慢性粒單核細胞白血病診治進展版課件

1、慢性粒單核細胞白血病診治進展慢性粒單核細胞白血病診治進展慢性粒單核細胞白血病診治進展版課件慢性粒單核細胞白血病診治進展版課件 1Definition 2Diagnosis 3Risk stratification 4Therapeutic options Contents 1Definition 2Diagnosis 3RDefinitionDefinitionWHO Classification of MDS/MPN 1CMML 2Atipical CML, BCR-ABL1 negative 3JMML 4MDS/MPN, U (RARS-T, refractory anemia with

2、 ringed sideroblasts associated with thrombocytosis)WHO Classification of MDS/MPN 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

3、 in the bone marrow.(WHO classification of myeloid neoplasms)Definition A clonal hematopoieNRM (nonrelapse mortality): 37%Levels of riskor abnormalities ofALC : absolute lympcyte count IMC : immature myeloid cellsPatients up to the age of 65-70 with a compatible donorImmunophenotypeOccasionally, ove

4、rexpression of CD56, aberrant expression of CD2, and decreased expression of HLA-DR, CD13, CD15, and CD36 may be observed.Patients up to the age of 65-70 with a compatible donor1,000 mg/day of oralAn increased percentage of CD34+ cells has been associated with early transformation to acute leukemia.

5、Myelomonocyticmonocytic proliferation can be difficult to appreciate (cytochemistry and immunohistochemistry)rarely bleeding2012 Oct 11;120(15):3080-8.OS at 5 years : 26%Leuk Res 2008;32:587591.RecommendationsOS: 19 monthsSurvival andDiagnosisNRM (nonrelapse mortality): 37Clinical manifestationMDS-t

6、ypeFatigue and dyspnea due to anemiasusceptibility to infectionsrarely bleedingMPN-typesignificant weight lossdrenching nigh sweatsleft upper quadrant pain from significant splenomegalyClinical manifestationMDS-type Morphology (PB)PB monocytes usually range from 2 to 5 109/L, but may exceed 80 109/L

7、.The monocytes generally are mature, but can exhibit abnormal granulation or unusual nuclear lobation or chromatin patten. (abnormal monocytes)Dysgranulopoiesis is present in most cases. Morphology (PB)PB monocytes 129/275 (47%) had SRSF2mutAt least one of the followingDiagnostic work-upFatigue and

8、dyspnea due to anemiaHypomethylating agentsFatigue and dyspnea due to anemiaSome of the more frequently reported recurring abnormalities include:Cancer 2007;109:713717.Monocytes with nuclear andCancer 2006;107:15251529.alone or in combination with hypomethylating agentscomplex karyotypeApproved by F

9、DAPB monocytes usually range from 2 to 5 109/L, but may exceed 80 109/L.BM blasts 10%isochromosome 17 (12%)SRSF2 Pro95His had a favorable impact on OS in the RUNX1mut subcohort.OS: 20 months vs 9 monthsCancer 2007;109:713717.CMML-1 (BM)chronic GVHD: 37 (44%)high-risk: trisomy 8 Morphology (BM)hyperc

10、ellular in over 75% of casesnormalcellular and hypocellular also occurdysgranulopoiesis, dyderythropoiesis, micromegakaryocytes and megakaryocytes with abnormally lobated nuclei (in up to 80% of patients)monocytic proliferation can be difficult to appreciate (cytochemistry and immunohistochemistry)1

11、29/275 (47%) had SRSF2mut MoMonocytosis 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

12、 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.Monocytosis with morphological ImmunophenotypeThe PB and BM cells usually express CD33 and CD13, with

13、variable expression of CD14, CD68, CD64.An increased percentage of CD34+ cells has been associated with early transformation to acute leukemia.Occasionally, overexpression of CD56, aberrant expression of CD2, and decreased expression of HLA-DR, CD13, CD15, and CD36 may be observed. ImmunophenotypeTh

14、e PB and BM grnulocytic proliferation an increase in erythroid precursorsmild to moderate increase in the amount of reticulin fibres (30%)Histopathology grnulocytic proliferation mi Immunohistochemistry on tissue sectionsthe most reliable markers : CD168R, CD163 monocytic cells : lysozym (+) CAE (-)

15、granulocytic cells : lysozym (+) CAE (+)relatively insensitive as compared with cytochemistry or flow cytometry Immunohistochemistry on tissChromosomal abnormalities No specific cytogenetic alterations have been identified in patients with CMML.Some of the more frequently reported recurring abnormal

16、ities 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 abnormalities No sChromosomal abnormalities Chromosomal abnormalities Chromosomal abnormalities 110/414 (27

17、%)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

18、: 4%Such E, Cervera J, Costa D, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011; 96(3):375-383. Chromosomal abnormalities MyelomonocyticClonal proliferationDiseaseprogressionSomatic mutationsMyelomonocyticDiseaseSomatic mSpliceosomal mutations Yoshida,

19、et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011;478(7367):64-9.Less conspicuously but significantly, SRSF2 mutations were more frequent in CMML casesSpliceosomal mutations YoshidaSRSF2 mutations in CMML(a new diagnostic marker?)129/275 (47%) had SRSF2mut SRSF2m

20、ut were correlated with higher age, less pronounced anemia and a normal karyotype.SRSF2mut and EZH2mut were mutually exclusive but associated with TET2mut.SRSF2 Pro95His had a favorable impact on OS in the RUNX1mut subcohort.Meggendorfer M, et al. SRSF2 mutations in 275 cases with chronic myelomonoc

21、ytic leukemia (CMML). Blood. 2012 Oct 11;120(15):3080-8.SRSF2 mutations in CMML129/275chronic GVHD: 37 (44%)Hypomethylat-ing agentsLeuk Res 2008;32:587591.all other abnormalitiesCytotoxic chemotherapyApproved by FDA慢性粒單核細胞白血病診治進展Less conspicuously but significantly, SRSF2 mutations were more frequen

22、t in CMML casesPatients up to the age of 65-70 with a compatible donorAn increased percentage of CD34+ cells has been associated with early transformation to acute leukemia.associated with thrombocytosis)OS: 19 monthsCancer 2007;109:713717.Clinical trialsImmunophenotype(b)An acquired clonal cytogene

23、tic abnormality or molecularrarely bleedingnucleoside analog, immunomodul-atory agent, and histone deacetylase inhibitorsRRs have ranged from 17 to 50% and treatment-related mortality from 12 to 52%.The monocytes generally are mature, but can exhibit abnormal granulation or unusual nuclear lobation

24、or chromatin patten.Patients up to the age of 65-70 with a compatible donorNRM (nonrelapse mortality): 37% WHO diagnostic criteria for CMML Persistent peripheral blood monocytosisPh chromosome or BCR-ABL1Arrangement of PDGFRA or PDGFRB (specially excluded in cases with eosinophilia)3 months1109/Lchr

25、onic GVHD: 37 (44%) WHO di Less than 20% blasts in PB and BMAt least one of the following(a)Dysplasia in one or more cell lines(b)An acquired clonal cytogenetic abnormality or moleculargenetic abnormality present in hematopoietic cells(c) No evidence of other causes of monocytosis (infection, inflam

26、mation or malignancy)CMML-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 stratificat

27、ionIPSS for Risk stratificationMDAPS (M. D. Anderson Prognostic Score) Risk stratificationMDAPS (M. One point for each of the following variablesHb 120g/LALC 2.5 109/L PB IMC 0%BM blasts 10%ALC : absolute lympcyte count IMC : immature myeloid cellsOne point for each of the follsubgroupsscoreMedian s

28、urvival(months)low0-124Intermediate-1215Intermediate-238high45Risk modelsubgroupsscoreMedian survivallNew MDS model applied in CMML with leukocytosis (WBC 12 109 /L)New MDS model applied in CMML Risk stratificationnormalcellular and hypocellular also occurRepresentative peripheral blood and BM smear

29、sMonosomy 7 (3.Abnormal monocytes have denser chromatin, nuclear convolutions and folds and a more greyish cytoplasm.myelomonocytic leukemia.normalcellular and hypocellular also occurClinical trialsChromosomal abnormalitiesBM blasts 10%Novel agentsdecitabine administered as 15 mg/m2 over 4 hr IV 3 t

30、imes a day (total dose of 135 mg/m2 per course) in 31 patientsSRSF2 mutations in 275 casesthe best option for patients who are willing to participateInduction mortality: 7%IPSS for survival in MDS originally proposed included 126 patients with CMML.in myelodysplasia.Abnormal monocytes have denser ch

31、romatin, nuclear convolutions and folds and a more greyish cytoplasm.An increased percentage of CD34+ cells has been associated with early transformation to acute leukemia.Clonal proliferationFrequent pathwayMonosomy 7 (3.ScoreRisk stratificationScorelowInt-1Int-2highLevels of risklowInt-1Int-2highL

32、evels of risTherapeutic optionsTherapeutic optionsTherapeutic optionsBest supportive careHypomethylating agents (azacitidine and decitabine)Cytotoxic chemotherapyAllogeneic stem cell transplantationTherapeutic optionsBest supporCytotoxic chemotherapyWattel et al.Blood 1996;88:24802487.1,000 mg/day o

33、f 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 morta

34、lity: 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 toleratedCytotoxic chemotherapyWattel eHypomethylating agentsAribi et al.Cancer 2007;109:713717.decitabine at a same total dos

35、e 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.

36、 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 monthsHypomethylating agentsAribi etAllogeneic stem cell transplantation(retrospective registry from large transplant centers)EGBMT283 patients245 patie

37、nts (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%A

38、llogeneic stem cell transplanRRs have ranged from 17 to 50% and treatment-related mortality from 12 to 52%.Persistent peripheral blood monocytosismonocytic proliferation can be difficult to appreciate (cytochemistry and immunohistochemistry)Immunophenotypehigh-risk: trisomy 8At least one of the foll

39、owingchronic GVHD: 37 (44%)RRs have ranged from 17 to 50% and treatment-related mortality from 12 to 52%.2011; 96(3):375-383.ORRs vary from 40 to 70% in selected groups of patients129/275 (47%) had SRSF2mutPromonocytes typically have a light-gray cytoplasm with a few lilac-colored granules and a sti

40、ppled nuclear chromatin.rarely bleedingBlood 1996;88:24802487.Therapeutic options(a)Dysplasia in one or more cell linesALC : absolute lympcyte count IMC : immature myeloid cellsNo specific cytogenetic alterations have been identified in patients with CMML.Risk stratificationNRM (nonrelapse mortality

41、): 37%Cytogenetic risk stratification in chronic(a new diagnostic marker?)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

42、 trials.the best option for patients who are willing to participateRRs have ranged from 17 to 50%high-risk: trisomy 8Chromosomal abnormalitiesMonosomy 7 (3.The PB and BM cells usually express CD33 and CD13, with variable expression of CD14, CD68, CD64.Histopathology245 patients (93%) successfully en

43、grafted.ALC : absolute lympcyte count IMC : immature myeloid cellsCytogenetic risk stratification in chronicMultivariableNo specific cytogenetic alterations have been identified in patients with CMML.ALC : absolute lympcyte count IMC : immature myeloid cellsinfusion and cytarabine 1.BM blasts 10%Pat

44、ients up to the age of 65-70 with a compatible donorHypomethylating agentsSRSF2 mutations in 275 casesthe best option for patients who are willing to participateAllogeneic stem cell transplantation(retrospective registry from large transplant centers)rarely bleedingArrangement of PDGFRA or PDGFRB (s

45、pecially excluded in cases with eosinophilia)Induction mortality: 7%Hypomethylat-ing agents245 patients (93%) successfully engrafted.Induction mortality: 7%Quintas-Cardama et al.rarely bleedingOS: 19 monthsSomatic mutationscomplex karyotypenormalcellular and hypocellular also occurSuch E, Cervera J,

46、 Costa D, et al.OS: 15 monthsPatients up to the age of 65-70 with a compatible donorArrangement of PDGFRA or PDGFRB (specially excluded in cases with eosinophilia)normalcellular and hypocellular also occuralone or in combination with hypomethylating agentsPersistent peripheral blood monocytosisalone

47、 or in combination with hypomethylating agentsFrequent pathwayrarely bleedingDiagnostic work-upRRs have ranged from 17 to 50% and treatment-related mortality from 12 to 52%.hydroxyurea to 150 mg/week of oral etoposide in 105Cancer 2011;117:26902696.Some of the more frequently reported recurring abno

48、rmalities include:BM blasts 10%Immunohistochemistry on tissue sectionsPromonocytes typically have a light-gray cytoplasm with a few lilac-colored granules and a stippled nuclear chromatin.alone or in combination with hypomethylating agentsNRM (nonrelapse mortality): 37%RR: 60% vs 36%associated with thrombocytosis)hypercellular in over 75% of casesFat