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HongzhiXu
ShandongProvincialHospital
MyeloproliferativeDisorders
CONTENTS
PathogenesisandmanagementofessentialthrombocythemiaIdiopathicerythrocytosis:adisappearingentityTherapeuticpotentialofJAK2inhibitorsPathogenesisandmanagementofessentialthrombocythemia
Severallinesofevidencesuggestablurringofthedistinctionbetweenthesedisorders.AproporationofpatientsdiagnosedwithET(seeTable1forcriteria)harborincreasedlevelsofbonemarrowreticulinintheabsenceofotherfeaturessuggestingadiagnosisofPMF
Thevariabledegreeofreticulinaccumulationreflectsthecombinedeffectsofgeneticbackground,diseaseduration,therapy,clonalburdenandtheacquisitionofadditionalgeneticlesions.Table1.Suggesteddiagnosticcriteriaforessentialthrombocythemia(ET)
DiagnosisrequiresA1-A3ORA1+A3-A5A1Sustainedplateletcount>450X109/L.A2Presenceofanacquiredpathogeneticmutation(eg,inJAK2orMPL).A3Noothermyeloidmalignancy,especiallypolycythemiavera(PV),primarymyelofibrosis(PMF),chronicmyeloidleukemia(CML)ormyelodysplasticsyndrome(MDS).A4Noreactivecauseforthrombocytosisandnormalironstores.A5Bonemarrowtrephinehistologyshowingincreasedmegakaryocyteswithprominentlargehyperlobatedforms;reticulinisgenerallynotincreased(≤2ona0-4scale).AreMutationsinJAK2Disease-initiatingEvents?TheacquisitionofaJAK2mutationwasprecededbyeitheradeletionofchromosome20q24oramutationinTET2.DirectevidencenowexistsdemonstratingthatJAK2mutationsarenotthedisease-initiatingeventinsomepatients,althoughthefrequencyofthisscenarioremainsunclear.
ProgressiontoAcuteMyeloidLeukemia
Progressiontoacutemyeloidleukemia(AML)occursinasmallminorityofETpatientsandinvolvestheaccrualoffurthergeneticevents.
DiagnosisandManagement
DiagnosticCriteria
MutationsinJAK2exon12arenotthoughttooccurinpatientswithET.Thecombinationofanisolatedthrombocytosiswithapathogeneticmutation,intheabsenceofirondeficiencyorfeaturesofPMF,isusuallysufficienttomakeadiagnosisofET.
Idiopathicerythrocytosis:adisappearingentity
ClassificationofErythrocytoses
Anerythrocytosiscanbeclassifieddependingontheidentifiedcause.Themaindivisionisonthebasisofprimarycauses,whereanintrinsicdefectintheerythroidprogenitorcellisassociatedwithanenhancedresponsetocytokines;orsecondary,wheretheincreasedredcellproductionisdrivenbyfactorsexternaltotheerythroidcompartment,suchasincreasederythropoietin(EPO)productionforanyreason.Primaryandsecondarycausescanbeclassifiedfurtheraseithercongenitaloracquired(Table2).Table2.CausesofanerythrocytosisPrimaryErythrocytosisSecondaryerythrocytosisIdiopathicerythrocytosisSecondaryerythrocytosisCongenitalDefectsoftheoxygensensingpathwayVHLgenemutation(Chuvash
erythrocytosis)PHD2mutationsHIF-2amutationsOthercongenitaldefectsHighoxygen-affinityhemoglobin
Bisphosphoglycerate
mutasedeficiency
AcquiredEPO-mediatedCentralhypoxiaChroniclungdiseaseRight-to-leftcardiopulmonaryvascularshuntsCarbonmonoxidepoisoningSmoker′serythrocytosisHypoventilationsyndromesincludingobstru-ctivesleepapneaHigh-altitude
LocalhypoxiaRenalarterystenosisEnd-stagerenaldiseaseHydronephrosisRenalcysts(polycystickidneydisease)Post-renaltransplanterythrocytosis
InvestigationofanErythrocytosis
Onceanerythrocytosishasbeenestablishedidentificationofthecauseisthenextfocus.
ClinicalConsequences
Araisedredcellcountwillincreasetheviscosityandthusmayhaveclinicalconsequences.
ManagementofanErythrocytosis
ReducingtheHctbyphlebotomy/venesectionreducesthebloodviscosityandmaybeofbenefit.CytoreductiveLow-doseaspirin
TherapeuticpotentialofJAK2inhibitors
TheV617Fmutationislocalizedinaregionoutsidetheadenosinetriphosphate(ATP)-bindingpocketofJAK2enzyme,ATP-competitiveinhibitorsofJAK2kinasearenotlikelytodiscriminatebetweenwild-typeandmutantJAK2enzymes.Therefore,JAK2inhibitors,byvirtueoftheirnearequipotentactivityagainstwild-typeJAK2thatisimportantfornormalhematopoiesis,mayhaveadversemyelosuppressionasanexpectedsideeffect,ifadministeredatdosesthataimtocompletelyinhibitthemutantJAK2enzyme.PreliminaryclinicalobservationsinselectedJAK2inhibitortrials.AgentCompanyTarget(s)JAKIC50(nM)CurrentphasePreliminaryclinicalobserbationsinmyelofibrosisstudiesINCB018424IncyteJAK1,JAK2JAK1=2.7*JAK2=4.5*JAK3=322*IIIDecreasedspleensizeirrespectiveofJAK2mutationalstatus;improvedqualityoflife,weightandperformance;decreasedinflammatorycytokinelevels.MyelosuppressionTG101384TargeGENJAK2JAK1=105JAK2=3JAK3=996IIDecreasedspleensize;decreaseinWBC.Myelosuppression;gastrointestinaldisturbanceXL019ExelixisJAK2JAK1=132JAK2=2JAK3=250discontinu
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