骨髓增殖性腫瘤課件

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).

FamilialPredispositiontoETandOtherMyeloproliferativeNeoplasms

Arelativeriskof7.4fordevelopingETinthosewithanaffectedfirst-degreerelative.

ProgressiontoAcuteMyeloidLeukemia

Progressiontoacutemyeloidleukemia(AML)occursinasmallminorityofETpatientsandinvolvestheaccrualoffurthergeneticevents.

Therapy

Low-doseaspirinCytoreductivetherapyHydroxyureaAnagrelideJAK2inhibitors

ClassificationofErythrocytoses

Anerythrocytosiscanbeclassifieddependingontheidentifiedcause.Themaindivisionisonthebasisofprimarycauses,whereanintrinsicdefectintheerythroidprogenitorcellisassociatedwithanenhancedresponsetocytokines;orsecondary,wheretheincreasedredcellproductionisdrivenbyfactorsexternaltotheerythroidcompartment,suchasincreasederythropoietin(EPO)productionforanyreason.Primaryandsecondarycausescanbeclassifiedfurtheraseithercongenitaloracquired(Table2).Table2.CausesofanerythrocytosisPrimaryErythrocytosisSecondaryerythrocytosisIdiopathicerythrocytosisTable2.CausesofanerythrocytosisPrimaryErythrocytosisCongenital

Erythropoietin(EPO)receptormutationsAcquired

Polycythemia

vera(includingJAK2exon12mutations)

SecondaryerythrocytosisCongenitalDefectsoftheoxygensensingpathwayVHLgenemutation(Chuvash

erythrocytosis)PHD2mutationsHIF-2amutationsOthercongenitaldefectsHighoxygen-affinityhemoglobin

Bisphosphoglycerate

mutasedeficiency

AcquiredEPO-mediatedCentralhypoxiaChroniclungdiseaseRight-to-leftcardiopulmonaryvascularshuntsCarbonmonoxidepoisoningSmoker′serythrocytosisHypoventilationsyndromesincludingobstru-ctivesleepapneaHigh-altitude

PathologicEPOproductionTumors

CerebellarhemangioblastomaMeningiomaParathyriodcarcinoma/adenomasHepatocellularcarcinomaRenalcellcancerPheochromocytomaUterineleiomyomasDrugassociatedErythropoietinadministrationAndrogenadministration

InvestigationofanErythrocytosis

Onceanerythrocytosishasbeenestablishedidentificationofthecauseisthenextfocus.

ClinicalConsequences

Araisedredcellcountwillincreasetheviscosityandthusmayhaveclinicalconsequences.

ManagementofanErythrocytosis

ReducingtheHctbyphlebotomy/venesectionreducesthebloodviscosityandmaybeofbenefit.CytoreductiveLow-doseaspirin

TheV617Fmutationislocalizedinaregionoutsidetheadenosinetriphosphate(ATP)-bindingpocketofJAK2enzyme,ATP-competitiveinhibitorsofJAK2kinasearenotlikelytodiscriminatebetweenwild-typeandmutantJAK2enzymes.Therefore,JAK2inhibitors,byvirtueoftheirnearequipotentactivityagainstwild-typeJAK2thatisimportantfornormalhematopoiesis,mayhaveadversemyelosuppressionasanexpectedsideeffect,ifadministeredatdosesthataimtocompletelyinhibitthemutantJAK2enzyme.

Whiletheymayprove