>> WELCOME, EVERYBODY TO THE
CONTEMPORARY CLINICAL MEDICINE
GREAT TEACHERS SERIES.
IT'S MY GREAT PLEASURE TO
INTRODUCE MY GOOD FRIEND AND
COLLEAGUE DR. AYALEO TEFFERI TO
OUR NIH GRAND ROUND.
DR. TEFFERI OBTAINED HIS DEGREE
IN THE UNIVERSITY OFAT ATHENS IN
HAPPIER TIMES THAN NOW BUT
CERTAINLY AFTER GREECE FELL,ó
; AND
SINCE THEN HE HAS BEEN SOLIDLY
AND PERMANENTLY AT THE MAYO
CLINIC IN ROCHESTER.
AND THAT'S SINCE 1989 AND HE
SERVES AS PROFESSOR OF MEDICINE
AND HEMAATOLOGY IN
THE--HEMATOLOGY IN THE MAYO
CLINIC.
HE'S A WORLD-RENOWNED EXPERT AND
LEADER IN CLINICAL RESEARCH
RELATED TO THE MANAGEMENT OF
CHRONIC LEUKEMIAS AND
PARTICULARLY MILE O PROLIF
RATILL DISORDERS AND HE'S IN THE
FIELD OF HEMATOLOGY AND CAN'T BE
DEFINE INDEED IN INTRODUCTION
BUT JUST TO GIVE YOU SOME
EXAMPLES, HE'S LED IN THE
DEVELOPMENT IN CYTOGENETIC RISK
CATEGORIZATION IN FIBROSIS, HE'S
A LONG HISTORY OF BEING INVOLVE
INDEED CLEANICAL TRANSLATIONAL
RESEARCH AND MALIGNANCYS AND
MYELOPROLIFERATIVE DISORDERS AND
SERVES AS PRINCIPLE INVESTIGATOR
O SINGLE SEVERAL CLINICAL TRIALS
ON MOLECULAR TARGETED THERAPIES
IN DISEASE AND HE CONTRIBUTED
GREATLY TO BOTH OUR
UNDERSTANDING OF THE BIOLOGY OF
MYELOPROLIFERATIVE DISORDERS AND
THE IDENTIFICATION OF THE
FACTORS AT THE TIME OF DIAGNOSE
THAT HELPED PROGNOSIS, SO IN
SHORT, DR. TEFFERI IS A TRUE AND
OUTSTANDING HEMATOLOGIST.
HE PUBLISHED MORE THAN 800
ARTICLES MORE THAN 500 ORIGINAL
RESEARCH ARTICLES ON SUBJECTS
MAINLY IN HEMATO LOGICAL
MALIGNANCIES IN MANY PEER REVIEW
JOURNALS AND HE SERVES AS AN
ASSOCIATE AT THE MAYO CLINIC
PROCEEDINGS AND SECTION NOTICEOT
JOURNAL OF LEUKEMIA AND
PARTICIPATES IN THE EDITORIAL
BOARD OF SEVERAL OTHER IMPORTANT
JOURNALS INCLUDING BLOOD AND
CANCER, GRADEST AMONG HIS
ACCOMPLISHMENTS AND REALLY WHY
HE'S HERE NOW, SPECIALLY IS HIS
REMARKABLE DEDICATION IS GIFT AS
A TEACHER, HE HAS A WONDERFUL
LECTURE STYLE AND IT MAKES INDEX
OF UNDERSTANDING, AND HAS YOU
HIDDEN HERE AND SO TODAY, MAYBE
TEACHER OF THE YEAR AWARD THAT
HE'S HAD IN THE MAY OR CLINIC.
SO PLEASE JOIN ME IN WELCOMING
DR. TEFFERI
TO THE NIH CLINICAL GROUND
ROUNDS LECTURE.
[ APPLAUSE ]
>> THAT WAS A WONDERFUL
INTRODUCTION, I SHOULD TAKE YOU
ALONG WITH ME.
YOU'RE LIKE JAPAN, WE CAN GO TO
JAPAN, TOO.
I'M HONORED.
THANK YOU, EVERYONE, VERY VERY
WONDERFUL HOSPITALITY I HAVE
RECEIVED SO FAR.
THIS IS A BIG HONOR TO BE
INVITED TO GIVE THIS LECTURE AND
I DON'T TAKE IT LIGHTLY.
YES, I WAS IN GREECE IN HAPPIER
TIMES.
THEY USED TO GIVE ME 7000
DRAKUMSs A MONTH AND I WAS
VERY RICH AND I USED TO GO
DANCING EVERY WEEKEND AND I HAD
EXTRA MONEY AND EVERYBODY WAS
HAPPY AND EVERYBODY TOOK SIESTA
AND I THINK AIL THAT SIESTA IS
COMING BACK TO THEM NOW.
BUT, COMPARED TO HEAR, WHERE
EVERYBODY WORKS 24 HOURS A DAY
AND THAT'S PROBABLY THE ONLY WAY
YOU COULD STAY AFLOAT AND I
THINK THE WORLD IS ACUTELY
RECOGNIZING THE NEED TO CARRY
EVERYBODY'S WEIGHT.
AT ANY RATE, I AM GOING TO TALK
TO YOU ABOUT MYELOPROLIFERATIVE
NEOPLASMS, AND I HAVE NOTHING TO
DISCLOSE.
OTHER THAN THE FACT THAT I DO
SERVE AS A PRINCIPLE
INVESTIGATOR OR CO INVESTIGATOR
ON MULTIPLE CLINICAL TRIALS,
SPONSORED BY ALL THESE DRUG
COMPANIES I HAVE LISTED BUT I AM
NOT IN THE ADVICERY BOARD, DON'T
OWN ANY STOCKS, I DON'T OWN ANY
OF THIS BECAUSE THIS ALLOWS ME
TO BE INDEPENDENT AND LOOK OUT
WHAT IS THE BEST INTEREST OF OF
THE PATIENT RATHER THAN THE BEST
INTEREST OF THE DRUG COMPANIES.
I'M AFRAID AND I'M SURE AT WHAT
I SEE HERE IS GOING TO BE POSTED
EVERYWHERE THAT MORE AND MORE
PERSON AND JOHN WOULD AGREE WITH
ME TURN INTOG THE PHARMACEUTICAL
SALES PERSONS AND THAT IS SAD
AND SO IT'S KIND OF NICE TO BE
NIH ORE PROTECTED BYLAW TO DO
THAT.
SO MILE O PROLIFFISMS ARE
FORMERLY INCLUDED IN THE
CATEGORY OF
AND AS YOU CAN SEE THE WORLD
HEALTH ORGANIZATION
CLASSIFICATION SYSTEM ORGANIZES
ALL THE MALIGNANCIES INTO ACUTE
LEUKEMIA.
AND CHRONIC MYELOID MALIGNANCY.
VERY SIMPLE CLASSIFICATION
SYSTEM THAT DEPENDSOT PERSONS OR
ABSENCE OF 20% MASTS OR BONE
MARROW, YOU GET ONE OR THE
OTHER.
ONCE YOU GET TO THE CHRONIC
MYELOID MALIGNANCIES FOR ALL
PRACTICAL PURPOSES, THERE ARE
THREE DISTINCT CLINICAL
PATHOLOGIC CLASSES.
ONE IS MYELOID DISPLASTIC
SYNDROMES AND IT IS
CHARACTERIZED BY TYPICALLY, TRI
LINEAGE DYSPLASIA YOU CAN SEE IN
THE BONE MARROW ALONG WITH
HEMEAT O POETICESIS ALMOST
ALWAYS ENDING UP IN THE
CYTOPENEUS DYSPLASIA, THE NEXT
ON THE OTHER ONE IS MYELOID
DYSPLASIA WHY THERE IS NONE AND
YOU HAVE SOME DEGREE OF
SIGNIFYITOSE NIGHS ANY ONE OF
THE MYELOID LINEAGE AND THE
THIRD ONE IS THE OVERLAP WHERE
YOU HAVE THE SIGNIFYITOSEIS BUT
YOU ALSO HAVE THE DYSPLASIA, THE
SO CALLED MDSPN OVERLAP.
TODAY I'M GOING TO FOCUS ON
MYELOID PROLIFERATIVE NEOPLASMS
AND THESE ARE THE EIGHT CLINICAL
PATHOLOGICKENTITIES IN THE WHO
CATEGORY OF MILE O PROLIFERATED
MYELOPROLIFERATIVENY O PLASMS.
THE FIRST IS THE AN
TOWITATING--ANNOTATING
DESCRIPTION, AND THE OTHER FAR
ARE LIKE THE MYELOPROLIFERATIVE
NEOPLASMS EXCEPT THEY ARE NEWER
AND THEY'RE MOSTLY ACENOPHILIC
AND MAST ORDERS.
THESE USED TO BE ALLERGER
DISEASE BUT NOW THEY'RE MORE AND
MORE HEMOTO LOGICAL DISEASES AND
AMONG THE CLASSIC
MYELOPROLIFERATIVE NEOPLASMS, MY
TALK TODAY WILL BE FOCUSED ON
THE BCR ABLE NEGATIVE
MYELOPROLIFERATIVE NEOPLASMS AND
THESE ARE LISTED THERE,
ESSENTIAL THROMBOW SIGNIFY
TEEMIA AND THROMBOSIS.
HERE ARE MY OBJECTIVES TODAY, ON
THOSE THREE DISEASES I'M GOING
TO PROVIDE A BRIEF OVERVIEW OF
PATHOGENITTIC MECHANISMS AND GO
THROUGH CONTEMPORARY DIAGNOSE,
VERY SIMPLE.
TELL YOU ABOUT HOW YOU
PROGNOSTICATE YOUR PATIENTS,
TALK ABOUT MANAGEMENT AND
FINALLY CLARIFY SOME MYTHS AND
FACT ABOUT JACK INHIBITOR
THERAPY FOR THESE DISORDERS.
NOW THE CURRENT DOGMA IS WE
BELIEVE THAT ALL MYELOID
MALIGNANCIES STEM FROM THE
HEMEAT O POETIC STEM CELL SO
IT'S A STEM CELL WHICH WE
BELIEVE IS PROBABLY PRONE TO DO
SO BECAUSE OF SOME HERITABLE
PREDISPOSING ALLELES THAT LEADS
TO THE OCCURRENCE OF AN
INITTIAIATING EVENT.
WE BELIEVE THAT THE EVENT IN
MYELOID LEUKEMIA IS BCR ABLE
ONE, WUY DON'T KNOW WHAT THE
EQUIVALENT IS FOR THE OTHER
THREE.
AND THAT'S PROBABLY WHY WE HAVE
THIS TREATMENT FOR CML AND THEN
AFTER THAT INITIATING PROCESS
THERE IS AN ISSUES ACCUMULATION
OF MUTATION WHICH IS WE BELIEVE
CONTRIBUTE TO DISEASE
PROGRESSION AND ULTIMATE
DISPEACES ACCUMULATION TO
LEUKEMIA.
WE DON'T KNOW EITHER IN CML OR
IN THE OTHER ONES WHAT THE
LEUKEMIA TRANSFORMING EVENT IS.
WE DON'T KNOW.
NOW WHAT WE DON'T KNOW IS SINCE
2004, THERE'S BEEN A NUMBER OF
GENES THAT HAVE BEEN IMPLICATED
AS BEING MUTATE INDEED THE BCR
MYELOPROLIFERATIVE NEOPLASMS AND
I HAVE LISTED THEM ALL HERE FOR
YOU.
NOW, OUTSIDE OF OF THE JACK TWO
MUTATION WHICH OCCURS IN THE
MAJORITY OF PATIENTS WITH THIS
DISEASE, THE OTHERS OCCURRED NOT
ONLY IN A VERY MINORITY, WE'RE
TALKING ABOUT ZERO-20%.
BUT ALSO THEY'RE NOT SPECIFIC,
THEY CAN BE FOUND IN DISPLASTIC
SYNDROME, ACUTE LEUKEMIA AND
SOME ARE FOUND IN LYMPHOID
MALIGNANCIES.
NOW WHAT'S IMPORTANT TO
RECOGNIZE HERE IS WHY WE KNOW
FOR SURE THAT THIS IS A
GENETICALLY TRANSFORMED STEM
CELL THAT PRODUCES CLONAL MILE O
PROLIFERATION WE DON'T KNOW IF
ANY OF THESE ARE INITIATING AND
WE KNOW THAT NONE OF THEM ARE
INITIATING BECAUSE THEY CANNOT
BE TRACED BACK TO THE STEM CELL,
THERE'S ALWAYS SOMETHING ELSE WE
CAN IDENTIFY BEFORE THEM SO THEY
ARE ACQUIRED LECTURED EVENTS.
SECOND WE DON'T KNOW WHETHER
ANYONE OF THEM ACTUALLY
CONTRIBUTES TO THIS
TRANSFORMATION INTO THE ACUTE
LEUKEMIA, EVEN THOUGH I MYSELF
HAVE WRITTEN SUGGESTING THAT
SOMETHING LIKE THAT OCCURS,
SOMETHING THAT I PERSONALLY
DON'T BELIEVE IN.
BUT YOU WRITE IT UP ANYWAY.
BUT WHAT WE KNOW IS THAT SOME OF
THIS MUTATIONS CONTRIBUTE TO
PHENOTYPE.
THERE ARE PHENOTYPE PATTERNING.
LET ME ELABORATE.
IF YOU ARE GOING TO HAVE
POLYSIGNIFY TEEMIA VERA, YOU
NEED MUTATION.
IN THE CONTEXT OF MILE O
PROLIFERATION AREG ROW
SIGNIFYITOSEIS APPEARS TO
REQUIRE THE MUTATION, SO IT'S
PHENOTYPE PATTERNING MUTATION.
ANOTHER EXAMPLE, THE NEW
MUTATION THAT WAS DISCOVERED,
THREE B ONE WHICH IS IN THE
LIAISON SO SOME, THAT APPEARS TO
BE REQUIRE THANKSGIVING CONTEXT
OF MALIGNANCIES FOR THE PRESENCE
OR FOR THE ACQUISITION OF RING
SID ROUGH ATOM BLASTS.
THOSE ACQUIRE SOME.
SO SOME OF THESE MUTATIONS WE
BELIEVE ARE PHENOTYPE
PATTERNING, THE QUESTION IS
WHENEVER WE THINK ABOUT
MANAGEMENT AND TARGETING, WE
HAVE TO THINK ABOUT WHAT THIS
MUTATION'S CAUSE AND IF WE HAVE
THE BEST--LET'S SAY WE HAVE THE
BEST SFTHREE B ONE TARGETING
MOLECULE, WHAT IS THE BEST WE
CAN GET OUT OF THAT, GET RID OF
SIDROPLASTS, THEY DON'T DO
ANYTHING TO YOU.
WHAT IS IMPORTANT IS THE ACTUAL
MYELOPROLIFERATIVE PROCESS THAT
IS WITH THE LEUKEMIA WITHOUT
NECESSARILY, NECESSARILY
REQUIRING THE SIDROBLAST FOR THE
PHENOTYPE OF PROGRESSION.
IT'S THE SIM WITH THE MUTATION.
SO IF WE FOR ONE SECOND ASSUME
THAT IN THE, THAT THE JACK TWO
MUTATION IS SIMPLY A PHENOTYPE
PATTERNING THAT CAUSES
ARITHROUGH ATOM SIGNIFYITOSEIS.
WHAT'S THE BEST THAT YOU CAN GET
FROM A VERY GOOD JACK INHIBITOR,
A JACK TWO INHIBITOR, YOU HAVE A
FANTASTIC INHIBITOR SO YOU CAN
ABOLISH IT, BUT THAT'S NOT THE
MAIN PROBLEM FOR THIS.
IN FACT, MOST OF THE LEUKEMIAS
THAT COME OUT OF JACK TWO
POSITIVE PATIENTS ARE JACK TWO
NEGATIVE, THE CLONES ARE JACK
TWO NEGAATIVE, THEREFORE AS WE
THINK ABOUT THIS MOLECULE AS
TARGETS, WE HAVE TO THINK DEEPER
AND SAY, OKAY, WHAT IS IT THAT
WE CAN ACCOMPLISH WITH TARGETED
THERAPY IN THESE DISEASES AND IS
THAT GOING TO END UP AS A
MEANINGFUL HEALTH OUTCOME FOR
THE PATIENTS.
NOW, HOWEVER, HOWEVER, MOST OF
THIS MUTATIONS, I THINK THE BEST
WAY I CAN DESCRIBE THEM ARE
ACUTE.
THEY'RE FOUND IN LESS THAN 10%
OF PATIENTS IN THIS DEC AND THAT
DISEASE AND SOMETIMES IN TWO%.
BUT, BUT, THEY ARE
SCIENTIFICALLY AND BIOLOGICALLY
VERY INTERESTING TO LOOK INTO
AND MOST OF THIS MUTATION, SOME
OF THE MUTATION, ESPECIALLY NOT
ONLY IN MYELOPROLIFERATIVE
NEOPLASM BUT ALSO IN MYELOID
PLASTIC SYNDROME AND ACUTE
MYELOID LEUKEMIA SEEM TO MODIFY
THE EPIGENETIC REGULATION OF
TRANSCRIPTION.
AND AS YOU CAN SEE HERE, THERE
ARE A NUMBER OF MUTATIONS AND IF
YOU CAN FOCUS ON THE YELLOW
ONES, NONE CANNONICLE, ASXL IS
THROUGH IDH, AND ALLÑO THIS,
MOLECULES, WHERE THEY'RE
DISCURBED BY SOME SORT OF
MUTATION, THEY AFFECT--IT
AFFECTS THE FUNCTIONAL
CONTRIBUTION TO THE EPIGENETIC
TRANSCRIPTION.
NOW YOU HAVE TO REMEMBER, DNA
METHYLATION IS NOT THE ONLY WAY
YOU CAN REGULATE THE EPIY
GENETIC REGULATION OF
TRANSCRIPTION.
HISTONES ARE VERY IMPORTANT,
THEY'RE NOT SIMPLY JUST
PACKAGING DNA BUT THE WAY YOU
METHALATE HISTONES, YOU
ACETALATE THEM, THE ORGANIZATION
OF THE CHROMATIN, THAT ALSO
AFFECTS THEIR INTERACTION, IT
WAS ACTUALLY DNA METHYLATION, SO
THERE ARE A NUMBER OF THIS
MUTATIONS ACTUALLY AFFECT THE
PHOSPHORYLATION, METHALATION OF
LYSINE OR ARE--ADMINISTRATIVE
GENERATEDDINE,OT HISTONES AND
ALSO DEPENDS ON WHICH HISTONE,
WHAT SIDE EFFECT YOU WANT AND
THAT ULTIMATELY DEFINES WHETHER
THE CHANGE SUPPRESSS
TRANSCRIPTION OR ACTIVATE
TRANSCRIPTION.
NOW THIS IS VERY, VERY,
INTERESTING SCIENTIFICALLY TO
THINK THROUGH AND BRAINSTORM.
THE QUESTION IS, ARE THIS
FUNCTIONAL CONSEQUENCES OF THESE
THINGS, HOW MUCH DO THEY
ACTUALLY CONTRIBUTE TO THE
PHENOTYPE THAT WE'RE LOOKING AT
INTO THE ACTUAL DISEASE BECAUSE
THEY'RE SO NONSPECIFIC, THEY'RE
FOUND EVERYWHERE ARE ARE THEY
SIMPLY NOISES WITHIN THE GENOMIC
PROFILE OF ANY CANCER?
CAN YOU FIND ANY OF THIS IN ANY
KIND OF CANCER?
BREAST CANCER?
COLON CANCER?
WHAT IS THE SPECIFICITY?
AND IS TARGETING THE EPIY
GENETICS GOING TO RESULT IN
BETTER OUTCOME FOR THE PATIENT?
ALL THESE THINGS ARE UNKNOWNS.
SO IN OTHER WORDS, THEY'RE VERY
NICE TO WRITE PAPERS ON, BUT I'M
NOT SURE THAT WE--I AM NOW
PATHOGENETICALLY HAVE HAD MUCH
MORE INSIGHT ABOUT THIS DISEASES
AS A RESULT OF ALL THIS
MUTATIONS THAT ARE BEING
DESCRIBED.
NOW, HOWEVER, THERE IS ONE
MUTATION WHICH IS INTERESTING.
THIS MUTATION, THE V61 MUTATION
WAS DISCOVERED IN 2004, THE
FIRST APPEARS APPEAR INDEED
2005, IS BY FAR THE MOST
FREQUENT MUTATION OF THESE
DISEASES, IT'S FOUND IN ALMOST
EVERYBODY WITH POLYSIGNIFY
TEEMIA VERA AND IN THE MAJORITY
OF PATIENTS, 60%% OF PATIENTS
AND PRIMARY MYELOID FIBROSIS AND
EVEN THOUGH 95% OF ALL JAK TWO
MUTATIONS ARE THE FMUTATION,
THERE ARE FIVE% THAT ARE
EVERYWHERE, AND ALL THIS
MUTATIONS APPEAR TO CLUSTER IN
THE JTWO, THE SO CALLY
PSEUDOKINASE REGION BUT NOW WE
KNOW THAT THIS IS NOT A
PSEUDOKINASE BUT A REAL KINASE
AND THERE IS A NATURE OR
STRUCTURE MOLECULAR BIOLOGY THAT
SHOW THIS IS IS A TRUE KINASE
THAT ACTUALLY PHOSPHORYLATES
SOME RESIDUES, WHICH ULTIMATELY
REGULATE SO SOMETHING NEW WE
KNOW THIS YEAR IS THAT THE
PSEUDOKINASE IS NO LONGER A
PSEUDOKINASE.
IT'S A TRUE KINASE AND THIS IS
WHERE ALL THE MUTATIONS OF
JAK-TWO ARE CURRENT.
NOW THIS IS ONE PART OF THE
PATHOGENESIS, SO THERE'S A LOT
OF MUTATIONS, NONE OF THEM HAVE
INTEREST IN THE INITIATING SOME
OF THEM ARE PHENOTYPE PATTERNING
AND THERE'S A LOT OF OTHER
MUTATIONS WHOSE FUNCTION IS NOT
CLEARLY KNOWN AT THIS POINT.
NOW IN ADDITION TO ALL THESE
MUTATIONS, IN MYELOID FIBROSIS
ESPECIALLY, BUT ALL MY
NEOPLASMS, THERE'S A SIGNIFICANT
CONTRIBUTION TO DISEASE
PHENOTYPE AND OUTCOME FROM AN
ACCOUNT INFLAMMATORY STATE.
AND IN FACT, ONE CAN ARGUE THAT
ALL CANCER HAS AN ACCOMPANY
MYELOID STATE WE'VE STUDIED THIS
IN SOME DETAIL AND WE KNOW THERE
ARE MANY CYTOKINES THAT ARE
ALTER SAID, MOSTLY INCREASED AND
WE ALSO HAVE SIGNIFICANTLY
ASSOCIATED SOME OF THE CYTOKINES
WITH CERTAIN DISEASE ASPECT AS
PRESSORS OF JAK-TWO MUTATION AND
WE BELIEVE, WE BELIEVE THAT THIS
INFLAMMATORY STATE--THAT IF YOU
TARGET IT, YOU CAN INFLUENCE
SOME OF THE DISEASE EFFECT
INCLUDING ANEMIA, SPLENY MEGALY,
AND WHAT HAVE YOU.
NOW WHAT THIS MEAN SYSTEM THAT
SUCH TREATMENT THAT AFFECTS
THIS, PROBABLY WILL AFFECT A
SIMILAR PHENOTYPE CONSEQUENCE,
ALSO NORMAL CYTOKINE EXPRESSION
INCLUDING DISEASES.
SO, THIS IS WHERE WE ARE WITH
PATHOGENESIS.
LET'S TALK ABOUT DIAGNOSIS.
THE MUTATION I TALKED ABOUT,
JAK671 F IS ALMOST THERE PRESENT
AND THEREFORE IT HAS TO BE A
VERY SENSITIVE MARKER FOR THE
PRESENCE OF THIS DISEASE, ALSO,
THIS MUTATION IS RESPONSIBLE FOR
CONSITUTIVE ACTIVATION OF NOT
ONLY JAK START BUT ALSO DOWN
STREAM PATHWAYS THAT COULD BE
TARPGETTED AS MUCH AS WE ARE
TARGETING JAK AS WELL, YOU CAN
HAVE INHIBITORS AND OTHERS THAT
CAN POSSIBLY GIVE YOU THE SAME
KIND OF RESULT AS IF YOU ARE
APPROXIMATELILY TARGETED AT JAK
STAT.
SO THIS IS WHAT WE HAVE
DISCOVERED BY THIS MUTATION, NOT
ONLY AS A VERY SENSITIVE MARKER
FOR DIAGNOSIS BUT ALSO
IDENTIFYING A POTENTIAL TARGET
FOR DRUGS.
ONE SLIDE FOR THE DIGSIS OF ALL
THREES DIAGNOSIS OF ALL THESE
DISEASES.
THIS IS ALL YOU NEED.
IF YOU SUSPECT PV, WE NO LONGER
DO RED CELL MASS, WE NO LONGER
DO BIOPSY, WE ORDER 2 TESTS,
REASONABLY CHEAP, LESS THAN $500
TOGETHER.
V617 F MUTATION SCREENING AND
SERUM FOR HEMEAT O POETIN LEVEL.
IF THE MUTATION IS POSITIVE, THE
DIAGNOSIS IS PV, YOU CAN PUT
YOUR HAT ON AND GO HOME, NO
DISCUSSIONS.
IF THE V617 F IS NEGATIVE, THEN
THERE'S STILL A POSSIBILITY THAT
YOU'RE DEALING WITH THE V61 F
NEGATIVE PV WHICH COULD BE A 12
YOU HADITATION OR WHAT HAVE YOU
AND THERE YOU LOOK AT THE REPORT
AND LEVEL BECAUSE THE SERUM
LEVEL WILL ALWAYS BE SUBNORMAL
IN THAT CONTEXT AND, IF THE V617
F IS NEGATIVE AND THE SERUM IS
NORMAL, THAT'S NOT PV.
ABSOLUTELY.
NOW IF YOU WANT TO ARGUEWn:q5ç ABOUT
THAT,EC MAIL--E-MAIL ME AND WE
CAN ELABORATE FURTHER ON THAT.
BUT IF THE SERUM IS SUBNORMAL IT
IS IMPORTANT THAT PROBABLY YOU
SHOULD DO BONE MARROW
EXAMINATION AND EXEC FOR
MUTATION AND THEN YOU CAN
CAPTURE THE REMAINING CASES OF
PV AND IF THAT IS NEGATIVE
THAT'S NOT PV.
WHEN IT COMES TO SIGNIFY TEEMIA
WE DON'T HAVE A GOOD TEST BUT
BECAUSE 70% OF THE PATIENTS
CARRY THIS MUTATION, IT IS GOOD
TO ORDER THIS BECAUSE IF IT IS
POSITIVE, IT TELLS YOU THERE IS
AN UNDERLYING MODEL OF NEOPLASMS
SO CAN YOU ACTUALLY DO THE BONE
MARROW BIOPSY EARLIER RATHER
THAN LATER BUT YOU DEPENDOT
PATHOLOGY TO TELL YOU WHETHER
IT'S CONSISTENT WITH THE
ESSENTIAL THROMBOW SIGNIFY
TEEMIA.
NOW THE OTHER QUESTION HERE IS
WHEN YOU DO THE JACK 2 SCREENING
IF IT IS NEGATIVE IT DOESN'T
HELP YOU.
>> MYELOID FIBROSIS, I DON'T
THINK YOU SHOULD WASTE ANY OF
TEAM, BUT THERE, AND BONE MARROW
EXAMINATION, SUSPECTING, YOU
HAVE TO ALWAYS INCLUDE
CYTOGENETICS AND V617 F
SCREENING BECAUSE A BONE MARROW
FIBROSIS IS ACCOMPANY BY V6 R 7
F OR MINUS IS PRIMARY MYELOID
FIBROSIS.
YOU DON'T HAVE--MD NEVER GIVES
YOU--VERY UNUSUAL FOR IT TO GIVE
YOU CTQ MINUS SO IT HELPS YOU
REFINE THE DIGSS OF MILE O
FIBROSIS, AS OPPOSE TO OTHER
MYELOID DISORDER WITH BONE
MARROW FIBROSIS.
SO, IT APPEARS TO BE STRAIGHT
FORWARD FOR PV, IT APPEARS TO BE
STRAIGHT FORWARD FOR MYELOID
FIBROSIS BUT FOR ET YOU
RELIAISON ON PATHOLOGY BECAUSE
THERE ARE A NUMBER OF THINGS
THAT CAN ACTUALLY MIMIC ET IN
THE CLINICAL PRESENTATION, CML
CAN PRESENT WITH ISOLATED
THROMBOAS AND I GUESS CAN LOOK
LIKE ET AND IT IS INCOMBENT ON
YOU TO MAKE SURE YOU'RE NOT
DEALING WITH CML BECAUSE IF YOU
MAKE THE WRONG DIAGNOSIS A
PATIENT CAN TURN IN LEUKEMIA IN
5 YEARS AND YOU COULD HAVE TREAT
THAD PATIENT WITH GLEVEK, AND
YOU COULD HAVE KRR--CML.
THEY'RE DWARF OR THEY LIKE LIKE
ET, THEY'RE BIG AND HAPPY.
NOW CAN YOU DID MUSEUM--YOU CAN
DO MUTATION SCREENING WHICH
WOULD RULE OUT CML BUT MORE
IMPORTANTLY THERE 24 OTHER
MYELOID MALIGNANCIES WHICH CAN
BE IMITATED AND HAVE TO BE RULED
OUT.
1 IS A TYPICAL MYELOID SIS
PLASTIC SYNDROME, THIS DISEASE,
CAN BE 50% POSITIVE FOR JAK2, SO
THEREFORE THE PATHOLOGIST NEEDS
TO LOOK AT THE BONE MARROW
BIOPSY AND MAKE SURE THERE IS
NOT A ARITHROADWAY DISPLASSIA
AND YOU DON'T MAKE THE WRONG
DIAGNOSIS.
HARDER WOULD BE THE 1 TO
DISTINGUISH BETWEEN ET AND
PREFIB ROTTIC MYELOIDOSEIS,
THERE YOU HAVE CARRY SIGHTS OF
THE KEY AND HAVE YOU A KEY
PATHOLOGY, BUT THE SERUM LDH,
THE LOOK AT THE PERIPHERAL BLOOD
SMEAR, YOU SHOULD NOT HAVE
ANEMIA, INCREASED LDH OR LOOK
THE FIBROBLASTIS IN ANY SORT OF
TRUE ET, AND AS A CLINICIAN YOU
CAN HAVE SOME IDEA AS TO WHETHER
YOU'RE DEALING WITH THE
FIBROSIS.
AND THIS IS IMPORTANT BECAUSE
THE PROGNOSIS IS DIFFERENT IF
YOU HAVE 2 ET VERSES PREFIB
ROTTIC AND LOOK AT THROUGH ET.
FIRST OF ALL SURVIVAL APPEARS TO
BE IDENTICAL TO THE MAGIC
CONTROL POPULATION AS YOU CAN
SEE, BUT NOT ONLY THAT, IF YOU
HAVE 2, THE 10 YEAR RISK OF
A-10UE AWGZ IS LESS THAN 1%,
BELIEVE IT OR NOT.
SAME WITH MYELOID FIBROSIS, BUT
IF HAVE YOU PREFIB ROTTIC IN THE
STATE OF THAT, THAT JUMPS UP TO
6% OR 12% FOR THAT MATTER FOR
MYELOID FIBROSIS SO THIS IS
IMPORTANT FOR THE PATIENT
BECAUSE IT CAN BE HAPPY TO TELL
THE PATIENT THEY'RE GOING TO
LIVE FOREVER IT IS TRUE ET.
OR YOU WILL NOT DO WELL, SOEE
HAVE TO FOLLOW THIS CAREFULLY,
THIS IS NOT A BAD CURVE, IT'S
JUST NOT AS GOOD AS ET CURVE.
SO NOW WE'RE GOING TO PROGNOSIS.
SO IF WE HAVE 2 ET, THERE ARE 3
THINGS THAT ARE PROGNOSTICLY
AVAILABLE.
ADVANCE STANCH, PRESENCE OF
LEUKOCYTOSIS, PRESENCE OF
DROMBOSIS.
MULT$AR
THESE ARE THE 3 FACTORS AND
USING THESE 3, KIND OF A VERY
GOOD IDEA AS TO HOW PATIENTS CAN
DO.
IF YOU'RE PATIENT IS YOUNG AND
DOES NOT HAVE LEUKOCYTOSIS OR
THROMBOSIS, THEY'LL LIVE BETTER
AS NORMAL POPULATION, AS YOU CAN
SEE HERE.
IF THEY'RE YOUNG AND THEY HAVE 1
OR THE OTHER I. E. LEUKOCYTOSIS
OR THROMBOSIS THEY'LL ACT AS IF
THEY'RE OLD.
OKAY?
THEY'RE GOING TO DIE SOONER.
AND IF THEY ARE OLDER, OR
AND HAVE EITHER LEUKOCYTOSIS OR
THROMBOSIS, THEN THE OUTCOME IS
NOT AS GED GOOD.
THIS IS IT, VERY SIMPLE.
VERY SIMPLE.
INTERESTINGLY,ND0E'RE STILL
IN THEROCESS, WE HAVE
1500 PATIENTS
INTERNATIONAL
INTERESTINGLY WE'RE FINDING OUT
EDGE, VERY, VERY, IMPORTANT IN
THE PREDICTION OF SURVIVAL BUT
ALSO LEUKOCYTOSIS AND 4 OTHER
THINGS THAT I CAN'T TELL YOU NOW
BECAUSE I HAVE TO PRESENT THAT
AT A. S. H., OKAY?
BUT IT REMAINS THE
IN
1 OF THEM.
ENTHROMBOSIS.
AND THE SAME THING
EVEN BETTERITH PV BECAUSE WE
H
LOOK
H
TERIOLE THROMBOSIS AND VENUS
THROMBOSIS AND IT WAS VENUS AT
PRESENTATION.
YOU HAVE THE MI AND EVERYDING,
THAT'S FINE BUT YOU CAN'T
DVT.
THIS IS A MORE DIFFICULT 1.
MILE O FIBROSIS.
BUT IF YOU CAN TAKE EVERYTHING
ABOUT THIS DISEASE AND
PERSONALLY IN 2011, ANY
PROGNOSTICATION, ANY RISK
STRATIFICATION THAT DOES NOT
INCLUDE CYTOGENETIC SYSTEM A
KNOWN STARTER FOR ME.
IT'S A KNOWN STARTER.
YOU HAVE TO HAVE THAT WHETHER
IT'S AML, WHETHER IT'S MDS,
CYTOGENETIC SYSTEM KEY, SO
THEREFORE IN THIS REFINED
DYNAMIC INTERNATIONAL PROGNOSTIC
SCORING SYSTEM, WHERE
CYTOGENETICS AND OTHER
ADDITIONAL THINGS ARE ADDED AND
YOU CAN ACTUALLY GOOGLE THIS.
YOU DON'T HAVE TO MEMORIZE IT,
WE CAN USE 8 EASILY CLINICALLY
ACCESSIBLE FEATURES OF THE
DISEASES INCLUDING CYTOGENETICS,
IN ORDER TO COME UP WITH A VERY
NICE RISK STRATIFICATION TO LET
YOU KNOW WHERE YOU SHOULD ACT
WITH AGGRESSIVE THERAPY VERY
EARLY, 4 OR MORE OF THIS RISK
FACTORS IS BAD OR RELATIVELY
AGGRESSIVELY, 2 OR 3 ARE ALMOST
AS BAD OR YOU SHOULD LEAVE THE
PATIENT ALONE.
NOTHING OR JUST 1.
SO THIS IS HOW WE PROGNOSTICATE
OUR PATIENT.
NOW LET'S TALK ABOUT HOW WE
MANAGE THIS IN OUR LAB.
NOW WHENEVER YOU START THINK
BEING THE MANAGEMENT OF THIS
DISEASES, AND EVERYBODY IS
EVERYWHERE WHEN IT COMES TO
THIS, BUT THE MOST IMPORTANT
THING AS A CLINICIAN WHEN YOU
SEE THIS PATIENT, WHAT ARE THE
CLINICALLY RELEVANT ISSUES IN
THIS DISEASES.
OKAY?
NUMBER 1 IS, SHORTENED SURVIVAL,
THAT PRIMARILY IN MYELOID
FIBROSIS, BECAUSE THE AVERAGE
OVERALL IS ABOUT 7 YEARS SO
THERE IS SHORTER, BUT IT WOULD
BE NICER DRUG THAT PROLONG
SURVIVAL, WE DON'T HAVE ANY SUCH
DRUG AND THIS SURVIVAL SHORTENED
BECAUSE OF LEUKEMIC-; RIGHT?
NOW FOR ET AND PV, THE SHOREDDEN
SURVIVAL IS NOT AS MUCH AS A
SURVIVAL, THEY LIVE A LONG TIME,
THEY LIVE A LONG TIME BUT THEY
TRANSFER TO LEUKEMIA AND 1% IN
10 YEARS, IN PV MAYBE ABOUT 5%
BUT IT CAN ALSO TRANSFER INTO A
DISEASE THAT COMPROMISES THE
QUALITY OF LIFE.
THEY CAN TRANSFORM TO MYELOID
FIBROSIS.
BUT MORE IMPORTANTLY MUCH MORE
FREQUENTLY, MAYBE 20-40% OF THE
TIME THEY CAN EXPERIENCE SEVERE
THROMBOSIS.
THESE ARE THE CLINICAL
RELEVANCE, SURVIVAL, CHEMICAL
TRANSFORMATION, FIB ROTTIC
TRANSFORMATION OR THROMBOSIS.
SO THEREFORE IN PV OR ET, IF
ANYBODY TALKS TO ME ABOUT HOW
GOOD THEIR DRUG IS BECAUSE THEY
CAN CONTROL THE PLATELET COUNT
OR THEY CAN CONTROL THE
LEUKOCYTE COUNT OR THEY CAN
CONTROL THE BIG SPLEEN MEANS
THAT THIS, WHOEVER IS TALKING
ABOUT THIS, HAVE NO IDEA WHAT
THEY'RE TALKING ABOUT.
NO IDEA WHATSOEVER.
THE PATIENTS, THAT'S NOT WHAT
THE PATIENTS NEED.
HIGH PLATELET COUNT IS ACTUALLY
PROTECTIVE OF THROMBOSIS IN ET,
BELIEVE IT NOR NOT.
SO YOU HAVE TO ANSWER THE
QUESTION:  IS THIS DRUG GOOD?
DOES IT ADDRESS THE RELEVANT
ISSUES IN THIS DISEASE?
NOW, IN MYELOID FIBROSIS, IN
ADDITION TO THESE, YOU HAVE POOR
QUALITY OF LIFE BECAUSE OF
ANEMIA, BECAUSE OF HUGE SPLEEN
AND BECAUSE OF SEVERE PROFOUND
CONSTITUTION OF CENTERS,
THEREFORE THERE, TO THE IMPROVE
QUALITY OF LIFE IF YOU DID
SOMETHING THAT IMPROVES QUALITY
OF LIFE, IT IS CHANGING, YOU
KNOW THE OUTCOME SOMEWHAT.
SO IN ET AND PV, WE SAY THAT
SURVIVAL IS GOOD.
WE SAY THAT LEUKEMIA
TRANSFORMATION IS LOW.
HYPER TRANSFORMATION IS LOW,
THEREFORE IN ORDER FOR YOU TO
SHOW ME WITH YOUR NEW DRUG IS
BETTER THAN THE STATUS QUO WHICH
IS HYDROXIA OR ASPIRIN, IT TAKES
MANY, MANY YEARS MANY, MANY,
PATIENT ANYPLACE EACH ARM AND
VERY, VERY, DIFFICULT AND SO FAR
NOBODY HAS SHOWN THAT ANY DRUG
IS BETTER THAN ANY OTHER DRUG OR
JUST MONITORING THE PATIENT IN
TERMS OF SURVIVAL OR DISEASE
TRANSFORMATION.
THEREFORE, WHAT PEOPLE HAVE
SHOWN IN THIS DISEASE IS IN
THOSE 20% OF PATIENTS WHO ARE AT
HIGH RISK FOR THROMBOSIS THAT
YOU CAN POTENTIALLY PROVENT THAT
AND WHO'S AT HIGH RISK FOR
THROMBOSIS, WELL, OLDER THAN AGE
60, ROUGHLY, CAN YOU CHANGE UP
TO 65, IF YOU WANT TO.
THAT'S ALL RIGHT WITH ME.
PLUS, HISTORY OF THROMBOSIS.
SO EITHER YOUR OLDER OR HAVE A
HISTORY OF THROMBOSIS, YOUR
RISKS ARE HIGH.
THAT'S THE KIND OF PATIENTS
WHICH YOU CAN POTENTIALLY
INFLUENCE THE RISK BUT IF YOU
ARE YOUNGER AND DON'T HAVE A
HISTORY OF THROMBOSIS, THEN
YOU'RE RISK OF THROMBOSIS
PROBABLY NOT SIGNIFICANTLY
DIFFERENT THAN MINE.
NOW THE QUESTION IS IF YOU ARE A
LOW RISK PATIENT WHOSE OTHER
WOIZ A PLATELET MILLIONAIRE, THE
QUESTION IS HOW--HOW SHOULD YOU
REACT TO THAT. WELL, THE BIG
INTERNATIONAL STUDY WAS SHOWED
THAT ACTUALLY THE HIGHER, THE
BETTER.
IF YOU HAVE A HIGH PLATELET
COUNT TWORKS LIKE A SYSTEMIC
ANTICO AGULATE BECAUSE IT
ACQUIRES THE DISEASE, AND
THEREFORE IT MAKES THE PLATELET
LESS STICKY SO YOUR PROBLEM IS
BLEEDING NOT THROMBOSIS.
TAKING THAT INTO CONSIDERATION,
WE CONSIDER ACTUALLY HIGH RISK
DISEASE IN THE LOW RISK WAS
EXTREME THROMBOW SIGNIFYITOSEIS,
WE TAKE NOTE, THE PLEADING, WE
DON'T CONSIDER THEM HIGH RISK
AND THE SAFETY OF ASPIRIN THAT
WE WANT TO USE.
EVIDENCE.
ASPIRIN IS BETTER THAN NOTHING.
PV IN TERMS OF THROMBOAS
ESTIMATE THAD, BUT THE
DIFFERENCE IS NOT THAT MUCH, IF
YOU DON'T TAKE ASPIRIN, IT'S
OKAY, DON'T SWEAT IT.
BUT THERE IS EVIDENCE, EVIDENCE,
HIDREADA IS BETTER THAN NOTHING
IN TERMS OF PREVENTING
THROMBOSIS THIS IS NOT
THROMBOSIS WE SURVIVE, BASED ON
THAT, THIS IS MY CURRENT
TREATMENT ALEGORITHMS IN PV OR
ET.
IF YOU ARE A LOW RISK WITHOUT
EXTREME THROMBOW SIGNIFYITOSEIS,
I GIVE YOU 1 BABY ASPIRIN A DAY
AND WE'RE DONE.
NOW IF YOU ARE A LOW RISK, BUT
THE 1 IN THERE, I WORRY ABOUT
BLEEDING SO BEFORE I GIVE YOU
ASPIRIN, I ORDER AN ACQUIRED
SYNDROME TEST, MY FAVORITE TEST
IS SPECIFIC CO FACTOR ACTIVITY,
IF IT IS GREATER THAN 30%, I
FEEL SAFE, BY ADMINISTERING
ASSPRING.
IF IT IS LESS THAN 30%, I SAY, I
THINK YOU'RE BODY'S ALREADY
GIVING YOU ASSPRING, I LEAVE THE
PATIENT ALONE.
IF IT'S HIGH RISK OF PATIENT, MY
FIRST LINE IS HYDROXIA, AND THEN
ASPIRIN ON TOP OF THAT AND ON
TOP OF ALL THIS, IF IT IS A PV
PATIENT I ASK THEM TO GET
PHLEBOT MYSELFED AND YOU ASK TO
WHAT%?
48, 47?
, 45?
38?
ASK THE PATIENT, ASK THE PATIENT
WHERE THEY FEEL THE BEST?
AS LONG AS YOU DON'T LET IT GO
OVER 50 AND THEY'RE ON ASPIRIN,
ANYTHING GOES.
THEN THE QUESTION COMES WITHIN
THE CONTEXT OF PV AND ET, WHAT
ABOUT ONSITE INTERFERON
INHIBITORS.
THERE ARE NEW DRUGS.
THEY MAKE MORE MONEY, THEY HAVE
MORE SIDE EFFECTS, OKAY?
SO THE QUESTION IS, ARE THEY
BETTER THAN STATUS QUO?
AND ONLY IN CONTROL STUDY CAN
YOU ADDRESS THAT ISSUE?
AND IT DOESN'T MATTER HOW MANY
TIMES YOU TELL ME THAT THERE HAS
BEEN MOLECULE INTERMISSIONS WITH
INTERFERON OR THIS OR THAT, IT
MEANS NOTHING TO ME.
TELL ME IF YOU CAN IMPROVE
PROTECTION FROM THROMBOSIS.
IMPROVE SURVIVAL.
PREVEPT LYM KEEPIA--LEUKEMIA
TRANSFORMATION.
OTHERWISE YOU KEEP YOUR NOISE TO
YOURSELF.
NOW HOW ABOUT TREATMENT DURING
PREGNANCY?
EXACTLY THE SAME, OKAY, ASPIRIN
IS ACTUALLY GOOD.
IT REDUCES THE RISK, AT LEAST
FROM RETROSPECTIVE STUDY OF
FIRST TERM MISCARRIAGES.
BUT USING HYDROXURIA IN A
PREGNANT PATIENT OR IN A WOMAN
THAT WANTS TO BE PREGNANT
DOESN'T SOUND VERY GOOD IN A
COURT OF LAW.
WHATEVER HAPPENED?
WELL WE'VE ALREADY SHOWN IT IS
BAD.
IN FACT THERE ARE SO MANY
CHILDREN THAT WERE BORN TO
MOTHERS THAT WERE EXPOSED TO
HYDROXURIA IN THE FIRST
TRIMESTER, NOTHING HAPPENED.
SO WHO NEEDS TO THE HEADACHE?
USE INTERFERON.
NEW EVIDENCE.
IF YOU HAVE INTRACTABLE PATHWAY
GIVES RIGHT ISOTOPE, I HAVE TO
DEBATE, THE BEST DRUG I EVER SAW
FOR PORRITEIS IS JAK INHIBITORS.
THAT'S WHY I TELL THEM, YOU
SHOULD MARKET YOUR DRUG AS
ANTIITCHING DRUG.
[LAUGHTER]
IT'S VERY GOOD.
NO QUESTION.
IT'S GONE OVERNIGHT.
BUT WHAT IF YOU CAN'T USE
HYDROXURA, PEOPLE HAVE SHOWN
OVER AND OVER AGAIN THAT
INTERFERON ALPHA CAN CONTROL THE
DISEASE AND I'LL SAY THIS, IT'S
PROBABLY THE BEST ANTIMYELOID
PROLIFERATIVE DRUG THAT I KNOW
AND DOLLAR'S ABSOLUTELY NO
EVIDENCE--THERE'S ABSOLUTELY NO
EVIDENCE THAT IT'S MORE THAN HID
DROKSURA, SO YOU SAY WAIT A
MINUTE.
YOU HAVE TO THINK OF OF
SOMETHING, THERE'S NO MONEY TO
BE MADE WITH HYDROXIA, SO WHEN
YOU CAN'T POSSIBLY SHOW IN A
CONTROLLED EVIDENCE THAT THIS
DROPPINGS ARE AS SAFE AS
ANYTHING, THEN IN ORDER TO
PROMOTE YOUR NEW DRUGS WHATEVER
THEY ARE, WHETHER THEY'RE
INTERFERON, YOU START SPREADING
RUMORS.
REALLY, YOU KNOW?
, WHERE DO YOU GET THAT?
HAVE THE LARGEST PATIENT
POPULATION STUDIED IN THE WORLD
AND WE'VE DONE INTRODUCTION OF
OF STUDY, THERE'S ABSOLUTELY NO
EVIDENCE, WHERE DID YOU HEAR IT.
>> WELL I READ THAT IN 1957.
OKAY, I GOT IT NOW.
>> SO, BASED ON THAT, IN
ADDITION TO THAT, IN MY PATIENTS
THAT ARE HYDROXURIA, RESISTANT
OR INTOLERANT, THEY'RE OLDER,
AND I'M A HUMAN BEING I HAVE
BLOOD, NOT YOGURT IN MY BLOOD
VESSELS AND THEREFORE I'M
SENSITIVE TO THESE THINGS SO IF
YOU'RE YOUNGER I HAVE IRPT
FERON, BECAUSE THERE ARE THINGS
THAT INTERFERON ARE GOOD FOR BUT
IF YOU'RE OLDER I THINK
LUCIFERIN AND GOOD.
YOU DON'T NEED THE ADDITIONAL
SWROMY EFFECT FROM INTERFEREON.
>> NOW THIS IS TREATMENT, IT
COMES FROM OBSERVATION TO ALOE
GENICS AND TRANSPLANTATION AND
THEN BETWEEN SPLENECTOMY,
RADIATION, CONVENTIONAL DRUGS
AND EVERYTHING COMES IN.
THIS IS A TOUGH DISEASE TO
TREAT.
AND HERE, YOUR TREATMENT
APPROACH SHOULD BE ADJUSTED TO
THE RISK OF DEATH.
OR LEUKEMIA TRANSFORMATION TO
THE PATIENT.
NOW WE'VE RECENTLY PUBLISHED IN
BLOOD, THAT IF YOU HAVE CERTAIN
GENETIC MARKERS, LIKE
[INDISCERNIBLE]--LIKE IN VERSION
3, OR 17 CHEMOKINES OR
CHROMOSOME 17 Q IF YOU HAVE
THINGS LIKE THAT OR ACCESSED
BLOOD, OR LYM O SYITOSEIS OR
OTHER CARIO TYPE, WITH EITHER
LUNG CANCER COSIGNIFYITOSEIS OR
ANY 1 OF THOSE, YOU'RE CERTAIN
TO DIE WITHIN 3 YEARS.
BUT THIS IS THIS GROUP.
DON'T PLAY AROUND WITH
INVESTIGATIONAL DRUGS THERE.
YOU SHOULD THEN SEND THIS
PATIENT FOR JOHN BARRETT TO
TRANSPLANT THIS IMMEDIATELY.
MOW THIS DOESN'T MEAN THE
TRANSPLANTATION WILL BE BETTER.
IT DOESN'T MEAN THEY'LL DO
BETTER WITH TRANSPLANT, BUT WE
WILL SEE.
WE WILL SEE.
NOW, OTHERWISE, I STILL FEEL
THAT HIGH RISK PATIENTS SHOULD
BE TRANSPLANTED.
I THINK HERE IS A PLACE WHERE
DIRECT THERAPY CAN BE
CONSIDERED, HERE YOU LEAVE THE
PATIENT ALONE AND SOME OF THIS
PATIENT CAN ALSO BE CONSIDERED.
AND BASED ON THAT, THIS IS MY
TREATMENT GALLORIT
IMPEDIMENTS--ALEGORITHMS FOR
MYELOID FIBROSIS.
VERY HIGH RISK, THE 1S I TOLD
YOU ABOUT IN VERSION 3,
ISOCHROMOSOME 17 Q, ACCESS
BLAST, TRANSPLANT AND I WOULD GO
WITH FULL CONVENTIONAL
INTENSITY.
IF THEY'RE HIGH RISK OR
INTERMEDIATE 2 RISK, AGAIN, I
ACTUALLY LIKE EITHER HIGH
INTENSITY REDUCED INTENSITY
CONDITIONING OR CONVENTIONAL
CONDITIONING TRANSPLANT FOR
YOUNGER PATIENTS, OLDER PATIENTS
45-65 RIG TRANSPLANT APPEARS TO
BE REASONABLE AND IF THEY'RE
ABOUT 65, I'M LESS ENTHUSIASTIC
ABOUT TRANSPLANTING PATIENTS
ABOUT 65 YEARS I WOULD GO WITH
INVESTIGATIONAL DRUG THERAPY IN
THIS SETTING.
NOW IF YOU ARE LOW RIDGE OR
INTERMEDIARY RISK, I USUALLY
LIKE TO OBSERVE THEM AND IF THEY
RUN INTO PROBLEMS YOU CAN
CONSIDER A INVESTIGATIONAL DRUG
THERAPY.
BUT I'VE JUST FINISHED REVIEWING
1000 MYELOID FIBROSIS, IN THE
MAYO CLINIC AND THAT EXPRESS
WITH THE MY O CLINIC WILL BE
PUBLISHED WITH PROCEEDINGS IN
JANUARY, AND WHAT I HAVE LEARNED
FROM THAT IS WHEN YOU LOOK AT
WHO IS A TRANSPLANT CANDIDATE,
HOW MANY OF THE PATIENTS
ACTUALLY CAN PROCEED IN THE
TRANSPLANT, IT'S 10%.
IF YOU TAKE AGE, CO-MORBIDITY,
EVERYTHING IN CONSIDERATION,
IT'S 10% AT MOST, THE PATIENT
THAT PRESENTS THIS MYELOID
FIBROSIS THAT ARE A CANDIDATE
AND WE STILL HAVE TO DO
SOMETHING FOR THE 90%, REMAINING
NIEBT% AND HERE HAVE YOU A LIST
OF CONVENTIONAL DRUG THERAPIES
AND WHEN YOU HAVE A LIST THAT
MEAN NOTHING WORKS GOOD.
OKAY?
AND THEN THERE'S TONS OF
EXPERIMENTAL DRUG THERAPY
BECAUSE THE CONVENTIONAL DRUG
THERAPIES DON'T WORK WELL, I
WILL FOCUS ON THE EXPERIMENTAL
DRUG THERAPY AND OUT OF
EVERYTHING WE HAVE, THE 3 KIND
OF INTERESTING AND PROMISING
DRUGS ARE THE IMMUNO MODEL
POLARIZED MID AND THE INHICK
IDENTITY ARES AND THE JAK INHICK
IDENTITY ARES AND THAT'S WHAT
WE'RE GOING TO COVER.
NOW YOU KNOW THAT IMMUNO DRUGS
HAVE A THERAPEUTIC ROLE IN
MYELOID FIBROSIS.
WE STARTED WITH THIS AND WE GOT
ABOUT A 20% RESPONSE IN ANEMIA
BUT EVERYBODY GOT NEUROPATHY.
WE WERE NOT HAPPY AND WE MOVED
TO ALENO MIGHT AND WE GOT ABOUT
THE SAME AMOUNT OF AIA RESPONSE
AND SOME SPLENORESPONSE BUT
THERE'S A LOT OF SPLENOIF YOU
HAVE 5 ASSOCIATE WIDE IT,
THERE'S PROBABLY MORE THAT'S A
VERY GOOD DRUG BUT IN THE
ABSENCE OF THIS, IT IS EASY,
PERHAPS 15%, SAME WITH MDS,
THEREFORE WE WERE INTERESTED IN
LOOKING AT THE NEWER DRUG THAT
IS SUPPOSEDLY LESS MYELOID
SEPARATED AND LESS NEUROTOXIC
AND THAT IS FORMA LID MIDS, AND
WE DID A STUDY AND THIS IS THE
MAYO CLINIC PHASE 2 STUDY AND
WHAT IS INTERESTING HERE IS THAT
THIS IS NOT A JACK INHIBITOR,
BUT IF YOU DON'T HAVE A JAK2
MUTATION IT DOESN'T WORK.
NOW I DON'T KNOW, DON'T ASK ME
WHY THAT IS, OKAY?
AND IF YOU HAVE A JAK2 MUTATION,
PATIENT, THEN IT WORKS BEST IF
YOU DON'T HAVE A BIG SPLEEN
BECAUSE IT DOESN'T DO ANYTHING
FOR THE SPLEEN.
IN FACT, WE LOOKED AT OUR ROTE
ROUGH ATOM SPECTIVE STUDY OF 94
PATIENTS TREATED WITH SPLENOMID
AND HERE'S WHAT WE FOUND:  IF
YOU ARE JAK2 NEGATIVE AND HAVE
YOU A BIG SPLEEN OR EXCESS
BLASTS THEN YOUR RESPONSE IS 0%.
IF YOU ARE JAK2 POSITIVE, WITH A
SMALL SPLEEN AND DON'T HAVE
EXCESS PLAST, RESPONSEERATE
COULD BE AS HIGH AS 50%.
SO BASED ON THIS, THERE IS NOW A
RANDOMIZED INTERNATIONAL STUDY
THAT IS ONGOING WHERE ABOUT 60%
ENROLLED NOW AND WE WILL SEE
WHAT HAPPENS WHEN IT ENDS.
AND SO, I DO THIS THINGS BECAUSE
I HAVE THIS BEAUTIFUL DATABASE
AND I CAN
CAN ADJUST THE RISK AND SO
FORTH, SO I COMPARED THOSE
PATIENTS, TREATED FOR THOSE AND
ALONG WITH THOSE THAT NEVER
RECEIVE THEM IN THE MAYO CLINIC
DATABASE SOPHISTICATED SEE WHAT
HAPPENS TO SURVIVAL, SUPER AND
POST.
mTOR INHIBITORS, INTERESTING.
INTERESTING THING ABOUT THIS IS
THEY HAVE AND HERE, ALICE
ANDROGEN ROUGH ATOM'S LAB USED
OO1 AND THEY HAD THE SAME KIND
OF ANTICONSTITUTIONAL SYMPTOM
EFFECT AS JACK INHIBITORS.
PATHWAY GIVES RIGHTUS TODAY,
GONE TOMORROW.
THE EFFECT ON THE SPLEEN IS NOT
AS GOOD.
NOT AS GOOD BUT IT'S INTRIGUING
TO SEE IF EVERYBODY HAD A
RESOLUTION TO PORITIS, ON THIS.
NOBODY KNOWS.
BUT THE QUESTION IS, THEY'RE NOT
AS GOOD IN THE RESPONSE AND THE
RESPONSE ARE NOT AS ROBUST AND
THEREFORE, I THINK IF WE'RE
GOING TO RUSE THIS, WE HAVE TO
COMBINE IT WITH SOMETHING ELSE,
THE QUESTION IS WITH WHAT?
AND THEN FINALLY THE JACK
INHIBITORS.
A TIME A DOZEN, BUT I'M GOING TO
CONCENTRATE ON THE 3 MOST
ADVANCED 1.
THE INC 424, THE TGOOD LUCK
348,--TG348 NOW ACQUIRED BY SON
OVERLAPPINGISSER, IT'S C-5 03
AND CYTC87 THAT RETAINS THE
NAME, THESE 3 DRUGS ARE VERY
SIMILAR IN THEIR EFFECT OF THE
SPLEEN.
IT HAS 1 OF THE INTERESTING
THINGTHE JAK INHIBITORS.
BUT MAKE NO MISTAKE, WE'RE NOT
TALKING ABOUT THE SPLEEN GOING
TO 0, WE'RE TALKING ABOUT A
30-CENTIMETER SPLEEN GOING TO
25, OR A 7-CENTIMETER SPLEEN
GOING TO 0.
THE THING IS, THE 7-CENTIMETER
SPLEEN NEVER NEEDED TO BE
TREATED TO BEBIN WITH.
SO, THERE IS A MODEST DECREASE
IN SPLEEN SIZE AND IN OUR HANDS
THAT BENEFIT LASTS FOR ABOUT A
YEAR.
SO YES, THERE IS A MODEST
TRANSIENT EFFECT ON SPLEEN SITES
WHICH IS GOOD, WHICH IS GOOD IF
YOU'RE THE PATIENT.
NOW THEY ALL CAUSE THROMBOW
CYTOPENIA AND SAMES GRADE 4.
SO THEY'RE NOT FANTASTIC,F?Fo
SIGNIFICANT THROMBOW CYTOPENIA,
NOW IN ADDITION, IN ADDITION
MOST OF THEM CAUSE ANEMIA AND
NOT SURPRISING BECAUSE JAK2,
JACK STAT IS A--IS THE INTEGRAL
PATHWAY FOR PHYSIOLOGIC AREA FOR
THIS, BUT INTERESTINGLY,
INTERESTINGLY, 1 OF THEM, CYT387
DOESN'T CAUSE AS MUCH ANEMIA AND
IN FACT, MIGHT ACTUALLY IMPROVE
ANEMIA IN SOME PATIENTS.
VERY INTERESTING, IT APPEARS
THAT IT HITS JACK 1 MORE THAN IT
HITS JAK2, SO THAT'S WHAT IT
SUGGESTS TO ME.
THE OTHER 2, CAUSE SIGNIFICANT
ANEMIA, AND THAT IS THEIR ACHILL
ZETAMIN HEEL SO THE ADVANTAGE
FOR THIS IS IT DOESN'T CAS AS
MUCH ANEMIA, SO THE ADVANTAGE
FOR THE INC 424, IS IT REALLY
HAS NOT MUCH SIDE EFFECT OTHER
THAN THE CYTOPENIAS AND ANEMIA
THROMBOW CYTOPENIA AND ALTHOUGH
IF YOU STOP THE DRUG, CAN YOU
END IN EMERGENCY ROOM OR ICU.
OKAY?
AND THE ADVANTAGE FOR THE TG348
NOW SAR 543 IS IT APPEARS TO BE
THE MORE IMPORTANT JAK2
INHIBITOR AND IT HAS AvXG
CONTROL OF LEUCOSIGNIFYITOSE AND
I GUESS THROMBOW SYITOSEIS AND
BUT IN THE SAME TOKEN IT CAUSES
MORE ANEMIA, SO ALL OF THE
ACHILL ZETAMIN HE'LL, SO
PERSONALLY, I DON'T LIKE ANY OF
THEM.
I THINK WE NEED TO TEST 20 MORE.
WE JUST DISCOVERING, IT'S NOT
TIME TO KIND OF SETTLE FOR 1.
SO IF I HAVE A A PATIENT, I
WOULD ENCOURAGE THEM TO
PARTICIPATE IN A NEWER JACK
INHICK THOR TRIAL RATHER THAN
SETTLE FOR ANY 1 OF THESE 3.
AND THE REASON WHY THEY'RE
DIFFERENT, THE ACTIVITY AND
BECAUSE THEY HAVE A DIFFERENTIAL
EFFECT ON THE DIFFERENT JACK
FAMILY OF CAIN ACEIS, SOME OF
THEM JACK 1 IS HARDER THAN JAK
2, SOME OF THEM HIT 1 OVER THE
OTHER AND SO FORTH, AND THERE'S
A NEW DRUG FROM BRISTOL MIERS
SQUIB WHICH IS SUPPOSED TO BE
CLEAN AND THEY'RE TESTING IT,
WE'LL SEE WHAT HAPPENS.
SO SOLITINIB IS THE THAT A BEST,
THEY HAVE COMPLETED TO STUDIES,
COMFORT 1 AND 2, AND THE RESULTS
ARE EXACTLY THE SAME AS YOU SAW
IN THE PHASE 2 EXCEPT WHEN YOU
DO IT--EXAMPLE, THIS IS A STUDY
THAT I WILL PAY ATTENTION TO.
BECAUSE THIS IS REAL LIFE.
I HAVE AN ETHICAL PROBLEM IN
PUTTING PATIENT WITH ADVANCE
DISEASE O SINGLE PLACEBO, JUST
BECAUSE YOU HAVE TO DO PHASE 3
STUDY.
I HAVE IT.
SCIENTIFICALLY DOESN'T MAKE ANY
SENSE AND I DON'T THINK IT'S
KOSHIER.
ALL RIGHT?
THAT'S IT.
THAT'S ME.
I'M SORRY.
BUT BEST SUPPORTIVE CARE?
REASONABLE AT LEAST YOU'RE NOT
LEAVING THEM OUT THERE TO DRY.
AND IN THIS STUDY, THE RESPONSES
TO THE SPLEEN ARE ALMOST
IDEBTICAL TO WHAT WE'VE SEEN IN
THE MAYO CLINIC PATIENTS THAT
WERE TREATED WITH IT.
BUT 29% AND HOW LONG DO THEY
LAST?
VERY SIMILAR TO WHAT WE'VE SEEN
AT THE MAYO CLINIC ABOUT A YEAR
AT THE MOST.
AND THIS PHASE 3 STUDY.
AND OBVIOUSLY, THERE ARE MORE
THROMBOW CYTOPENIA AND ANEMIA
AND THEN WHAT WE DID IS, I DID
THE SAME THING I DID WITH SPLI
LID O MID,--FIRST I COMPARED
SURVIVAL SUPERIMPOSED, 3 YEARS
89% OF THE PATES WERE NO LONGER
TAKES GROUPS, VERY HIGH
DISCONTINUATION RATE, PATES ARE
NOT STAY O GBA THAT, BENEFIT
LASTED FOR ABOUT A YEAR, MOST
IMPORTANT THING FROM THIS STUDY
THAT WE JUST PUBLISHED AS A LET
TORTE NEW MANAGER OF MEDICINE IS
THE FACT THAT WHEN YOU STOP THE
DRUG, GOD HELP YOU.
YOU HAVE TO BE VERY CAREFUL
BECAUSE CAN YOU HAVE SUCH A
CYTOKINE REBOUND THAT OVERNIGHT
THE SPLEEN CAN BE SO BIG THAT
CAN YOU GET THE SPLENNITEIS,
THEY CAN END UP INTENSIVE CARE
UNIT AND THIS HAS BEEN
ELABORATED AND I THINK IT'S BEEN
PUBLISHED ALREADY IN THE PRO
SEEDINGS MORE ELABORATION, NOW,
SOMEBODY SAW THIS AND SAID, WELL
YOU'RE NOT ADJUSTING FOR RISK, I
SAID OH, SORRY.
OKAY.
I ADJUSTED FOR RISK, THESE ARE
PATIENT THARS DIAGNOSED IN THE
LAST 10 YEARS TO MAKE SURE THAT
EVERYTHING--AND THERE'S
ABSOLUTELY NO EFFECT ON
SURVIVAL.
AND THEREFORE--I'M PROUD OF
MYSELF BECAUSE I'VE FINISHED IN
TIME AND THESE ARE MY CONCLUDING
REMARKS.
NO RISK PATIENTS WHETHER IT'S ET
OR PV OR PMF.
I WOULD STRONGLY COMMENT YOU BE
AS CONSERVATIVE AS POSSIBLE
BECAUSE CAN YOU ONLY HURT THE
PATIENT BY YOUR THERAPEUTIC
ADVENTURES.
SO UNLESS THERE IS A CONTROL
STUDY THAT TELLS YOU THAT
SOMETHING IS BETTER THAN THE
OTHER, I WOULD AVOID IT BECAUSE
THESE PATIENTS ARE GOING TO DO
VERY WELL.
DON'T HASTEN THEIR DEMISE.
IF YOU HAVE A HIGH RISK PATIENT
IN P VOR ET, MY FIRST LINE DRUG
IS HYDROXIA, AND NOBODY HAS
SHOWN IN A CONTROL STOWED THAT
HYDROXIA IS CO MURED BIDGENIC ON
ANYTHING ELSE.
I CAN ASSURE YOU THAT ON THE
OVER 1500 PATIENTS I'M STUDYING
AND DOING ANALYSIS, ABSOLUTELY
NO EFFECT OF HYDROXIA, NO
DIFFERENT THAN TAKING A DRUG.
IF YOU CAN'T TAKE HYDROXURIA,
YOUNGER PATIENTS INTERFERON,
NOBODY HAS SHOWN THAT THESE
DRUGS ARE COMO GENIC OR ANY
WORSE RINGS THEY'RE NOR TOXIC
THAN HICRUXURIA,--HYDROXURIA,
THE ROLE OF THIS INHIBITORS FOR
ATP V, FOR ME IS IRRATIONAL.
YOU DON'T GET ANYMORE, OKAY,
THIS DRUG DON'T HAVE AN
ANTICLONAL ACTIVITY, THEY HAVE
AN ANTICYTOKINEKIVITY.
WHY WOULD YOU TREAT A PATIENT
WITH AT OR PV WHEN YOU HAVE
HYDROXIA THEY WILL DO SO WELL,
WHY DO YOU WANT TO GIVE
THEM--WHAT IS IT YOU'RE TRYING
TO ACHIEVE.
THEY'RE NOT GLEEVEC.
IPT GREATER CREASE IN MARKET,
YES?
NOW I GOT IT.
I'M WITH THAT BUT NOT FOR THE
PATIENTS INTEREST.
JAK INHIBITOR IN LOW RISK OR
INTERMEDIATE 1 RISK MYELOID
FIBROSIS SHOULD NOT BE USED.
THEY HAVE RISK.
CAN YOU MAKE THIS INTERMEDIATE
RISK BY GIVING THEM ANEMIA.
ALOE GENIC TRANSPLANT AND I'M
SURE JOHN WILL LIKE HIS, I
THINK SHOULD STILL BE THE FIRST
TREATMENT OF CHOICE FOR HIGH
RISK PATIENTS.
THIS PAIBTS DON'T HAVE TIME TO
PLAYo[[ AROUND.
--PATIENT DON'T HAVE TIME TO
PLAY AROUND.
TELL MY PATIENTS.
I SAID LET'S LOOK AT ENTIRE
PROGNOSTIC PROFILE AND THEN
DECIDE WHETHER WE HAVE TIME TO
PLAY OR WE DON'T.
IN F WE DON'T HAVE TIME TO PLAY,
WE GO TO TRANSPLANT.
IF WE HAVE TIME TO PLAY, THEN WE
CAN CONSIDER SOME DRUGS AND SEE
WHAT HAPPENS.
AND THEN FINALLY, I THINK
CURRENTLY AVAILABLE
JAK INHIBITORS ARE NOT THERE
YET.
IN TERMS OF VALUE, AND I THINK
WE SHOULD CONTINUE TO TEST MORE
AND MORE OF THEM.
HOPEFULLY TO GET THE BEST IN
CLASS.
I THANK YOU FOR YOUR ATTENTION
AND I AM HAPPY TO ANSWER
QUESTIONS.
WE HAVE 5 MINUTES.
[ APPLAUSE ]
>> THANK YOU SO MUCH, LIKE ALL
EXPERTS YOU MAKE A VERY
COMPLICATED FIELD JUST SEEM VERY
SIMPLE.
I THINK THERE ARE QUESTIONS.
CAN I START THOUGH BECAUSE THE
QUESTION OF MYELOID FIBROSIS,
THE FIBROSIS DO WE HAVE ANY
AGENTS OR APPROACHES?
WHAT'S YOUR INSIGHT ON HOW WE
DEAL WITH THAT, THE COMPONENTS
OF THE PROBLEM SO FIBROSIS IS A
NOISE, BACKGROUND NOISE, IF YOU
HAVE CML, IT'S FIBROSIS, IT GOES
AWAY.
MYELOID FIBROSIS YOU TREAT THEM
AND YOU HAVE A VERY GOOD
ANTICLONAL ACTIVITY AND THE
PHOBE OSIS GOES AWAY, WE HAVE
SHOWN THAT.
IT IS NOISE, SO IT REALLY--IT
SHAZ NEVER BEEN SHORT OF ANY
PROGNOSTIC RELEVANCE LIKE ANEMIA
AND EVERYTHING ELSE.
SO, I CONSIDER IT AS A NOISE AND
ANYBODY WHO WANTS TO TARGET THE
FIBROSIS TO ME, IS A LOW YIELD,
LOW YIELD.
>> [INDISCERNIBLE]
>> YES BECAUSE IT WOULD GET RID
OF THE CLUMP.
>> ONE QUESTION.
COULD YOU COMMENTOT ROLE OF
SPLENECTOMY AND THE TRANSPLANT
AND MAKE AN REFERENCE TO CORE
TRANSPLANTS?
>> SO, WE'VE DONE OVER 700
SPLENECTOMYS IN MYELOID FIBROSIS
AND THERE IS NO QUESTION ABOUT
THE PALLIATIVE VALUE OF THIS
DRUG, IN FACT 50 OF THE PATIENTS
BECOME TRANSPLANTATION DEPENDENT
AND IT ALL BECOMES BETTER AND SO
FORTH AND SO FORTH.
IT'S A GOOD PALLIATIVE
TREATMENT.
IT'S A GOOD JAK INHIBITOR IN A
WAY.
NOW, THEN THE QUESTION BECOMES
WHAT ABOUT IN THE SETTING OF
TRANSPLANTING?
NOW AS YOU KNOW VERY WELL, THERE
ARE DIFFERENCES OF OPINION HERE.
PRIMARILY THE FRED HUTCH GROUP
DON'T THINK THAT YOU NEED TO DO
ANY SPLEN ECTOMYOSIN ORDER OF
MICRONSY BECAUSE IF YOU'RE
TRANSPLANT IS SUCCESSFUL, OKAY,
YOU DON'T NEED IT, THE SPLEEN
GOES AWAY IN TIME AND SO FORTH.
AND THEN THERE IS MOST OF THE
OTHER GROUP ANDcdHr-ñ OTHERS THAT HAVE
SUGGESTED THAT IF YOU DON'T HAVE
A BIG SPLEEN AND ESPECIALLY IF
YOU HAVE A PATIENT THERE WITH
SPLEN ECTO MYSELFED BEFORE
TRANSPLANT AND THEN NOT ONLY CAN
YOU SHORTEN THE TIME TO GRAFT
THE PLATELETS PRIMARILY BUT ALSO
THE OUTCOME MIGHT BE BETTER.
SO, THE QUESTION IS WHAT SHOULD
YOU DO?
SHOULD YOU TAKE THE SPLEEN OUT
OR NOT TAKE THE SPLEEN OUT?
WHEN THEY CAN ME, I SAY TALK TO
YOUR TRANSPLANTER.
REALLY, I THINK BECAUSE I DON'T
CARE, EITHER WAY.
SO I SAY LET THE TRANSPLANTERS
DECIDE BECAUSE I WOULDN'T OBJECT
WHICHEVER DECISION BUZZ THERE'S
REALLY NO GOOD SOLID OPINION TO
SAY, THIS IS BETTER THAN THE
OTHER.
WHAT I HAVE SEEN IS IN SOME
PATIENTS AFTER TRANSPLANT, THEY
REMAIN APLASTIC, THEY REMAIN AND
SO FORTH AND SOMETIME WHEN IS
YOU TAKE THE SPLEEN OUT AFTER
TRANSPLANT, ALL OF A SUDDEN THEY
STILL--THEY FEEL BETTER, THE
VISION VS GOOD INCREMENT, STAY
STAY IN THE BLOOD AND WHAT HAVE
YOU, THERE HAVE BEEN SEVERAL
CASES AND I WONDER IF YOU WANT
TO KIND OF--
>> NO, I CAN ADD NOTHING.
THAT'S EXACTLY THE PROBLEM THAT
WE SOMETIMES WISH WE HAD TAKEN
THE SPLEEN OUT WHEN THE COUNTS
DON'T COME BACK UP AND THEN CAN
YOU BE GRATIFIED BY THE COUNTS
COMING UP EVEN WITH THE SPLEEN
IN, SO, DIFFICULT.
>> THANK YOU.
>> SO 1 MORE QUESTION, AND THEN
WE'LL LET YOU GO, ASPIRIN, DO
YOU THINK IT ALSO HAS AN
EFFECTOT CYTOKINES THAT ARE
SWIMMING AROUND IN SOME OF THESE
DISEASES?
>> THAT'S A VERY GOOD QUESTION.
IT HAS TO BE LOOKED INTO.
WE HAVE THIS PLASMA, I HAVE DONE
TONS OF CYTOKINES NOW THAT I'VE
HEARD YOUR QUESTION, I WILL GO
BACK AND ASK THEM TO IDENTIFY
THOSE WHO ARE ON ASPIRIN WITH
THE CYTOKINES AND THEN THOSE
AND, YES, A CHANCE.
>> THEY THINK YOU VERY MUCH AND
THANK YOU ALL FOR BEING SUCH A
WONDERFUL AUDIENCE.
>> THANK YOU.
>> [ APPLAUSE ]