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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 REFERENCES 1. 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