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AUTHORS

LaTeseBriggs,PhD

YooRiKim,MS

ErikLontok,PhD*

EkeminiA.U.Riley,PhD

MelissaStevens,MBA

*CorrespondingAuthor:elontok@fastercures.org

CMMLSCIENTIFICADVISORYGROUP

WegraciouslythankthemembersoftheCMMLScientificAdvisoryGroupfortheirparticipationandcontributiontotheCMMLProjectandGivingSmarterGuide.Theinformativediscussionsbefore,during,andaftertheCMMLRetreatwerecriticaltoidentifyingthekeyunmetneedsandidealresearchopportunitiestobenefitpatientsandadvanceCMMLresearch.Inparticular,wethankDr.RossLevineforhisleadershipandrecruitmentofScientificAdvisoryGroupmembers.RafaelBejar,MD,PhDAssistantProfessorofMedicineDivisionofHematology-OncologyUniversityofCalifornia,SanDiegoJohnM.Bennett,MDProfessorEmeritusofMedicine,PathologyandLaboratoryMedicineUniversityofRochesterMedicalCenterCoreyS.Cutler,MD,MPH,FRCPCSeniorPhysician,DanaFarberCancerInstituteAssociateProfessorofMedicineHarvardMedicalSchoolMichaelDeininger,MD,PhDProfessorandChiefofHematologyandHematologicMalignancies,DepartmentofInternalMedicineHuntsmanCancerInstitute,UniversityofUtahMargaret“Peggy”A.Goodell,PhDProfessor,DepartmentofPediatricsSectionofHematology/OncologyBaylorCollegeofMedicineStevenD.Gore,MDDirectorofHematologicalMalignanciesYaleUniversitySchoolofMedicineLeeGreenberger,PhD ChiefScientificOfficerTheLeukemia&LymphomaSociety

JaniceKapty,PhD AssociateScientificDirectorGlobalMedicalAffairs—MyeloidDiseasesCelgeneCorporationAlyKarsan,MD MedicalDirector,CentreforClinicalGenomicsandCancerGeneticsLaboratory,BritishColumbiaCancerAgency;Professor,DepartmentofPathologyandLaboratoryMedicineUniversityofBritishColumbiaRamiKomrokji,MDProfessorofOncologicSciencesClinicalDirector,SeniorMemberDepartmentofMalignantHematologyH.LeeMoffittCancerCenterRossLevine,MD(Chair) PhysicianScientistMemorialSloanKetteringCancerCenterMignonLee-CheunLoh,MD PediatricCancerSpecialistBenioffChildren’sHospitalJaroslawP.Maciejewski,MD,PhDDepartmentChair,TranslationalHematologyandOncologyResearchClevelandClinic

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MichaelMauro,MD Leader,MyeloproliferativeNeoplasmsProgram MemorialSloanKetteringCancerCenterMichaelMontgomery,MDExecutiveMedicalDirectorIncyteCorporationHanMyint,MD,FACP,FRCP,FRCPathVicePresident,GlobalMedicalAffairsMyeloidDiseaseLeadCelgeneCorporationOlatoyosi“Toyosi”Odenike,MDAssociateProfessorofMedicineTheUniversityofChicagoMedicineEricPadron,MDClinicalInstructor,DepartmentofMalignantHematology;AssistantMember&SectionHead,GenomicsandPersonalizedMedicineSection,DepartmentofMalignantHematologyH.LeeMoffittCancerCenter

GailJ.Roboz,MDProfessorofMedicineDirector,ClinicalandTranslationalLeukemiaWeillMedicalCollegeofCornellUniversity/NewYorkPresbyterianHospitalEllenSalkeld,PhDSeniorDirectorofResearchandHealthAplasticAnemia&MDSInternationalFoundationMarkShapiro,MD,PhDSeniorDirector,GlobalMedicalAffairsLeadHematologyProgramsPfizerOncologyEricSolary,PUPHDirectorofResearchInstitutGustave-RoussyKathleenWeisChiefExecutiveOfficerAplasticAnemia&MDSInternationalFoundationAdrianWoolfson,MD,PhDSeniorDirector&GlobalClinicalLeadPfizerIncorporated

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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

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EXECUTIVESUMMARY

Leukemiaisacanceroftheblood-formingcellsofthebody.EachyearintheUnitedStates,thediseaseclaimsthelivesofmorethan24,000peopleandaffectsanother330,000.Whiledaunting,sustainedpublicandprivateinvestmentsinleukemiaresearchhaverefinedwhatwasknownasa“diseaseoftheblood”intoapproximately38differenttypesofleukemia.Withtargetedresearchintospecificleukemias,medicalbreakthroughshaveledtoanimpressivequadruplingofthefive-yearsurvivalrateforleukemiapatientssince1960.

Thisreportwillfocusonthediseasechronicmyelomonocyticleukemia,orCMML.Patientssufferingfromthisdiseaseareaffectedbydramaticoverproductionofabnormalwhitebloodcells,which,althoughnumerous,areineffectiveagainstfightinginfections.Patientsalsoexperiencelowlevelsofredbloodcellsandplatelets,leadingtoconstantfatigueandbleedingdisorders.Asaresearchfield,CMMLhasbeenhinderedbyitsincorrectleukemicclassificationformanyyears,dearthoffunding,andlimiteddiagnostictools.Asaresult,thefewapprovedCMMLtreatmentsarenotoptimized,withlittleunderstandingoftheirlimitedandtransienteffectsonCMMLpatients.

However,ifthehistoricalarcofleukemiaresearchisappliedtoCMML,thenimproveddiagnosisanddedicatedresearcheffortswillgreatlybenefitCMMLpatients.PhilanthropicsupportcanbuildtheneededfoundationforCMMLresearch,which,ifcoupledwithexistingeffortsandinfrastructure,canofferabrighterfutureforCMMLpatientsandtheirfamilies.Furthermore,researchintoCMMLwilllikelybenefitthecloselyrelateddiseasejuvenilemyelomonocyticleukemia,whichaffectsyoungchildrenandsharesmanybiologicalandpathologicalfeatureswithCMML.

TheMilkenInstitutePhilanthropyAdvisoryServicehasdevelopedthisGivingSmarterGuideforCMMLwiththeexpresspurposeofempoweringpatients,supporters,andstakeholderstomakestrategicandinformeddecisionswhendirectingtheirphilanthropicinvestmentsandenergyintoresearchanddevelopmentefforts.Readerswillbeabletousethisguidetopinpointresearchsolutionsalignedwiththeirinterests.Thisguidewillhelpanswerthefollowingquestions:

• WhyshouldIinvestinCMMLresearch?• Whatisthecurrentstandardofcare?• Whatarethebarrierspreventing

developmentofnewtherapeutics?• WhatisthecurrentstateofCMML

researchefforts?

• WhatkeythingsshouldIknowaboutthisdisease?

• HowcanphilanthropyexpandinfrastructuretosupportCMMLresearchandadvancenewtherapies?

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OVERVIEW

Leukemiaiscanceroftheblood-formingcellsofthebody.Thediseaseaffectsaround330,000peopleintheUnitedStates,withanestimated54,000newdiagnosesin2015.Althoughtheincidenceandburdenofthediseasearestaggering,focusedandsustainedleukemiaresearchhasledtoaquadruplingofthefive-yearsurvivalratesince1960.

Publicandprivateinvestmentsinleukemiaresearchhaverefinedwhatwasknownasa“diseaseoftheblood”intoapproximately38differenttypesofleukemia(Figure1).Asthediseasehasbecomebetterunderstood,betterdiagnosesandtreatmentshavefollowed.Forexample,adiagnosisofchronicmyeloidleukemiawasaccompaniedwithadismalprognosis,oroutlook.However,researchidentifyingthekeygeneticmutationresponsibleforchronicmyeloidleukemia(BCR-ABL1positive)anddevelopmentoftargetedtherapyhaveledtoanastonishing90percentfive-yearsurvivalrate.

Similarbreakthroughsareneededforotherformsofleukemia,particularlythechronicandaggressivedisease,chronicmyelomonocyticleukemia(CMML).Lessthan20percentofpatientsdiagnosedwithCMMLlivebeyondfiveyearsafterdiagnosis.UnfortunatelyCMMLhasnotgarneredthewidespreadattentionthatotherformsofleukemiahave,primarilybecauseonly1,100peoplearediagnosedeachyear.However,breakthroughdiscoveriesinCMMLhavethepotentialtoinformresearchinotherformsofleukemia,particularlythosethatshareitsclassificationMDS/MPNclassification,namelyjuvenile

Myelodysplastic/MyeloproliferativeSyndromesbytheNumbersCMML JMML aCML

• 1,100diagnoseseachyear

• 90%ofdiagnosesareinpersonsaged>60years

• Twicemoreprevalentinmen

• 6-12%ofcasesarisefrompreviouschemotherapeuticregimens

• Patientsfacea10-20%five-yearsurvivalrate,with30%ofpatientsprogressingtoacutemyeloidleukemia

• Bonemarrowtransplantationhasa30%curativerate

• Majorityofpatientsbecometransfusion-dependentandsusceptibletoinfections

• 25-50diagnoseseachyear

• Mostdiagnosesoccuratage<5years,withamedianageof1.8years

• Malesaremoreaffected

• Relatedtothechildhooddiseasesneurofibromatosistype1andNoonansyndrome

• Chemotherapyhasaverylowsuccessrate

• Bonemarrowtransplantationhasa50%curativerate

• Rarely,JMMLpatientswithNoonansyndromespontaneouslyresolvethedisease

• Veryrare,with1-2casesforevery100casesofBCR-ABL1mutation-positivepatients

• Majorityofdiagnosesoccurinpersonsages70-80years

• Nomaleorfemalepredominance

• Upondiagnosis,patientsdemonstrate14-29monthsmediansurvivaltime

• 15-40%ofpatientsprogresstoacutemyeloidleukemia

• Bonemarrowtransplantationhasa50-90%curativerate

Figure1:Leukemiaclassifications Acutemyeloidleukemia(∼12types) Acutelymphoblasticleukemia(2types) Acutepromyelocyticleukemia(2types) Acutemonocyticleukemia(2types) Acuteerythroidleukemia(2types) Acutemegakaryoblasticleukemia Acutemyelomonocyticleukemia(2types) Chronicmyeloidleukemia Chronicmyeloproliferativedisorders(5types) Myelodysplasticsyndromes(6types) Mixedmyelodysplastic/myeloproliferativesyndromes(MDS/MPN,3types)

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Figure2:Originandmajorcellularcomponentsofblood.Hematopoietic/bloodstemcellsarefoundinthebonemarrowandgiverisetobloodcells:whitebloodcells/monocytes,redbloodcells,andplatelets.(ModifiedfromNCBI)

myelomonocyticleukemia(JMML),whichisusuallydiagnosedinchildrenundertheageoffiveyears,andatypicalchronicmyeloidleukemia(aCML).

ETIOLOGY

Bloodisprimarilycomposedofthreecelltypes:whitebloodcells(WBCs),redbloodcells(RBCs),andplatelets.Thesecellsoriginatefromthehematopoieticorbloodstemcellthatresidesinthebonemarrow,theblood-formingorganofthebody

(Figure2).

WhatcausesCMMLispoorlyunderstood,butthediseaseissuspectedtooriginatefromanabnormalbloodstemcell.Normally,bloodstemcellsreceivesignalstodifferentiateintooneofthethreecelltypes,whichthenenterthecirculatorysystemtoperformtheirvariousfunctions—WBCstohelpfightinfections,RBCstodeliveroxygentotissues,andplateletstofacilitatebloodclotting.InCMMLpatients,however,theprocessbecomesdysregulated,andtoomanyimmatureWBCsareproduced(hencethemyeloproliferativedesignation).Furthermore,thebloodstemcellbecomesabnormalandfailstoproducesufficientplateletsandRBCs(hencethemyelodysplasticdesignation).

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DIAGNOSISANDDISEASESTAGING

SIGNSANDSYMPTOMS

CMMLpatientspresentaseriesofsymptomsthatarisefromtheabnormalbloodstemcell:

• TheincreasednumbersofabnormalWBCs(CMMLcells)invadethebloodandcancausepainbecauseofenlargementofthespleen(splenomegaly)asitfilterstheblood

• ThelackofnormallyfunctioningWBCs(leukopenia)makesthepatientpronetoinfections

• ThemyelodysplasticaspectofthediseaseaffectstheRBCsandplateletsandcauses

o insufficientRBCs(anemia),whichcanleadtofatigue,shortnessofbreath,andpaleskin

o insufficientplatelets(thrombocytopenia),whichcanleadtoeasybruisingandbleeding

DIAGNOSIS

MultipletestsareneededtoaccuratelydiagnoseCMML.Eachtestbuildsupontheresultsoftheprecedingtestandhelpstoeliminateotherpotentialdiseases.

• AcompletebloodcountisthefirsttestandmeasurestheabsolutenumberofcelltypesinthebloodincludingWBCs,RBCs,andplatelets.AhighandsustainedWBCcountof>1,000cells/mm3ofblood(monocytosis)isthefirstpossiblesignofaCMMLdiagnosis.MorethanonecompletebloodcounttestisrequiredtodeterminewhetherthehighWBCisduetoaninfection,becausethenumberwilldecreaseifaninfectionisclearedbutwillremainhighduringthesecondtestinapotentialCMMLpatient.Furthermore,CMMLpatientspresentasmallnumberofimmatureWBCsinthecirculatingblood,whichwouldnotbedetectedinahealthyperson’sblood

• BloodsmearsarethenperformedtoviewthestructureofcirculatingWBCs,becauseCMMLWBCsdisplayabnormalitiesinsize,shape,andcontents

• Thenextstepsareabonemarrowbiopsyandaspiration.Moreinvasivethantheprevioustwo,thesetestsinvolveinjectinganeedleintothebonemarrowtoobtainasampleoftheliquidportion(aspirate)andcore(biopsy)ofthemarrow.ThesetestsallowforacloserexaminationofthecellspresentinthebonemarrowtodeterminewhethertheimmatureWBCsappeartohaveCMML-likecharacteristics(Figure3).Thebiopsywillalsoallowforanabsolutecountofthecellsinthebonemarrow.AlthoughnormallevelsofimmatureWBCsarenomorethan10percentofallbonemarrowcells,CMMLimmatureWBCsrepresentaround10-20%ofallbonemarrowcellsinapatient.Avaluehigherthan20percentisconsideredadiagnosisforacutemyeloidleukemia

Figure3:BonemarrowaspiratesampleofanormalimmatureWBC(left)andaCMMLimmatureWBC(right).Notetheenlargednucleus(darkpurple)andminimalcytoplasm(lightpurple)oftheCMMLimmatureWBC.(CourtesyofJ.Bennet,UniversityofRochester)

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• Usingsamplesfromthebonemarrow,cytogeneticstudiesareperformedtoassessthestructuralintegrityofapatient’schromosomes.AbnormalchromosomesarecommoninCMMLpatientswithmultiplegrossstructuralchangesarisingfromdeletions,duplications,inversions,ortranslocationsofchromosomes(Figure4).WhenCMMLpatientspresentmorethanthreegrosschromosomalrearrangements,thisisreferredtoasacomplexkaryotypeandisapoorprognosticindicator

• AkeycytogenicresultthatCMMLphysicianslookforisarearrangementofthePDGRFBgene,alongwithaclinicalpresentationofahighnumberofeosinophils(aparticularWBCthattargetsparasites),becausethisresultindicatesthattheCMMLpatientmayrespondtotyrosinekinaseinhibitortherapy(seeTreatments)

• AdvancementsinCMMLresearchhaveledtotheuseofmoleculartestingtoidentifyspecificgeneticmutationsinCMMLpatientcells.Usingsamplesfromthecirculatingbloodorbonemarrowbiopses,around8-40genesassociatedwithCMMLdiseasearesequencedtodeterminewhethertheyaremutated.ThisinformationhelpstodeterminethediseaseprognosisofaCMMLpatient,aswellastoidentifypotentialdysregulatedpathwaysthatmaybetargetedbyspecifictherapeutics(seeMolecularBiologyandUnmetNeeds)

DISEASECLASSIFICATIONANDSTAGING

AsevidencedbythemyriadoftestsrequiredtoidentifyanddiagnoseaCMMLpatient,notenoughisknownaboutthedisease.OnereasonforthedearthofinformationisthepreviouslylongstandingmisclassificationofCMMLassolelyamyelodysplasticsyndrome.Asaresult,manyCMMLpatientswerenotproperlydiagnosed,andevenfewerwererecruitedintoclinicaltrialstudiesthatmayhaveclarifiedoraffectedthediseasedirectly.In2008theWorldHealthOrganization(WHO)redesignatedCMMLasastandalonediseasewithproliferative(fast-growing)anddysplastic(abnormalcell)characteristics.

ThefirststepofCMMLclassificationistodeterminewhetherthepatientisaffectedbyoneofthefollowing:

• CMML-1:ImmatureWBCincirculatingblood<5percent,immatureWBCinbonemarrow<10percent

• CMML-2:ImmatureWBCincirculatingblood5-19percent,immatureWBCinbonemarrow10-19percent

• CMML-1or2witheosinophilia:Abovecriteriawithcirculatingbloodeosinophils>1.5x109cells/Lofblood

Theclassification/stageofCMMLdisease,incombinationwithdiagnosticresultssuchasWBC/RBC/plateletcounts,percentageofimmatureWBCsinthebonemarrow,complexkaryotype,historyoftransfusion,andpresenceoftheASXL1mutationarefactoredintoprognosticscoringsystemsthatdeterminewhetherthepatienthaslow-riskorhigh-riskCMML.

A)

B)

C)

D)

Figure4:Typesofchromosomalrearrangements.A)Deletion,notethelossoftheBgene.B)Duplication,notethegainofasecondBgene.C)Inversion,notethatthechromosomalarmscrossandgeneorderisinverted.D)Translocation,whentwodifferentchromosomesrearrangeresultingingenemovement.(CourtesyofL.Bridges)

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DISEASEBIOLOGY

ResearcherssuspectthatCMMListheresultofanabnormalbloodstemcellthatbeginstodivideandcrowdoutothernormalbloodstemcellsinthemarrow.TheimagebelowisagraphicalrepresentationofthepopulationofimmatureWBCsinthebonemarrow(y-axis)overtime(x-axis,years)andhypotheticallyillustrateshowanormalbonemarrowpopulationisselectedintoaCMML-likebonemarrow.

A)Outset:AllthebloodstemcellsarenormalandgrowintothecorrectimmatureWBCs,RBCs,platelets,andbloodstemcells.ThewhitecirclesindicatenormalimmatureWBCswithoutCMML-relatedmutations.

B)TheDriverandPassengerMutations:Ifonestemcellacquiresamutation(yellowcircle)thatbeginstodriveincreasedcellulardivisionandgrowth,thenitwillbegintooutgrowandcrowdoutnormalcells.Thisprocessmaytakemanyyearswithfewsymptomsforthepatient,andmaycontributetowhythemajorityofCMMLdiagnosesoccurinolderpatients.Themutatedcellgrowthisvisualizedbythenumberofyellowcirclesinthefigure.Randommutationsareanaturaloccurrenceduringnormalcelldivision.However,becausethemutatedstemcellnowdividesatahigherrate,itispronetodevelopingothercancer-drivingmutations,therebyacquiringasecondmutation(orangecircle)thatresultsinacontinuallyexpandingpopulationofmutantstemcells.

C)TheMoretheDividier:Oncekeygenesaremutated(althoughwhichgenesexactlyisnotfullyknownforCMML),themutatedstemcellswillexpandtobecomethedominantcellsinthepopulation.NormalstemcellswillnolongerprevailasadominantproportionoftheimmatureWBCs,butratheroneinapopulationofsinglemutation-(yellow),doublemutation-(orange),andtriplemutation-containing(red)cells.Furthermore,mutantcellswillcontinuetoexpandfasterbecausetheyhaveaselectivegrowthadvantageovernormalcells.

D)Onset:Overtime,thepopulationofnormalcellsdrop,concomitantwithanincreaseofimmatureWBCscontainingmultipleCMML-relatedmutations.Atthisstage,thepatientwillbegintoshowsymptomsofCMML,becausethenormalstemcellsfailtoproducesufficientnormalWBCs,RBCs,andplatelets(diagnosedviabloodcellcounts),andthemutantstemcellsbegintoproducealargeamountofabnormalimmatureWBCs.Cytogeneticrearrangementsandabnormalcellstructureswillalsobecomeevidentbloodsmears.

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CELLULARBIOLOGY

AlthoughtheexactmutationsthatleadtoCMMLarenotcompletelyunderstood,multiplecellularpathwayshavebeenimplicatedinthedisease:

• IncreasedCellGrowthandDecreasedCellDeath—CMMLcellsdemonstrateabnormalactivationofcellgrowthanddivisionpathways,aswellasdown-regulationofcelldeathorapoptoticpathways

• ImpairedImmuneSurveillance—RecentworkhasshownthatCMMLcellsexpresshighlevelsoftheimmunecheckpointproteinPD-1,indicatingthatthediseaseemploysmechanismsthathideitsdramaticcellgrowthanddivisionfromtheimmunesystem,whichwouldnormallyattackcancerouscells

• AbnormalBloodVesselGrowth—Inordertofacilitatetheirrapidcellgrowthanddivision,CMMLcellssecretefactorsthataltertheenvironmentofthebonemarrowtopromotebloodvesselgrowth,orangiogenesis.TheincreaseinbloodvesselsthenallowsgreaterdeliveryofnutrientsthatprovidefuelandbuildingblockstoproducetheinvasiveCMMLimmatureWBCs

MOLECULARBIOLOGYANDTHERAPEUTICTARGETAREAS

Alteredsignaling,epigeneticregulation,andRNAsplicinghavebeenimplicatedindevelopmentofCMML.Advancementofresearchintotheseareaswillfacilitatetheidentificationofpotentialdruggabletargets.

• SignalingPathwaysreceivesignalsfromoutsidethecellandactivatedownstreamproteinsthatalterDNAtranscriptionandsubsequentproteinexpression

o TheJAK/STATpathwayisinvolvedincellgrowthandhasbeenshowntobeupregulatedinCMMLcells.ResearchhasshownthatCMMLcellsarehypersensitivetogranulocytemacrophagecolony-stimulatingfactor(GM-CSF),akeyactivatoroftheJAK/STATpathway

o TheRASpathwayisalsoinvolvedincellgrowth.Amongbloodcancers,CMMLpresentsthehighestincidenceofRASpathwaymutations,primarilyintheNRAS-andKRAS-relatedgenes.MousemodelswithmutantNRAShavealsobeenshowntodevelopCMML-likedisease,indicatingthatproteinsinthispathwayarepotentialtherapeutictargets

SeveralepigeneticandsplicingmutationsarestronglyassociatedwithCMML:TET2,ASXL1,SRSF2,andSETBP1.

• EpigeneticeventsregulatetheexpressionofgeneswithoutchangingtheDNAsequence.DifferentgenesareactivateddependingonthemarksattachedtoDNAitselfandtheproteinsaroundwhichDNAiswound,orhistones.MethylgroupscanbeaddedtoDNAorhistones,whereasacetylgroups,phosphates,andsmallproteinssuchasubiquitinonlymarkhistones.

o TET2isanenzymethatepigeneticallymodifiesDNAbyremovingmethylgroups.MutationsthatreduceTET2activityhavebeenimplicatedinmultiplebloodcancers,indicatingitscriticalroleinbloodcelldevelopment.Furthermore,mutationsinTET2arehypothesizedtobeadrivermutationforCMMLdevelopment,becauseitresultsinanincreaseinDNAmethylationandasubsequentincreaseinWBCproduction.AlongwithASXL1,TET2isthemostfrequentlyidentifiedmutationinCMMLpatients.

GM-CSFhypersensitivityisamajorpointofconvergenceforCMMLandJMML,asbothdiseasesupregulatetheJAK/STATpathway.DevelopmentandapprovaloftherapeuticstargetingthispathwaymaybenefitbothCMMLandJMMLpatients.

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• Splicingfactors

o ASXL1isanRNAsplicingfactorthatmodifiesthetranscriptsgeneratedfromDNA.WhenASXL1ismutatedandlosesactivity,anepigeneticcascadeoccursthatultimatelydrivestheproductionofCMMLimmatureWBCs.SimilartoTET2,ASXL1isthemostfrequentlyidentifiedmutationinCMMLpatients

o SRSF2isacomponentofthespliceosome,themulti-proteinmachinerythatmodifiesRNAtranscriptsgeneratedfromDNA.MutationsinSRSF2arethethirdmostcommonmutationsinCMMLpatients

• MutationsinSETBP1arealsocommonlyfoundinCMMLpatients.SETBP1isaproteinthatinteractswiththeSETprotein,whichitselfisinvolvedinapoptosis,transcription,andhistoneassembly.Researchhasshownthatdefectsinthisinteractionresultinhigherratesofcelldivision

ThepresenceofSETBP1mutationsinJMMLpatientsconfersaparticularlypooroutcome.

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TREATMENTS

SeveraltreatmentoptionsareavailableforCMMLpatients—withtheregimendependentonthepatient’sdiseaseprognosisandclinicalsymptoms.SpecificexamplesoftheapprovedtreatmentsarelistedinTable1.

• Allogeneicstemcelltransplantisapossiblecourseofactionforhigh-riskCMMLpatients

o Thisprocesswillreplacethepatient’sabnormalbonemarrowwithadonor’sgeneticallydifferent(allogeneic)bonemarrow.Althoughacurativetreatmentoption,astemcelltransplantisaveryriskyprocedurewitha70percentmortalityrate.Factorsthatincreasethechancesofsuccessareyoungageaswellasfewchromosomalabnormalities

• Hypomethylatingagents(HMA)arealikelycourseoftreatmentifthepatientsuffersprimarilyfromalackofRBCs,platelets,andnormalWBCs(cytopenia)

o CMMLcellspresentanincreaseinmethylmarksontheirDNA,resultinginalteredepigeneticsversusnormalcells.AgentsthatgloballyreducetheamountofDNAmethylationhaveshownlimitedsuccessinslowingdiseaseprogression.TheprimaryshortcomingsofHMAsareasfollows:

§ Selectiveeffectiveness—NotallCMMLpatientsrespondthesamewaytoHMA,withsomedemonstratinganoticeabledropinWBCsandnormalizationofRBCsandplatelets,whileothersshownochangewhatsoever.MoreresearchisneededtounderstandwhomayormaynotrespondtoHMAtreatment

§ Short-termeffectiveness—FortheCMMLpatientsthatdodemonstrateagoodresponseratetoHMA,thesetendtobeshort-lived,withthediseasereturninginamatterofmonths.TreatmentfailureoccurswhenthecancerdevelopsresistancetotheHMA

• ChemotherapyisalikelycourseoftreatmentifthepatientsuffersfromahighamountofcirculatingabnormalWBCs

o Chemotherapygloballyreducescellgrowthanddivision,andithasshownsomeeffectivenessincontrollinglow-riskCMML.However,thetreatmentinvolvesawiderangeofsideeffectsbecauseitaffectsbothnormalandcancerouscells.AkeyquestionsurroundingchemotherapyiswhetheritaffectsthesourceofCMMLdisease—namelytheabnormalstemcell—oronlytreatssymptomsofthecancer

Table1:FDA-approvedtherapeuticsforCMMLBrandName GenericName MechanismofActionVidaza azacytidine HMADacogen decitabine ChemotherapyandHMACytosar-U cytarabine ChemotherapyHydrea hydroxyurea Chemotherapy

“Thesepatientsneedbetterdrugs.Theoneswehavedon’twork,andifthey

havesomeeffect,wehavenoideawhy.”

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CLINICALTRIALSANDINVESTIGATIONALTHERAPIES

Clinicalresearchisabranchofbiomedicalresearchinvolvinghumansubjects.Thegoalofclinicalresearchistoevaluatethesafetyandefficacyofdrugs,medicaldevices,ordiagnosticsintendedforuseinhumanpatients.

Clinicaltrialsareanimportantcomponentofclinicalresearchastheyareusedtoevaluatethesafetyandefficacyofanexperimentaldrugortherapyinhumansubjects.Theycanalsobeusedtocollectspecimensfromhumansubjectsforfurtherresearch.Importantly,informationonpotentialsideeffectsaregatheredduringtheclinicaltrialandweighedagainstthepotentialtherapeuticbenefitofthetreatmentunderinvestigation.ClinicalresearchisdividedintothreekeyphasesandisdescribedinFigure5:

AkeychallengethathashinderedCMMLinvestigationaltherapieswasthemisclassificationofCMMLasamyelodysplasticdisease.Asaresult,fewstudieshavefocusedonCMMLalone(Figure6).Althoughagentsthataffectthefast-growing(MPN)orabnormalcellularaspects(MDS)ofCMMLholdsomepromise,targetedtherapiesthatfocusontheuniqueaspectsofCMMLareneededtomakeatransformativeimpactonthedisease.

0

5

10

15

20

Phase1 Phase1/2 Phase2 Phase2/3 Phase3

CMMLonlyTrials CMML,MDS,andMPNTrials

Figure6:CMML-relatedclinicaltrialsasof2015.TrialsspecifictoCMMLareinblue,whiletrialsthatincludeCMMLasasubtypeofMDSorMPNareinorange.

Figure5:PhasesofClinicalTrials.DuringPhase1studies,researcherstestanewdrugortreatmentforthefirsttimeinasmallgroupofpeopletoevaluateitssafety,determineasafedoserange,andidentifypotentialsideeffects.DuringPhaseII,proof-of-conceptstudiesareperformedasthedrugortreatmentisgiventoalargergroupofpeopletodetermineitsefficacyandoptimaldose.DuringPhaseIII,thedrugortreatmentisgiventolargegroupsofpeopletoconfirmitseffectiveness,monitorsideeffects,andassessitsimpactcomparedtothecurrentstandardofcare(SOC).SomeclinicalstudiesinvolvemultiplephasestofacilitateseamlesstransitionfromonetoanotherandarewrittenasPhaseI/IIorPhaseII/III.Thesedesignationsarealsousedinadaptivetrials,whereinstudyparametersforthePhaseIIstudyaremodifiedwithrespecttoongoingPhaseItrialresults,etc.

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AsshowninTable2,basedwhatisknownaboutthecellularandmolecularbiologyofCMML,investigationaltherapiescanbeclassifiedintothefollowingcategories.

Table2:ExperimentaltherapiesforCMMLDrugName(s) MechanismofAction PathwayTargetedtopotecansapacitabinebirinapantclofarabine

Chemotherapy Celldivisionandgrowth

thalidomidelenalidomidepomalidomide

Immunomodulators Immunesystemandangiogenesis

entinostatpanobinostatvorinostat

Histonedeacetylaseinhibitors Epigenetics

lonafarnibtipifarnib

Farnesyltransferaseinhibitors RASpathway

glasdegiberismodegib

Hedgehogpathwayinhibitors Stemcelldifferentiationandangiogenesis

rigosertib Kinaseinhibitor Celldivisionandgrowthmidostaurin Kinaseinhibitor Celldivisionandgrowthandangiogenesisruxolitinib Kinaseinhibitor JAK/STATpathwayimatinibdasatinib

Kinaseinhibitors CMMLdiagnosisofPDGFRBrearrangementandincreasedeosinophils

E6201 Kinaseinhibitor RASpathway

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RESEARCHCHALLENGESANDPHILANTHROPICOPPORTUNITIES

CMMLhaslongbeenanorphaneddiseasebecauseofthedifficultyinaccuratelydiagnosingthediseaseinpatients,coupledwithitsmisclassificationformanyyearsasasubsetofMDS.Asaresult,CMMLisbesetbyanumberofunmetneedsincludingthefollowing:

• Limitedtherapeuticoptions

• Absenceofapatientregistryandclinicaltrialinfrastructure

• Overalllackofunderstandingofthebasicandtranslationalbiology

ToaddresstheseneedsandultimatelybenefitCMMLpatients,thePhilanthropyAdvisoryServiceheldaretreatwithacademic,clinical,industry,patientadvocate,andfoundationpartnerstochartascientificroadmaptochangethetrajectoryofthisdisease.

CMMLPATIENTREGISTRY

THEPROBLEM

AcentralissueinCMMLresearchisthelackofCMML-specificinformation.Manyoftheapproved,andgenerallyineffective,treatmentsforthediseasearebasedontheinclusionofCMMLpatientsasasubsetoftrialparticipantsforMDSstudies.ThusthechallengeofdiagnosingapatientwithCMML,coupledwithpoortherapeuticoptions,resultsinlittleincentiveforphysicianstoaccuratelydiagnoseCMML,becausetheeventualtreatmentissimilartoanMDSregimen.

POTENTIALSOLUTION

TheCMMLresearchcommunityneedsaformalizedpatientregistry.Currentlyresearchershavebandedtogethertoinformallysharede-identifiedCMMLpatientinformationfromacrossmultipleclinicaltrialsandresearchstudies.Thegoalofthiseffortisto:

• BetterdefineCMML-specificcharacteristics

• Clarifypatientresponsetoapprovedandinvestigationaltherapies

• AssessprognosticscoringsystemsthatincludegeneticdriversofCMML

Withadditionalsupporttoexpandandformalizethiseffort,theinitiativecanserveasthetouchpointforafederatedsystemoftissuebanking.TheregistrycanprovideaprospectivecohortofCMMLpatientstoevaluateovertimeandcansupportclinicaltrialenrollment.

PHILANTHROPICOPPORTUNITIES

FormalizetheCMMLpatientregistryefforttofacilitatepatientrecruitmentandbiobankingofpatientsamples.Thiswillprimarilyrequireinfrastructuresupporttodevelopthefollowing:

• Web-baseddataentryportalwithanalyticcapacitytoincreasethepoolofCMMLpatientcases

• Resourcesfordatamanagementtofacilitategeneticdatacurationandscreeningofpatients

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• FederatedtissuesamplebankingtofacilitatecollaborationacrosstheCMMLfield

DIAGNOSTICANDPROGNOSTICBIOMARKERSOFCMML

THEPROBLEM

CMMLdiagnosisisprimarilydependentoncellmorphology–based(pathological)assessmentofimmatureWBCsasapercentageofcirculatingbloodandbonemarrowsamples.AlthoughWHOdiagnosticcriteriaarecontinuouslyimprovedandrefined,theprocessisdependentonskilledpathologistsaccuratelydeterminingaCMMLversusMDSpatient.Thisposesanissueinaccuratelydiagnosingapatientattheinitialpointofcare.Furthermore,thecurrentclassificationschemeindicateswherethediseaseisgoing,ratherthanwhereitcamefrom.

POTENTIALSOLUTIONS

CMMLdiagnosisandprognosismaybeenhancedwiththeadditionofgeneticmarkersofthedisease.Geneticsequencingofpatientsampleshaveidentified8-40genesthatarehighlyrepresentedinCMMLversusMDSpatients.DespitetheprevalenceofthesegenesinCMMLpatients,thereisnosinglegeneuniquetothedisease.However,manyofthesebiomarkersarehighlyassociatedwithoneanother,and,ifvalidatedandincorporatedintothecurrentCMMLdiagnosticscheme,wouldimprovetheidentificationofCMMLpatientsatearlierdiseasestages.ResearchinassociatedCMMLgeneswouldalsoassesstheirabilitytopredictpatientresponsetotreatment.

PHILANTHROPICOPPORTUNITIES

CMMLDiagnosis

• SupportresearchtoexpandtheWHOCMMLdiagnosticcriteriatoincludegeneticbiomarkers

o ThiseffortcouldvalidatenovelassayssuchasWBCsortingbasedonexpressedsurfacemarkers

o ThiseffortwouldalsoaidinthedevelopmentofastandardJMMLdiagnosticpanel

• SupportanationalefforttoidentifyindividualswhopresenthighlevelsofWBCs,thensubsequentlytestthemforCMMLgeneticbiomarkerstoidentifyearly-stagepatients

o SimilartotheLeukemia&LymphomaSocietyPre-malignancyprogram,thiseffortwouldaidinthedevelopmentofaprospectivecohortofCMMLpatientsandpossiblyidentifypatientssufferingfromcloselyrelateddiseases

o PotentialCMMLpatientswouldbedirectedtoawebsitetofacilitatereferraltoatertiarycarecenter

CMMLPrognosis

• SupportresearcheffortssuchastheInternationalWorkingGrouponPrognosticMarkersforMDS(IWG-PM),whosegoalistovalidateMDSbiomarkersviacarefulassessmentofpatientsamples

o ACMML-focusedeffortwouldcarefullyassesspatientsamplestobetterunderstandpatientdiseaseprogressionandresponsetotreatment

• SupportaCancerGenomeAtlasdiscoveryeffortfocusedonCMML

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o Aprospectivestudywithlong-termcollectionandtestingofsamplescouldidentifynewbiomarkersandpotentialdrugtargets

CMMLCLINICALTRIALNETWORK

THEPROBLEM

Stymiedbythelackofablockbusterdrug,broadgeographicdistributionofthecomparativelysmallnumberofCMMLpatients,andlackofawarenesssurroundingCMML,veryfewclinicaltrialsdedicatedtothediseasehavebeencompleted.Furthermore,currentlyapproveddrugshavenotbeenfullyoptimizedforCMMLpatients,withlimitedresearchtoassesstheirtruebenefitinpatients.

POTENTIALSOLUTIONS

DevelopmentofaCMML-focusedclinicaltrialnetworkisacriticalstepinimpactingthetrajectoryofthisdisease.MultipleCentersofExcellenceacrosstheU.S.areactiveinCMMLclinicalstudies,andprovidinginfrastructuresupporttopoolresourceswouldenhancethewell-beingofandtreatmentoptionsforCMMLpatients.

Proposedclinicaltrialswould:

• OptimizecurrenttreatmentoptionstodeterminetheinitialregimenforCMMLpatients

• Buildatrialnetworkfoundationtotestcombinationswithexperimentaltherapeutics

• Standardizeclinicaltrialmeasurementsofdrugefficacyandtrialendpoints

PHILANTHROPICOPPORTUNITIES

• SupportexpansionoftheMDS-focusedclinicaltrialnetwork

o ThiseffortwillleveragetheexistinginfrastructuretotestnewCMMLtreatmentsandimproveexistingclinicalcarestandards

o ThiseffortwillfacilitateCMMLpatientengagement,education,andclinicaltrialenrollment,whilebenefittingMDSclinicalresearchefforts

o DevelopmentofthisnetworkwilldrivethecollectionofpatientsamplestosupportbasicandtranslationalstudiestoadvanceCMMLscience

• SupportdevelopmentofaCMMLClinicalTrialMasterProtocol,whichinvolvesdeterminationoftheidealstartingregimenandastructuredapproachtoassessingnewexperimentaltherapeutics

• Supporteffortstoaddresspatientengagement,education,andpatient-specificroadblockstotrialparticipationsuchastransportationandcompensationoptions

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CMMLBASICANDTRANSLATIONALSCIENCE

THEPROBLEM(S)

AkeyunansweredresearchquestionishowmultiplegeneticmutationsmanifestintotheclinicalpresentationofCMML.CurrentresearchhassuccessfullyidentifiedmanyofthegeneticdriversofCMML,whichrangefromsplicingdefects,alteredepigenetics,anddysregulatedsignalingpathways.However,howthesepathwaysinteractarepoorlyunderstoodandyetpresentapotentialtroveofdrugtargets.ForknownCMML-relatedgenes,singlegeneknockout(KO)mousemodelshavebeendevelopedforpreclinicaltestingofexperimentaltreatments,buttheKOcombinationsandmodelsthatbestmimichumandiseasearecurrentlyunknown.Lastly,currentlyapproveddrugsthattargetepigeneticregulationhaveshownsomemeasureofefficacyinCMMLpatients,buthowtheyworkandtheirmechanismsofactionarenotwell-defined.

PROPOSEDSOLUTIONS

CMMLGENOTYPEàPHENOTYPE

IdentificationofthegenesmostcommonlyassociatedwithCMML(genotype)presentsanexcellentopportunitytounderstandhowthebloodstemcellabnormallydifferentiatesandresultsinCMMLdisease(phenotype).

Proposedscientificeffortsincludethefollowing:

• Identificationofthekeymutation(s)thatresultsintheinitialabnormaldifferentiation,andthesecondarymutationsthatthendrivedevelopmentofthedisease.

• TargeteddrugdevelopmentperformedwithCMMLpatientsamples

TheultimategoaloftheseeffortsistousethebasicunderstandingofCMMLgeneticsandcellgrowthtoidentifythekeypathwaysthatdrivethedisease.AdvancementsinthisresearchwillcontributetothedevelopmentofthenextgenerationofCMMLdrugs.

CMMLMOUSEMODELS

ThenextkeystepinCMMLmousemodelsistounderstandwhichmodelbestmimicshumandisease.UnderstandingwhetherKOorxenograftmodels(whereinpatientcellsaregraftedontomice)aretheidealvehiclestotestexperimentaltherapiesandwillgreatlyfacilitatethepreclinicalprocess.

EPIGENETICSOFCMML

InordertocapitalizeonthelimitedefficacyofhypomethylatorsforCMMLpatients,researchisneededtounderstandhowthesedrugsworkinpatientswhorespondtotreatment.Epigeneticsresearchwilldeterminethemechanismofactionofhypomethylators,aswellaswhetheryoungerversusolderpatientsresponddifferently.IdentificationofwhichcellsrespondtohypomethylatorsmayalsodeterminethepotentialuseofimmunotherapyinCMML.

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PHILANTHROPICOPPORTUNITIES

CMMLGENOTYPEàPHENOTYPE

Supportresearcheffortto:

• Initiateafunctionalgenomicsstudytodeveloptargetedtherapeutics

o Utilizepatientregistry/databasetoidentifygeneticmutationspresentinCMMLpatients

o Utilizepatientsamplestoidentifypotentialtherapeutictargets

• UtilizepatientsamplestoidentifytheinitialgeneticmutationsthatdevelopCMMLversusthesecondarymutationsthatdrivethedisease

• AddressthepotentialoftheRASpathwayandGM-CSFhypersensitivityasapointofconvergenceforCMMLandJMML

CMMLMOUSEMODELS

• Supportresearcheffortstodeterminetheidealmouseforpreclinicaltherapeuticstudies

• Supportabiobankoftransplantablepatientsamplesforuseinmousexenograftstudies

o Sampleswouldbecollectedfromclinicaltrialsandthepatientregistry

• Supportresearcheffortstoextensivelytestnoveltherapiesandcombinationsoftherapiesinmousemodels

EPIGENETICSOFCMML

• SupportresearcheffortstoidentifycommonepigeneticchangesacrosstreatedCMMLpatients,whichwouldalsoexpandtheunderstandingoftheroleofepigeneticsinJMML

o Comparepatientsamplesbeforeandduringtreatmenttoassessapatient’sepigeneticresponsebasedontheirownCMML-relatedmutations

o Identifythecorrecttargetcellaffectedbyhypomethylatingagents

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JMMLUNMETNEEDS

ThegreatestunmetneedofJMMLpatientsisaccesstodrugs.Pediatricstudiesoftenposerecruitmentandlogisticalchallengesfordrugdevelopers,andarethusnotalwaysperformedalongsideadultstudies.Furthermore,mostclinicaltrialshaveanagerestrictionof18-to65-years-old,therebydeprivingchildrensufferingfromleukemiatheopportunitytoparticipateintrialsthatmayaffecttheirdisease.AdvancesinCMMLresearchwillaidnotonlypatientswhosufferfromthedisease,butalsoJMMLpatients.Althoughtherearedifferencesbetweenthetwodiseases,severalCMMLinitiativeswouldsupportandadvanceJMMLresearch.

• SupportresearcheffortstodevelopastandardCMMLdiagnosticpanelwithgeneticbiomarkers

o ThemajorityofJMMLdiagnosesareaccomplishedviageneticsequencing.EffortstodevelopacombinedpathologyandgeneticbiomarkersdiagnosticpanelwouldbenefitbothCMMLandJMMLdiagnosis

o CMMLepigeneticstudieswouldalsocontributetotheepigeneticprofileofJMMLcellsaffectedbyhypomethylatingagents

• SupportdevelopmentofCMMLmousemodelswithgeneticlesionssimilartoJMMLtofacilitatesharedpreclinicalscreeningofapprovedandexperimentaldrugs

• SupportresearchtounderstandthecentralroleofGM-CSFhypersensitivityinCMMLandJMML

o UnderstandingdownstreampathwaysofJAK/STATactivationmayidentifycommondrugtargetsbetweenthetwodiseases

• SupportclinicaltrialsthatplantouseaMEKkinaseinhibitortoassessitsimpactonJMMLpatients

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RESEARCHGRANTMAKINGORGANIZATIONSINTHELEUKEMIAANDCMMLCOMMUNITY

ThissectionprovidesabriefoverviewofthenonprofitorganizationsinvolvedinCMMLresearch.Theirinvolvementcanbethroughdirectfundingofresearchorsupportofresearchefforts.

APLASTICANEMIAANDMDSINTERNATIONALFOUNDATIONCLINICALRESEARCHCONSORTIUM

Establishedin1983,theAA&MDSInternationalFoundationisaleadingnonprofitthatfocusesonsupportingpatientsandfamilieslivingwithaplasticanemia,myelodysplasticsyndromes,andparoxysmalnocturnalhemoglobinuria.Thefoundation’spatient-centeredeffortsfocusondiagnosis,treatment,andlife-longimplicationsoflivingwithachronicdisease.SupportedbytheEdwardP.EvansFoundation,AA&MDSdevelopedandfundstheMDSClinicalResearchConsortium,asix-institutioneffortdesignedtofacilitateMDSclinicaltrials.TheConsortiumfillsamajorgapinMDS-relatedclinicalresearchbyprovidingacriticalmassofpatientsandpatientdatatoevaluatenewtherapiesforMDS.ConsortiumactivitiesaredirectedbyasteeringcommitteecomposedofMDSresearcherswhowillassessandapproveproposedstudies.

THELEUKEMIAANDLYMPHOMASOCIETY

ThemissionofTheLeukemiaandLymphomaSociety(LLS)istocureleukemia,lymphoma,Hodgkin’sdisease,andmyelomaandtoimprovethequalityoflifeofpatentsandtheirfamilies.Giventhedifficultyofpreventionorearlyscreeningforbloodcancers,theLLSresearchagendaisfocusedonfindingcures.LLSactivelyfundsallstagesofbloodcancerresearch,fromdiscoverysciencetoclinicaltrials,andprovidescareersupporttoearlyandestablishedinvestigators.LLSdrivesresearchinareasofunmetclinicalneed,andviainnovativeprogramssuchastheTherapyAcceleratorProgram(TAP),helpstobridgethegapbetweenacademicdrugdiscoveryanddrugdevelopment.TheTAPprogramhastwoprimaryfacets:

• TheBiotechnologyAcceleratorDivisionidentifiescompaniesdevelopingnovelanti-cancertherapies,supportivecareordiagnosticsandco-fundsspecificprojectsthatwillenableacompanytopartnerorraiseadditionalfundingtocompletethetesting,registrationandmarketingofnewtherapiesordiagnosticsforbloodcancerindications.

• TheAcademicConciergeDivisioncapitalizesonLLS'sacademicgrant-supportedportfolioofdevelopment-stageprojects.Thisdivisionsupportsthefurtherdevelopmentofselectedacademicprojects(withorwithoutpriorLLSgrantsupport)togainclinicalproofofconcept.Successfulprojectswillpotentiallybeadvancedforfurtherclinicaldevelopmentbycreatingadditionalpartnershipswithpharmaceuticalorbiotechnologycompanies.

THEMYELODYSPLASTICSYNDROMEINTERNATIONALFOUNDATION

TheMDSFoundationwasestablishedbyaninternationalgroupofphysiciansandresearcherstoprovideanongoingexchangeofinformationrelatingtoMDS.Sinceitsinception,ithasconducted13internationalsymposiaacross12countries.ThefoundationservesasanexusforMDSresearchandinformationthatprovides:

• PatientswithreferralstoCentersofExcellenceandactiveclinicaltrials

• Disseminationoftreatmentoptionsandeducationalsupportforhealthproviders

SupportedbytheMDSFoundation,theIWG-PManalyzedclinicalfeaturesandoutcomedatafrommorethan7,000patientsandrevisedtheinternationalprognosticscoringsystemforMDS.Bycomprehensivelyintegrating

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knownclinicalfeaturesofMDS,therevisedscoringsystemhasimprovedthepredictionofclinicaloutcomesinuntreatedMDSpatients,whileaidingthedesignandanalysisofclinicaltrials.

GLOSSARYOFTERMS

Acutemyeloidleukemia Anaggressivecancerofthebloodandbonemarrowthatresultsinincreasedimmaturebloodcellgrowth

Allogeneicbonemarrowtransplant Asurgicalprocedurethatreplacesapatient’sabnormalbonemarrowwithadonor’sgeneticallydifferent(allogeneic)bonemarrow

Anemia Aconditiondescribinginsufficientredbloodcells,whichcanleadtofatigue,shortnessofbreath,andpaleskin

Atypicalchronicmyeloidleukemia Araresubtypeofmyelodysplastic/myeloproliferativeneoplasm(MDS/MPN)largelydefinedmorphologically.ItiscurrentlyunclearwhetheraCML-associatedfeaturesaredistinctiveenoughtoallowitsseparationfromunclassifiableMDS/MPN

Biomarker Adistinctbiochemical,genetic,ormolecularcharacteristicthatisobjectivelymeasuredandevaluatedasanindicatorofaparticularbiologicalconditionorprocess

Bloodsmears Adiagnostictestusedtolookforabnormalitieswithintheblood,whereincelltypesareexaminedunderamicroscopeforunusualshapesorsizes

Bonemarrow Asoftfattysubstanceinthecavitiesofbonesfromwhichbloodcellsareproduced

Bonemarrowaspiration Aprocedurethatinvolvesinjectinganeedleintothebonemarrowtoobtainasampleoftheliquidportionofthemarrow

Bonemarrowbiopsy Aprocedurethatinvolvesinjectinganeedleintothebonemarrowtoobtainasampleofthecoreofthemarrow

Chronicmyeloidleukemia Atypeofleukemia,designatedbytheBCR-ABLtransgene,thatdrivesexpansionofcertainblood-formingcellsofthebonemarrow

Completebloodcount AdiagnostictestthatmeasurestheabsolutenumberofcelltypesinthebloodincludingWBCs,RBCs,andplatelets

Complexkaryotype Asituationwhereapatientpresents>3chromosomalrearrangements

Cytogeneticstudies Teststhatassessthestructuralintegrityofapatient’schromosomesusingbonemarrowsamples

Cytopenia AconditionthatdescribesalackofRBCs,platelets,and/ornormalWBCs

Cytoplasm Thematerialwithinalivingcellexcludingthenucleusandothermembrane-boundcompartments

DNA Amoleculethatcarriesmostofthegeneticinformationusedinthedevelopment,function,andreproductionoflivingorganismsandviruses

Eosinophils/Eosinophilia Atypeofwhitebloodcellthattargetsparasites;eosinophiliareferstoanabnormallyhighamountofthesecells

Epigenetics Changesinthegenomerelatingtoorarisingfromnongeneticinfluences

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ongeneexpression

Genotype Identificationofthegenesmostcommonlyassociatedwithadisease

Hematopoieticstemcell Locatedinthebonemarrow,thesecellsthatgiverisetoallthebloodcells

Histones TheproteinsaroundwhichDNAiswound

ImmatureWBC Thecelldifferentiationstageinbetweenthehematopoeiticstemcellandthefullydifferentiatedwhitebloodcell

Juvenilemyelomonocyticleukemia Aseriouschronicleukemiathataffectschildrenmostlyaged4andyounger

Karyotype Thenumberandvisualappearanceofthechromosomesinthecellnucleiofanorganism

Leukopenia AconditionwhereinapatientpresentsareductioninthenumberofWBCsintheblood

Monocytosis AhighandpersistentWBCcountof>1,000cells/mm3ofblood

Myelodysplasticsyndrome Agroupofdiseasesinwhichimmaturebloodcellsinthebonemarrowdonotmatureorbecomehealthybloodcells

Myeloproliferativeneoplasms AgroupofdiseasesinwhichthebonemarrowmakestoomanyRBCs,platelets,orcertainWBCs

Myeloproliferative/myelodysplasticsyndromes

Agroupofdiseasesthathavefeaturesofbothmyelodysplasticsyndromesandmyeloproliferativeneoplasms

Nucleus Adenseorganelle,typicallyasingleroundedstructureboundedbyadoublemembrane,containinggeneticmaterialofthecell

Pathologicalassessment Thescienceofthecausesandeffectsofdiseases,especiallythebranchofmedicinethatdealswiththelaboratoryexaminationofsamplesofbodytissuefordiagnosticpurposes

Phenotype Thecompositeofanorganism’sobservablecharacteristicsortraits,suchasitsmorphology,development,biochemical,orphysiologicalproperties

Platelet Abloodcellwhoseprimaryfunctionistofacilitatebloodclotting

Redbloodcell Abloodcellwhoseprimaryfunctionistocarryoxygentotissues

RNA AmoleculesimilartoDNA,itplaysaroleincoding,decoding,regulationandexpressionofgenes

Signalingpathways AprocessbywhichcellsreceivesignalsfromoutsidethecellandactivatedownstreamproteinsthatalterDNAtranscriptionandsubsequentproteinexpression

Splenomegaly Aconditionthatdescribesenlargementofthespleen

Thrombocytopenia Aconditionthatdescribesinsufficientplatelets,whichcanleadtoeasybruisingandbleeding

Whitebloodcell Abloodcellwhoseprimaryfunctionistohelpfightinfections

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