骨髓增殖性肿瘤课件

HongzhiXu Shandong Provincial HospitalShandong Provincial Hospital 1 1 HongzhiXu Shan CONTENTS Pathogenesis and management of essential thrombocythemia Idiopathic erythrocytosis:a disappearing entity Therapeutic potential of JAK2 inhibitors2 2 CONTENTS PathogenesPathogenesis and management of essential thrombocythemia3 3Pathogenesis and management ofPathogenesisRelationship of ET to PV and PMF The level of JAK2-STAT5 signaling provides a rheostat that determines whether the disease phenotype is predominantly erythroid or megakaryocytic.4 4PathogenesisRelationship of E Several lines of evidence suggest a blurring of the distinction between these disorders.A proporation of patients diagnosed with ET(see Table 1 for criteria)harbor increased levels of bone marrow reticulin in the absence of other features suggesting a diagnosis of PMF5 5 Several lines of evide The variable degree of reticulin accumulation reflects the combined effects of genetic background,disease duration,therapy,clonal burden and the acquisition of additional genetic lesions.6 6 The variable degree of Table 1.Suggested diagnostic criteria for Table 1.Suggested diagnostic criteria for essential thrombocythemia(ET)essential thrombocythemia(ET)Diagnosis requires A1-A3 OR A1+A3-A5Diagnosis requires A1-A3 OR A1+A3-A5 A1 Sustained platelet count 450X10A1 Sustained platelet count 450X109 9/L./L.A2 Presence of an acquired pathogenetic mutation(eg,in JAK2 or A2 Presence of an acquired pathogenetic mutation(eg,in JAK2 or MPL).MPL).A3 No other myeloid malignancy,especially polycythemia A3 No other myeloid malignancy,especially polycythemia vera(PV),primary myelofibrosis(PMF),chronic myeloid vera(PV),primary myelofibrosis(PMF),chronic myeloid leukemia(CML)or myelodysplastic syndrome(MDS).leukemia(CML)or myelodysplastic syndrome(MDS).A4 No reactive cause for thrombocytosis and normal iron stores.A4 No reactive cause for thrombocytosis and normal iron stores.A5 Bone marrow trephine histology showing increased A5 Bone marrow trephine histology showing increased megakaryocytes with prominent large hyperlobated forms;reticulin megakaryocytes with prominent large hyperlobated forms;reticulin is generally not increased(2 on a 0-4 scale).is generally not increased(2 on a 0-4 scale).7 7Table 1.Suggested diagnostic c Familial Predisposition to ET and Other Myeloproliferative Neoplasms A relative risk of 7.4 for developing ET in those with an affected first-degree relative.8 8 Familial Predisposition to Are Mutations in JAK2 Disease-initiating Events?Are Mutations in JAK2 Disease-initiating Events?The acquisition of a JAK2 mutation was The acquisition of a JAK2 mutation was preceded by either a deletion of chromosome preceded by either a deletion of chromosome 20q20q24 24 or a mutation in TET2.or a mutation in TET2.Direct evidence now exists demonstrating Direct evidence now exists demonstrating that JAK2 mutations are not the disease-that JAK2 mutations are not the disease-initiating event in some patients,although the initiating event in some patients,although the frequency of this scenario remains unclear.frequency of this scenario remains unclear.9 9Are Mutations in JAK2 Disease-Progression to Acute Myeloid Leukemia Progression to acute myeloid leukemia(AML)occurs in a small minority of ET patients and involves the accrual of further genetic events.1010 Progression to Acute Myeloid Diagnosis and Management Diagnostic CriteriaDiagnostic Criteria Mutations in JAK2 exon 12 are not thought Mutations in JAK2 exon 12 are not thought to occur in patients with ET.to occur in patients with ET.The combination of an isolated The combination of an isolated thrombocytosis with a pathogenetic mutation,thrombocytosis with a pathogenetic mutation,in the absence of iron deficiency or features of in the absence of iron deficiency or features of PMF,is usually sufficient to make a diagnosis PMF,is usually sufficient to make a diagnosis of ET.of ET.1111 Diagnosis and Management11 Therapy Low-dose aspirin Cytoreductive therapy Hydroxyurea Anagrelide JAK2 inhibitors1212 Therapy12Idiopathic erythrocytosis:a disappearing entity1313Idiopathic erythrocytosis:a Classification of ErythrocytosesClassification of Erythrocytoses An erythrocytosis can be classified depending on An erythrocytosis can be classified depending on the identified cause.The main division is on the basis the identified cause.The main division is on the basis of primary causes,where an intrinsic defect in the of primary causes,where an intrinsic defect in the erythroid progenitor cell is associated with an erythroid progenitor cell is associated with an enhanced response to cytokines;or secondary,where enhanced response to cytokines;or secondary,where the increased red cell production is driven by factors the increased red cell production is driven by factors external to the erythroid compartment,such as external to the erythroid compartment,such as increased erythropoietin(EPO)production for any increased erythropoietin(EPO)production for any reason.Primary and secondary causes can be reason.Primary and secondary causes can be classified further as either congenital or classified further as either congenital or acquiredacquired(Table2)(Table2).1414 Classification of ErythrocTable 2.Causes of an erythrocytosisPrimary ErythrocytosisSecondary erythrocytosisIdiopathic erythrocytosis1515Table 2.Causes of an erythrocyTable 2.Causes of an erythrocytosisPrimary Erythrocytosis Congenital Erythropoietin(EPO)receptor mutations Acquired Polycythemia vera(including JAK2 exon 12 mutations)1616Table 2.Causes of an erythrocySecondary erythrocytosisSecondary erythrocytosis Congenital Congenital Defects of the oxygen sensing pathway Defects of the oxygen sensing pathway VHL gene mutation(Chuvash erythrocytosis)VHL gene mutation(Chuvash erythrocytosis)PHD2 mutations PHD2 mutations HIF-2a mutations HIF-2a mutations Other congenital defects Other congenital defects High oxygen-affinity hemoglobin High oxygen-affinity hemoglobin Bisphosphoglycerate mutase deficiency Bisphosphoglycerate mutase deficiency 1717Secondary erythrocytosis17 Acquired Acquired EPO-mediated EPO-mediated Central hypoxia Central hypoxia Chronic lung disease Chronic lung disease Right-to-left cardiopulmonary vascular shunts Right-to-left cardiopulmonary vascular shunts Carbon monoxide poisoning Carbon monoxide poisoning Smokers erythrocytosis Smokers erythrocytosis Hypoventilation syndromes including obstru-Hypoventilation syndromes including obstru-ctive sleep apnea ctive sleep apnea High-altitude High-altitude1818 Acquired18 Local hypoxiaLocal hypoxia Renal artery stenosis Renal artery stenosis End-stage renal disease End-stage renal disease Hydronephrosis Hydronephrosis Renal cysts(polycystic kidney disease)Renal cysts(polycystic kidney disease)Post-renal transplant erythrocytosis Post-renal transplant erythrocytosis 1919 19 Pathologic EPO production Pathologic EPO production Tumors Tumors Cerebellar hemangioblastomaCerebellar hemangioblastoma Meningioma Meningioma Parathyriod carcinoma/adenomas Parathyriod carcinoma/adenomas Hepatocellular carcinoma Hepatocellular carcinoma Renal cell cancer Renal cell cancer Pheochromocytoma Pheochromocytoma Uterine leiomyomas Uterine leiomyomas Drug associated Drug associated Erythropoietin administration Erythropoietin administration Androgen administration Androgen administration2020 Pathologic EPO production Investigation of an ErythrocytosisInvestigation of an Erythrocytosis Once an erythrocytosis has been established identification of the cause is Once an erythrocytosis has been established identification of the cause is the next focus.the next focus.Clinical ConsequencesClinical Consequences A raised red cell count will increase the viscosity and thus may have A raised red cell count will increase the viscosity and thus may have clinical consequences.clinical consequences.Management of an ErythrocytosisManagement of an Erythrocytosis Reducing the Hct by phlebotomy/venesection reduces the blood viscosity Reducing the Hct by phlebotomy/venesection reduces the blood viscosity and maybe of benefit.and maybe of benefit.Cytoreductive Cytoreductive Low-dose aspirin Low-dose aspirin 2121 Investigation of an ErythroTherapeutic potential of JAK2 inhibitors2222Therapeutic potential of JAK2 The V617F mutation is localized in a region The V617F mutation is localized in a region outside the adenosine triphosphate(ATP)-outside the adenosine triphosphate(ATP)-binding pocket of JAK2 enzyme,ATP-binding pocket of JAK2 enzyme,ATP-competitive inhibitors of JAK2 kinase are not competitive inhibitors of JAK2 kinase are not likely to discriminate between wild-type and likely to discriminate between wild-type and mutant JAK2 enzymes.Therefore,JAK2 mutant JAK2 enzymes.Therefore,JAK2 inhibitors,by virtue of their near equipotent inhibitors,by virtue of their near equipotent activity against wild-type JAK2 that is important activity against wild-type JAK2 that is important for normal hematopoiesis,may have adverse for normal hematopoiesis,may have adverse myelosuppression as an expected side effect,myelosuppression as an expected side effect,if administered at doses that aim to completely if administered at doses that aim to completely inhibit the mutant JAK2 enzyme.inhibit the mutant JAK2 enzyme.2323 The V617F mutation is l While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET,they may not be able to eliminate mutant clones.Most importantly,patients with and without the JAK2 V617F mutation appear to benefit to the same extent.2424 While they may prove toPreliminary clinical observations in selected JAK2 Preliminary clinical observations in selected JAK2 Preliminary clinical observations in selected JAK2 Preliminary clinical observations in selected JAK2 inhibitor trials.inhibitor trials.inhibitor trials.inhibitor trials.AgentAgentCompanyCompanyTarget(sTarget(s)JAK JAK ICIC5050(nM)(nM)CurreCurrent nt phasephasePreliminary clinical Preliminary clinical obserbations in myelofibrosis obserbations in myelofibrosis studiesstudiesINCB0INCB01842418424 Incyte IncyteJAK1,JAK1,JAK2JAK2JAK1=2.7*JAK1=2.7*JAK2=4.5*JAK2=4.5*JAK3=322*JAK3=322*IIIIIIDecreased spleen size irrespective Decreased spleen size irrespective of JAK2 mutational status;of JAK2 mutational status;improved quality of life,weight improved quality of life,weight and performance;decreased and performance;decreased inflammatory cytokine levels.inflammatory cytokine levels.MyelosuppressionMyelosuppressionTG101TG101384384TargeGETargeGEN NJAK2JAK2JAK1=105JAK1=105JAK2=3JAK2=3JAK3=996JAK3=996II IIDecreased spleen Decreased spleen size;decrease in size;decrease in WBC.Myelosuppression;WBC.Myelosuppression;gastrointestinal disturbancegastrointestinal disturbanceXL019XL019ExelixisExelixisJAK2JAK2JAK1=132JAK1=132JAK2=2JAK2=2JAK3=250JAK3=250discondiscontinuedtinuedDecreased spleensize only in Decreased spleensize only in patients with JAK2 V617F or MPL patients with JAK2 V617F or MPL mutation;decreased pruritis and mutation;decreased pruritis and improved fatigue.improved fatigue.NeurotoxicityNeurotoxicityCEP701(CEP701(lestaurtinlestaurtinib)ib)CephalonCephalonJAK2,FJAK2,FLT3LT3JAK2=1JAK2=1I/III/IIDecreased spleen size,Decreased spleen size,improvement in blood cell improvement in blood cell count.Myelosuppression;gastrointcount.Myelosuppression;gastrointestinal disturbanceestinal disturbance2525Preliminary clinical observati写在最后写在最后成功的基成功的基础在于好的学在于好的学习习惯The foundation of success lies in good habits26写在最后成功的基础在于好的学习习惯26谢谢大家荣幸这一路，与你同行ItS An Honor To Walk With You All The Way讲师：XXXXXX XX年XX月XX日 27谢谢大家讲师：XXXXXX 27