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Center at the National Institutes of Health in
Bethesda, MD.
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TODAY IT IS MY GREAT HONOR TO
PRESENT TWO SPEAKERS DR. STEVE
HOLLAND, AND DR. DENNIS
HICKSTEIN, OUR FIRST SPEAKER IS
DR. HOLLAND, SCIENTIFIC DIRECTOR
OF NIAID AS WELL AS ITS DIRECTOR
OF INTRAMURAL RESEARCH AND CHIEF
OF THE IMMUNO PATHOGENESIS
SECTION OR NIAID.
DR. HOLLAND EARNED HIS MEDICAL
DEGREE FROM JOHNS HOPKINS
UNIVERSITY WHERE HE STAYED FOR
HIS INTERNAL MEDICINE RESIDENCY,
CHIEF RESIDENCY AND FELLOWSHIP
IN INFECTIOUS DISEASES.
HE CAME TO NIAID, THE NATIONAL
RESEARCH COUNCIL FELLOW IN 1989
TO THE LABORATORY OF MOLECULAR
MIKE O BIOLOGY, WORKING ON
TRANSCRIPTIONAL REGULATION OF
HIV.
IN 1992 HE JOINED A NEWEL FORMED
LABORATORY OF HOST INTERESTS,
SHIFTING HIS INTEREST TO HOST
SIDE FOCUSING ON INFECTIONS.
HIS WORK FOCUSED ON THE
PATHOGENESIS OF CHRONIC LUNG
DISEASES AS WELL AS IMMUNE
DEFECTS, FAIG O SIGHTS
ESPECIALLY THOSE PREDISPOSED TO
MICROBACTERIAL DISEASES, HE WAS
THE CHIEF OF THE LABORATORY OF
CLINICAL INFECT YOWZ DISEASES IN
2004-2016 AND THEN BECAME
SCIENTIFIC DIRECTOR FOR NIAID IN
2016.
DR. HOLLAND IS ALSO AN ASSOCIATE
PROFESSOR AT MEDICINE AT JOHNS
HOPKINS.
DR. HOLLAND LEADS THE IMMUNO
PATHOGENESIS SECTION WHICH TAKES
A FULL APPROACH OF LOOKING AT
DISEASE WITH PATHOGENS AND
MECHANISMS OF PATHOGENESIS TO
IDENT FIELD FUNCTIONS NOVEL
THERAPEUTICS.
THE CLOSEST BIOLOGIST OF THESE
MDs, Ph.D.s AND
BACCALAUREATE CREATE A
ENVIRONMENT WHERE HAPPEN LO
INSUFFICIENCY WAS FIRST
PHENOTYPICALLY AND GENO
TYPICALLY IDENTIFIED AND HIS
GROUP NOW FOLLOWS OVER 100
PATIENTS FOR PREE AND POST
TRANSPLANT.
DR. HOLLAND IS THE RECIPIENT OF
NUMEROUS AWARDS, BOARD CERTIFIED
IN INFECT YOWZ DISEASES AND HAS
OVER 600 PEER REVIEWED
PUBLICATIONS.
OUR SECOND SPEAKER AND
DR. HICKSTEIN WITH THE THERAPY
PROGRAM AND THE CENTER FOR
CANCER RESEARCH AT THE NCI.
DR. HICKSTEIN EARNED HIS MEDICAL
DEGREE FROM THE UNIVERSITY OF
NEBRASKA, COLLEGE OF MEDICINE IN
1978 AND CONTINUED MEDICAL
TRAINING WITH AN INTERNSHIP AND
RESIDENCY OF INTERNAL MEDICINE
AT THE MEDICAL CENTER.
HE THEN COMPLETED TRAINING AT
THE HEMEATOLOGY AT THE
WASHINGTON SCHOOL OF MEDICINE
AND A FRED HUTCHISON CANCER
RESEARCH CENTER IN SEATTLE
WASHINGTON WHERE HE WORKED IN
HIS DIRECTION OF NOBEL PRIZE
WINNER EDONALD THOMAS.
DR. HICK STEIN BEGAN HIS
ACADEMIC CAREER AT THE
UNIVERSITY OF WASHINGTON SCHOOL
OF MEDICINE AND THE DIVISION OF
HEMEATOLOGY AND HELD EFFECTIVE
EQUIPMENTSA THE VETERAN AFFAIR
PIEWJET SOUND SYSTEMS AND THE
FRED HUTCHISON CANCER RESEARCH
CENTER.
IN 2000 DR. HICKSTEIN WAS
RECRUITED TO JOIN THE NCI IN
GENE TRANSPLANTATION AND THERAPY
FOR CHILDREN AND ADULTS WITH
GENETIC IMMUNO DEFICIENCY
DISEASES.
DR. HICKSTEIN'S LAB FOCUSES ON
RECEIPTLY DESCRIBED BONE FAILURE
SYNDROME AND GATA INSUFFICIENCY,
IN PARTICULAR THE LAB IS
INVESTIGATING NUMEROUS MUTATIONS
OUTSIDE OF GATA 2 EXONS IN
PATIENTS WITH CAD WHAT SYNDROME
AND MYELOID PATIENTS WHO HAVE
DEFICIENCY OF MYELOID
PROGRESSION AND DEVELOPING NEW
APPROACHES TO THE TREATMENT OF
THE DEFICIENCY WITH STEM CELL
TRANSPLANTEDDATION,
DR. HICKSTEIN IS THE AUTHOR OF
OVER 100 PEER REVIEW ARTICLES
AND AMERICAN OF THE COLLEGE OF
PHYSICIANS AND AMERICAN SOCIETY
OF HEMEATOLOGY AND AMERICAN
SOCIETY OF CLINICAL
INVESTIGATION.
HE IS BOARD CERTIFIED IN
HEMEATOLOGY AND INTERNAL
MEDICINE.
PLEASE WELCOME OUR FIRST SPEAKER
DR. HOLLAND FOR HIS TALK
ENTITLED MICROBACTERIA
MONOSIGHTED O PENIA, DISPLASSIA
COME TPGHT AT GATA 2.
>> THANK YOU SO MUCH TOM.
IT REALLY IS A GREAT PLEASURE TO
BE HERE AND HAVE THE PRIVILEGE
TO SPEAK TO YOU TODAY ABOUT THIS
TOPIC THAT I THINK IS EXCITING
FOR US AND DENNIS AND I HAVE
BEEN WORKING ON THIS FOR A
LANGUAGE TIME TOGETHER.
OF COURSE AS IS TRUE FOR SO MANY
OF MY COLLEAGUES HERE, I HAVE NO
FINANCIAL DISCLOSURES.
IN TERMS OF LEARNING
OBJECTEDDIVES I'M ALWAYS A
LITTLE CONFUSED, FOR MANY OF
THESE TOPICS ARE COMPLEX, BUT IF
I COULD GET YOU TO APPRECIATE
HOW EXCITING THE DISCOVERY WAS
AND HOW DIFFICULT THE
PRESENTATIONS ARE TO RECOGNIZE
AND THEN WHY IT'S SO IMPORTANT
TO MOVE ON FOR TRANSPLANT FOR
THESE PATIENTS, I WILL HAVE FELT
THAT I HAVE DONE MY JOB.
SO GATA 2 IS THE QUINTESSENTIAL
EXAMPLE OF THE BLIND AND THE
ELEPHANT AND AS I WILL TRY AND
SHOW YOU MANY DIFFERENT GROUPS
AROUND THE WORLD OVER MANY YEARS
HAVE SEEN THIS DISEASE AND
RECOGNIZED IT IN OTHER SORT OF
CONTEXT WITH DIFFERENT
APPROACHES.
SO IT REALLY CAN SHOW UP AS
EVERYTHING SHOWN ON THIS SLIDE,
AML, PULMONARY HYPE OR TENSION,
LYMPHDEEMIA, PROGNOSIS AND IT
WAS VERY DIFFICULT FOR PEOPLE TO
COME UP WITH RECOGNITION THAT
ALL OF THIS WAS 1 SINGLE
COMPREHENSIVE BEAST.
SO OUR STORY STARTS HERE IN 1984
WHEN WHEN IN [INDISCERNIBLE]
MASSACHUSETTS A 13 YEAR-OLD GIRL
PRESENTED TO THE MEDICAL CENTER
WITH LIFE THREATENING VERA CELLA
INFECTION, BAD CHICKEN POX, HER
BODY WAS COVERED WITH CHICKEN
POX LESIONS AND THERE WAS
CLINICAL AND X-RAY EVIDENCE FOR
PNEUMONIA CAUSED BY THIS.
THEY TREATED HER VERY PROPERTILY
WITH ALL THE RIGHT DRUGS AT THE
TIME, STILL FRANKLY, THE DRUGS
WE WOULD USE NOW BUT THEY
REALIZED THAT SHE HADN'T BEEN
WELL ALL HER LIFE AND SHE HAD
RECURRENT EAR INFECTIONS WITH
PERFORATIONS AND HAD A LOW WHITE
COUNT.
AND THEY WERE VERY CONCERNED
THAT HER WHITE CELL COUNT RANGED
SOMEWHERE BETWEEN NORMAL AND
HALF OF WHAT IT SHOULD BE BUT
THERE WAS NO FAMILY HISTORY.
BECAUSE IT WAS 1984, BECAUSE
BONE MARROW TRANSPLANT WAS NOT
AS AVAILABLE AND NOT AS GOOD,
FRANKLY, SHE DIDN'T MAKE IT ALL
THE WAY TO TRANSPLANT.
BUT THE GROUP THAT MET HER LED
BY JOHN SULLIVAN, THE GROUP THAT
MET HER THOUGHT THAT THEY SAW
SOMETHING IMPORTANT BECAUSE IN
THAT LEUKOPENIA SHE HAD VERY FEW
OR NO NK CELLS, THAT IS NATURAL
KILLER CELLS FOR KILLING VIRUS
INFECTED CELLS AND THEY DID THE
EXPERIMENTS SHOWN HERE FROM
THEIR PAPER, IN WHICH THEY
SHOWED THAT THE CELLS FROM THE
PATIENT DIDN'T KILL TARGET CELLS
THAT WERE VIRUS INFECTED OR
SURROGATES FOR VIRUS INFECTION
INVITRO.
AND YOU CAN SEE IN THE RED
BOXES, THE PATIENT CELLS ARE
DOING NADA WHEREAS NORMAL CELLS
ARE DOING PLENTY.
AND THEY WENT TO TO PUBLISH THIS
IN THE NEW ENGLAND JOURNAL 5
YEARS AFTER THIS CHILD
PRESENTED.
SO REMEMBER, THAT 5 YEAR LEG,
THAT'S A THEME THAT WILL KEEP
COMING BACK AND THEY POINTED OUT
THIS WAS SEVERE HERPES VIRUS
INFECTION, IN AN ADOLESCENT
WITHOUT NK CELLS.
WELL, AT THE SAME TIME THEY
PUBLISHED THAT IN 1989, I WAS
COMING HERE TO THE NIH AND SORT
OF STANDING AROUND IN THE FIELD
WAITING FOR MEDICAL LIGHTNING TO
STRIKE AND IT WAS IN 1992 IN THE
LAB RUN BY JOHN GOWAN THAT I
FIRST GOT REFERRED THIS PATIENT
SHOWN HERE, A 41 YEAR-OLD WOMAN
WHO HAD SEVERE REFRACTORY
MICROBACTERIUM AVIAN COMPLEX
INFECTION, NOW FOR THOSE WHO ARE
LIKE, FM THIS
NOT REMEMBER THAT BACK IN THE
1980S AND 90S, DISSEMINATED MAC,
THE ORGANISM THAT LIVES IN WATER
AND DIRT ALL AROUND THE WORLD
THAT INFECTION WAS JUST PROFOUND
IN PATIENTS WITH ADVANCED HIV
INFECTION AND WE WERE TRYING
DESPERATELY TO UNDERSTAND WHAT
IT WAS, WHAT TO DO ABOUT IT, HOW
TO TREAT IT.
SO WE WERE VERY INTERESTED IN
PATIENTS WHO DID NOT HAVE HIV
INFECTION WHO HAD THESE
DISSEMINATED INFECTIONS.
AND THIS WOMAN AT AGE 41 HAD THE
M-AI HAVE UMKC ON THE SIDE OF
THE SCREEN, HUGE PUOF THULES
THAT WERE OOZING, AND SHE WAS
COMPLAINING OF TROUBLE WITH HER
VISION AND IN FACT, HER RIGHT
EYE--SORRY HER LEFT EYE HAD THIS
MASS AT THE BACK OF IT, YOU SEE
WITH THE ARROW THAT TURNED OUT
TO BE A SMOOTH MUSCLE TUMOR THAT
WAS CHOKED FULL OF EPSTEIN BAR
VIRUS.
SO WHAT WAS THE STORY WITH THIS
WOMAN, WELL SHE HAD A NORMAL
CHILDHOOD, BUT STARTING IN LATE
ADOLESCENT AND EARLY ADULTHOOD
SHE HAD SEVERE WARTS THAT KEPT
ON OCCURRING IN THE VAGINAL AND
ANNAL AREA, IN HER THIRDS SHE
DEVELOPED PNEUMONIA WHICH WAS
TREATED WITH A LOBECTOMY,
NONAPOPTOTIC THE YOUR TYPICAL
APPROACH TO PNEUMONIA THERAPY
BUT THAT TELLS YOU HOW DESPERATE
THEY WERE TO GET HER PNEUMONIA
UNDER CONTROL AND HOW UNABLE
THEY WERE TO DO IT WITH
ANTIBIOTICS AND THEN IN HER LATE
30S SHE DEVELOPED THIS
DISSEMINATED MICROBABLGHTERIAL
INFECTION THAT REAL LE THEY WERE
NONAPOPTOTIC THE SUCCESSFUL IN
HANDLING.
WHEN THEY SENT HER TO US WE
REALIZED THAT AMONG ALL THE
OTHER PROBLEMS THAT SHE HAD IN
HER PERHIVERAL BLOOD, THERE WERE
NO MONOCYTES, NO B-CELLS AND NO
NK CELLS, DESPITE THAT, SHE HAD
NORMAL IMMUNOGLOBULINS AND HER
T-CELL NUMBER WAS ROUGHLY OKAY.
SO AT THE TIME, UNDER JOHN
GOWAN'S LEADERSHIP BECAUSE OF
THE EXPERIENCE IN CHRONIC
GRANULA'S DISEASE, WE TREATED
HER WITH INTERFERON-GAMMA FOR A
VARIETY OF REASONS WHICH TURNED
OUT TO BE GOOD REASONS BECAUSE
IN ADDITION TO THE DRUGS SHE WAS
RECEIVING HER MICROBACTERIAL
DISEASE REALLY DISAPPEARED AND
IT WAS EXTREMELY GRATIFYING TO
WATCH THAT HAPPEN.
HOWEVER, ABOUT 2 YEARS INTO HER
TREATMENT SHE DEVELOPED CHRONIC
MILE O MONOSITTIC LEUKEMIA AND
BECAUSE OF THAT WE WERE WORRIED
THAT OUR DRUG MIGHT HAVE BEEN
RESPONSIBLE, WE STOPPED THE
INTERFERON-GAMMA, AND SENT HER
MIKE PROBACTERIAL INFECTION DID
RETURN BUT BY THAT TIME WE HAD
SENT HER ON TO BONE MARROW
TRANSPLANT DOWN AT HER HOME IN
TEXAS.
SHE HAD A SUCCESSFUL TRANSPLANT
BUT UNFORTUNATELY DEVELOPED A
PNEUMONIA BACK WHEN SHE HAD
RETURNED HOME WITH HER COMMUNITY
RESPIRATORY VIRUS AND SHE DIED.
BUT AS PART OF OUR COMMITMENT TO
UNDERSTANDING THESE DISEASES WE
BROUGHT HER BACK FOR AN
AUTOPSIES SO I WANT TO SAY HOW
CRITICALLY IMPORTANT IT IS TO DO
THOSE AUTOPSIESS, IN THAT LAST
MEASURE OF DEVOTION TO THE
FAMILY, TO THE DISEASE TO FIGURE
OUT WHAT WAS GOING ON.
AND IN THE AUTOPSIES WE SAW
COUPLE THINGS THAT WERE REALLY
SORT EVER SURPRISING.
NUMBER 1, DESPITE THE FACT THAT
SHE HAD NO MONOCYTES IN HER
PERIPHERAL BLOOD, THERE WERE
LOTS OF MACROPHAGES IN HER
TISSUE AND YOU CAN SEE HERE IN
THE BROWN STAINING, THE
MACROPHAGES THAT WE SAW IN HER
TISSUE, AND DESPITE THE FACT
THAT SHE HAD NO B-CELLS IN HER
PERIPHERAL BLOOD, SHE HAD PLENTY
OF PLASMA CELLS IN HER TISSUE
AND AS I MENTIONED, HER IMMUNO
GLOBEUE LYNN LEVELS WERE NORMAL.
THIS WAS ALL REALLY CONFUSING
AND I CAN TELL YOU THERE WERE
PLENTY OF DISCUSSIONS ABOUT
DIFFERENT POSSIBILITIES, MOST OF
WHICH TURNED OUT TO BE WRONG.
SO IN THE PROCESS OF WORKING HER
UP FOR HER TRANSPLANT, WE HAD TO
EVALUATE HER FAMILY MEMBERS TO
LOOK FOR A DONOR, SO SHOWN HERE
WITH THE ARROW IS OUR INDEX
PATIENT WHO HAD WARTS, MAC AND
AS YOU SEE NO B-CELLS, MONOOR NK
CELLS AND THEN DEVELOPED CMML,
YOU ALSO SEE THERA HER METHOD
INTERESTING ENOUGH HAD DIED IN
HER EARLY 50S WITH CHRONIC MILE
O MONOSITTIC LEUKEMIA AND
MICROBACTERIAL DISEASE, SHE DIED
BEFORE WE MET HER BUT HER SISTER
IN THE PROCESS OF OUR TRYING TO
EVALUATE FOR TRANSPLANT, WE
REALIZE THAT HER SISTER ALSO HAD
SEVERE WARTS, AND NO B-CELLS,
MONOCYTES OR NK CELLS ALTHOUGH
SHE HAD NOT AT THAT TIME HAD ANY
OTHER SERIOUS INFECTIONS.
NOW WE REALIZED LOOKINGA THE
THIS PATTERN, THIS IS A VERTICAL
DISEASE.
IT'S GOT TO BE BEING TRANSMITTED
FROM GENERATION TO GENERATION BY
A SINGLE GENE.
AND IF IT'S A SINGLE GENE OUR
HYPOTHESIS WAS IN 1992 THAT WE
SHOULD BE ABLE TO FIND IT.
NOW JUST TAKING A DIVERSION FOR
A SECOND ABOUT HER SISTER, HER
34 YEAR-OLD SISTER WHO WAS--YOU
KNOW PHENOTYPICALLY FINE, SHE
WAS LIVING IN DENVER, HAD
SEVERAL CHILDREN, WHEN WE
EVALUATED HER AND WE LOOKED AT
HER PERIPHERAL BLOOD COUNTS.
WE SAID WE PROBABLY OUGHT TO
LOOK AT YOUR CHEST TO MAKE SURE
IT'S OKAY, AND YOU CAN SEE HER
CHEST CT WAS NOT OKAY, YOU CAN
SEE THAT THERE WAS SOME VERY
SUBTLE DIFFUSE ABNORMALITIES,
THE LUNG FIELDS THAT ARE IN THE
CENTER OF THE CT SCAN THERE,
SHOULD BE PRETTY, YOU KNOW BLACK
AND CLEAR AND HERS WEREN'T.
AND SO, WE SAID TO HER, YOU
KNOW, IT MIGHT BE WORTH DOING A
LUNG BIOPSY AND SHE SAID, I LIVE
IN DENVER, I'M FEELING FINE, I'M
TAKING CARE OF MY KIDS, YOU'RE
CRAZY AND I THOUGHT, YOU KNOW
THAT'S NOT A BAD ARGUMENT, SO WE
SAID WE'LL KEEP IN TOUCH AND SEE
HOW THINGS GO.
UNFORTUNATELY 9 YEARS LATER, SHE
CAME BACK AND NOW HE WASN'T SO
OKAY, AND SHE WASN'T LIVING IN
DENVER AND THIS DIFFUSE PROCESS
THAT YOU SEE HERE IS CALLED
PULMONARY ALVEOLAR PROGNOSIS IN
WHICH THE SECRETIONS INSIDE THE
ALVEOLAR SPACE ACCUMULATE
BECAUSE THE MACROPHAGES IN THE
LUNG CAN'T DIGEST IT AND EXCRETE
IT.
AND THE COMMON--THE MOST COMMON
CAUSE OF THIS ARE AUTO
ANTIBODIES TO GMCSF, THAT WAS
NOT IT, IT WAS SOMETHING ELSE
RELATED TO THIS DISEASE.
UNDER THE GUIDANCE OF KEN
OLIVIER, MAJOR PULMONARY
COLLABORATOR HERE, SHE UNDER
WENT WHOLE LUNG LAVAGE AND YOU
SEE THAT THE FLUID GOES FROM
BEING OPAQUE AT THE TOP LEFT TO
BE VERY CLEAR AT THE LOW RIGHT
AND WHEN WE LOOKEDDA THE THAT
FLUID WE SAW PLENTY OF ALVEOLAR
MACK RAPHAGES AND YET THERE HAD
BEEN NONE IN HER CIRCULATING
BLOOD.
SO WE BEGIN TO SAY, WOW, THIS IS
REALLY AN UNUSUAL SYNDROME.
SO YOU REMEMBER WE STARTED IN
1992 WITH OUR FIRST PATIENT.
THIS PATIENT WE SAW BACK IN THE
EARLY PART OF THE 2000S AND INTO
THE MIDPART OF THE FIRST DECADE
OF THE CENTURY.
AND THOSE 18 PATIENTS THAT WE
SAW OVER THAT TIME WE COLLECTED
18 PATIENTS OVER 18 YEARS INTO A
PAPER DESCRIBING THE PHENOTYPE
OF THIS CONDITION THAT WE KNEW
HAD TO BE A SINGLE DISEASE
BECAUSE THERE WAS SUCH A
SIMILARITY IN THE PATIENTS THEY
HAD MICROBACTERIAL INFECTIONS AS
YOU CAN SEE, HPV INFECTIONS AS
WELL AS MANY OF THEM GOING TO TO
DEVELOP MYELODYSPLASIA, LEUKEMIA
AND MANY OTHER PROBLEMS AND THIS
WAS DONE OVER MANY YEARS BY DON
VINH AND SMITA, P A TEL OVER
SEVERAL YEARS.
AND WHAT DID THIS COHORT LOOK
LIKE TO GIVE A FEW EXAMPLES,
THIS 1 MAN SHOWN HERE, A 32
YEAR-OLD MAN WHO WAS THE 1
IDENTIFIED THERE WITH THE
HISTOPLASMOSIS AND MAC, CAN YOU
SEE ON THE TOP SCREEN THERE'S
MAC IN HIS ALVEOLAR LAVAGE AND
AT THE BOTTOM YOU CAN SEE A
MACROPHAGE CHOKED FULL OF
HISTOPLASMA, BUT WHAT YOU ALSO
SEE IN HIS FAMILY TREE IS THAT
HIS SISTER HAD DIED AT AGE 12 OF
DISSEMINATED VERA CELLA ZOSTER
VIRUS JUST LIKE THE GIRL IN THE
1989 CASE REPORT AND THAT HIS
MOTHER AT 61 HAD LIMP EDEMA AND
THAT'S HER LEG THERE, IT'S
SWOLLEN COMPARED TO THE LEFT
LEG, AND SHE HAS MULTIPLE SPOTS,
THEY LOOK LIKE SCARS OR BURNS
BUT IN FACT THEY ARE FLAT WARTS,
WARTS THAT ARE VERY TYPICAL FOR,
YOU KNOW IMMUNO DEFICIENT VIRAL
INFECTIONS AND WE REALIZED THAT
THE RATE OF SEVERE HPV INFECTION
JUST LIKE IN OUR INDEX CASE AND
HER SISTER WAS REALLY A PROBLEM
AND THE NUMBER OF THESE PEOPLE,
YOUNG WOMEN WHO HAD SEVERE HPV
INFECTION IN THE VAGINAL AND
ANALL REGION AND IN THE CERVIX
WAS TERRIBLE AND IT WAS
DEVASTATING BECAUSE OF
VUFULLECTOMYS AND EXTENSIVE
SURGERY AS WELL AS THEN WARDS
THAT PERSISTED ON MANY DIFFERENT
BODY SURFACES, WELL INTO
ADULTHOOD AND THEN THIS UNIFYING
PROBLEM WAS THAT MANY OF THESE
PATIENTS HAD MYELODYSPLASIA AND
WHAT YOU SEE HERE IS THIS ENDITY
OF HYPOBONE MARROW, THAT IS THE
BONE MARROW SHOULD HAVE THE
PURPLE ELEMENTS, THE RED
ELEMENTS ARE BONE, THE PURPLE
ELEMENTS ARE CELLS AND THE WHITE
ELEMENTS ARE FAT AND FOR MOST
PEOPLE BELOW THE AGE OF 50, YOU
WOULD LIKE TO SEE IT'S MORE
CELLS AND BONE THAN IT IS FAT
AND THAT'S NOT THE CASE HERE, IN
ADDITION, YOU SEE ALL OF THESE
ABNORMAL MEGACARIO SIGHTS, THIS
IS WORK DONE WITH CATHY CALVO,
OUR CRITICAL HEMEAT O PATHOLOGY
COLLABORATOR AND YOU CAN SEE
THAT THESE EUKARYOTE SIGHTS HAVE
SEPARATED NUCLEI WHICH IS
ABNORMAL AND ATYPICAL AND A
HALLMARK FOR DISPLASSIA.
SO THEN OUR PROBLEM HERE IS THAT
AFTER 18 YEARS I'M ABLE TO SAY,
YEAH, THAT'S ABNORMAL AND WE'VE
GOT A SERIES OF PATIENTS THAT
HAVE CYTOPENIAS, INFECTIONS,
BONE MARROW DYSFUNCTION,
LYMPHDEMA, PULMONARY FOR A
SINGLE GENE AND HO WILL WE PUT
ALL THAT TOGETHER AND THEY SAY
GOOD JUDGMENT COMES FROM BAD
JUDGMENT AND I UNDERWENT MANY
YEARS OF BAD JUDGMENT ABOUT THIS
BUT IT WAS REALLY THE KRILICAL
INSIGHT OF AMY SUH A BIOLOGIST
IN THE LAB AT THAT TIME THAT
SAID IT ALL HAS TO BE IN THE
HEMATOPOIETIC STEM CELL AND THIS
IS HOW THEY ALL CONNECT.
YOU CAN SEE THAT THE SOLID RED
LINE THERE TIES EVERYTHING
TOGETHER EXCEPT THE T-CELLS
WHICH WERE ROUGHLY NORMAL AND
SUGGESTED THAT SOMETHING NORTH
OF THOSE CELLS SHOULD BE THE
PROBLEM.
AND ON MAY THIRD, 2011 AMY
CALLED ME UP, SHOUTING INTO THE
PHONE THAT ALL THE PATIENTS THAT
SHE SEQUENCED FOR THIS
PARTICULAR GENE GATA 2 HAD
SPECIFIC MUTATIONS IN IT.
AND WHY IS THAT IMPORTANT?
BECAUSE THIS IS A TRANSCRIPTION
FACTOR.
THAT IS TRANSCRIPTION FACTORS
CAN SUBTEND MANY DIFFERENT ARCS
AND ARE ABLE TO CONTROL MULTIPLE
DIFFERENT PATHWAYS WHICH IS
EXACTLY WHAT WE WANTED FOR THE
COMPLEXITY OF WHAT WE SAW HERE.
SO THAT WAS MAY THIRD AND FROM
MAY THIRD TO THE TIME THIS PAPER
WAS PUBLISHED ON JUNE 13th IN
BLOOD, IT WAS ONLY ABOUT 5 AND
HALF WEEKS, DESPITE THAT, THAT
EXTRAORDINARY OUTPUT OF WORK
THAT AMY DID, IT DID TAKE ME 19
YEARS FROM THE TIME WE STARTED
TO SEE THIS DISEASE TO GET IT
OUT.
NOW 1 OF THE REALITIES OF
SCIENCE IS THAT IT'S AWFULLY
HARD TO HAVE A COMPLETELY
ORIGINAL IDEA, I DON'T SAY IT
DOESN'T HAPPEN BUT IT DOESN'T
HAPPEN TO ME VERY OFTEN.
AND IN FACT WHILE WE WERE DOING
THIS, IT TURNED OUT OTHER GROUPS
WERE IDENTIFYING EXACTLY THE
SAME GENE BUT WITH DIFFERENT
MANIFESTATIONS, SO THIS GROUP
FROM AUSTRALIA AND SEATTLE
RECOGNIZED GATA 2 MUTATIONS WITH
MILE DISPLASSIA AND ACUTE
LEUKEMIA.
THIS GROUP FROM ENGLAND
RECOGNIZED THE DENDRITIC CELL
MONOCYTE I HAVE AN NK CELL
DEFICIENCY AND EVENTUALLY WENT
ON, THIS IS THEIR PHENOTYPIC
DESCRIPTION, WENT ON TO IDENTIFY
THE GENE IN THEIR COHORT
SUBSEQUENTLY.
THIS GROUP FROM EUROPE
IDENTIFIED MUTATIONS IN GATA 2
IN THOSE WHO HAD LYMPHDEEMIA AND
DEAFNESS AND ACUTE LEUKEMIA AND
THEN WE--AS WE REALIZE THAT ALL
OF THESE WERE MANIFESTATIONS OF
GATA 2 DEFICIENCY, IT MADE US
STOP AND GO BACK AND SAY WAIT A
MINUTE THAT VERY FIRST CASE FROM
1989, THAT GIRL SOUNDS LIKE
SOMEBODY THAT WOULD BE IN OUR
COHORT AND SO I CALLED CHRISTINE
BYRON AND JOHN SULLIVAN, AND
SAID, YOU KNOW WE THINK THAT
YOUR PATIENT MIGHT HAVE OUR
PROBLEM.
AND THEY SAID, WELL, YOU KNOW,
THAT SOUNDS POSSIBLE, LET'S SEE.
AND JOHN WAS ABLE TO SEND ME
CELLS AND IN FACT WHEN AMY
SEQUENCED IT, THIS GIRL ALSO HAD
A DELETION IN THE GATA 2 GENE
LEADING TO GATA 2 DEFICIENCY, SO
AFTER ALL OF THIS TIME, WE WERE
ABLE TO SAY THERE ARE 5 NAMES
FOR 1 DISEASE, WE CALLED IT
MONOMAC, BUT OTHERS HAD OTHER
NAMES FOR IT, THEY'RE ALL THE
SAME, AND IT IS A RIDICULOUS
HUGHING TO REGIONAL PREJUDICE TO
CONTINUE TO CALL IT BY OUR
DIFFERENT ACRONYMS, I STILL DO
BUT THE TRUTH IS, IT'S 1 DISEASE
THAT HAS MANY DIFFERENT
MANIFESTATIONS.
AND THESE AREN'T ALL OF THEM.
THERE ARE LOTS OF OTHER WAYS
THAT THIS CAN PRESENT, THESE
HYPOPLASTIC MARROW DISORDERS,
ABOUT 50% OF CHILDREN WITH
MONOSTUDIES OF MULTIPLE
ENDOCRINEY 7 HAVE UNDERLYING
GATA 2 DEFICIENCY, ABOUT 5% OF
THE APLASTIC ANEMIA THAT HAVE
BEEN SEEN HERE TURN OUT TO HAVE
THIS AS WELL AS CHILDREN WITH
NEWT ROW PENIA, PEOPLE WITH CMML
AND EVEN CASES OF COMMON
VARIABLE IMMUNO DEFICIENCY THAT
TURN OUT TO BE GATA 2
DEFICIENCY.
NOW, YOU KNOW AT SOME LEVEL,
PEOPLE SAY MY GOD WHAT WAS ALL
THIS GOING ON ABOUT MAKING A
GENETIC DIAGNOSIS, WHO CARES?
YOU KNOW HAVE YOU A DISEASE, YOU
KNOW YOU HAVE TO TREAT IT WHY
NOT JUST GET TO BUSINESS AND
STOPIACKING ABOUT IT BUT YOU
GOTTA HAVE THE GENE, WHY?
BECAUSE IT MAKES POSSIBLE
DIAGNOSIS, PROGNOSIS, FIGURING
OUT WHAT THE EXPRESSION AND
PENETRANTS OF THE DISEASE ARE,
TARGETED THERAPY AS OPPOSE TO
THIS SORT OF SLEDGE HAMMER THAT
WE USE AS WELL AS THE CRITICAL
ISSUE ABOUT MAKING SURE YOU
CHOOSE THE RIGHT DONOR FOR THE
TRANSPLANT.
IF YOU CHOOSE A SIBLING WHO'S
ALSO MUTATED YOU COULD MAKE A
DISASTROUS MISTAKE AND THEN
FINALLY, GENO TYPE, PHENOTYPE
CORRELATION, I'M ONLY GOING TO
TOUCH ON 3 OF THOSE IN THE NEXT
COUPLE OF MINUTES.
NUMBER 1, ONCE YOU HAVE THE
GENE, CAN YOU IDENTIFY PEOPLE
BEFORE THEY'RE PHENOTYPICALLY
EFFECTIVE.
AND SO, WITH THAT INFORMATION,
WE WERE ABLE TO START LOOKING
WITHIN FAMILIES AND SAY, YOU
KNOW WE KNOW THAT THIS PERSON
CARRIES THE SAME GENE AND WE
COULD BEGIN TO SAY, LOOK AT HOW
THE BLOOD COUNTS CHANGE OVER
TIME.
WE DIDN'T KNOW AT THE BEGINNING
WAS THIS SOMETHING THEY WERE
BORN WITH AND ONLY SHOWED NUP
ADULTHOOD OR THEY WERE BORN
NORMAL AND IT CHANGED IN
ADULTHOOD, NOW THAT WE HAVE THE
GENE, WE CAN SAY, OH, LOOK AT
THAT.
IF PEOPLE HAVE NO SYMPTOMS,
THEIR CELL COUNTS ARE PRETTY
MUCH NORMAL, HERE WE'RE LOOKING
AT B-CELLS, NK-CELLS AND CD4
CELLS, BUT AS TIME GOES ON AND
DISEASE GETS MORE SEVERE, THE
CYTOPENIA PROGRESSES SUGGESTING
THAT THE BONE MARROW IS FAILING
OVER TIME.
IT'S NOT BORN THAT WAY, IT
DEVELOPS, THAT MEANS THERE'S A
WINDOW AT WHICH WE COULD DO
THINGS.
IT ALSO TURNS OUT THAT THERE'S A
SIGNIFICANT AMOUNT OF LUNG
DISEASE THAT A COMPANY'S GATA 2
DEFICIENCY AND THAT LUNG DISEASE
VARIES OVER TIME HERE, HERE YOU
SEE RIGHT BELOW THE WALL OF THE
CHEST AND ALONG THE FISHER'S IN
THE LUNG, YOU SEE THAT THERE ARE
THESE SMALL CYSTS THAT ARE
FORMING THAT'S PARASEPTORSAL 'EM
SEEMA WHICH A COMMON PROBLEM IN
THIS DISEASE.
NOW THERE ARE LOTS OF DIFFERENT
PROBLEMS THAT SHOW UP IN GATA 2
DEFICIENCY ONCE YOU KNOW THAT
PEOPLE HAVE DISEASE.
EVERYTHING FROM INFILTRATES LIKE
PNEUMONIAS TO THIS POLARIZED
MONITORARY ALVEOLAR PROGNOSIS I
MENTIONED EARLYY BUT WITH THE
GENE YOU CAN SAY WHAT ABOUT THE
PEOPLE WHO ARE SICK COMPARED
THOSE THAT AREN'T SICK?
AND IN THOSE RELATIVES THAT ARE
MUTATED BUT NOT CLINICALLY ILL
YET, YOU CAN SEE THAT LEGAL
THEIR DIFFUSION CAPACITY FOR
CARBON MONOXIDE, A MEASURE OF
LUNG MEMBRANE THICKNESS, EVEN
THOUGH THEY'RE CERTAINLY BETTER
THAN THOSE THAT ARE SICK,
THEY'RE STILL NOT COMPLETELY
NORMAL SUGGESTING THAT EVEN IN
THOSE WHO ARE--WHO ARE NOT
CLINICALLY AFFECTED, THERE ARE
STILL EFFECTS OF THIS.
FINALLY, AS WE BEGIN TO LOOK
THEN AT THE DIFFERENT MUTATIONS
IN THE GENE, WE BEGENERATED TO
PICK OUT DIFFERENT ISSUES.
SO, IN THIS SCHEMA HERE WHAT YOU
SEE IS THE JEAN ON THE TOP IS
THE WILD-TYPE NORMAL COPY OF THE
GENE, ZF1 AND 2 REFER TO THE
ZINC FINGERS SO THIS IS A 2
DIGIT ZINC FINGER TRANSCRIPTION
FACTOR THAT USES THOSE 2 FINGERS
TO BIND TO THE DNA AND RECRUIT
OTHER TRANSCRIPTION FACTORS,
WELL, THERE ARE REALLY 5
DIFFERENT KINDS OF MUTATIONS
HERE.
ONE OF THEM, THE 1 IN PURPLE IS
WHERE IT'S JUST THE AMOUNT
THAT'S MADE IS LOW, IT'S NOT
ABSENT, IT'S JUST LOW BUT
EVERYTHING THAT'S MADE IS NORMAL
QUALITY, JUST THE QUANTITY IS
DOWN.
AND THEN THERE ARE THOSE WHO
HAVE MUTATIONS IN THE SECOND
ZINC FINGER IN RED, THOSE WHO
HAVE MUTATIONS IN THE
C-TERMINUS, DOWN @ AT THE
C-TERMINUS DOWN TO THE RIGHT
SIDE, THOSE WHO HAVE TRUNCATIONS
OF LARGE PARTS OF THE MOLECULES
SHOWN IN BRIGHT GREEN AT THE
BOTTOM, AND AT THE VERY BOTTOM,
THOSE WHO HAVE NO ALLELE AT ALL
BECAUSE OF A BIG DELETION IN THE
GENE.
AND SO JUST A COUPLE OF
INTERESTING POINTS THAT AGAIN
HAVING THE GENE LETS YOU SORT
OUT.
NUMBER 1, THE RATE OF DISEASE IN
MALES AND FEMALES IS PRETTY MUCH
THE SAME, HOWEVER, THE KIND OF
DISEASE IS NOT AND WHAT YOU SEE
AT THE BOTTOM LEFT IS THAT MALES
SHOW UP WITH MUCH MORE
MICROBACTERIAL DISEASE THAN DO
FEMALES WHERE FEMALES SHOW UP
WITH ALL THE OTHER INFECTIONS IN
PARTICULAR, THE HPV.
WE HAVE BEEN REFERRED MULTIPLE
YOUNG WOMEN NOW WHO HAVE BEEN
FOLLOWED BY GYNECOLOGISTS FOR
YEARS BEFORE SOMEBODY SAYS, YOU
KNOW THAT'S TOO MANY HPV
SURGERIES FOR YOU IN YOUR EARLY
20S AND IT'S THE GYNECOLOGY I
ISTS
WHO ARE FIGURING OUT, BOY, YOU
HAVE A PROBLEM YOU NEED TO BE
WORKED UP FOR THAT.
BUT THEN WHEN WE DISSECT IT OUT
FURTHER AND THIS IS ALL WORK
THAT AMY HSU HAS DONE CHA IS
UNDER REVIEW, WHEN YOU DISSECT
IT OUT FURTHER, IT TURNS OUT
THERE ARE REALLY ARE DIFFERENCES
BETWEEN THE DIFFERENT MUTATIONS
IN THE GENE, SO THOSE THAT HAVE
THE ENHANCER MUTATION THAT IS
THE RIGHT QUALITY, LOW QUANTITY,
THEY'VE ACTUALLY GOT THE BEST
SURVIVAL SO HERE WE'RE LOOKINGA
THE PERCENT ASYMPTOMATIC AT A
CERTAIN HAIJ.
SO YOU SEE THAT BY AGE 50, ABOUT
50% OF THE PEOPLE WHO HAVE
ENHANCER MUTATIONS ARE STILL
OKAY.
WHEREAS FOR THE OTHER MUTATIONS,
THAT'S NOT THE CASE.
AND IN FACT, WHEN WE LOOK EVEN
FURTHER AND DISSECT OUT AMONG
THOSE WITH YOU HADITATIONS IN
THE SECOND ZINC FINGER THERE ARE
CLEARLY DIFFERENCES IN THAT
GROUP AS WELL WITH THE MUTATIONS
LIKE A396 AND 354 BEING THE MOST
SEVERE AND R398 BEING LESS
SEVERE.
THEY'RE STILL BAD, BUT IT'S
ABOUT DEGREES OF BAD.
AGAIN, THIS SHOWS US WHERE THE
WINDOW IS THAT WE CAN SNEAK IN
AND TRY TO LOOK FOR HOW TO MAKE
DIFFERENCES.
SO WE CAN PUT ALL OF THIS ON A
CURVE THAT HELPS US UNDERSTAND
THIS DEC BETTER AND HELPS US
UNDERSTAND EXACTLY WHAT IT IS
THAT WE'VE GOT AN OPPORTUNITY TO
ADDRESS.
SO IN SUMMARY, WHAT MAKES THIS
DISEASE SO IMPORTANT TO
UNDERSTAND IS THAT PEOPLE ARE
BORN NORMAL AND DEVELOP
CYTOPENIAS OVER TIME.
THERE ARE A VARIETY OF
INFECTIONS, EVERYTHING FROM
VIRUSES TO FUNGI THAT ARE
CHARACTERISTIC OF THIS DISEASE.
THEY ALSO DEVELOP YOU KNOW
POLARIZED MONITORARY
AVEALULOSEIS, AND I'VE NOT
TALKED ABOUT THOSE TODAY AND A
STRONG CORRELATION AND A
PENETRANTS THAT VARIES FROM 1
MUTATION TO THE NEXT AND AS
DENNIS WILL GO ON TO SHOW YOU
TRANSPLANT IS VERY SUCCESSFUL
AND SO HAVE ARE IMPORTANT TO TEE
PEOPLE UP FROM THE VERY GET GO.
SO HOW DOES GATA 2 DO ALL THIS?
IT'S GOT REG LA THORY EFFECTS IN
NUMEROUS TISSUES EACH 1 BEING A
LITTLE BIT DIFFERENT.
THERE ARE ABNORMAL VESSELS IN
LYMPHATICS, OVERLAPPING TARGETS
OF THE GATA 2, EARLY POPULATION
MACROPHAGES AND PLASMA CELLS,
IMPAIRED DEFINITIVE HEMEAT O
POETICESIS, INFECTION-DRIVEN
BONE MARROW EXHAUSTION AND
SECONDARY MUTATIONS AND
CYTOGENETIC DEFECTS.
SO LASTLY WHY ARE WE GOING TO
KEEP GOING ON THIS?
BECAUSE WE HAVE LOTS OF
REQUESTYS TO ANSWER.
WHAT IS IT THAT DETERMINES PEN
TRABTS, WHAT ARE THE FACTORS
OUTSIDE OF GATA 2 THAT MIGHT BE
AFFECTING IT.
WHY DOES IT COME ON LATER IN
LIFE, WHAT IS IT THAT CHILDREN
ARE DOING SO RIGHT AND ADULTS
ARE DOING SO WRONG.
WHAT ARE THE TRANSFACTORS ON
OTHER GENES THAT ARE INVOLVED IN
GATA 2 REGULATION, IS THERE ANY
WAY WE COULD GO ON TO PREVENT
MDS/AML?
AND WHEN DO YOU DECIDE TO
TRANSPLANT WHEN THEY'RE ILL,
IT'S HARDER TO FIGURE OUT, HOW
DO YOU KNOW SOMEONE'S NOT GOING
TO GET SICK SO YOU NEVER WIND UP
WAITING JUST 1 DAY TOO LONG.
SO I TRIED TO INTRODUCE YOU TO
MY FAVORITE ELEPHANT AND TELL
YOU A LITTLE BIT ABOUT IT AND
TRY TO SHOW YOU ALL THE
DIFFERENT MANIFESTATIONS THAT
WE'VE DEALT WITH OR AT LEAST
SOME OF THE MANIFESTATIONS,
THERE ARE MANY MORE AND I DON'T
DOUBT FOR A MOMENT THERE WILL
CONTINUE TO BE MANY MORE TO COME
BUT I HOPE THAT WE'VE GOT THE
TOOLS IN PLACE, AND I KNOW THAT
WE HAVE THE TEAM IN PLACE TO
REALLY MAKE THIS WORK.
I JUST WANT TO ACKNOWLEDGE IN
PARTICULAR, THE CRITICAL PEOPLE
IN THIS IN MY OWN GROUP, AMY
HSU, LAUREN, MIKE, OUR
COLLABORATORS, CATHY, MIKE,
STEPHANIA, AND SO MANY OF OUR
COLLABORATORS WHO HAVE BEEN
CRITICAL TO IT.
DENNIS I WILL WILL TAKE IT AWAY
ON THE CLINICAL SIDE ON OUR OWN
SIDE, WE'VE HAD SOME SPECTACULAR
ID AND IMMUNOLOGY COLLABORATORS
LISTED HERE.
SO I WILL STOP THERE AND SAY
THANK YOU VERY MUCH.
I LOOK FORWARD TO TAKING YOUR
QUESTIONS AT THE END.
THIS IS DENNIS HICKSTEIN, THANK
YOU SO MUCH FOR TEEING UP THE
PATIENTS FOR TRANSPLANT AND
TEEING ME UP FOR PART 2 OF THIS.
SO I WILL TALK ABOUT THE ROLE OF
ALOE GENERATED AIC TRANSPLANT
AND GATA 2 DEFICIENCY WITH A
SHAKESPEAREAN QUOTE THAT THE
PAST IS PROLOGUE TO THE FUTURE.
SO I HAVE NO FINANCIAL
DISCLOSURES, THE MAIN LEARNING
OBJECTIVE IS HAVE YOU THINK LIKE
A TRANSPLANTER ABOUT THIS
DISEASE.
SO REALLY TO UNDERSTAND THE ROLE
OF ALOE GENERATED AIC TRANSPLANT
AND GENETIC BLOOD SEIZES
ESPECIALLY GATA 2 DEFICIENCY.
SO THE FIRST QUESTION, I THINK
STEVE GAVE A GREAT BACKGROUND OF
WHRA THESE PATIENTS WERE LIKE,
HARD TO CONVEY HOW REALLY SICK
THE FIRST 1S WE SAW WERE, THEY
HAD BEEN LINGERING WITH THIS
DISEASE FOR A DECADE OR MORE.
SO WE KNOW THE PATIENTS OF GATA
2 DEFICIENCY, ONCE THEY BECOME
SYMPTOMATIC WE'RE AT HIGH RISK
OF DEATH, THE INFECTIONS CAN
KILL THEM, THESE TERRIBLE
NONTUBERCULOSE MICROIN
INFECTIONS WE SEE LESS PULMONARY
PROGNOSIS, BUT THAT CAN BE
LETHAL AND THEN THE DREADED
COMPLICATION THAT THEY CAN TURN
INTO LEUKEMIA, SO, WE THOUGHT AT
THE BEGINNING IT LOOKED LIKE A
STEM CELL DISEASE, GATA 2 IS A
MARKER OF STEM CELLS AND IT
LOOKED LIKE NORMAL DONOR
SEMESTER CELLS SHOULD REVERSE
THE PHENOTYPE.
WE KNOW TRANSPLANT CAN CURE
IMMUNO DEFICIENCY DISEASES AS
WELL AS LEUKEMIA.
SO THE QUESTION I WILL GET INTO
IN A IF YOU MINUTES IS WHEN TO
TRANSPLANT THEM AND'S REALLY
TRICKY AS FAR AS THE OPTIMAL
TIME.
TRANSPLANTS NOT A BENIGN
UNDERTAKING.
SO THEN THE QUESTION THAT CAME
TO US IS HOW TO TRANSPLANT THESE
PATIENTS, THESE ARE VERY HIGH
RISK PATIENTS AT THE TIME BACK
IN 2009, THAT WAS 2 YEARS BEFORE
WE KNEW IT WAS GATA 2.
AND THEY WERE NOT POPULAR
PATIENTS BECAUSE THE LEUKEMIA
DOCTORS WERE INTERESTED IN THEM
BECAUSE THEY HAD SO MANY
INFECTIONS, THE INFECT YOWZ
DISEASE DOCTORS WEREN'T
INTERESTED IN TRANSPLANTING THEM
BECAUSE THEY HAD LEUKEMIA.
SO YOU HAVE TO FIND THE BALANCE,
HOW--IF YOU GIVE THEM TOO MUCH
CHEMO OR RADIATION TO GET THEM
READY FOR TRANSPLANT, YOU WILL
HAVE A LOT OF MORBIDITIES AND
THESE PATIENTS WERE VERY SICK.
ON THE OTHER HAND IF YOU GIVE
THEM TOO LITTLE CHEMO THERAPY TO
PREPARE THEM, THEY CAN REJECT
THE DONOR CELLS OR IF THEY HAVE
MYELOID DISPLASTIC SYNDROME IT
CAN PERSIST OR RECUR.
SO YOU'RE TRYING TO GO BETWEEN
TOO LITTLE AND TOO MUCH.
AND WHAT TYPE OF DONORS YOU ARE
GOING TO USE, WE WORK ON THIS
AND THINK ABOUT THIS A LOT
WHETHER YOU HAVE MATCH SIBLING,
UNRELATED DONOR UMBILICAL CORD
BLOOD AND HAPLO AND OUR OPROACH
HAS EVOLVED OVER TIME.
SO TO GET YOU TO THINK LIKE A
TRANSPLANTER, HAVE YOU HAVE YOK
ABOUT TRANSPLANT AS A PACKAGE,
YOU HAVE TO THINK ABOUT THE
DISEASE, WHERE IS THE PATIENT IN
THE NATURAL HISTORY DISEASE, WE
KNOW THAT FROM LEUKEMIA, YOU
WANT TO TRANSPLANT PEOPLE IN
REMISSION, SO STANDARD TREATMENT
IS TO INDUCE THEM INTO REMISSION
WITH A COUPLE CYCLES OF CHEMO
THERAPY AND THEN GO TO
TRANSPLANT.
WE THINK A LOT ABOUT THE DONOR
AND THE DONOR PRODUCT, BACK AND
FORTH AS TO DIFFERENT DONOR
ADVANTAGES, DISADVANTAGES AND
THEN WE THINK ABOUT THE BIG
THING IS HOW WE PREPARE THEM FOR
TRANSPLANT WHAT KIND OF CHEMO
THERAPY OR CONDITIONING REGIMEN
AND THEN THE LAST 2 GRAFT
REJECTION, YOU DON'T WANT TO
DEAL WITH REJECTION, YOU WANT TO
GET THAT GRAFT IN AND MAKE IT
STICK.
SOME PEOPLE DEVELOP GRAFT VERSUS
HOST DISEASE, HIGH DOSE
STEROIDS, OTHER INFECTIONS LIKE
ASPER GILLIS, SO THOSE ARE ALL
THE THINGS A TRANSPLANTER IS
THINKING ABOUT IN HIS REGIMEN.
SO,--SO START WITH THE DISEASE,
STEVE DID A NICE JOB OF
SUMMARIZING GATA 2, WE GOT 1
CLUE CORRECTION USING
HEMATOPOIETIC STEM CELL
TRANSPLANT COULD CORRECT THE
DISEASE, THAT WAS THE 1 PATIENT
WHO GOT A GRAFT IN TEXAS AND
THEN DIED OF COMPLICATIONS OF
TRANSPLANT.
SO IT LOOKED LIKE YOU COULD GET
GRAFTS IN, BECAUSE--AND THEN
WHAT ARE THE NONHEMATOPOIETIC
MANIFESTATIONS, I THINK
DR. HOLLAND SHOWED YOU THE
PICTURE OF THE LYMPHDEEMIA IN
THAT PATIENT, THAT DOES NOT GET
BETTER WITH TRANSPLANT, IT'S THE
VALVES AND THE VAINS DON'T FIT
RIGHT, THEY'RE LEAKY AND AND WE
CORRECT THE BONE MARROW BUT WE
DON'T FIX THE LYMPHDEEMIA AND
THEN YOU COULD FIGURE OUT IF YOU
HAVE I MOUSE MODEL AND IN 2009
WE DIDN'T KNOW IT WAS GATA 2, IS
HOW MUCH CORRECTION IS NEEDED.
IF YOU HAVE A LTLE YOU COULD CUT
BACK ON YOUR CONDITIONING JUST
GET A TOE HOLD OF THOSE STEM
CELLS COMING IN, OTHER DISEASES
YOU WANT TO GO TO 100%, YOU WANT
TO ERADICATE THAT DISEASE AND
THEN WE TALKED ABOUT WHERE IS
THE PATIENT IN THE NATURAL
HISTORY AND THAT BECOMES AN
IMPORTANT ISSUE ISSUE SO LET ME
JUST SAY A COUPLE THINGS ABOUT
GATA 2 THOUGH, WHAT WE KNOW IS
THAT SYMPTOMS GENERALLY APPEAR
IN CHILDHOOD, THEY CAN WORSEN
THROUGH EARLY ADULTHOOD, DISEASE
MANIFESTATIONS ARE HIGHLY
VARIABLE, WE HAVE A 20 YEAR-OLD
I TRANSPLANTED BUT HER MOTHER
HAS A MUTATION, SHE'S FINE, HER
GRANDMOTHER HAS A MUTATION,
SHE'S FINE AND HER GREAT GRAND
MARKET WAS 95 AND SHE HAD THE
MUTATION SO THERE'S A LOT WE
DON'T KNOW ABOUT WHO GETS
SYMPTOMATIC AND WHO DOESN'T.
WE DO KNOW THEY PROGRESS FROM A
NORMAL MARROW TO A VERY
HYPOCELLULAR MARROW THAT CAN
LOOK AT APLASTIC ANEMIA, AND
NEAL YOUNG'S GROUP TAKES CARE OF
APLASTIC ANEMIA, SEND US A HALF
DOZEN PATIENTS AND THEN THEY CAN
SEGUE RIGHT ON TO AML.
AND THAT'S THE DEADLY
COMPLICATION BECAUSE THIS IS A
VERY REFRACTORY AML.
THERE IS SOME SUGGESTION, CAN
YOU TELL THAT BY DR. HOLLAND'S
SLIDES OF ANTICIPATION IT SEEMS
TO APPEAR EARLIER IN EACH
GENERATION.
SO WHAT DOES IT LOOK LIKE IN THE
REAL WORLD.
THIS IS A WOMAN WE SAW IN A 38
YEAR-OLD WOMAN, LOT NORMAL
MARROW, VERY FATTY MARROW, VERY
LITTLE HEMEAT O POETICESIS, ONLY
10% IS CELLULAR THE REST IS THE
FAT TISSUE.
HOWEVER, IT LOOKED NORMAL IN
2009, IT WAS HYPOCELLULAR, BUT
SHE HAD NORMAL LOOKING
NUTRIFILLS AND METAMILE O
SIGHTS, NORMAL ARITHROADWAY
PRECURSORS NO INCREASED BLASTS
AND THE PLAN WAS TO FOLLOW HER
EVERY YEAR, HOWEVER, SHE STAYED
AWAY AND SHOWED UP IN DURANGO
COLORADO 1 FINE DAY, 2 YEARS
LATER WITH THIS MARROW.
ALL RIGHT THIS, IS BAD, HYPER
CELLULAR, IT'S 95% CELLULAR,
THIS CAN'T BE GOOD.
EVEN WORSE, WAS ALL THESE CELLS,
THESE ARE BLASTS, BIG CELLS, BIG
NUCLEI, NUCLEI, YOU CAN SEE 1,
2, 3, 4, 5, 6, 7, 7 BLASTS HERE,
SHE HAD A TOTAL 10% CELLS WERE
BLAST IN HERE.
THIS IS COMPLICATED, YOU GOTTA
GIVE THEM A CYCLE OF CHEMO
THERAPY AT LEAST, GET IT TO LESS
THAN 5% BLASTS AND THEN GO TO
TRANSPLANT.
SO SHE SLIPPED THROUGH OUR HANDS
BUT WE SUCCESSFULLY DID AN
UNRELATED DONOR TRANSPLANT AND
SHE'S ALIVE NOW 9 YEARS LATER.
MORE TRAGIC, SPEAKING OF
SLIPPING BY, 24 YEAR-OLD WOMAN
LONG HISTORY OF DYSPLASIA AND
[INDISCERNIBLE] SHE CAME TO DC
TO WORK ON THE ROLL OUT OF THE
AFFORDABLE CARE ACT, THEY WERE
THE GOOD CONTRACTORS BROUGHT IN
TO FIX IT, SO WE SAW HER FOR THE
FIRST TIME IN APLASTIC ANEMIA
CLINIC AND THEY THOUGHT, THIS
COULD BE GATA 2 SO THEY DID A
BONE MARROW, OF THE NORMAL
CELLULAR, MAYBE THAT WAS A CLUE,
SHE HAD PROBABLY BEEN
HYPOCELLULAR ALL THESE YEARS,
BUT IT WAS A NORMAL LOOKING
MARROW.
THESE ARE NORMAL LOOKING
NUTRIFILLS RIGHT HERE, SHE HAS
NORMAL LOOKING ERYTH ROADWAY
PRECURSORS, NO INCREASE IN
BLASTS, SO WE LOOKED AT THIS
MANY TIMES, SO THE TESTING WAS
SET OUT, IT WAS A LITTLE
CUMBERSOME THEN TO DO, SHE
FINALLY TURNED OUT TO BE GATA 2
POSITIVE.
FOUR MONTHS LATER WE GOT HER
BACK TO CLINIC, BOOM,
DR. HOLLAND AND I SAW HER IN THE
CLINIC, SHE'S BLOODING FROM A
VENA PUNCTURE WHERE HEBLOOD WAS
DRAWN AND SHE HAD THIS BONE
MARROW PACKED WITH CELLS.
AND WHAT ARE THEY PACKED WITH?
LEUKEMIA ACUTE MILE O MONOSITTIC
LEUKEMIA OR MONOBLASTIC
LEUKEMIA.
SO SHE AND 4 MONTHS AND A NEW
CYTOGENIC CHANGES, BOOM WITHIN 4
MONTHS SHE TURNED INTO ACUTE
LEUKEMIA.
THAT EXPLAINS WHY WE HAVE A LOT
OF VIGILANCE FOR THESE PATIENTS
BECAUSE NOW THIS WAS A DIFFICULT
CASE.
SHE HAD 3 CYCLES OF CHEMO
THERAPY NEVER GOT A REMISSION,
WE WENT TO TRANSPLANT, SHE
RELAPSED AT DAY 30, REPEATED THE
TRANSPLANT, RELAPSED AT DAY 100
AND DIED.
SO A TRAGED EDDIE WHICH PROBABLY
COULD HAVE BEEN AVERTED HAD WE
DIAGNOSED EARLIER.
SO WE'VE BEEN KIND OF IN MY LAB
TRYING TO FIGURE OUT WHAT
MUTATIONS CAN HELP TRIGGER GATA
2, AND WE HAVE A RECENT
PUBLICATION SHOWING 2 MUTATIONS,
ASXL1 WHICH IS A CHROMATIN
REMODELING ENZYME AND STAG 2
WHICH IS A COHESION MOLECULE,
COMMON MUTATIONS, THEY ARE IN
THE MDS, AML TYPE OF PATHWAY, SO
YOU START SEEING THESE, YOU
START WORRYING.
WHAT WAS NOTABLE THOUGH IS WE
DIDN'T FIND ANY OF THE COMMON
MDS, AML ASSOCIATED GENES, ALL
THESE SPLICING FACTORS TATTOO,
WE DIDN'T SEE THOSE, SO I SAID
THAT THOSE WERE THE 2 ASXL1, AND
STAG 2, THESE ARE COMMON IN 25%
OF THE PATIENTS IN ASXL1 IN 20%
OF THE PATIENTS SO ARE THEY
WELL OUR CONCLUSION WAS THAT
GATA 2 PATIENTS HAVE A NOVEL
PATHWAY TO LEUKEMIA, AND THAT
THEY LACK THE COMMON MDSA
MUTATIONS, AND THAT THEY HAVE
DIFFERENT MUTATIONS LIKE ASXL1
AND STAG 2 ARE SECOND HITS.
AND THOSE ARE PROGNOSTIC AND
THEY HAVE A LOWER SURVIVAL RATE.
BUT THAT'S NOT ENOUGH, THOUGH,
SO THEN THE QUESTION COMES SO
ARE WE GOING TO TRANSPLANT THEM.
IT'S ACTUALLY STILL A CLINICAL
DECISION PRIMARILY, IT'S THE
RECURRENT SEVERE OPPORTUNISTIC
INFECTIONS THEY'VE HAD 1
NONTUBERC LOWIS INFECTION AND
THEY WILL GET MORE AND BE IN
WORSE PLACE FOR TRANS.
WE SEE PEOPLE REQUIRING LAVAGE
AS PEOPLE SHOWED YOU IN THAT
WE'RE PICKING UP PATIENTS
EARLIER.
THE OTHER THING THAT DRIVES US
IN ABOUT HALF OUR PATIENTS, IT'S
CLINICAL AS THE PATIENTS ARE
MOVING TOWARDS MDS OR AML, THEY
HAVE INCREASED BLASTS, INCREASED
CELLULARITY AND NEW CYTOGENIC
CHANGES SO, IT'S SORT OF A
COMPOSITE THAT LEADS US TO
TRANSPLANT, THE INFECTIONS, I
DON'T SHOW ON HERE, BUT THE BONE
MARROW'S QUITE IMPORTANT
ESPECIALLY IF THEY'RE STRARTING
TO FAIL AND BECOME NEWT ROUGH
ATOM PENIC, NEWT CYTOGENETIC
CHANGES, MONO7 AND NOW WE ADD IN
THESE SOMATIC MUTATIONS THAT I
ALLUDED TO.
SO LET ME JUST SAY A FEW THINGS
TO GET YOU TO THINK LIKE A
TRANSPLANTER, WE THINK ABOUT
DONORS A LOT, WE LIKE MATCHED
SIBLINGS, SO WE'VE TALKED ABOUT
THE DISEASE, HOWEVER THE PROBLEM
WITH GATA 2 IS YOU--YOU SEQUENCE
THESE PEOPLE AND THE CHANCE IS
50% OF THEIR SIBLINGS CAN BE
GATA 2 POSITIVE SO THE ODDS ARE
UNLIKELY FOR A MATCH, BUT YOU
CAN GET A UNRELATED DONOR AND IF
YOU'RE OF NORTHERN EUROPEAN
STOCK YOU HAVE A ABOUT A 60%
CHANCE OF BEING AN UNRELATED
DONOR.
THERE'S A BANK IN GERMANY
SOPHISTICATEDY IT DROPS DOWN
HOWEVER IF YOU'RE BLACK OR
HISPANIC BECAUSE THE UNRELATED
DONOR BANK IS UNDERREPRESENTED
FOR THESE POPULATIONS, SO WE
ALWAYS LOOK AT UNRELATED
DONORSES ARE WE START OUT USING
UMBILICAL CORDS, YOU CAN GET
THEM QUICK, YOU CAN GET THEM IN
7-14 DAYS, THEY'RE ALREADY IN
THE FREEZER, THEY REFLECT THE
OUTBRED NATURE OF SOCIETY, THEY
COST ABOUT 80 GRAND SO THEY'RE
NOT CHEAP.
HERE'S THE PROBLEM, YOU ARE
DEALING WITH 1 TENTH OF A STEM
CELLS THAT YOU GET FROM A SIB OR
MATCHED UNRELATE DONOR SO
THERE'S INGRAFTMENT, VIRAL
COMPLICATIONS,
CERTAINLY--CERTAINLY SPECIALLY
WITH OUR PATIENTS THAT ARE
ADULTS THERE'S A SIZE DIFREBTIAL
SO THE OTHER ALTERNATIVE DONOR
WHICH IS THE BIG STRAIN COMING
DOWN THE TRACT OR HAPPEN LO
IDENTICAL RELATED DONORS THIS IS
A MOTHER, FATHER, BROTHER,
SISTER, DAUGHTER SO THESE ARE
FAST AND MOTIVATED.
SOEE LOOK FOR DONORS A LOT.
WE DO LOST LOTS OF SEARCHES WE
WANT TO GET A 10 OUT OF 10
MATCHED DONOR, WE USED TO DO 6
OUT OF 6 BACK AT 2000, NOW WE DO
10 BY DEN, THE GBH HAS DONE MORE
BY MATCHING AND THAT TRUMPS ADO,
EVERYTHING.
NATURAL DONOR PROGRAM LOOKED
BACK 10 YEARS AGO AND FOUND
THERE'S A 15% INCREASE MORTALITY
FOR EVERY DECADE OVER THE AGE OF
32.
SO IF YOU SIGN UP TO THE MATCH
AND YOU'RE OVER 32, THEY WILL
CHARGE YOU A HUNDRED DOLLARS TO
SIGN UP THEN IF YOU CAN GET A
BLOOD TYPE MATCH, THAT'S
HELPFUL, THAT WAY YOU DON'T HAVE
THE RED CELL DEPLETE AND THE
LIKE, AND THE OTHER THING IS IF
THE PATIENTS CMV POSITIVE, YOU
REALLY WANT A DONOR TO BE CMV
POSITIVE SO THOSE DONOR T-CELLS
HIT THE GROUND RUNNING AND YOU
DON'T GET THESE BAD VIRAL
REACTIVATIONS.
AND THE OTHER THING YOU DON'T
WANT A TINY DONOR AND A LARGE
RECIPIENT AND WE ARE DEALING
WITH THAT NOW, WE HAVE A TINY
DONOR LIKE 40-50 KILOGRAMS,
YOUNG WOMEN AND THE RECIPIENT'S
120 KILOS SO AUTOMATICALLY WE'RE
AT A DISADVANTAGE.
SO THE DONORS WE THINK ABOUT, WE
THINK ABOUT THE DONOR PRODUCT,
ARE WE GOING TO COLLECT
PERIPHERAL BLOOD STEM CELLS,
THERE'S A LOT MORE LYMPHOCYTES
THERE, MORE GBH, IT'S A BETTER
CHOICE IF YOU'RE WORRY BODY
RELAPSE, IT'S BEEN USED A LOT 94
DURING COVID BECAUSE PERIPHERAL
BLOOD STEM CELLS FREEZE BETTER
THAN MARROW.
SO THEN THE QUESTION IS
HAPLO-IDENTICALS CAME UP BECAUSE
THEY'RE SO MISMATCHED, THEY ARE
50% MISMATCHED AND THE INITIAL
STUDIES FROM HOPKINS USED
EXCLUSIVELY MARROW, NOW HE'S
TOLD ME THEY'RE BACK TO ABOUT
50/50 MARROW VERSUS PBS Cs FOR
THEIR HAPLOs, A LOT OF THINGS
PEOPLE DO IS I WILL CONSIDER GET
RID OF THE LYMPHOCYTES, CD34
SELECT THE STEM CELLS, RISK IS
THERE'S MORE GRAFT REJECTION
WHEN YOU DO THESE SELECTIONS.
A LOT OF GROUPS ARE NOW DOING
T-CELL RECEPTOR ALPHABETTA
DELETION, THESE ARE THE TYPE OF
T-CELLS THAT CAUSE GRAFT VERSUS
HOST DISEASE, SO YOU PUT THE
DONOR PRODUCT OVER A COLUMN,
THESE GUYS STICK AS WELL AS CD19
CELLS AND THEN YOU TAKE THE FLOW
THROUGH AND THAT'S WHAT YOU
INFUSE INTO THE PATIENT.
CORDS HAVE THEIR PROBLEMS, I
ALLUDED TO, SMALL NUMBER OF
CELLS.
SO LET ME JUST SAY A FEW THINGS
ABOUT CONDITIONING REGIMENS,
THAT'S OUR BIG THING, CAN YOU
GIVE A REALLY--YOU THINK ABOUT
IT A LOT.
YOU CAN GET A LOW DOSE
TRANSPLANT, NONMILE ABLATIVE,
THEY DON'T RECONSITUTE.
THIS IS HOW WE START OUT WITH
GATA 2, THEY WERE SO SICK.
IF WE GIVE THEM ANYTHING MORE
THAN THE MINIMUM, IT WILL BE THE
END OF THEM.
THREE OF THEM WERE ON OXYGEN,
THE END IS MILE O ABLATIVE,
THAT'S WHERE YOU GIVE
IMMUNOSUPPRESSIVE AND CHEMO
THERAPY DRUG, AND A LOT DO
EVERYTHING IN BETWEEN, SOME DO
SUPPRESSION.
FOR GRAFT REJECTION, THE BEST
WAY IS APLATE THEM, YOU KNOCK
OUT THE MYELOID CELLS AND THEIR
IMMUNE SYSTEM, THE OTHER THING,
IT GIVES A PERFECT MATCH, YOU
CAN GET IT, DON'T MESS WITH THE
GRAFT, THE MORE YOU T-CELL
DEPLETE, THE MORE YOUR CHANCE AT
REJECTION, ALSO IF YOU GET IT,
USE A HIGH DOSE OF STEM CELLS,
NOT ALWAYS POSSIBLE DEPENDING ON
THE DONOR AND THE RECIPIENT.
AND THEN I TALKED ABOUT BRIEFLY
GRAFT VERSUS HOST, IT'S BEEN THE
BUGGA POO OF TRANSPLANT FOR 50
YEARS, THE METHOTREKSATE WAS
USED FOR MANY YEARS IN SEATTLE,
THEN THEY COUPLED IT IN THE
EARLY 80S WITH CYCLOSPORIN OR
[INDISCERNIBLE].
AND NOW THE BIG TRAIN OVER THE
LAST 10-15 YEARS AND POST
TRANSPLANT CYCLOFOSTER NURSED
FACAS MID AND THAT WILL BE USED
FOR ALL THE HAPLOs AND USED
ALMOST FOR EVERYONE MATCH
RELATED AND UNRELATED BECAUSE IT
REALLY IS GOOD AT APLATING THE
DONOR T-CELLS THAT WILL CAUSE
GRAFT VERSUS HOST SO I WILL
BRIEFLY SUMMARIZE IN 2009, WE
DIDN'T KNOW IT WAS GATA 2, ALL
PATIENTS HAD MAJOR ISSUES, 3
WERE ON OXYGEN, I SAID I USED
THIS SEATTLE REGIMEN, THE MOST
REDUCED INTENSITY OR NONMILE
ABLATIVE REGIMEN OUT THERE,
SINGLE LOW DOSE OF RADIATION, 3
DAYS OF CHEMO THERAPY AND IT
WASN'T TERRIBLE, WE HAD 3 OUT OF
4 MATCHED UNRELATED DONORS WHO
WERE ALIVE AND DISEASE FREE, 1
REJECTED YOU WOULD EXPECT WITH A
LOWER DOSE REGIMEN AND DIED OF A
SECOND TRANSPLANT OF THE MATCHED
RELATED DONORS THIS IS THE CAP
LANMIER SURVIVAL CURVE WHICH ALL
TRANSPLANTERS SHOW, SURVIVAL ON
THE AXIS AND TIME ON THE X-AXIS
AND 1 OF THESE MATCHED DONORS
RELAPSED AND ULTIMATELY DIED.
THE BIG PROBLEM WITH THE CORDS,
1 EARLY IN AND 1 EARLY DEATH, 1
REJECTION AND DEATH WAS A SECOND
TRANSPLANT AND THEN 1 DONOR CELL
LEUKEMIA, OCCURRING 2 YEARS
AFTER TRANSPLANT WHICH IS--THESE
DONOR CELLS ARE JUST UNDER A LOT
OF STRESS AND THEY HAVE TO REP
LITICATE MANY TIMES AND THE
TELOMERES SHORTEN AND DEVELOP
STICKY ENDS, NEW TRANSLOCATIONS,
NEW LE KEEMIAS, THE HAPPEN LO
SURPRISINGLY ALTHOUGH 1 HAD
ACUTE LEUKEMIA AND DIED RIGHT
AWAY WITH TRANSPLANT, THE OTHER
IS ALIVE NOW, 9 YEARS LATER AND
SHE WAS ON DETH'S DOOR WHEN SHE
CAME TO THE NIH.
SO, THE CONCLUSIONS FROM THAT
REGIMEN IS THAT TRANSPLANT
REVERSES THE PHENOTYPE, WE NEED
TO GET THEM BEFORE THEY WERE SO
DEBILITATED AND LUKELY DURING
THIS TIME, STEVE COLLYNN'S GROUP
IDENTIFIED THE GATA 2 GENES SO
WE COULD THEN SCREEN DONORS,
IT'S PRETTY RISKY IF YOU DIDN'T
KNOW IF THE DONOR HAD IT BUT
THAT RELAPSE AND THE REJECTION,
COUPLE PATIENTS REQUIRE TD CHEEM
TO GET THE TRANSPLANT, WE NEEDED
MORE CONDITIONING AND WE
CONCLUDED CORD BLOOD WAS A
PROBLEM, WE ARE GOING TO DO
HAPLOs, THE HAPPY STORY IS
THIS WAS THE FIRST GUY WE DID
AND HE WAS SO SICK THEY
WOULDN'T--HE WENT TO SUBSUSH AN
TO HAVE HIS LUNGS WASHED OUT,
GOT INBAITED, EXTUBATED AND GOT
TRANSPLANTED FROM HIS BROTHER
BEFORE WE KNEW IF HE WAS GATA 2
NEGATIVE, THAT'S ALL HE HAD, NO
OTHER NUMBERS, HE LATER WENT ON
TO GET A LUNG TRANSPLANT BECAUSE
HIS LUNGS HAD BEEN SO BAD AND
THEN HE LATER FATHERED A CHILD.
SAME WITH THIS GIRL, SHE WAS
STEVE HOLLAND SPECIAL FROM LA
COUNTY TO THE ICU TO THE ICU AT
THE NIH, SHE BARELY LIVED
THROUGH THE NIGHT IN THE ICU AND
I SAID IF SHE LIVES THROUGH
TONIGHT I'LL TRANSPLANT HER FORM
WE TRANSPLANTED HER IN 2013 FROM
HER SISTER IN THE DONOR AND NOW
SHE'S 9 YEARS OUT, SHE'S HAD A
CHILD, SHE STILL HAS A COLOSTOMY
BECAUSE SHE HAS 2 LITTLE BOWEL
TO REANEGHT MOWS, SOPHISTICATEDY
THAT'S IT, WE WILL DO PROTOCOL,
I WILL MAKE IT MERCIFUL.
WE USED A STRAIGHT FORWARD
LEUKEMIA PROTOCOL,
[INDISCERNIBLE], WE CHANGED A
DIFFERENT TYPES OF POST
TRANSPLANT IMMUNOSUPPRESSION,
AND WE SWITCHED TO HAPLO-DONORS
AND WE HAD LONG DISCUSSION AT
JOHNS HOPKIN WHO IS DEVELOPED
THAT SO I WILL SHOW YOU THERE
REGIMEN AND WHAT HE TOLD ME
THEIR REGIMEN IS YOU GIVE A
LITTLE BIT OF CYTOXAN, MUCH LIKE
THE SETTLE REGIMEN BUT THEIR
PATIENTS ARE HEAVILY PRETREATED
FOR LEUKEMIAS SO I ADDED CY TO
THE PLAN AND THEN ON 3 AND 4
THEY GET TRANSPLANT, AND THIS
HAS BEEN EFFECTIVE AT PREVENTING
INFECTION AND PREVENTING GRAFT
VERSUS HOST DISEASE.
SO I'LL JUST SAY, OUR DISEASE
FREE SURVIVAL, THE FIRST 22
PATIENTS, THIS IS SURVIVAL,
MONTHS AFTER TRANSPLANT, THEY'RE
REALLY OVERALL PRETTY GOOD, THE
HAPLOs WERE ALL ALIVE, DONORS
WERE ALL ALIVE, UNRELATED
DONORS, WE HAD A COUPLE DEATHS
MOSTLY RELATED TO GRAFT VERSUS
HOST DISEASE, AND THIS IS BEFORE
THE KRIST TOXIN, AND YOU SEE THE
PROBLEM WE HAD ACUTE GBHD IN
THESE TRANSPLANTS. THIS IS
SERIOUS GRAFT VERSUS HOST
DISEASE THAT PEOPLE DIE FROM.
SO THE GOOD NEWS IS WE HAD GOOD
SURVIVAL WE HAD NASTY GRAFT
VERSUS HOST DISEASE, SO IN 2017
I SAID WE WILL GIVE MATCH
RELATED AND UNRELATED DONORS
JUST LIKE THE HAPLOs POST
TRANSPLANT.
AND OVERALL, NOW, COMPARING ALL
OF THEM, SINCE 2013, 71
PATIENTS, WE HAVE 1 YEAR FOLLOW
UP ON 61, OF THE MATCH RELATED
DONORS, 1 DEATH, WE THOUGHT HE
WAS RECTAL CANCER WAS IN
REMISSION BUT IT WAS RELAPSED
AFTER TRANSPLANT, THE 30
UNRELATED DONORS, YOU SEE THESE
ARE THE EARLY GRAFT VERSUS HOST
DISEASE DEATHS RELATED TO TACK
ROUGH ATOM MEX O TREKSATE WHICH
WASN'T AS GOOD AS
[INDISCERNIBLE].
THIS A REFREQUENTRY AML YOUNG
WOMEN I MENTIONED IN 1 LATE
METASTATIC SQ CELL CARCINOMA.
STRIKING THESE HAPLOOs, WE HAD
1 DEATH FROM RELAPSE, 2 HAD
CHRONIC GVHD, THE HAPLOs WERE
ALMOST PHENOLINAL, ALMOST OVER
ALL SURVIVAL, 83% EVENT FREE
SURVIVAL, NO GRAFT VERSUS HOST
DISEASE, NO SECOND TRANSPLANTS.
SO JUST TO SHOW YOU THE SURVIVOR
CURVE ON ALL OF THAT, THE TOTAL
GROUPS THE HAPLOs DID THE
BEST, WHO KNEW?
AND THE SECOND BEST WERE THE
MATCH RELATED AND UNRELATED GOT
POST TRANSPLANT SIGNIFY TOXIN
AND THE LOWEST WAS MATCH RELATED
AND UNRELATED TO THE MEX O
TREKSATE, SO AGAIN THE STRIKING
THING WAS THE GRAFT VERSUS HOST
DISEASE ISSUES THE HAPLOs HAD
VERY LITTLE AND THE POST
TRANSPLANT SIDE MATCH RELATED
AND UNRELATED DONOR, THAT'S ARE
RIGHT ALONG BASE LINE, THERE WAS
NO GRADE 3-4 ACUTE GRAFT VERSUS
HOST DISEASE, IF YOU GOT POST
TRANSPLANT SIGNIFY TOXIN.
SO THAT IS REMARKABLE, I'LL JUST
SAY THAT THE--AFTER WE PUBLISHED
OUR HIGHER DOSE REGIMEN, THE
BRITISH GROUPS PUBLISHED 4
PATIENTS WHERE THEY HAD LOW
DOSE, THEY USED REDUCED
INTENSITY SO THEN ASK ME TO
WRITE THE REVIEW AND SAID WHOSE
RIGHT?
ARE THEY RIGHT OR ARE YOU RIGHT?
AND I SAID WELL THERE'S A
SPECTRUM OF BONE MARROW FINDING
IN GATA 2 IF YOU'RE AT THIS END
AND YOU HAVE A HYPER CELLULAR
AND NEUROCYTOGENETICS AND IT'S
EASY TO GET GRAFTS IN EVEN IF
YOU HAVE THIS, REDUCED INTENSITY
WILL WORK IF YOU ARE UP HERE
WITH HYPER CELLULAR, YOU HAVE
THESE KIND OF [INDISCERNIBLE]
YOU WANT A HIGH DOSE REGIMEN SO
IT REALLY DEPENDS ON WHERE
YOU'RE AT IN THE COURSE, WHICH
SEGUES INTO OUR NEWEST REGIMEN
IS GOING TO USE REALLY TARGET
THESE 2 GROUPS SO IT'S A NEW
PROTOCOL FOR GOOD RISK GATA 2S,
HYPOCELLULAR MARROW, NO
CYTOGENETIC ABNORMALITIES, NO
INCREASED BLAST, IT'S GOING TO
USE A MONOCLONAL ANTIBODY THAT
BINDS TO C-KIT ON THE HOST STEM
CELLS, IT STARVES THEM OF STEM
CELL FACTOR AND YOU GIVE IT
ABOUT 2 WEEKS BEFORE TRANSPLANT
AND THE STEM CELLS DIE OFF.
YOU COUPLE IT WITH A LITTLE LOW
DOSE TDI AND YOU HAVE CHEMO FREE
CONDITIONING.
SO DANNY IS WRITING THAT ARTICLE
AND THE PROGRAM IS HEADED TO THE
IRB.
SO, SO, OKAY, SO WHAT I
SUMMARIZED A TOLD YOU ALOE
GENERATED AIC THINK LIKE A
TRANSPLANTER, KNOW YOUR DISEASE,
NATURAL HISTORY, DONOR, DONOR
PRODUCT AND THINK HARD ABOUT
CONDITIONING REGIMEN AND THINK
HOW YOU WILL PREVENT GRAFT
REJECTION AND HOW YOU WILL
PREVENT GRAFT VERSUS HOST
DISEASE, THOSE ARE 5 THINGS YOU
HAVE TO DO TO THINK LIKE A
TRANSPLANTER.
I SAID THE PAST IS PART OF THE
FUTURE IT'S FROM THE TEMPEST BY
SHAKESPEARE, HIS POINT IS ALL
OUR LIVES WERE MERELY A PROLOGUE
TO THE GREAT STORY TO AM CAN.
EVERYTHING THAT CAME BEFORE
DOESN'T MATTER BECAUSE A NEW AND
AND GLORIOUS FUTURE AWAYS BUT I
LIKE EVERYBODY ELSE USED IT IN
THE OPPOSITE MEANING, TODAY WE
USE IT IS THE PAST IS GREAT
IMPORTANCE BECAUSE IT DEFINES
THE PRESCRIBING EXPEBT SETS THE
STAGE FOR THE FUTURE, WHAT WE DO
WITH GATA 2 IS BASED ON WHAT
WE'VE DONE WITH THE PAST.
OKAY, THAT'S THE END OF MY
STORY.
I'LL STOP HERE.
>> THANK YOU DOCTOR, THANK YOU
FOR SHARING THE STORY AND TO
DR. HOLLAND AS LI WANT TO THANK
BOTH OF YOU FOR SHARING THE WORK
OF YOUR YEARS COLLABORATION
WHERE FROM THE CLINICAL INSIGHT
PROVIDED BY DR. HOLLAND AND HIS
COLLABORATORS, BRIDGING OVER TO
THE SUCCESSES NOW STEM CELL
TRANSPLANT, SO AGAIN, THANK YOU
TO BOTH OF YOU.
UNFORTUNATELY OR FORTUNATELY IT
TAKES [INDISCERNIBLE] SO I WON'T
BE ABLE TO SHARE ANY QUESTIONS
WITH YOU ALL TODAY, THERE ARE A
COUPLE CAME IN TO THE
CERTAINLY--CERTAINLY MAIL
VIDEOCAST AND I WILL SHARE THAT
WITH YOU BUT I WANT TO SAY THANK
YOU GONE FOR PRESENTING TO THE
NIH COMMUNITY AND EVERYONE, I
WISH EVERYONE A GREAT AFTERNOON
THANK YOU.