1、CMML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 ContentsDefinitionWHO 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 clo
2、nal 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)DiagnosisClinical manifestation MDS-typ
3、e Fatigue and dyspnea due to anemia susceptibility to infections rarely bleeding MPN-type significant weight loss drenching nigh sweats left upper quadrant pain from significant splenomegalyMorphology(PB)PB monocytes usually range from PB monocytes usually range from 2 to 52 to 5 10109 9/L,but may e
4、xceed/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
5、 monocytesmonocytes)DysgranulopoiesisDysgranulopoiesis is present in most is present in most cases.cases.Morphology(BM)in over 75%of casesin over 75%of casesnormalcellular and hypocellular also normalcellular and hypocellular also occuroccurdysgranulopoiesis,dyderythropoiesis,dysgranulopoiesis,dyder
6、ythropoiesis,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 a
7、ppreciate(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 abn
8、ormal 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 expr
9、ess 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 transformati
10、on 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 C
11、D36 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%)HistopathologyImmunohistochemi
12、stry 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
13、 compared with cytochemistry or flow cytometrycytochemistry or flow cytometryChromosomal 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 kary
14、otype involving 3 abnormalities(4.46.3%)trisomy 21(12%)isochromosome 17(12%)deletion 5q(1.5%)deletion 20q(0.71%)Chromosomal abnormalities Chromosomal abnormalities 110/414(27%)patients had cytogeneticabnormalitiesMultivariableanalysisSurvival and Progressionto AMLLow-risk:normal or-Y as a single ano
15、malyOS 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.M
16、yelomonocyticClonal proliferationDiseaseprogressionSomatic mutationsSpliceosomal 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)
17、:64-9.Less conspicuously Less conspicuously but significantly,but significantly,SRSF2 mutationsSRSF2 mutations were were more frequent in more frequent in CMML casesCMML casesSRSF2 mutations in CMML(a new diagnostic marker?)129/275(47%)had SRSF2mut 129/275(47%)had SRSF2mut SRSF2mut were correlated w
18、ith 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.SRSF2SR
19、SF2 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,WHO diagnostic criteria for CMML Persistent peripheral blood Persistent peripheral blood monocytosismonocytosisPh chromosome or BCR-ABL1Ph
20、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/LLess than Less than 20%blasts20%blasts in PB and BM in PB and BMAt least one of the followingAt least one of
21、 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 P
22、Band 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 stratificationMDAPS(M.D.Anderson Prognostic Score)One point for each of the follow
23、ing variablesHb Hb 120g/L120g/LALC ALC 2.5 2.5 10 109 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 cellssubgroupsscoreMedian survival(months)low0-124Intermediate-1215Intermediate-238high45Risk
24、 modelNew MDS model applied in CMML with leukocytosis(WBC 12 109/L)ScorelowInt-1Int-2highLevels of riskTherapeutic optionsTherapeutic optionsBest supportive careBest supportive careHypomethylating agents Hypomethylating agents(azacitidine and decitabine)(azacitidine and decitabine)Cytotoxic chemothe
25、rapyCytotoxic chemotherapyAllogeneic stem cell Allogeneic stem cell transplantationtransplantationCytotoxic 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
26、;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 patien
27、tsCR:11%PR:16%OS:12 monthsWell toleratedHypomethylating 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 ove
28、r 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 monthsAllogeneic stem cell transplantation(r
29、etrospective 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 institution
30、III/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 b
31、est option for patients who are willing to participateAllo-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 investigatedRecommendationsThanks for your Thanks for your AttentionAttention！
