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AUTHORS
LaTeseBriggs,PhD
YooRiKim,MS
ErikLontok,PhD*
EkeminiA.U.Riley,PhD
MelissaStevens,MBA
*CorrespondingAuthor:[email protected]
CMMLSCIENTIFICADVISORYGROUP
WegraciouslythankthemembersoftheCMMLScientificAdvisoryGroupfortheirparticipationandcontribution
totheCMMLProjectandGivingSmarterGuide.Theinformativediscussionsbefore,during,andaftertheCMML
Retreatwerecriticaltoidentifyingthekeyunmetneedsandidealresearchopportunitiestobenefitpatientsand
advanceCMMLresearch.Inparticular,wethankDr.RossLevineforhisleadershipandrecruitmentofScientific
AdvisoryGroupmembers.
RafaelBejar,MD,PhD
JaniceKapty,PhD
AssistantProfessorofMedicine
AssociateScientificDirector
DivisionofHematology-Oncology
GlobalMedicalAffairs—MyeloidDiseases
UniversityofCalifornia,SanDiego
CelgeneCorporation
JohnM.Bennett,MD
AlyKarsan,MD ProfessorEmeritusofMedicine,Pathologyand
MedicalDirector,CentreforClinicalGenomicsand
LaboratoryMedicine
CancerGeneticsLaboratory,BritishColumbiaCancer
UniversityofRochesterMedicalCenter
Agency;Professor,DepartmentofPathologyand
LaboratoryMedicine
CoreyS.Cutler,MD,MPH,FRCPC
UniversityofBritishColumbia
SeniorPhysician,DanaFarberCancerInstitute
AssociateProfessorofMedicine
RamiKomrokji,MD
HarvardMedicalSchool
ProfessorofOncologicSciences
ClinicalDirector,SeniorMember
MichaelDeininger,MD,PhD
DepartmentofMalignantHematology
ProfessorandChiefofHematologyandHematologic
H.LeeMoffittCancerCenter
Malignancies,DepartmentofInternalMedicine
HuntsmanCancerInstitute,UniversityofUtah
RossLevine,MD(Chair) PhysicianScientist
Margaret“Peggy”A.Goodell,PhD
MemorialSloanKetteringCancerCenter
Professor,DepartmentofPediatrics
SectionofHematology/Oncology
MignonLee-CheunLoh,MD
BaylorCollegeofMedicine
PediatricCancerSpecialist
BenioffChildren’sHospital
StevenD.Gore,MD
DirectorofHematologicalMalignancies
JaroslawP.Maciejewski,MD,PhD
YaleUniversitySchoolofMedicine
DepartmentChair,TranslationalHematologyand
OncologyResearch
LeeGreenberger,PhD ClevelandClinic
ChiefScientificOfficer
TheLeukemia&LymphomaSociety
1
MichaelMauro,MD
Leader,MyeloproliferativeNeoplasmsProgram
MemorialSloanKetteringCancerCenter
MichaelMontgomery,MD
ExecutiveMedicalDirector
IncyteCorporation
HanMyint,MD,FACP,FRCP,FRCPath
VicePresident,GlobalMedicalAffairs
MyeloidDiseaseLead
CelgeneCorporation
Olatoyosi“Toyosi”Odenike,MD
AssociateProfessorofMedicine
TheUniversityofChicagoMedicine
EricPadron,MD
ClinicalInstructor,DepartmentofMalignant
Hematology;AssistantMember&SectionHead,
GenomicsandPersonalizedMedicineSection,
DepartmentofMalignantHematology
H.LeeMoffittCancerCenter
GailJ.Roboz,MD
ProfessorofMedicine
Director,ClinicalandTranslationalLeukemia
WeillMedicalCollegeofCornellUniversity/
NewYorkPresbyterianHospital
EllenSalkeld,PhD
SeniorDirectorofResearchandHealth
AplasticAnemia&MDSInternationalFoundation
MarkShapiro,MD,PhD
SeniorDirector,GlobalMedicalAffairsLead
HematologyPrograms
PfizerOncology
EricSolary,PUPH
DirectorofResearch
InstitutGustave-Roussy
KathleenWeis
ChiefExecutiveOfficer
AplasticAnemia&MDSInternationalFoundation
AdrianWoolfson,MD,PhD
SeniorDirector&GlobalClinicalLead
PfizerIncorporated
2
CONTENTS
AUTHORS....................................................................................................................................................................0
CMMLSCIENTIFICADVISORYGROUP..................................................................................................................1
EXECUTIVESUMMARY.............................................................................................................................................4
Overview.......................................................................................................................................................................5
Etiology.....................................................................................................................................................................6
DiagnosisandDiseaseStaging......................................................................................................................................7
SignsandSymptoms.................................................................................................................................................7
Diagnosis...................................................................................................................................................................7
DiseaseClassificationandStaging............................................................................................................................8
DiseaseBiology.............................................................................................................................................................9
Cellularbiology.......................................................................................................................................................10
MolecularBiologyandTherapeuticTargetAreas...................................................................................................10
Treatments.................................................................................................................................................................12
ClinicalTrialsandInvestigationalTherapies...............................................................................................................13
ResearchChallengesandPhilanthropicOpportunities..............................................................................................15
CMMLPatientRegistry...........................................................................................................................................15
DiagnosticandPrognosticBiomarkersofCMML....................................................................................................16
CMMLClinicalTrialNetwork..................................................................................................................................17
CMMLBasicandTranslationalScience...................................................................................................................18
JMMLUnmetNeeds...................................................................................................................................................20
ResearchGrantmakingOrganizationsintheLeukemiaandCMMLcommunity........................................................21
GlossaryofTerms.......................................................................................................................................................22
References..................................................................................................................................................................24
3
EXECUTIVESUMMARY
Leukemiaisacanceroftheblood-formingcellsofthebody.EachyearintheUnitedStates,thediseaseclaimsthe
livesofmorethan24,000peopleandaffectsanother330,000.Whiledaunting,sustainedpublicandprivate
investmentsinleukemiaresearchhaverefinedwhatwasknownasa“diseaseoftheblood”intoapproximately38
differenttypesofleukemia.Withtargetedresearchintospecificleukemias,medicalbreakthroughshaveledtoan
impressivequadruplingofthefive-yearsurvivalrateforleukemiapatientssince1960.
Thisreportwillfocusonthediseasechronicmyelomonocyticleukemia,orCMML.Patientssufferingfromthis
diseaseareaffectedbydramaticoverproductionofabnormalwhitebloodcells,which,althoughnumerous,are
ineffectiveagainstfightinginfections.Patientsalsoexperiencelowlevelsofredbloodcellsandplatelets,leadingto
constantfatigueandbleedingdisorders.Asaresearchfield,CMMLhasbeenhinderedbyitsincorrectleukemic
classificationformanyyears,dearthoffunding,andlimiteddiagnostictools.Asaresult,thefewapprovedCMML
treatmentsarenotoptimized,withlittleunderstandingoftheirlimitedandtransienteffectsonCMMLpatients.
However,ifthehistoricalarcofleukemiaresearchisappliedtoCMML,thenimproveddiagnosisanddedicated
researcheffortswillgreatlybenefitCMMLpatients.Philanthropicsupportcanbuildtheneededfoundationfor
CMMLresearch,which,ifcoupledwithexistingeffortsandinfrastructure,canofferabrighterfutureforCMML
patientsandtheirfamilies.Furthermore,researchintoCMMLwilllikelybenefitthecloselyrelateddiseasejuvenile
myelomonocyticleukemia,whichaffectsyoungchildrenandsharesmanybiologicalandpathologicalfeatureswith
CMML.
TheMilkenInstitutePhilanthropyAdvisoryServicehasdevelopedthisGivingSmarterGuideforCMMLwiththe
expresspurposeofempoweringpatients,supporters,andstakeholderstomakestrategicandinformeddecisions
whendirectingtheirphilanthropicinvestmentsandenergyintoresearchanddevelopmentefforts.Readerswillbe
abletousethisguidetopinpointresearchsolutionsalignedwiththeirinterests.Thisguidewillhelpanswerthe
followingquestions:
•
•
•
•
WhyshouldIinvestinCMMLresearch?
Whatisthecurrentstandardofcare?
Whatarethebarrierspreventing
developmentofnewtherapeutics?
WhatisthecurrentstateofCMML
researchefforts?
•
•
WhatkeythingsshouldIknowaboutthis
disease?
Howcanphilanthropyexpand
infrastructuretosupportCMMLresearch
andadvancenewtherapies?
4
OVERVIEW
Leukemiaiscanceroftheblood-formingcellsofthebody.Thediseaseaffectsaround330,000peopleintheUnited
States,withanestimated54,000newdiagnosesin2015.Althoughtheincidenceandburdenofthediseaseare
staggering,focusedandsustainedleukemiaresearchhasledtoaquadruplingofthefive-yearsurvivalratesince
1960.
Publicandprivateinvestmentsinleukemiaresearchhave
refinedwhatwasknownasa“diseaseoftheblood”into
approximately38differenttypesofleukemia(Figure1).
Asthediseasehasbecomebetterunderstood,better
diagnosesandtreatmentshavefollowed.Forexample,a
diagnosisofchronicmyeloidleukemiawasaccompanied
withadismalprognosis,oroutlook.However,research
identifyingthekeygeneticmutationresponsiblefor
chronicmyeloidleukemia(BCR-ABL1positive)and
developmentoftargetedtherapyhaveledtoan
astonishing90percentfive-yearsurvivalrate.
Figure1:Leukemiaclassifications
Acutemyeloidleukemia(∼12types)
Acutelymphoblasticleukemia(2types)
Acutepromyelocyticleukemia(2types)
Acutemonocyticleukemia(2types)
Acuteerythroidleukemia(2types)
Acutemegakaryoblasticleukemia
Acutemyelomonocyticleukemia(2types)
Chronicmyeloidleukemia
Chronicmyeloproliferativedisorders(5
types)
Myelodysplasticsyndromes(6types)
Mixedmyelodysplastic/myeloproliferative
syndromes(MDS/MPN,3types)
Similarbreakthroughsareneededforotherformsof
leukemia,particularlythechronicandaggressivedisease,
chronicmyelomonocyticleukemia(CMML).Lessthan20
percentofpatientsdiagnosedwithCMMLlivebeyondfiveyearsafterdiagnosis.UnfortunatelyCMMLhasnot
garneredthewidespreadattentionthatotherformsofleukemiahave,primarilybecauseonly1,100peopleare
diagnosedeachyear.However,breakthroughdiscoveriesinCMMLhavethepotentialtoinformresearchinother
formsofleukemia,particularlythosethatshareitsclassificationMDS/MPNclassification,namelyjuvenile
CMML
Myelodysplastic/MyeloproliferativeSyndromesbytheNumbers
JMML
aCML
•
1,100diagnoseseachyear
•
25-50diagnoseseachyear
•
•
90%ofdiagnosesarein
personsaged>60years
•
•
Twicemoreprevalentinmen
Mostdiagnosesoccuratage
<5years,withamedianageof
1.8years
Veryrare,with1-2casesfor
every100casesofBCR-ABL1
mutation-positivepatients
•
Majorityofdiagnosesoccurin
personsages70-80years
•
6-12%ofcasesarisefrom
previouschemotherapeutic
regimens
•
Nomaleorfemale
predominance
•
Upondiagnosis,patients
demonstrate14-29months
mediansurvivaltime
•
•
•
Patientsfacea10-20%fiveyearsurvivalrate,with30%of
patientsprogressingtoacute
myeloidleukemia
Bonemarrowtransplantation
hasa30%curativerate
Majorityofpatientsbecome
transfusion-dependentand
susceptibletoinfections
•
Malesaremoreaffected
•
Relatedtothechildhood
diseasesneurofibromatosis
type1andNoonansyndrome
•
Chemotherapyhasaverylow
successrate
•
Bonemarrowtransplantation
hasa50%curativerate
•
15-40%ofpatientsprogressto
acutemyeloidleukemia
•
Rarely,JMMLpatientswith
Noonansyndrome
spontaneouslyresolvethe
disease
•
Bonemarrowtransplantation
hasa50-90%curativerate
5
myelomonocyticleukemia(JMML),whichisusuallydiagnosedinchildrenundertheageoffiveyears,andatypical
chronicmyeloidleukemia(aCML).
ETIOLOGY
Bloodisprimarilycomposedofthreecelltypes:
whitebloodcells(WBCs),redbloodcells(RBCs),
andplatelets.Thesecellsoriginatefromthe
hematopoieticorbloodstemcellthatresidesinthe
bonemarrow,theblood-formingorganofthebody
(Figure2).
Figure2:Originandmajorcellularcomponentsofblood.
Hematopoietic/bloodstemcellsarefoundinthebone
WhatcausesCMMLispoorlyunderstood,butthe
diseaseissuspectedtooriginatefromanabnormal marrowandgiverisetobloodcells:whiteblood
bloodstemcell.Normally,bloodstemcellsreceive cells/monocytes,redbloodcells,andplatelets.(Modified
fromNCBI)
signalstodifferentiateintooneofthethreecell
types,whichthenenterthecirculatorysystemtoperformtheirvariousfunctions—WBCstohelpfightinfections,
RBCstodeliveroxygentotissues,andplateletstofacilitatebloodclotting.InCMMLpatients,however,theprocess
becomesdysregulated,andtoomanyimmatureWBCsareproduced(hencethemyeloproliferativedesignation).
Furthermore,thebloodstemcellbecomesabnormalandfailstoproducesufficientplateletsandRBCs(hencethe
myelodysplasticdesignation).
6
DIAGNOSISANDDISEASESTAGING
SIGNSANDSYMPTOMS
CMMLpatientspresentaseriesofsymptomsthatarisefromtheabnormalbloodstemcell:
•
TheincreasednumbersofabnormalWBCs(CMMLcells)invadethebloodandcancausepainbecauseof
enlargementofthespleen(splenomegaly)asitfilterstheblood
•
ThelackofnormallyfunctioningWBCs(leukopenia)makesthepatientpronetoinfections
•
ThemyelodysplasticaspectofthediseaseaffectstheRBCsandplateletsandcauses
o
insufficientRBCs(anemia),whichcanleadtofatigue,shortnessofbreath,andpaleskin
o
insufficientplatelets(thrombocytopenia),whichcanleadtoeasybruisingandbleeding
DIAGNOSIS
MultipletestsareneededtoaccuratelydiagnoseCMML.Eachtestbuildsupontheresultsoftheprecedingtest
andhelpstoeliminateotherpotentialdiseases.
•
Acompletebloodcountisthefirsttestandmeasurestheabsolutenumberofcelltypesintheblood
3
includingWBCs,RBCs,andplatelets.AhighandsustainedWBCcountof>1,000cells/mm ofblood
(monocytosis)isthefirstpossiblesignofaCMMLdiagnosis.Morethanonecompletebloodcounttestis
requiredtodeterminewhetherthehighWBCisduetoaninfection,becausethenumberwilldecreaseif
aninfectionisclearedbutwillremainhighduringthesecondtestinapotentialCMMLpatient.
Furthermore,CMMLpatientspresentasmallnumberofimmatureWBCsinthecirculatingblood,which
wouldnotbedetectedinahealthyperson’sblood
•
Bloodsmearsarethenperformedtoview
thestructureofcirculatingWBCs,because
CMMLWBCsdisplayabnormalitiesinsize,
shape,andcontents
•
Thenextstepsareabonemarrowbiopsy
andaspiration.Moreinvasivethanthe
previoustwo,thesetestsinvolveinjecting
aneedleintothebonemarrowtoobtaina
sampleoftheliquidportion(aspirate)and
core(biopsy)ofthemarrow.Thesetests
allowforacloserexaminationofthecells
presentinthebonemarrowtodetermine Figure3:Bonemarrowaspiratesampleofanormal
immatureWBC(left)andaCMMLimmatureWBC(right).
whethertheimmatureWBCsappearto
haveCMML-likecharacteristics(Figure3). Notetheenlargednucleus(darkpurple)andminimal
Thebiopsywillalsoallowforanabsolute
cytoplasm(lightpurple)oftheCMMLimmatureWBC.
countofthecellsinthebonemarrow.
(CourtesyofJ.Bennet,UniversityofRochester)
AlthoughnormallevelsofimmatureWBCs
arenomorethan10percentofallbonemarrowcells,CMMLimmatureWBCsrepresentaround10-20%
ofallbonemarrowcellsinapatient.Avaluehigherthan20percentisconsideredadiagnosisforacute
myeloidleukemia
7
•
•
•
Usingsamplesfromthebonemarrow,
cytogeneticstudiesareperformedto
assessthestructuralintegrityofa
patient’schromosomes.Abnormal
chromosomesarecommoninCMML
patientswithmultiplegrossstructural
changesarisingfromdeletions,
duplications,inversions,or
translocationsofchromosomes(Figure
4).WhenCMMLpatientspresentmore
thanthreegrosschromosomal
rearrangements,thisisreferredtoasa
complexkaryotypeandisapoor
prognosticindicator
AkeycytogenicresultthatCMML
physicianslookforisarearrangement
ofthePDGRFBgene,alongwitha
clinicalpresentationofahighnumber
ofeosinophils(aparticularWBCthat
targetsparasites),becausethisresult
indicatesthattheCMMLpatientmay
respondtotyrosinekinaseinhibitor
therapy(seeTreatments)
A)
B)
C)
D)
Figure4:Typesofchromosomalrearrangements.A)Deletion,
notethelossoftheBgene.B)Duplication,notethegainofa
secondBgene.C)Inversion,notethatthechromosomalarms
crossandgeneorderisinverted.D)Translocation,whentwo
differentchromosomesrearrangeresultingingenemovement.
(CourtesyofL.Bridges)
AdvancementsinCMMLresearchhave
ledtotheuseofmoleculartestingtoidentifyspecificgeneticmutationsinCMMLpatientcells.Using
samplesfromthecirculatingbloodorbonemarrowbiopses,around8-40genesassociatedwithCMML
diseasearesequencedtodeterminewhethertheyaremutated.Thisinformationhelpstodeterminethe
diseaseprognosisofaCMMLpatient,aswellastoidentifypotentialdysregulatedpathwaysthatmaybe
targetedbyspecifictherapeutics(seeMolecularBiologyandUnmetNeeds)
DISEASECLASSIFICATIONANDSTAGING
AsevidencedbythemyriadoftestsrequiredtoidentifyanddiagnoseaCMMLpatient,notenoughisknownabout
thedisease.OnereasonforthedearthofinformationisthepreviouslylongstandingmisclassificationofCMMLas
solelyamyelodysplasticsyndrome.Asaresult,manyCMMLpatientswerenotproperlydiagnosed,andevenfewer
wererecruitedintoclinicaltrialstudiesthatmayhaveclarifiedoraffectedthediseasedirectly.In2008theWorld
HealthOrganization(WHO)redesignatedCMMLasastandalonediseasewithproliferative(fast-growing)and
dysplastic(abnormalcell)characteristics.
ThefirststepofCMMLclassificationistodeterminewhetherthepatientisaffectedbyoneofthefollowing:
•
CMML-1:ImmatureWBCincirculatingblood<5percent,immatureWBCinbonemarrow<10percent
•
CMML-2:ImmatureWBCincirculatingblood5-19percent,immatureWBCinbonemarrow10-19percent
•
CMML-1or2witheosinophilia:Abovecriteriawithcirculatingbloodeosinophils>1.5x10 cells/Lofblood
9
Theclassification/stageofCMMLdisease,incombinationwithdiagnosticresultssuchasWBC/RBC/plateletcounts,
percentageofimmatureWBCsinthebonemarrow,complexkaryotype,historyoftransfusion,andpresenceofthe
ASXL1mutationarefactoredintoprognosticscoringsystemsthatdeterminewhetherthepatienthaslow-riskor
high-riskCMML.
8
DISEASEBIOLOGY
ResearcherssuspectthatCMMListheresultofanabnormalbloodstemcellthatbeginstodivideandcrowdout
othernormalbloodstemcellsinthemarrow.Theimagebelowisagraphicalrepresentationofthepopulationof
immatureWBCsinthebonemarrow(y-axis)overtime(x-axis,years)andhypotheticallyillustrateshowanormal
bonemarrowpopulationisselectedintoaCMML-likebonemarrow.
A)Outset:AllthebloodstemcellsarenormalandgrowintothecorrectimmatureWBCs,RBCs,platelets,and
bloodstemcells.ThewhitecirclesindicatenormalimmatureWBCswithoutCMML-relatedmutations.
B)TheDriverandPassengerMutations:Ifonestemcellacquiresamutation(yellowcircle)thatbeginstodrive
increasedcellulardivisionandgrowth,thenitwillbegintooutgrowandcrowdoutnormalcells.Thisprocessmay
takemanyyearswithfewsymptomsforthepatient,andmaycontributetowhythemajorityofCMMLdiagnoses
occurinolderpatients.Themutatedcellgrowthisvisualizedbythenumberofyellowcirclesinthefigure.Random
mutationsareanaturaloccurrenceduringnormalcelldivision.However,becausethemutatedstemcellnow
dividesatahigherrate,itispronetodevelopingothercancer-drivingmutations,therebyacquiringasecond
mutation(orangecircle)thatresultsinacontinuallyexpandingpopulationofmutantstemcells.
C)TheMoretheDividier:Oncekeygenesaremutated(althoughwhichgenesexactlyisnotfullyknownforCMML),
themutatedstemcellswillexpandtobecomethedominantcellsinthepopulation.Normalstemcellswillno
longerprevailasadominantproportionoftheimmatureWBCs,butratheroneinapopulationofsinglemutation-
(yellow),doublemutation-(orange),andtriplemutation-containing(red)cells.Furthermore,mutantcellswill
continuetoexpandfasterbecausetheyhaveaselectivegrowthadvantageovernormalcells.
D)Onset:Overtime,thepopulationofnormalcellsdrop,concomitantwithanincreaseofimmatureWBCs
containingmultipleCMML-relatedmutations.Atthisstage,thepatientwillbegintoshowsymptomsofCMML,
becausethenormalstemcellsfailtoproducesufficientnormalWBCs,RBCs,andplatelets(diagnosedviabloodcell
counts),andthemutantstemcellsbegintoproducealargeamountofabnormalimmatureWBCs.Cytogenetic
rearrangementsandabnormalcellstructureswillalsobecomeevidentbloodsmears.
9
CELLULARBIOLOGY
AlthoughtheexactmutationsthatleadtoCMMLarenotcompletelyunderstood,multiplecellularpathwayshave
beenimplicatedinthedisease:
•
IncreasedCellGrowthandDecreasedCellDeath—CMMLcellsdemonstrateabnormalactivationofcell
growthanddivisionpathways,aswellasdown-regulationofcelldeathorapoptoticpathways
•
ImpairedImmuneSurveillance—RecentworkhasshownthatCMMLcellsexpresshighlevelsofthe
immunecheckpointproteinPD-1,indicatingthatthediseaseemploysmechanismsthathideitsdramatic
cellgrowthanddivisionfromtheimmunesystem,whichwouldnormallyattackcancerouscells
•
AbnormalBloodVesselGrowth—Inordertofacilitatetheirrapidcellgrowthanddivision,CMMLcells
secretefactorsthataltertheenvironmentofthebonemarrowtopromotebloodvesselgrowth,or
angiogenesis.Theincreaseinbloodvesselsthenallowsgreaterdeliveryofnutrientsthatprovidefueland
buildingblockstoproducetheinvasiveCMMLimmatureWBCs
MOLECULARBIOLOGYANDTHERAPEUTICTARGETAREAS
Alteredsignaling,epigeneticregulation,andRNAsplicinghavebeenimplicatedindevelopmentofCMML.
Advancementofresearchintotheseareaswillfacilitatetheidentificationofpotentialdruggabletargets.
•
SignalingPathwaysreceivesignalsfromoutsidethecellandactivatedownstreamproteinsthatalterDNA
transcriptionandsubsequentproteinexpression
o
TheJAK/STATpathwayisinvolvedincellgrowth
andhasbeenshowntobeupregulatedin
CMMLcells.ResearchhasshownthatCMML
cellsarehypersensitivetogranulocyte
macrophagecolony-stimulatingfactor(GMCSF),akeyactivatoroftheJAK/STATpathway
o
TheRASpathwayisalsoinvolvedincellgrowth.
Amongbloodcancers,CMMLpresentsthehighestincidenceofRASpathwaymutations,
primarilyintheNRAS-andKRAS-relatedgenes.MousemodelswithmutantNRAShavealsobeen
showntodevelopCMML-likedisease,indicatingthatproteinsinthispathwayarepotential
therapeutictargets
GM-CSFhypersensitivityisamajorpointof
convergenceforCMMLandJMML,asboth
diseasesupregulatetheJAK/STAT
pathway.Developmentandapprovalof
therapeuticstargetingthispathwaymay
benefitbothCMMLandJMMLpatients.
SeveralepigeneticandsplicingmutationsarestronglyassociatedwithCMML:TET2,ASXL1,SRSF2,andSETBP1.
•
EpigeneticeventsregulatetheexpressionofgeneswithoutchangingtheDNAsequence.Differentgenes
areactivateddependingonthemarksattachedtoDNAitselfandtheproteinsaroundwhichDNAis
wound,orhistones.MethylgroupscanbeaddedtoDNAorhistones,whereasacetylgroups,phosphates,
andsmallproteinssuchasubiquitinonlymarkhistones.
o
TET2isanenzymethatepigeneticallymodifiesDNAbyremovingmethylgroups.Mutationsthat
reduceTET2activityhavebeenimplicatedinmultiplebloodcancers,indicatingitscriticalrolein
bloodcelldevelopment.Furthermore,mutationsinTET2arehypothesizedtobeadriver
mutationforCMMLdevelopment,becauseitresultsinanincreaseinDNAmethylationanda
subsequentincreaseinWBCproduction.AlongwithASXL1,TET2isthemostfrequentlyidentified
mutationinCMMLpatients.
10
•
•
Splicingfactors
o
ASXL1isanRNAsplicingfactorthatmodifiesthetranscriptsgeneratedfromDNA.WhenASXL1is
mutatedandlosesactivity,anepigeneticcascadeoccursthatultimatelydrivestheproductionof
CMMLimmatureWBCs.SimilartoTET2,ASXL1isthemostfrequentlyidentifiedmutationin
CMMLpatients
o
SRSF2isacomponentofthespliceosome,themulti-proteinmachinerythatmodifiesRNA
transcriptsgeneratedfromDNA.MutationsinSRSF2arethethirdmostcommonmutationsin
CMMLpatients
MutationsinSETBP1arealsocommonlyfoundinCMMLpatients.
SETBP1isaproteinthatinteractswiththeSETprotein,whichitselfis
involvedinapoptosis,transcription,andhistoneassembly.Research
hasshownthatdefectsinthisinteractionresultinhigherratesofcell
division
ThepresenceofSETBP1
mutationsinJMMLpatients
confersaparticularlypoor
outcome.
11
TREATMENTS
SeveraltreatmentoptionsareavailableforCMMLpatients—with
theregimendependentonthepatient’sdiseaseprognosisand
clinicalsymptoms.Specificexamplesoftheapprovedtreatments
arelistedinTable1.
•
Allogeneicstemcelltransplantisapossiblecourseofactionforhigh-riskCMMLpatients
o
•
Thisprocesswillreplacethepatient’sabnormalbonemarrowwithadonor’sgeneticallydifferent
(allogeneic)bonemarrow.Althoughacurativetreatmentoption,astemcelltransplantisavery
riskyprocedurewitha70percentmortalityrate.Factorsthatincreasethechancesofsuccessare
youngageaswellasfewchromosomalabnormalities
Hypomethylatingagents(HMA)arealikelycourseoftreatmentifthepatientsuffersprimarilyfroma
lackofRBCs,platelets,andnormalWBCs(cytopenia)
o
•
“Thesepatientsneedbetterdrugs.The
oneswehavedon’twork,andifthey
havesomeeffect,wehavenoideawhy.”
CMMLcellspresentanincreaseinmethylmarksontheirDNA,resultinginalteredepigenetics
versusnormalcells.AgentsthatgloballyreducetheamountofDNAmethylationhaveshown
limitedsuccessinslowingdiseaseprogression.TheprimaryshortcomingsofHMAsareasfollows:
§
Selectiveeffectiveness—NotallCMMLpatientsrespondthesamewaytoHMA,with
somedemonstratinganoticeabledropinWBCsandnormalizationofRBCsand
platelets,whileothersshownochangewhatsoever.Moreresearchisneededto
understandwhomayormaynotrespondtoHMAtreatment
§
Short-termeffectiveness—FortheCMMLpatientsthatdodemonstrateagoodresponse
ratetoHMA,thesetendtobeshort-lived,withthediseasereturninginamatterof
months.TreatmentfailureoccurswhenthecancerdevelopsresistancetotheHMA
Chemotherapyisalikelycourseoftreatmentifthepatientsuffersfromahighamountofcirculating
abnormalWBCs
o
Chemotherapygloballyreducescellgrowthanddivision,andithasshownsomeeffectivenessin
controllinglow-riskCMML.However,thetreatmentinvolvesawiderangeofsideeffectsbecause
itaffectsbothnormalandcancerouscells.Akeyquestionsurroundingchemotherapyiswhether
itaffectsthesourceofCMMLdisease—namelytheabnormalstemcell—oronlytreatssymptoms
ofthecancer
Table1:FDA-approvedtherapeuticsforCMML
BrandName
GenericName
Vidaza
azacytidine
Dacogen
decitabine
Cytosar-U
cytarabine
Hydrea
hydroxyurea
MechanismofAction
HMA
ChemotherapyandHMA
Chemotherapy
Chemotherapy
12
CLINICALTRIALSANDINVESTIGATIONALTHERAPIES
Clinicalresearchisabranchof
biomedicalresearchinvolvinghuman
subjects.Thegoalofclinicalresearchis
toevaluatethesafetyandefficacyof
drugs,medicaldevices,ordiagnostics
intendedforuseinhumanpatients.
Clinicaltrialsareanimportant
componentofclinicalresearchasthey
areusedtoevaluatethesafetyand
efficacyofanexperimentaldrugor
therapyinhumansubjects.Theycanalso
beusedtocollectspecimensfromhuman
subjectsforfurtherresearch.
Importantly,informationonpotential
sideeffectsaregatheredduringthe
clinicaltrialandweighedagainstthe
potentialtherapeuticbenefitofthe
treatmentunderinvestigation.Clinical
researchisdividedintothreekeyphases
andisdescribedinFigure5:
AkeychallengethathashinderedCMML
investigationaltherapieswasthe
misclassificationofCMMLasa
myelodysplasticdisease.Asaresult,few
studieshavefocusedonCMMLalone
(Figure6).Althoughagentsthataffect
thefast-growing(MPN)orabnormal
cellularaspects(MDS)ofCMMLhold
somepromise,targetedtherapiesthat
focusontheuniqueaspectsofCMMLare
neededtomakeatransformativeimpact
onthedisease.
Figure5:PhasesofClinicalTrials.DuringPhase1studies,researchers
testanewdrugortreatmentforthefirsttimeinasmallgroupof
peopletoevaluateitssafety,determineasafedoserange,andidentify
potentialsideeffects.DuringPhaseII,proof-of-conceptstudiesare
performedasthedrugortreatmentisgiventoalargergroupof
peopletodetermineitsefficacyandoptimaldose.DuringPhaseIII,the
drugortreatmentisgiventolargegroupsofpeopletoconfirmits
effectiveness,monitorsideeffects,andassessitsimpactcomparedto
thecurrentstandardofcare(SOC).Someclinicalstudiesinvolve
multiplephasestofacilitateseamlesstransitionfromonetoanother
andarewrittenasPhaseI/IIorPhaseII/III.Thesedesignationsarealso
usedinadaptivetrials,whereinstudyparametersforthePhaseII
studyaremodifiedwithrespecttoongoingPhaseItrialresults,etc.
20
15
10
5
0
Phase1
Phase1/2
CMMLonlyTrials
Phase2
Phase2/3
Phase3
CMML,MDS,andMPNTrials
Figure6:CMML-relatedclinicaltrialsasof2015.Trialsspecificto
CMMLareinblue,whiletrialsthatincludeCMMLasasubtypeofMDS
orMPNareinorange.
13
AsshowninTable2,basedwhatisknownaboutthecellularandmolecularbiologyofCMML,investigational
therapiescanbeclassifiedintothefollowingcategories.
Table2:ExperimentaltherapiesforCMML
DrugName(s)
MechanismofAction
topotecan
Chemotherapy
sapacitabine
birinapant
clofarabine
thalidomide
Immunomodulators
lenalidomide
pomalidomide
entinostat
Histonedeacetylaseinhibitors
panobinostat
vorinostat
lonafarnib
Farnesyltransferaseinhibitors
tipifarnib
glasdegib
Hedgehogpathwayinhibitors
erismodegib
rigosertib
Kinaseinhibitor
midostaurin
Kinaseinhibitor
ruxolitinib
Kinaseinhibitor
imatinib
Kinaseinhibitors
dasatinib
E6201
Kinaseinhibitor
PathwayTargeted
Celldivisionandgrowth
Immunesystemandangiogenesis
Epigenetics
RASpathway
Stemcelldifferentiationandangiogenesis
Celldivisionandgrowth
Celldivisionandgrowthandangiogenesis
JAK/STATpathway
CMMLdiagnosisofPDGFRBrearrangementandincreased
eosinophils
RASpathway
14
RESEARCHCHALLENGESANDPHILANTHROPICOPPORTUNITIES
CMMLhaslongbeenanorphaneddiseasebecauseofthedifficultyinaccuratelydiagnosingthediseaseinpatients,
coupledwithitsmisclassificationformanyyearsasasubsetofMDS.Asaresult,CMMLisbesetbyanumberof
unmetneedsincludingthefollowing:
•
Limitedtherapeuticoptions
•
Absenceofapatientregistryandclinicaltrialinfrastructure
•
Overalllackofunderstandingofthebasicandtranslationalbiology
ToaddresstheseneedsandultimatelybenefitCMMLpatients,thePhilanthropyAdvisoryServiceheldaretreat
withacademic,clinical,industry,patientadvocate,andfoundationpartnerstochartascientificroadmaptochange
thetrajectoryofthisdisease.
CMMLPATIENTREGISTRY
THEPROBLEM
AcentralissueinCMMLresearchisthelackofCMML-specificinformation.Manyoftheapproved,andgenerally
ineffective,treatmentsforthediseasearebasedontheinclusionofCMMLpatientsasasubsetoftrialparticipants
forMDSstudies.ThusthechallengeofdiagnosingapatientwithCMML,coupledwithpoortherapeuticoptions,
resultsinlittleincentiveforphysicianstoaccuratelydiagnoseCMML,becausetheeventualtreatmentissimilarto
anMDSregimen.
POTENTIALSOLUTION
TheCMMLresearchcommunityneedsaformalizedpatientregistry.Currentlyresearchershavebandedtogether
toinformallysharede-identifiedCMMLpatientinformationfromacrossmultipleclinicaltrialsandresearch
studies.Thegoalofthiseffortisto:
•
BetterdefineCMML-specificcharacteristics
•
Clarifypatientresponsetoapprovedandinvestigationaltherapies
•
AssessprognosticscoringsystemsthatincludegeneticdriversofCMML
Withadditionalsupporttoexpandandformalizethiseffort,theinitiativecanserveasthetouchpointfora
federatedsystemoftissuebanking.TheregistrycanprovideaprospectivecohortofCMMLpatientstoevaluate
overtimeandcansupportclinicaltrialenrollment.
PHILANTHROPICOPPORTUNITIES
FormalizetheCMMLpatientregistryefforttofacilitatepatientrecruitmentandbiobankingofpatientsamples.
Thiswillprimarilyrequireinfrastructuresupporttodevelopthefollowing:
•
Web-baseddataentryportalwithanalyticcapacitytoincreasethepoolofCMMLpatientcases
•
Resourcesfordatamanagementtofacilitategeneticdatacurationandscreeningofpatients
15
•
FederatedtissuesamplebankingtofacilitatecollaborationacrosstheCMMLfield
DIAGNOSTICANDPROGNOSTICBIOMARKERSOFCMML
THEPROBLEM
CMMLdiagnosisisprimarilydependentoncellmorphology–based(pathological)assessmentofimmatureWBCs
asapercentageofcirculatingbloodandbonemarrowsamples.AlthoughWHOdiagnosticcriteriaare
continuouslyimprovedandrefined,theprocessisdependentonskilledpathologistsaccuratelydetermininga
CMMLversusMDSpatient.Thisposesanissueinaccuratelydiagnosingapatientattheinitialpointofcare.
Furthermore,thecurrentclassificationschemeindicateswherethediseaseisgoing,ratherthanwhereitcame
from.
POTENTIALSOLUTIONS
CMMLdiagnosisandprognosismaybeenhancedwiththeadditionofgeneticmarkersofthedisease.Genetic
sequencingofpatientsampleshaveidentified8-40genesthatarehighlyrepresentedinCMMLversusMDS
patients.DespitetheprevalenceofthesegenesinCMMLpatients,thereisnosinglegeneuniquetothedisease.
However,manyofthesebiomarkersarehighlyassociatedwithoneanother,and,ifvalidatedandincorporated
intothecurrentCMMLdiagnosticscheme,wouldimprovetheidentificationofCMMLpatientsatearlierdisease
stages.ResearchinassociatedCMMLgeneswouldalsoassesstheirabilitytopredictpatientresponseto
treatment.
PHILANTHROPICOPPORTUNITIES
CMMLDiagnosis
•
•
SupportresearchtoexpandtheWHOCMMLdiagnosticcriteriatoincludegeneticbiomarkers
o
ThiseffortcouldvalidatenovelassayssuchasWBCsortingbasedonexpressedsurfacemarkers
o
ThiseffortwouldalsoaidinthedevelopmentofastandardJMMLdiagnosticpanel
SupportanationalefforttoidentifyindividualswhopresenthighlevelsofWBCs,thensubsequentlytest
themforCMMLgeneticbiomarkerstoidentifyearly-stagepatients
o
SimilartotheLeukemia&LymphomaSocietyPre-malignancyprogram,thiseffortwouldaidin
thedevelopmentofaprospectivecohortofCMMLpatientsandpossiblyidentifypatients
sufferingfromcloselyrelateddiseases
o
PotentialCMMLpatientswouldbedirectedtoawebsitetofacilitatereferraltoatertiarycare
center
CMMLPrognosis
•
SupportresearcheffortssuchastheInternationalWorkingGrouponPrognosticMarkersforMDS(IWGPM),whosegoalistovalidateMDSbiomarkersviacarefulassessmentofpatientsamples
o
•
ACMML-focusedeffortwouldcarefullyassesspatientsamplestobetterunderstandpatient
diseaseprogressionandresponsetotreatment
SupportaCancerGenomeAtlasdiscoveryeffortfocusedonCMML
16
o
Aprospectivestudywithlong-termcollectionandtestingofsamplescouldidentifynew
biomarkersandpotentialdrugtargets
CMMLCLINICALTRIALNETWORK
THEPROBLEM
Stymiedbythelackofablockbusterdrug,broadgeographicdistributionofthecomparativelysmallnumberof
CMMLpatients,andlackofawarenesssurroundingCMML,veryfewclinicaltrialsdedicatedtothediseasehave
beencompleted.Furthermore,currentlyapproveddrugshavenotbeenfullyoptimizedforCMMLpatients,with
limitedresearchtoassesstheirtruebenefitinpatients.
POTENTIALSOLUTIONS
DevelopmentofaCMML-focusedclinicaltrialnetworkisacriticalstepinimpactingthetrajectoryofthisdisease.
MultipleCentersofExcellenceacrosstheU.S.areactiveinCMMLclinicalstudies,andprovidinginfrastructure
supporttopoolresourceswouldenhancethewell-beingofandtreatmentoptionsforCMMLpatients.
Proposedclinicaltrialswould:
•
OptimizecurrenttreatmentoptionstodeterminetheinitialregimenforCMMLpatients
•
Buildatrialnetworkfoundationtotestcombinationswithexperimentaltherapeutics
•
Standardizeclinicaltrialmeasurementsofdrugefficacyandtrialendpoints
PHILANTHROPICOPPORTUNITIES
•
SupportexpansionoftheMDS-focusedclinicaltrialnetwork
o
ThiseffortwillleveragetheexistinginfrastructuretotestnewCMMLtreatmentsandimprove
existingclinicalcarestandards
o
ThiseffortwillfacilitateCMMLpatientengagement,education,andclinicaltrialenrollment,
whilebenefittingMDSclinicalresearchefforts
o
Developmentofthisnetworkwilldrivethecollectionofpatientsamplestosupportbasicand
translationalstudiestoadvanceCMMLscience
•
SupportdevelopmentofaCMMLClinicalTrialMasterProtocol,whichinvolvesdeterminationoftheideal
startingregimenandastructuredapproachtoassessingnewexperimentaltherapeutics
•
Supporteffortstoaddresspatientengagement,education,andpatient-specificroadblockstotrial
participationsuchastransportationandcompensationoptions
17
CMMLBASICANDTRANSLATIONALSCIENCE
THEPROBLEM(S)
Akeyunansweredresearchquestionishowmultiplegeneticmutationsmanifestintotheclinicalpresentationof
CMML.CurrentresearchhassuccessfullyidentifiedmanyofthegeneticdriversofCMML,whichrangefrom
splicingdefects,alteredepigenetics,anddysregulatedsignalingpathways.However,howthesepathwaysinteract
arepoorlyunderstoodandyetpresentapotentialtroveofdrugtargets.ForknownCMML-relatedgenes,single
geneknockout(KO)mousemodelshavebeendevelopedforpreclinicaltestingofexperimentaltreatments,but
theKOcombinationsandmodelsthatbestmimichumandiseasearecurrentlyunknown.Lastly,currently
approveddrugsthattargetepigeneticregulationhaveshownsomemeasureofefficacyinCMMLpatients,buthow
theyworkandtheirmechanismsofactionarenotwell-defined.
PROPOSEDSOLUTIONS
CMMLGENOTYPEàPHENOTYPE
IdentificationofthegenesmostcommonlyassociatedwithCMML(genotype)presentsanexcellentopportunity
tounderstandhowthebloodstemcellabnormallydifferentiatesandresultsinCMMLdisease(phenotype).
Proposedscientificeffortsincludethefollowing:
•
Identificationofthekeymutation(s)thatresultsintheinitialabnormaldifferentiation,andthesecondary
mutationsthatthendrivedevelopmentofthedisease.
•
TargeteddrugdevelopmentperformedwithCMMLpatientsamples
TheultimategoaloftheseeffortsistousethebasicunderstandingofCMMLgeneticsandcellgrowthtoidentify
thekeypathwaysthatdrivethedisease.Advancementsinthisresearchwillcontributetothedevelopmentofthe
nextgenerationofCMMLdrugs.
CMMLMOUSEMODELS
ThenextkeystepinCMMLmousemodelsistounderstandwhichmodelbestmimicshumandisease.
UnderstandingwhetherKOorxenograftmodels(whereinpatientcellsaregraftedontomice)aretheidealvehicles
totestexperimentaltherapiesandwillgreatlyfacilitatethepreclinicalprocess.
EPIGENETICSOFCMML
InordertocapitalizeonthelimitedefficacyofhypomethylatorsforCMMLpatients,researchisneededto
understandhowthesedrugsworkinpatientswhorespondtotreatment.Epigeneticsresearchwilldeterminethe
mechanismofactionofhypomethylators,aswellaswhetheryoungerversusolderpatientsresponddifferently.
Identificationofwhichcellsrespondtohypomethylatorsmayalsodeterminethepotentialuseofimmunotherapy
inCMML.
18
PHILANTHROPICOPPORTUNITIES
CMMLGENOTYPEàPHENOTYPE
Supportresearcheffortto:
•
Initiateafunctionalgenomicsstudytodeveloptargetedtherapeutics
o
Utilizepatientregistry/databasetoidentifygeneticmutationspresentinCMMLpatients
o
Utilizepatientsamplestoidentifypotentialtherapeutictargets
•
UtilizepatientsamplestoidentifytheinitialgeneticmutationsthatdevelopCMMLversusthesecondary
mutationsthatdrivethedisease
•
AddressthepotentialoftheRASpathwayandGM-CSFhypersensitivityasapointofconvergencefor
CMMLandJMML
CMMLMOUSEMODELS
•
Supportresearcheffortstodeterminetheidealmouseforpreclinicaltherapeuticstudies
•
Supportabiobankoftransplantablepatientsamplesforuseinmousexenograftstudies
o
•
Sampleswouldbecollectedfromclinicaltrialsandthepatientregistry
Supportresearcheffortstoextensivelytestnoveltherapiesandcombinationsoftherapiesinmouse
models
EPIGENETICSOFCMML
•
SupportresearcheffortstoidentifycommonepigeneticchangesacrosstreatedCMMLpatients,which
wouldalsoexpandtheunderstandingoftheroleofepigeneticsinJMML
o
Comparepatientsamplesbeforeandduringtreatmenttoassessapatient’sepigeneticresponse
basedontheirownCMML-relatedmutations
o
Identifythecorrecttargetcellaffectedbyhypomethylatingagents
19
JMMLUNMETNEEDS
ThegreatestunmetneedofJMMLpatientsisaccesstodrugs.Pediatricstudiesoftenposerecruitmentand
logisticalchallengesfordrugdevelopers,andarethusnotalwaysperformedalongsideadultstudies.Furthermore,
mostclinicaltrialshaveanagerestrictionof18-to65-years-old,therebydeprivingchildrensufferingfrom
leukemiatheopportunitytoparticipateintrialsthatmayaffecttheirdisease.AdvancesinCMMLresearchwillaid
notonlypatientswhosufferfromthedisease,butalsoJMMLpatients.Althoughtherearedifferencesbetweenthe
twodiseases,severalCMMLinitiativeswouldsupportandadvanceJMMLresearch.
•
SupportresearcheffortstodevelopastandardCMMLdiagnosticpanelwithgeneticbiomarkers
o
ThemajorityofJMMLdiagnosesareaccomplishedviageneticsequencing.Effortstodevelopa
combinedpathologyandgeneticbiomarkersdiagnosticpanelwouldbenefitbothCMMLand
JMMLdiagnosis
o
CMMLepigeneticstudieswouldalsocontributetotheepigeneticprofileofJMMLcellsaffected
byhypomethylatingagents
•
SupportdevelopmentofCMMLmousemodelswithgeneticlesionssimilartoJMMLtofacilitateshared
preclinicalscreeningofapprovedandexperimentaldrugs
•
SupportresearchtounderstandthecentralroleofGM-CSFhypersensitivityinCMMLandJMML
o
•
UnderstandingdownstreampathwaysofJAK/STATactivationmayidentifycommondrugtargets
betweenthetwodiseases
SupportclinicaltrialsthatplantouseaMEKkinaseinhibitortoassessitsimpactonJMMLpatients
20
RESEARCHGRANTMAKINGORGANIZATIONSINTHELEUKEMIAANDCMMLCOMMUNITY
ThissectionprovidesabriefoverviewofthenonprofitorganizationsinvolvedinCMMLresearch.Their
involvementcanbethroughdirectfundingofresearchorsupportofresearchefforts.
APLASTICANEMIAANDMDSINTERNATIONALFOUNDATIONCLINICALRESEARCHCONSORTIUM
Establishedin1983,theAA&MDSInternationalFoundationisaleadingnonprofitthatfocusesonsupporting
patientsandfamilieslivingwithaplasticanemia,myelodysplasticsyndromes,andparoxysmalnocturnal
hemoglobinuria.Thefoundation’spatient-centeredeffortsfocusondiagnosis,treatment,andlife-long
implicationsoflivingwithachronicdisease.SupportedbytheEdwardP.EvansFoundation,AA&MDSdeveloped
andfundstheMDSClinicalResearchConsortium,asix-institutioneffortdesignedtofacilitateMDSclinicaltrials.
TheConsortiumfillsamajorgapinMDS-relatedclinicalresearchbyprovidingacriticalmassofpatientsand
patientdatatoevaluatenewtherapiesforMDS.Consortiumactivitiesaredirectedbyasteeringcommittee
composedofMDSresearcherswhowillassessandapproveproposedstudies.
THELEUKEMIAANDLYMPHOMASOCIETY
ThemissionofTheLeukemiaandLymphomaSociety(LLS)istocureleukemia,lymphoma,Hodgkin’sdisease,and
myelomaandtoimprovethequalityoflifeofpatentsandtheirfamilies.Giventhedifficultyofpreventionorearly
screeningforbloodcancers,theLLSresearchagendaisfocusedonfindingcures.LLSactivelyfundsallstagesof
bloodcancerresearch,fromdiscoverysciencetoclinicaltrials,andprovidescareersupporttoearlyand
establishedinvestigators.LLSdrivesresearchinareasofunmetclinicalneed,andviainnovativeprogramssuchas
theTherapyAcceleratorProgram(TAP),helpstobridgethegapbetweenacademicdrugdiscoveryanddrug
development.TheTAPprogramhastwoprimaryfacets:
•
TheBiotechnologyAcceleratorDivisionidentifiescompaniesdevelopingnovelanti-cancertherapies,
supportivecareordiagnosticsandco-fundsspecificprojectsthatwillenableacompanytopartneror
raiseadditionalfundingtocompletethetesting,registrationandmarketingofnewtherapiesor
diagnosticsforbloodcancerindications.
•
TheAcademicConciergeDivisioncapitalizesonLLS'sacademicgrant-supportedportfolioofdevelopmentstageprojects.Thisdivisionsupportsthefurtherdevelopmentofselectedacademicprojects(withor
withoutpriorLLSgrantsupport)togainclinicalproofofconcept.Successfulprojectswillpotentiallybe
advancedforfurtherclinicaldevelopmentbycreatingadditionalpartnershipswithpharmaceuticalor
biotechnologycompanies.
THEMYELODYSPLASTICSYNDROMEINTERNATIONALFOUNDATION
TheMDSFoundationwasestablishedbyaninternationalgroupofphysiciansandresearcherstoprovidean
ongoingexchangeofinformationrelatingtoMDS.Sinceitsinception,ithasconducted13internationalsymposia
across12countries.ThefoundationservesasanexusforMDSresearchandinformationthatprovides:
•
PatientswithreferralstoCentersofExcellenceandactiveclinicaltrials
•
Disseminationoftreatmentoptionsandeducationalsupportforhealthproviders
SupportedbytheMDSFoundation,theIWG-PManalyzedclinicalfeaturesandoutcomedatafrommorethan
7,000patientsandrevisedtheinternationalprognosticscoringsystemforMDS.Bycomprehensivelyintegrating
21
knownclinicalfeaturesofMDS,therevisedscoringsystemhasimprovedthepredictionofclinicaloutcomesin
untreatedMDSpatients,whileaidingthedesignandanalysisofclinicaltrials.
GLOSSARYOFTERMS
Acutemyeloidleukemia
Anaggressivecancerofthebloodandbonemarrowthatresultsin
increasedimmaturebloodcellgrowth
Allogeneicbonemarrowtransplant
Asurgicalprocedurethatreplacesapatient’sabnormalbonemarrow
withadonor’sgeneticallydifferent(allogeneic)bonemarrow
Anemia
Aconditiondescribinginsufficientredbloodcells,whichcanleadto
fatigue,shortnessofbreath,andpaleskin
Atypicalchronicmyeloidleukemia
Araresubtypeofmyelodysplastic/myeloproliferativeneoplasm
(MDS/MPN)largelydefinedmorphologically.Itiscurrentlyunclear
whetheraCML-associatedfeaturesaredistinctiveenoughtoallowits
separationfromunclassifiableMDS/MPN
Biomarker
Adistinctbiochemical,genetic,ormolecularcharacteristicthatis
objectivelymeasuredandevaluatedasanindicatorofaparticular
biologicalconditionorprocess
Bloodsmears
Adiagnostictestusedtolookforabnormalitieswithintheblood,
whereincelltypesareexaminedunderamicroscopeforunusualshapes
orsizes
Bonemarrow
Asoftfattysubstanceinthecavitiesofbonesfromwhichbloodcellsare
produced
Bonemarrowaspiration
Aprocedurethatinvolvesinjectinganeedleintothebonemarrowto
obtainasampleoftheliquidportionofthemarrow
Bonemarrowbiopsy
Aprocedurethatinvolvesinjectinganeedleintothebonemarrowto
obtainasampleofthecoreofthemarrow
Chronicmyeloidleukemia
Atypeofleukemia,designatedbytheBCR-ABLtransgene,thatdrives
expansionofcertainblood-formingcellsofthebonemarrow
Completebloodcount
Adiagnostictestthatmeasurestheabsolutenumberofcelltypesinthe
bloodincludingWBCs,RBCs,andplatelets
Complexkaryotype
Asituationwhereapatientpresents>3chromosomalrearrangements
Cytogeneticstudies
Teststhatassessthestructuralintegrityofapatient’schromosomes
usingbonemarrowsamples
Cytopenia
AconditionthatdescribesalackofRBCs,platelets,and/ornormalWBCs
Cytoplasm
Thematerialwithinalivingcellexcludingthenucleusandother
membrane-boundcompartments
DNA
Amoleculethatcarriesmostofthegeneticinformationusedinthe
development,function,andreproductionoflivingorganismsandviruses
Eosinophils/Eosinophilia
Atypeofwhitebloodcellthattargetsparasites;eosinophiliareferstoan
abnormallyhighamountofthesecells
Epigenetics
Changesinthegenomerelatingtoorarisingfromnongeneticinfluences
22
ongeneexpression
Genotype
Identificationofthegenesmostcommonlyassociatedwithadisease
Hematopoieticstemcell
Locatedinthebonemarrow,thesecellsthatgiverisetoalltheblood
cells
Histones
TheproteinsaroundwhichDNAiswound
ImmatureWBC
Thecelldifferentiationstageinbetweenthehematopoeiticstemcell
andthefullydifferentiatedwhitebloodcell
Juvenilemyelomonocyticleukemia
Aseriouschronicleukemiathataffectschildrenmostlyaged4and
younger
Karyotype
Thenumberandvisualappearanceofthechromosomesinthecellnuclei
ofanorganism
Leukopenia
Aconditionwhereinapatientpresentsareductioninthenumberof
WBCsintheblood
Monocytosis
AhighandpersistentWBCcountof>1,000cells/mm ofblood
Myelodysplasticsyndrome
Agroupofdiseasesinwhichimmaturebloodcellsinthebonemarrow
donotmatureorbecomehealthybloodcells
Myeloproliferativeneoplasms
AgroupofdiseasesinwhichthebonemarrowmakestoomanyRBCs,
platelets,orcertainWBCs
3
Myeloproliferative/myelodysplastic Agroupofdiseasesthathavefeaturesofbothmyelodysplastic
syndromes
syndromesandmyeloproliferativeneoplasms
Nucleus
Adenseorganelle,typicallyasingleroundedstructureboundedbya
doublemembrane,containinggeneticmaterialofthecell
Pathologicalassessment
Thescienceofthecausesandeffectsofdiseases,especiallythebranch
ofmedicinethatdealswiththelaboratoryexaminationofsamplesof
bodytissuefordiagnosticpurposes
Phenotype
Thecompositeofanorganism’sobservablecharacteristicsortraits,such
asitsmorphology,development,biochemical,orphysiologicalproperties
Platelet
Abloodcellwhoseprimaryfunctionistofacilitatebloodclotting
Redbloodcell
Abloodcellwhoseprimaryfunctionistocarryoxygentotissues
RNA
AmoleculesimilartoDNA,itplaysaroleincoding,decoding,regulation
andexpressionofgenes
Signalingpathways
Aprocessbywhichcellsreceivesignalsfromoutsidethecellandactivate
downstreamproteinsthatalterDNAtranscriptionandsubsequent
proteinexpression
Splenomegaly
Aconditionthatdescribesenlargementofthespleen
Thrombocytopenia
Aconditionthatdescribesinsufficientplatelets,whichcanleadtoeasy
bruisingandbleeding
Whitebloodcell
Abloodcellwhoseprimaryfunctionistohelpfightinfections
23
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