慢性粒单核细胞白血病诊治进展.ppt

CMML诊治进展诊治进展江苏省人民医院江苏省人民医院 血液科血液科 洪鸣洪鸣.1Definition 2Diagnosis 3Risk stratification 4Therapeutic options Contents Contents.Definition.WHO Classification of MDS/MPN 1CMML 2Atipical CML,BCR-ABL1 negative 3JMML 4MDS/MPN,U(RARS-T,refractory anemia with ringed sideroblasts associated with thrombocytosis).Definition A clonal hematopoietic stem cell disorder that is characterized by the presence of an absolute monocytosis(1109/L)in the peripheral blood and the presence of myelodysplastic and myeloproliferative features in the bone marrow.(WHO classification of myeloid neoplasms).Diagnosis.Clinical manifestationMDS-typeMDS-typeFatigue and dyspnea due to anemiasusceptibility to infectionsrarely bleedingMPN-typeMPN-typesignificant weight lossdrenching nigh sweatsleft upper quadrant pain from significant splenomegaly.Morphology(PB)PB monocytes usually range from PB monocytes usually range from 2 to 52 to 5 10109 9/L,but may exceed/L,but may exceed 8080 10109 9/L./L.The monocytes generally are mature,The monocytes generally are mature,but can exhibit abnormal granulation but can exhibit abnormal granulation or unusual nuclear lobation or or unusual nuclear lobation or chromatin patten.(chromatin patten.(abnormal abnormal monocytesmonocytes)DysgranulopoiesisDysgranulopoiesis is present in most is present in most cases.cases.Morphology(BM)hypercellularhypercellularhypercellularhypercellular in over 75%of casesin over 75%of casesnormalcellular and hypocellular also normalcellular and hypocellular also occuroccurdysgranulopoiesis,dyderythropoiesis,dysgranulopoiesis,dyderythropoiesis,micromegakaryocytes and micromegakaryocytes and megakaryocytesmegakaryocytes with abnormally with abnormally lobated nuclei(in up to 80%of patients)lobated nuclei(in up to 80%of patients)monocytic proliferation can be difficult monocytic proliferation can be difficult to appreciate(to appreciate(cytochemistry and cytochemistry and immunohistochemistryimmunohistochemistry).Monocytosis with morphologicallynormal monocytes(PB)Monocytes with nuclear andCytoplasmic abnormalities(PB)CMML-1(BM)CMML-2(BM)Representative peripheral blood and BM smears distinction between promonocytes and abnormal monocytes may be problematicPromonocytes typically have a light-gray cytoplasm with a few lilac-colored granules and a stippled nuclear chromatin.Abnormal monocytes have denser chromatin,nuclear convolutions and folds and a more greyish cytoplasm.ImmunophenotypeThe PB and BM cells usually express The PB and BM cells usually express CD33 CD33 and and CD13CD13,with variable,with variable expression of expression of CD14CD14,CD68CD68,CD64CD64.An increased percentage of CD34+An increased percentage of CD34+cells has been associated with early cells has been associated with early transformation to acute leukemia.transformation to acute leukemia.Occasionally,overexpression of CD56,Occasionally,overexpression of CD56,aberrant expression of CD2,and aberrant expression of CD2,and decreased expression of HLA-DR,CD13,decreased expression of HLA-DR,CD13,CD15,and CD36 may be observed.CD15,and CD36 may be observed.grnulocytic proliferation grnulocytic proliferation an increase in erythroid precursorsan increase in erythroid precursorsmild to moderate increase in the mild to moderate increase in the amount of reticulin fibres(30%)amount of reticulin fibres(30%)Histopathology.Immunohistochemistry on tissue sectionsthe most reliable markers:the most reliable markers:CD168RCD168R,CD163CD163 monocytic cells:monocytic cells:lysozym lysozym(+)(+)CAE CAE(-)(-)granulocytic cells:lysozym(+)CAE(+)granulocytic cells:lysozym(+)CAE(+)relatively insensitive as compared with relatively insensitive as compared with cytochemistry or flow cytometrycytochemistry or flow cytometry.Chromosomal abnormalitiesChromosomal abnormalities No specific cytogenetic alterations have been identified in patients with CMML.Some of the more frequently reported recurring abnormalities include:Monosomy 7(3.98.5%)Trisomy 8(4.17.8%)complex karyotype involving 3 abnormalities(4.46.3%)trisomy 21(12%)isochromosome 17(12%)deletion 5q(1.5%)deletion 20q(0.71%).Chromosomal abnormalitiesChromosomal abnormalities .Chromosomal abnormalities Chromosomal abnormalities 110/414(27%)patients had cytogeneticabnormalitiesMultivariableanalysisSurvival and Progressionto AMLLow-risk:normal or-Y as a single anomalyOS at 5 years:35%Intermediate-risk:all other abnormalitiesOS at 5 years:26%high-risk:trisomy 8 or abnormalities ofchromosome 7 or complex karyotype OS at 5 years:4%Such E,Cervera J,Costa D,et al.Cytogenetic risk stratification in chronic myelomonocytic leukemia.Haematologica.2011;96(3):375-383.MyelomonocyticClonal proliferationDiseaseprogressionSomatic mutations.Spliceosomal mutations Yoshida,et al.Frequent pathway Yoshida,et al.Frequent pathway mutations of splicing machinery mutations of splicing machinery in myelodysplasia.in myelodysplasia.Nature 2011;478(7367):64-9Nature 2011;478(7367):64-9.Less conspicuously Less conspicuously but significantly,but significantly,SRSF2 mutationsSRSF2 mutations were were more frequent in more frequent in CMML casesCMML cases.SRSF2 mutations in CMML(a new diagnostic marker?)129/275(47%)had SRSF2mut 129/275(47%)had SRSF2mut SRSF2mut were correlated with higher age,SRSF2mut were correlated with higher age,less pronounced anemia and a normal less pronounced anemia and a normal karyotypekaryotype.SRSF2mut and EZH2mut were mutually SRSF2mut and EZH2mut were mutually exclusive but associated with TET2mut.exclusive but associated with TET2mut.SRSF2SRSF2 Pro95His had a Pro95His had a favorablefavorable impact on impact on OS in the OS in the RUNX1RUNX1mut subcohort.mut subcohort.Meggendorfer M,Meggendorfer M,et al.et al.et al.et al.SRSF2 mutations in 275 cases SRSF2 mutations in 275 cases SRSF2 mutations in 275 cases SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia(CMML).with chronic myelomonocytic leukemia(CMML).with chronic myelomonocytic leukemia(CMML).with chronic myelomonocytic leukemia(CMML).Blood.2012 Oct 11;120(15):3080-8.Blood.2012 Oct 11;120(15):3080-8.Blood.2012 Oct 11;120(15):3080-8.Blood.2012 Oct 11;120(15):3080-8.WHO diagnostic criteria for CMML Persistent peripheral blood monocytosisPersistent peripheral blood monocytosisPh chromosome or BCR-ABL1Ph chromosome or BCR-ABL1Arrangement of PDGFRA or PDGFRB Arrangement of PDGFRA or PDGFRB(specially excluded in cases with(specially excluded in cases with eosinophilia)eosinophilia)3 months1109/L.Less than Less than 20%blasts20%blasts in PB and BM in PB and BMAt least one of the followingAt least one of the following(a)(a)Dysplasia in one or more cell lines(b)(b)An acquired clonal cytogenetic abnormality or moleculargenetic abnormality present in hematopoietic cells(c)(c)No evidence of other causes of monocytosis(infection,inflammation or malignancy)CMML-1CMML-1:blast(including promonocytes)5%in PBand 12 109/L)were excluded from this analysis,because these individuals were believed to predominantly represent MPN rather than MDS.The IPSS classification scheme therefore cannot be used for patients with CMML.Risk stratificationRisk stratificationMDAPS(M.D.Anderson Prognostic Score)MDAPS(M.D.Anderson Prognostic Score).One point for each of the following variablesHb Hb 120g/L120g/LALC ALC 2.5 102.5 109 9/L/L PB IMC PB IMC 0%0%BM blasts 10%BM blasts 10%ALC:absolute lympcyte count IMC:immature myeloid cellsALC:absolute lympcyte count IMC:immature myeloid cells.subgroupsscoreMedian survival(months)low0-124Intermediate-1215Intermediate-238high45Risk model.New MDS model applied in CMML with leukocytosis(WBC 12 109/L).Score.lowInt-1Int-2highLevels of risk.Therapeutic options.Therapeutic optionsBest supportive careBest supportive careHypomethylating agents Hypomethylating agents(azacitidine and decitabine)(azacitidine and decitabine)Cytotoxic chemotherapyCytotoxic chemotherapyAllogeneic stem cell Allogeneic stem cell transplantationtransplantation.Cytotoxic chemotherapyWattel et al.Blood 1996;88:24802487.1,000 mg/day of oralhydroxyurea to 150 mg/week of oral etoposide in 105patientsRR:60%vs 36%OS:20 months vs 9 monthsBeran et al.J Clin Oncol 1999;17:28192830topotecan at a dose of 1.25 mg/m2 as a continuousinfusion and cytarabine 1.0g/m2 over 2 hr,both for5 days,27 patientsCR:44%OS:9.4 monthsInduction mortality:7%Quintas-Cardama et al.Cancer 2006;107:15251529.9-nitro-campothecin,at a dose of 2mg/m2 orally daily for 5 days a week in 32 patientsCR:11%PR:16%OS:12 monthsWell tolerated.Hypomethylating agentsAribi et al.Cancer 2007;109:713717.decitabine at a same total dose of 100 mg/m2 per course in 3 different schedules in 19 patientsCR:58%PR:0%HI:11%OS:19 monthsWijermans et al.Leuk Res 2008;32:587591.decitabine administered as 15 mg/m2 over 4 hr IV 3 times a day(total dose of 135 mg/m2 per course)in 31 patientsCR:10%PR:16%HI:19%OS:15 monthsCosta et al.Cancer 2011;117:26902696.azacitidine 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days,every 4 weeks in 38 patients.CR:11%PR:3%HI:25%OS:12 months.Allogeneic stem cell transplantation(retrospective registry from large transplant centers)EGBMT283 patients245 patients(93%)successfully engrafted.III/IV acute GVHD:85/258(30%)chronic GVHD:58/102(57%)NRM(nonrelapse mortality):37%Eissa et al.Biol Blood Marrow Transplant2011;17:908915.85 patients between 1986 and 2008 at their institutionIII/IV acute GVHD:21/81(26%)chronic GVHD:37(44%)Ten-year RFS:40%.Recommendationscytotoxic chemotherapyHydroxyurea remains the cornerstoneof therapyPatients with elevated WBC count(13109/L)Hypomethylat-ing agentsORRs vary from 40 to 70%in selected groups of patientsApproved by FDAClinical trials.the best option for patients who are willing to participate.Allo-SCTRRs have ranged from 17 to 50%and treatment-related mortality from 12 to 52%.Patients up to the age of 65-70 with a compatible donorRIC has been shown to improve NRM,OS,and RFSNovel agentsalone or in combination with hypomethylating agentsnucleoside analog,immunomodul-atory agent,and histone deacetylase inhibitorsBeing actively investigatedRecommendations.Thanks for your Thanks for your AttentionAttention！.