DOWN REGULATION AT
THE -- LEVEL.
HOWEVER MICE ONLY HAVE ONE --
GENE WHEREAS DISOSH MOUSE MODEL
DOES NOT REPLICATE WHAT WE SEE
IN HUMANS.
SO OUR MODEL IS THAT IN SICKLE
CELL, NUCLEAR CELLS, WE HAVE A
NUMBER OF CELLS UPREGULATED
INCLUDING APOBEC3A, CH25H, BUT
ALSO FACTORS WHICH HIGH BER LOW
LATE, INCLUDING P21, HMOX1, SO
THE INTERFERON IS LIKELY TO COME
FROM THE MACROPHAGES -- INDUCE
INTERFATHER ON PRODUCTION, AND
ALL GIVES MUCH PROTECTION
AGAINST HIV INFECTION AND I
GUESS LACK OF HIV INFECTION IN
PATIENTS WITH SICKLE CELL
DISEASE.
SO WE THINK -- AND THIS DUE TO
DECREASED -- INTERFERON INDUCED
FACTORS IN THE -- IN PATIENTS
LEADING TO INHIBITION, AND THIS
CAN BE -- LACK OF INFECTION BY
SICKLE CELL MICE.
I WOULD LIKE TO STOP AND THANK
OUR MEMBERS OF THE SICKLE CELL
CENTER.
NAMITA KUMARI WHO DID MOST OF
THE WORK AND POSTDOC THAT
CONTRIBUTED TO THE STUDY,
MARINA, FUNDING, AND GENOMICS
FACILITY AT GEORGE WASHINGTON
UNIVERSITY.
THANK YOU.
>>THANK YOU, SERGEI.
ANY QUESTIONS FOR SUR JAY?
SERGEI.
ANYTHING ONLINE?
NO?
THANK YOU SO MUCH AGAIN.
SO LET'S MOVE ON TO OUR NEXT
TALK.
THIS PANEL OF MULTIPLE URINARY
BIOMARKERS FOR EARLY DETECTION
OF CHRONIC KIDNEY DISEASE IN
SICKLE CELL ANEMIA.
MARINA JEREBTSOVA, ALSO FROM
HOWARD UNIVERSITY.
>>GO ON TO THE NEXT SLIDE.
>>NEXT SLIDE, PLEASE.
>>JUST CLICK TO ADVANCE.
>>OKAY, THANK YOU.
SO THANK YOU FOR HAVING ME HERE
TO PRESENT ON THIS CONFERENCE.
THIS IS ONE OF THE MAJOR
COMPLICATIONS IN SICKLE CELL
DISEASE.
PATIENTS WITH SICKLE CELL ANEMIA
HAVE APPROXIMATELY THREE FOURTHS
HIGHER RISK OF DEVELOPING
CHRONIC KIDNEY DISEASE THAN THE
GENERAL POPULATION.
OKAY.
30 TO 60% OF SICKLE CELL ANEMIA
PATIENTS DEVELOP CHRONIC KIDNEY
DISEASE.
14 TO 18% OF THEM PROGRESS TO
THE END STAGE OF RENAL DISEASE.
RENAL DISEASE IN SICKLE CELL
DISEASE PATIENTS AFFECT ALL
PARTS OF THE NEPHRON.
IT'S NOT WORKING.
>>NEXT SLIDE.
>>USE THE MOUSE TO CLICK
FORWARD.
THE CURR
>>THE CURRENT STANDARD OF CARE
FOR KIDNEY DISEASE BEGINNING AT
AGE 10 FOR SICKLE CELL DISEASE
PATIENTS -- IF PROTEIN AMOUNT IN
THE YOU' URINE IS HIGHER THAN
30 MILLIGRAMS BER DL, PATIENTS
ARE REFERRED TO A FR NEPHROLOGI.
SICKLE CELL ANEMIA PATIENTS,
TRAIT PATIENTS, DEVELOP
HYPOSTENURIA, INABILITY TO
CONCENTRATE URINE, THAT AFFECTS
DETECTION OF THE PROTEIN BY
DIPSTICK.
SO THE PATIENTS WHO REFER TO
NEPHROLOGIST USUALLY HAVE ALL
THEIR ADVANCED STAGE OF CHRONIC
KIDNEY DISEASE.
WHEN PATIENT IS REFERRED TO
NEPHROLOGIST, THEY DETECT THE
STAGE OF CHRONIC KIDNEY DISEASE
BASED ON THE STANDARD
GUIDELINES.
THESE GUIDELINES ARE BASED ON
THE GLOMERULAR FILTRATION RATE.
MORE THAN 40% OF SICKLE CELL
ANEMIA PATIENTS HAVE
HYPERFILTRATION.
HYPER FILTRATION IS DEFINED AS
THE EGFR RATE MORE THAN
130-MILLILITER PER MINUTE PER
1.73 SQUARE METERS, GREATER THAN
140 FOR MALES.
SO THIS HYPERFILTRATION MASKS
THE STAGE OF RENAL CHRONIC -- OF
CHRONIC KIDNEY DISEASE, AND THEN
THE GLOMERULAR FILTRATION --
DROP IN THE LATE STAGE OF
CHRONIC DISEASE.
-- THE EGFR CALCULATION IS NOTL
PATIENTS.
-- RESULTS ARE NOT COMPATIBLE.
BECAUSE OF THIS, A LOT OF
PATIENT ARE UNDETECTED AND RENAL
DISEASE IS NOT TREATED IN THESE
PATIENTS.
OR EVEN PREVENTED.
THE EFFECTIVENESS OF RENAL
DISEASE TREATMENT IS LIMITED BY
THE LEVEL OF -- MARKERS.
SO THE DISCOVERY OF KNOWN
BIOMARKERS FOR CHRONIC KIDNEY
DISEASE IN SICKLE CELL DISEASE
PATIENTS ARE URGENTLY NEEDED.
URINE PROTEOMICS FOR DISCOVERY
OF MARKERS FOR CHRONIC KIDNEY
DISEASE FOR SICKLE CELL
PATIENTS.
WHY URINE?
URINE IS AN EASILY ACCESSIBLE
BIOFLUID.
IT'S MAINLY FROM THE KIDNEY AND
LOW URINARY TRACT ORGANS, SO
IT'S VERY RELEVANT TO WHAT'S
HAPPENING IN THE KIDNEY.
UNFORTUNATELY THERE ARE SEVERAL
MAJOR OBSTACLES FOR DEVELOPMENT
OF CLINICALLY RELEVANT URINARY
BIOMARKERS.
URINE HAS A HIGH LEVEL OF
VARIABILITY IN VOLUME AND
PROTEIN CONCENTRATION.
DEBRIS OF SPONTANEOUSLY DYING
RENAL CELLS IS RELEASED INTO THE
URINE AND UNCONTROLLED AMOUNTS
OF THESE PEPTIDES FROM CELL
DEBRIS IS DETECTED.
AND -- NORMALIZED.
PATIENTS WITH CHRONIC KIDNEY
DISEASE RELEASE LARGE AMOUNT OF
SERUM PROTEINS INTO THE URINE,
MAKING IT DIFFICULT TO FIND THE
RELIABLE MARKER IN THE LIST OF
THE PROTEIN.
SO WE USE QUANTITATIVE
PROTEOMICS IN HOWARD UNIVERSITY.
THIS IS THEIR SCHEME FOR -- OF
QUANTITATIVE PROTEOMICS.
IT STARTS WITH THE URINE
COLLECTION -- OF THE PROTEINS,
AND HE USED SEVERAL PLATFORMS
FOR ANALYSIS OF THIS DATA,
INCLUDING THE SIEVE LABEL-FREE
QUANTIFICATION, INGENUITYRATE
ANALYSIS.
THESE ANALYSES GIVE US A --
FOR -- OF CHRONIC KIDNEY
DISEASE.
SO FOR THIS STUDY YOU USE SAMPLE
FROM 54 PATIENTS FROM UNIVERSITY
OF CHICAGO.
SPOT URINE SAMPLES WERE
COLLECTED DURING A CLINIC VISIT
WHEN THE PATIENTS WERE IN A
STEADY STATE.
AS I TOLD ONE OF THE MAJOR
CHALLENGES FOR THE PROTEOMIC
STUDY, THE PATIENTS WITH CHRONIC
KIDNEY DISEASE RELEASE A LARGE
AMOUNT OF SERUM PROTEINS IN
URINE.
LARGE LIST OF THE PROTEINS
COMPARED TO THE PATIENTS WHO
DON'T HAVE ANY CHRONIC KIDNEY
DISEASE, SO THAT SELECTION OF
RELIABLE MARKERS FOR THESE
PATIENTS IS VERY DIFFICULT.
SO TO SOLVE THIS PROBLEM, WE
DECIDE TO USE SAMPLES FROM
SICKLE CELL ANEMIA PATIENTS
WITHOUT PROTEINURIA.
BUT WE DECIDE TO SEPARATE THEM
IN TWO GROUPS THAT HAVE AT LEAST
ONE FACTOR OF PREDISPOSITION TO
DEVELOPMENT OF RENAL DISEASE.
COMPARED TO PATIENTS WHO DON'T
HAVE ANY KNOWN FACTORS THAT
PREDISPOSE THEM TO DEVELOPMENT
OF RENAL DISEASE.
SO 20-SOME SAMPLES WITH
UNDETECTABLE URINARY PROTEIN
LEVELS WERE USED FOR MASS
SPECTROMETRY ANALYSIS.
FROM THESE SAMPLES, WE DETECTED
PEPTIDES FROM 270 PROTEINS.
UNFORTUNATELY MOST OF THESE
PROTEINS WERE STILL FROM THE
TUBULAR EPITHELIAL CELL DEBREA.
SO AT THIS STAGE, WE DECIDED TO
APPLY ADDITIONAL CRITERIA FOR
URINARY BIOMARKER DISCOVERY.
THE FIRST WOULD BE BIOMARKERS
SHOULD BE SOLUBLE PROTEINS, LIVE
CELLS, NOT THE DEAD CELLS.
BIOMARKERS SHOULD CORRELATE WITH
THE KNOWN FACTORS OF
PREDISPOSITION TO DEVELOPMENT OF
CHRONIC KIDNEY DISEASE.
AND BIOMARKERS SHOULD REFLECT
KNOWN PATHOLOGY OF SICKLE CELL
ANEMIA.
SO -- WE DECIDED TO USE
HEMOGLOBIN AS A RISK FACTOR FOR
DEVELOPMENT OF CHRONIC KIDNEY
DISEASE.
IRON, INFLAMMATION ARE TWO
WELL-KNOWN PATHOLOGY CONDITION
IN SICKLE CELL ANEMIA.
SO BASED ON THESE CRITERIA, WE
SELECTED 14 PROTEINS FROM THE
LIST.
TWO OF THEM -- PROTEIN THAT
EXPRESS IN THE -- THIS IS IMMUNE
PROTEIN, CERULOPLASMIN IS A
PROTEIN INVOLVED IN THE
REGULATION OF HOMEOSTASIS.
SO WE CONCENTRATED ON THESE TWO
PROTEINS BECAUSE THEY WERE
CONNECTED WITH THE KNOWN
PATHOLOGY IN SICKLE CELL DISEASE
PATIENTS.
THIS IS JUST A SCHEME HOW LABEL
FREE QUANTIFICATION OF MASS
SPECTROMETRY RESULTS.
-- DIVIDED INTO GROUPS,
PATIENTS WITH HIGH HEMOGLOBIN
AND PATIENTS WITHOUT
HEMOGLOBINURIA, TO CHOOSE THREE
SAMPLES FROM EACH GROUP.
-- THE LEVEL OF PROTEINS
ANALYSIS BY LCMS.
SO THIS IS A REPRESENTATIVE
PICTURE OF THE RESULT FROM THE
SIEVE LABEL FREE QUANTIFICATION.
THE FIRST GRAPH SHOW A PLOT THAT
DEMONSTRATES A LOT OF PEPTIDES
ARE DIFFERENT BETWEEN THE HIGH
HEMOGLOBIN AND LOW HEMOGLOBIN
GROUPS.
THE SECOND PRESENT
QUANTIFICATION FOR ONE OF THE
SERULOPLASMIN GUIDE, IT
DEMONSTRATED THAT THE LEVEL WAS
SIGNIFICANTLY HIGHER IN THE
SAMPLES WITH HIGH HEMOGLOBIN
COMPARED TO THE SAMPLES WITH LOW
HEMOGLOBIN.
WE VALIDATE URINE BIOMARKERS BY
ELI IS A.
ELISA.
SO BIOMARKERS -- THEY ARE
INCREASED IRON METABOLISM.
SO PLASMIN WAS SIGNIFICANTLY
HIGH IN THE SICKLE CELL DISEASE
PATIENT SAMPLES COMPARED TO THE
CONTROL PATIENTS.
THERE WAS A -- FOR THE HIGH
LEVEL OF CERULOPLASMIN --
COMPARED TO THE PATIENTS WITH
LOW HEMOGLOBIN.
BOTH OF THEM ARE SICKLE CELL
DISEASE PATIENTS.
WE'RE INTERESTED THAT -- RELATES
WITH CHRONIC KIDNEY DISEASE IN
SICKLE CELL DISEASE PATIENTS.
-- HIGH SENSITIVITY AND
SPECIFICITY OF THESE MARKERS TO
DISCRIMINATE BETWEEN THEIR --
CHRONIC KIDNEY DISEASE AND --
CHRONIC KIDNEY DISEASE.
-- THEY ARE BOTH MARKERS OF
INCREASED METABOLISM.
THE LEVEL OF -- BIOMARKER, THE
LEVELS WERE SIGNIFICANTLY HIGHER
IN SICKLE CELL DISEASE -- THEY
DID NOT CORRELATE BECAUSE OF
CHRONIC KIDNEY DISEASE
PROGRESSION.
WE ALSO -- WITH LIKE A BIOMARKER
OF INFLAMMATION.
OROSOMUCOID WAS SI -- STAGE OF
CHRONIC KIDNEY DISEASE, AND IT
PRODUCES EVEN HIGHER SENSITIVITY
AND SPECIFICITY COMPARED TO THE
CERULOPLASMIN.
NEXT WE DECIDED TO TEST IF THE
COMBINATION OF TWO OR THREE
BIOMARKERS WILL INCREASE THEIR
ACCURACY OF DIFFERENT -- OF
SINGLE BIOMARKERS TO
DISCRIMINATE BETWEEN THE
PRESSURES -- STAGE OF CHRONIC
KIDNEY DISEASE.
THE COMBINATION OF ALL THREE
BIOMARKERS SIGNIFICANTLY
INCREASE THEIR -- UNDER THEIR --
IN THE ANALYSIS.
INTERESTING -- COMBINATION OF --
ALSO SIGNIFICANTLY INCREASE
THE -- UNDER THE -- ANALYSIS.
SO IT'S MORE ACCURATE FOR
DETECTION OF STAGE OF CHRONIC IK
DISEASE.
IN CONCLUSION, CERUMOPLASMIN,
ORM AND HEMOGLOBINURIA ARE GOOD
CANDIDATES FOR NONINVASIVE
BIOMARKERS OF YEARLY STAGES OF
CHRONIC KIDNEY DISEASE IN SICKLE
CELL PATIENTS.
EACH OF THESE PROTEINS REFLECTS
A DISTINCT PATHOLOGICAL PROCESS
IN THE KIDNEY OF SICKLE CELL
PATIENTS.
THE USE OF COMBINED BIOMARKERS
SIGNIFICANTLY IMPROVES THE
ACCURACY OF DETECTION OF EARLIER
STAGE CHRONIC KIDNEY DISEASE.
SO WHAT'S THE NEXT STEP?
WE STILL HAVE -- WE WANT TO
STUDY THESE BIOMARKERS
DISCOVERED IN PROTEOMICS OF
URINE.
NOT ALL BIOMARKERS CAN BE FOUND
BY MASS SPECTROMETRY.
SO THE STUDY OF OTHER BIOMARKERS
OF CHRONIC KIDNEY DISEASE IN THE
LITERATURE -- TWO OF THEM,
SOLUBLE UROKINASE-TYPE
PLASMINOGEN ACTIVATOR RECEPTOR,
AND -- LIMITATION OF THIS STUDY.
IT'S SMALL SAMPLE SIZE.
IT'S CROSS-SECTIONAL NATURE OF
THE STUDY.
LIMITED NUMBER OF THE TESTED
BIOMARKERS.
AND LONGITUDINAL STUDIES IN
LARGE COHORT ARE NEEDED FOR
VALIDATION OF THIS STUDY.
SO I ACKNOWLEDGE THE SICKLE CELL
DISEASE CENTER AND ALSO STUDENTS
THAT WORK IN MY LAB, UNIVERSITY
OF ILLINOIS AT CHICAGO.
THANK YOU.
>>THANK YOU, DR. JEREBTSOVA.
QUESTIONS?
ANY QUESTIONS ONLINE?
NO QUESTION ONLINE.
THANK YOU SO MUCH FOR YOUR TALK.
SO OUR NEXT -- WE'VE SAVED THE
BEST FOR THE LAST.
STEPPING UP INTO ADULT CARE: AN
UPDATE ON THE ST3P UP STUDY.
PRESENTING IS DR. IFY OSUNKOWO.
>>GOOD EVENING, EVERYBODY.
I'M STANDING BETWEEN YOU AND
YOUR SHUTTLE RIDE RECEPTION AT
THE DOUBLETREE SO I'M GOING TO
MAKE THIS SHORT AND SWEET AND
PRETTY INTERESTING.
MY NAME IS DR. IFY OSUNKOWO.
THE VIEWS AND OPINIONS EXPRESSED
IN THIS PRESENTATION REPRESENT
MY OWN AND NOT THOSE OF MY
CURRENT OR PREVIOUS EMPLOYERS,
AND THESE ARE THE DISCLOSURES
FOR BOTH MYSELF AROUND THE
COLLABORATORS WHO WORKED ON THIS
AMAZING STUDY.
I DO WANT TO TAKE A MINUTE TO
RECOGNIZE SOME OF OUR
COLLABORATORS AND
CO-INVESTIGATORS WHO PASSED AWAY
OVER THE PAST SIX YEARS.
THIS IS PROBABLY THE MOST
HEART-WRENCHING PART OF THIS
PRESENTATION IN MY CAREER AS A
HEMATOLOGIST.
WHERE SOME STELLAR INVESTIGATORS
AND PEOPLE IN THE SICKLE CELL
SPACE GAVE THEIR LIFE TO THE
CAUSE OF SICKLE CELL DISEASE.
TREVOR THOMPSON WAS A COI. ON
THE GRANT.
HE DIED AS WE WERE WRITING THE
GRANT.
SHARON LEWIS AND JOHNSON HAYNES
WERE CO-AIs IN ALABAMA AND
THEY BOTH PASSED AWAY DURING THE
STUDY, AND CATHY NORCOTT PASSED
AWAY EARLY THIS MONTH AND SHE
WAS ONE OF OUR COIs IN NORTH
CAROLINA.
CAN YOU QUEUE THE VIDEO, PLEASE.
>>ONE SECOND.
>>I'M SHOWING YOU A VIDEO OF A
PUBLIC SERVICE ANNOUNCEMENT THAT
HIGHLIGHTS THE CHALLENGES OF
TRANSITION IN SICKLE CELL
DISEASE AND REALLY BRINGS THIS
HOME THAT THIS IS SOMETHING THAT
IS NOT A YESTERDAY PROBLEM, BUT
A TODAY AND A TOMORROW PROBLEM.
THE GOAL IS FOR US TO TRY TO
SOLVE FOR TRANSITION IN SICKLE
CELL DISEASE.
ANY LUCK?
IF YOU WOULD CARE TO LOOK AT THE
PUBLIC SERVICE -- IT'S ON THE
SCD WEBSITE, IT TALKS ABOUT A
TEENAGE BOY IN COLLEGE AND WHAT
LIFE IS LIKE WITH SICKLE CELL
DISEASE AND WHY IT'S IMPORTANT
THAT WE ENCOURAGE OUR PROVIDERS
TO BELIEVE THEM WHEN THEY SAY
THEY HAVE PAIN.
SO THR ST3P-UP STUDY BEGAN IN
2016 RIGHT AT THE NHLBI MEETING.
CAME ON THE TUESDAY AT THE
MEETING AND THE TEAM ASSEMBLED
AND WE HAD TO PUT IN A LETTER OF
INTENT IN A MONTH, PUT IN THE
GRANT WITHIN TWO MONTHS AND
QUICK TURN AROUND TIME, WE WERE
AWARDED A $9.8 MILLION GRANT FOR
A MULTICENTER COMPARATIVE
EFFECTIVE STUDY OF TRANSITIONING
IN ADULTS WITH SICKLE CELL
DISEASE ACROSS 14 SITES IN THE
SOUTHEAST AND THE NORTHEAST USA.
THESE ARE THE PIs OF THIS
GRANT.
RAYMONA LAWRENCE IS SITTING IN
THE BACK.
SHE WAS MY PARTNER IN CRIME FOR
THE FIRST 4 1/2 YEARS, AND AS I
WAS LEAVING CLINICAL PRACTICE,
WE CONVINCED PAYAL DESAI TO JOIN
AT NOW WE HAVE A TRIAD PI TEAM.
THESE ARE THE GROUPS THAT WORKED
WITH US.
SICKLE CELL REMAINS A DISEASE OF
YUJ PEOPLE.
YOUNG PEOPLE.
THIS IS A PROBLEM WE HAVE TO
SOLVE FOR IN THE FUTURE.
WE WANT THESE PEOPLE TO LIVE
LONG.
IT'S ALSO A GLOBAL DISEASE.
IT'S NOT JUST AN AMERICAN
PROBLEM.
SO WHAT DO WE TRY TO SOLVE FOR
IN ST3P UP?
WE KNEW THERE WERE POOR OUTCOMES
TO TRANSITION.
THREE TIMES ACU, TWO TIMES
READMISSION RATE, THEY DON'T DO
WELL ON STANDARDIZED TESTING BUT
THERE WAS ALSO NO MODEL FOR
TRANSITION FOR SICKLE CELL
DISEASE THAT WAS WELL
ESTABLISHED AND APPLIED IN THE
POPULATION OF CLINICAL CARE.
THERE WAS ALSO VERY SHORT TERM
FOLLOW-UP AMONG PILOTS THAT WERE
DONE.
NO TWO PROGRAMS DID IT THE SAME
WAY.
THERE WAS NO DEFINITION OF
SUCCESS IN TRANSITION.
AND IT ALL RELIED ON THE
HEALTHCARE SYSTEM TO EXECUTE.
NOW LIFE HAPPENS MOSTLY OUTSIDE
OF HEALTHCARE.
ALSO, WHO REALLY CARED?
WHO'S GOING TO PAY FOR THIS
EFFORT?
AND WE WANTED TO SOLVE FOR THAT
AS WELL AS PART OF THE ST3P UP
STUDY.
BUT WE DID A NEEDS ASSESSMENT OF
THE COMMUNITY, A
MULTI-STAKEHOLDER ASSESSMENT,
MEDICAL PROVIDERS,
ADMINISTRATORS, PATIENTS,
COMMUNITIES, ORGANIZATIONS, AND
WE FOUND TWO MAIN THINGS.
EVERYBODY WANTED THERE TO BE A
CARE STANDARD, AND EVERYBODY
WANTED TO HAVE MULTI-STAKEHOLDER
ENGAGEMENT IN THE PROCESS OF
TRANSITION.
AND THE GOAL WAS TO ACHIEVE
INTERDEEPEN DENSE.
WHEN YOU TALK TO THE COMMUNITY,
THEY SAY I DON'T WANT TO BE
DEPENDENT ON MY DOCTOR TO
SURVIVE.
I WANT TO KNOW WHERE I CAN GET
HELP, USE IT WHEN I NEED IT --
WHEN IT COMES TO IND DEPENDENCE
INTERDEPENDENCEWAS THE BEDROCK S
YOU GET OLDER, YOU BUILD SKILLS
OF SELF MANAGEMENT, SELF-CARE,
SELF-EFFICACY, BUT YOU COULD TAP
INTO YOUR FAMILY, YOUR CBU, YOUR
MEDICAL PROVIDER WHEN AND IF YOU
NEEDED TO BE ABLE TO LIVE A FULL
LIFE UNLIMITED BY SICKLE CELL
DISEASE.
SO OUR STUDY WAS DESIGNED AS A
PERSPECTIVE RANDOMIZED STUDY
LOOKING AT A STANDARDIZED ARM
INTERVENTION WHICH WAS PUT IN
PLACE ACROSS ALL 14 CLINICS,
THEN WE'RE GOING TO COMPARE IS
IT EVEN BETTER IF YOU ADD PEER
MENTORING, AND THE OUTCOME OF
INTEREST WAS ACUTE CARE
UTILIZATION AND QUALITY OF LIFE.
EACH TEAM WAS MADE UP OF THREE
COMPONENTS: THE PROVIDER TEAM,
THE MEDICAL, SO PEDS AND ADULTS
TOGETHER, THE ORGANIZATION AS A
SOCIAL SUPPORT OUTSIDE OF
HEALTHCARE, AND THEN THE
PATIENT.
AND YOU WILL HEAR MORE ABOUT THE
TRIAD IN THE SYMPOSIUM TOMORROW.
SO WE CAME UP WITH A STRUCTURED
PROGRAM BASED ON ELEMENTS
DESIGNED BY CORE TRANSITION.
WE DECIDED TO USE QUALITY
IMPROVEMENT TO IMPLEMENT THIS
STANDARD ACROSS 14 SITES AND OF
COURSE THE PEER MENTORING ARM
WAS GIVEN TO SEVEN SITES OF THE
14.
WHY DO WE PICK PEER MENTORING?
BECAUSE THERE IS A LOT OF DATA
OUTSIDE OF SICKLE CELL DISEASE
THAT IF YOU HAVE A MENTOR WHO IS
A PEER, YOU'RE MORE LIKELY TO
GET INFORMATION FROM THIS, I'M
MOTIONAL SUPPORT AND ACHIEVE
RECIPROCITY AND THIS LEADS TO
BETTER OUTCOMES IN TERMS OF
QUALITY OF LIFE, IMPROVED HEALTH
BEHAVIOR AND -- FOR CHRONIC
DISEASES, WE NEED TO SEE IF THIS
DATA IS TRUE IN SICKLE CELL
DISEASE.
SO WHAT WAS THE STRUCTURED
PROCESS IN TRANSITIONING OUR
STUDY?
GETTING ENGAGED AND FOSTER
COMMUNICATION ACROSS THE THREE
PARTS OF THE TRIAD.
SO YOU HAVE TO TALK TO EACH
OTHER.
COMMUNICATE WELL AND ENGAGE EACH
OTHER TO BE ABLE TO BUILD A
PROGRAM THAT IS SERVED BY ALL OF
YOU FOR THE PATIENT COMMUNITY.
WE HAD TO PUT UP A STANDARD.
WHAT DOES -- FOR A 16-YEAR-OLD
WITH SICKLE CELL DISEASE?
WHAT SHOULD YOU DO AT EACH
VISIT, WHAT SCREENING TESTS DO
YOU DO?
AND WE WANTED THIS FOR NOT JUST
SS BUT FOR SC AND SB -- WE
ESTABLISHED A MODEL WHERE EVERY
PATIENT SAW THE DRR EITHER
VIRTUALLY OR IN PERSON, BECAUSE
IF YOU DON'T SEE YOUR PROVIDER,
YOU MAY MISS OUT ON CRITICAL
EDUCATION YOU NEED TO LEARN HOW
TO MANAGE YOUR DISEASE OR TO BE
LINKED TO THE COMMUNITY
RESOURCES.
WE ASSESSED THEIR READINESS NOT
JUST IN PEDIATRICS BUT ADULT
CARE.
YOU LOSE SKILLS YOU THOUGHT YOU
GAINED BECAUSE IT'S A DIFFERENT
ENVIRONMENT AND WE ALL HAVE
YOUNG ADULTS IN OUR LIVES WHO
ARE OUR CHILDREN THAT WE KNOW
WHEN THEY'RE 21 THEY LEARN
SOMETHING, WHEN THEY'RE 25, THEY
FORGET IT SO YOU WANT TO MAKE
SURE YOU RE-BOOST THEIR
KNOWLEDGE AS THEY MOVE ON TO
DIFFERENT PHASES OF LIFE.
USE THEIR KNOWLEDGE AND SKILL
BUILDING TO FIX THE GAPS YOU
FIND OUT IN YOUR ASSESSMENT AND
ALSO SHOW WITH THEM WHAT IS
DIFFERENT IN PEDIATRIC CARE AND
ADULT CARE.
THEY NEED TO KNOW THIS.
WE NEED TO KNOW THIS I NEED TO
KNOW AS A PEDIATRICIAN -- ADULT
CARE AND VICE VERSA BECAUSE IF
NOT, WE SET UP THE WRONG
EXPECTATION.
CONNECT AND REFER.
MOST PATIENTS LEAVE HEALTHCARE
BEFORE THEY TURN 16.
THE SC, THE S BETA PLUS THAL AND
THE -- PATIENTS ARE NOT IN
HEALTHCARE.
SO HOW DO WE GET THEM BACK INTO
HEALTHCARE WHEN THEY NEED TO
MANAGE THEIR LIFE?
THE STE IS THAT SCAFFOLD AND
THEN REFERS THEM BACK INTO
HEALTHCARE.
AND OF COURSE THE MEDICAL CENTER
SHOULD REFER TO THE CBO FOR
SOCIETAL SUPPORT THAT YOU CANNOT
GIVE IN THE CLINIC.
EQUIPPING THE CARE TEAM, NOT
JUST THE PATIENTS BUT THE
DOCTOR, THE ER, THE HOSPITAL,
THEY NEED TO KNOW, HOW DO I TAKE
CARE OF THE PATIENT?
WHAT IS A CARE PLAN?
GIVE ME A STRUCTURED PLAN, WHEN
SOMETHING GOES WRONG, DO XYZ.
AND UPDATE THIS ANNUALLY, MAKE
THIS ACCESSIBLE IN THE MEDICAL
RECORD OR IN WHATEVER FORMAT YOU
HAVE, BUT ALSO ADD SOMETHING
SPECIAL ABOUT EACH PATIENT.
WHAT MAKES JOHN DIFFERENT FROM
JANE, DIFFERENT FROM OSCAR,
DIFFERENT FROM VICTOR?
BECAUSE THAT'S GOING TO MAKE
THEM DO WELL OR NOT DO WELL WHEN
THEY GET ADMITTED TO THE
HOSPITAL.
AND THEN MONITOR AND TRACK HOW
WELL YOUR PLAN IS DOING WITH
THIS PROCESS, HOW WELL YOUR
TRIAD IS WORKING TOGETHER
SEAMLESSLY, AND THEN HOW ARE YOU
DOING WITH PUTTING THIS
STRUCTURE IN PLACE FOR YOUR
PATIENTS?
DATA IS KING.
THE MORE DATA YOU HAVE, THE MORE
YOU CAN GET THIS PAID FOR BY
PUBLIC AND PRIVATE INSURANCE.
AND THEN TRACK WHAT WORKS AND
DIDN'T WORK, AND THAT'S WHAT QI
IS ALL ABOUT.
SO HOW DO WE DO IT?
WE PUT TOGETHER A QI PROCESS, WE
BUILT A TEAM AT EACH SITE.
WE HAD A QI COORDINATOR WHO'S IN
THE BACK WHO HELPED COACH THESE
SITES ON HOW TO IMPLEMENT
QUALITY IMPROVEMENT BEGINNING
WITH QI101.
AND THE GOAL WAS TO PUT IN PLACE
THESE SIX CORE ELEMENTS IN THE
PEDIATRIC CLINIC AND THE ATULT T
CLINIC.
HOW TO COLLECT DATA, HOW TO MAKE
CHANGES, HOW TO ACCESSORY
SOURCES IN OUR CHANGE PACKAGE,
AND PUT THEM IN PLACE IN THEIR
CLINIC.
HOW TO TRY SK THAT DOESN'T WORK,
DON'T WASTE TIME -- AND THEN
MOVE ON WITH THE NEXT ITERATION.
THEN WE ALSO HAD MONTHLY
MEETINGS WHERE WE TALKED ABOUT
WHAT WAS HAPPENING IN EACH
CLINIC.
WE HAD EVERY SIX MONTHS SITE
VISIT, AND ANNUAL INVESTIGATIVE
CONFERENCE, AND A HEALTHY DOSE
OF COMPETITION.
SITES WANT TO DO WELL COMPARED
TO THEIR PEERS.
YOU KNOW HOW DOCTORS ARE.
SO THE AIM STATEMENT IS THAT
SICKLE CELL DISEASE IS A COMPLEX
DISEASE AND YOU NEED TO IMPROVE
THE TEAMS IN BOTH THE PEDIATRIC
CLINIC AND THE ADULT CLINIC, WE
HAD A TIMELINE, AND WE HAD A
MODEL THAT WE WERE GOING TO USE.
WE PICKED OUR PROCESS MEASURE,
WHICH IS WHAT WILL WE DO TO SHOW
THAT WE SUCCEEDED, AND THEN WE
PICKED OUR OUTCOME MESSAGE, HOW
WE GOT THERE.
AND THIS IS OUR OUT COME
MEASURE, THE PROCESS MEASUREMENT
TOOL.
EVERY CLINIC HAD TO SCORE
THEMSELVES ALONG THESE SIX CORE
ELEMENTS WITH PACKUP DATA, I
THINK HE WITH ACTUALLY MET THIS
CRITERIA.
THE POLICY.
DO YOU HAVE A POLICY, WAS IT
DEVELOPED WITH YOUNG ADULTS IN
MIND, WITH PATIENT ENGAGEMENT,
COMMUNITY, WAS IT A
MULTI-STAKEHOLDER PROCESS, AND
IS IT VISIBLE IN YOUR CLINIC AND
DO THEY KNOW ABOUT IT.
THAT'S JUST ONE EXAMPLE.
WE HAD ONE FOR THE PIED TRICK
CPEDIATRICCLINIC AND ONE FOR THT
CLINIC.
WHAT DO WE DO WITH THE PMT?
WE SCORE CLINICS EVERY SIX
MONTHS.
THE PEDS AND THE ADULT CLINIC,
AND WE ASK PEOPLE TO SCORE
THEMSELVES AND SEND IN THEIR
DATA, AND THEN THE DCC WOULD NOW
SCORE THEM AND VALIDATE THOSE
SCORES.
I'LL SHOW YOU THE DATA IN A
LITTLE BIT, BUT THE GOAL WAS TO
MAKE SURE THAT EVERYBODY
UNDERSTOOD HOW TO MEASURE
YOURSELF AND IF YOU'RE REALLY
PUTTING IN PLACE THIS PROCESS IN
A SYSTEM THAT WOULD BE
SUSTAINABLE.
WE HAVE A MONTHLY CALL, WE HAVE
THE BIANNUAL SITE VISIT,
INVESTIGATOR MEETING, AND EVERY
SIX MONTHS WE RE-SCORE THE SITES
UNTIL THE END OF THE STUDY.
NOW THIS IS HOW PEOPLE SCORE
THEMSELVES IN THE BEGINNING
VERSUS WHAT WE VALIDATED.
SO THE BLUE LINES CAME DOWN
DRASTICALLY IN SOME SITE.
ONLY ONE SITE WAS QUITE ACCURATE
IN THEIR SCORE.
BUT AFTER TWO YEARS IT LOOKED
LIKE THIS.
THEY WERE ABLE TO TRULY ASSESS
THEMSELVES AGAINST SEMI SEFS AND
SEE WHAT THEY ARE REALLY DOING
AND THAT THEY VALIDATE THEIR
DATA BEFORE THEY PUT IT OUT
THERE.
NOW THIS IS OUR OVERALL SUMMIT
OF OUR RESULTS.
SO OVER THE FIRST TWO YEARS OF
THE STUDY -- OVER THE FIVE YEARS
OF THE STUDY, WE NOTICED AN
INCREASE -- THIS TELLS ME THEY
WERE ABLE TO PUT IN PLACE THIS
STRUCTURED PROGRAM 80% OF THE
TIME.
SORRY, 80% OF THE CLINICS WERE
ABLE TO PUT THIS PROCESS IN
PLACE.
IN THE PEDIATRIC PROGRAM, WE HAD
A RISE IN THEIR SCORE OF 76%,
AND THE ADULT SIDE BY 84%.
SO IT'S NOT AN ADULT PROBLEM OR
A PEDIATRIC PROBLEM, IT'S A KNOW
HOW T TO DO WHAT TO DO PROBLEM.
THIS IS THE SCORES OVER TIME.
AT THE END OF OUR STUDY, 13 OUT
OF THE 14 ADULT PROGRAMS REACHED
THE RESULT -- WE HAD ONE SITE
WHO HAD MULTIPLE P.I. CHANGES
AND SOME OTHER CHANGES WE HAD TO
DEAL WITH THAT NEVER MET THE
SCORE BUT OVERALL IT IS
POSSIBLE, FEASIBLE AND ACTUALLY
DOABLE TO PUT THIS
SYSTEM/PROCESS IN PLACE IN YOUR
CLINICS, NO MATTER WHERE YOU
ARE.
WE HAVE PEOPLE IN RURAL, URBAN,
ACADEMIC CLINICS, IT DIDN'T
REALLY MATTER.
SO AT THE END OF THE DAY, WE
KNOW THE TRANSITION IS A BIG
PROBLEM.
YOU CAN ACTUALLY IMPLEMENT AND
YOU SHOULD IMPLEMENT A
STRUCTURED PROGRAM FOR YOUR
SICKLE CELL PROGRAMS BOTH ON --
ADULT CARE.
IT IS VERY, VERY IMPORTANT THAT
YOU USE THESE COMMUNITY
ORGANIZATIONS AS PART OF THIS
MODEL, BECAUSE HEALTHCARE
HAPPENS NOT JUST IN HEALTHCARE
BUT ALSO OUTSIDE OF HEALTHCARE.
LIFE HAPPENS.
AND WE NEEDED A COORDINATOR TO
BE ABLE TO PUT THESE PIECES
TOGETHER, BE THE BRIDGE BETWEEN
THE COMMUNITY, BETWEEN THE PEDS
AND ADULTS PROGRAM AND PROVIDES
A STRONG IMPLEMENTATION FOR
THESE KINDS OF PROGRAMS, BUT
YOU'VE GOT TO -- WE SPENT A LOT
OF TIME WORKING ON RELATIONSHIP
BUILDING, TRUST BUILDING,
PSYCHOLOGICAL SAFETY ACROSS --
IN ANY PROGRAM WE DON'T TRUST
EACH OTHER, WE DON'T BELIEVE
YOU'RE DOING AS GOOD A JOB FOR
MY PATIENT AS I THINK YOU SHOULD
S AND VICE VERSA.
AND WE ALL COME TO TRYING TO DO
THE RIGHT THING FOR OUR PATIENTS
SO WE SPENT A LOT OF TIME
WORKING ON THAT PIECE AND I
THINK THAT'S ONE OF THE KEYS
THAT WORKED VERY WELL.
I WANT TO THANK OUR PATIENTS
FIRST AND FOREMOST, THE CBOs,
AT OUR SITES, ALL OF OUR
CONSULTANTS, AND I WANT TO SAY
THANK YOU, I HAVE 3 MINUTE FOR
QUESTIONS.
I DID IT.
THANK YOU VERY MUCH, EVERYBODY.
>>THANK YOU SO MUCH, IFY, FOR
AN EXCITING TALK.
QUESTIONS FOR IFY?
ANYTHING ONLINE?
NO?
I GUESS YOU WERE VERY CLEAR.
BUT IT WAS A GREAT SEGUE FOR
TOMORROW.
SO WE'RE GOING TO START TOMORROW
WITH GLOBAL SICKLE CELL DISEASE
FROM INDIA, FROM AFRICA, FROM
BRAZIL, AND ALSO TALK ABOUT GGIT
AND ALL THAT, SO IT SHOULD BE AN
EXCITING DAY.
SEE YOU TOMORROW, ALL, AT 9:00.
WE START THE SESSION TOMORROW
HERE AT 9:00.
THANK YOU VERY MUCH.
>>THANK YOU.