慢性粒单核细胞白血病诊治进展版课件.ppt

1、慢性粒单核细胞白血病诊治进展 1Definition 2Diagnosis 3Risk stratification 4Therapeutic options Contents 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 clonal hematop

2、oietic 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)NRM(nonrelapse mortality):37%Levels of riskor abno

3、rmalities ofALC:absolute lympcyte count IMC:immature myeloid cellsPatients up to the age of 65-70 with a compatible donorImmunophenotypeOccasionally,overexpression 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

4、 with a compatible donor1,000 mg/day of oralAn increased percentage of CD34+cells has been associated with early transformation to acute leukemia.Myelomonocyticmonocytic proliferation can be difficult to appreciate(cytochemistry and immunohistochemistry)rarely bleeding2012 Oct 11;120(15):3080-8.OS a

5、t 5 years:26%Leuk Res 2008;32:587591.RecommendationsOS:19 monthsSurvival andDiagnosisClinical manifestation MDS-typeMDS-typeFatigue and dyspnea due to anemiasusceptibility to infectionsrarely bleeding MPN-typeMPN-typesignificant weight lossdrenching nigh sweatsleft upper quadrant pain from significa

6、nt splenomegalyMorphology(PB)PB monocytes usually range from 2 to 5 PB monocytes usually range from 2 to 5 10109 9/L,but may exceed 80/L,but may exceed 80 10109 9/L./L.The monocytes generally are mature,The monocytes generally are mature,but can exhibit abnormal granulation but can exhibit abnormal

7、granulation or unusual nuclear lobation or or unusual nuclear lobation or chromatin patten.(abnormal chromatin patten.(abnormal monocytes)monocytes)Dysgranulopoiesis is present in most Dysgranulopoiesis is present in most cases.cases.129/275(47%)had SRSF2mutAt least one of the followingDiagnostic wo

8、rk-upFatigue and 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 karyo

9、typeApproved by FDAPB 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 8Morphology(B

10、M)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 abnorm

11、ally 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(cytochemistry and to appreciate(cytochemistry and immunohistochemistry)immunohistochemistry)Monocytosis with morphologica

12、llynormal 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 granul

13、es 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 and CD13,with variable CD33 and CD13,with variable expression of CD14,C

14、D68,CD64.expression of CD14,CD68,CD64.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,overexpre

15、ssion 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 in

16、crease in erythroid precursorsmild to moderate increase in the mild to moderate increase in the amount of reticulin fibres(30%)amount of reticulin fibres(30%)HistopathologyImmunohistochemistry on tissue sectionsthe most reliable markers:CD168R,the most reliable markers:CD168R,CD163CD163 monocytic ce

17、lls:lysozym(+)CAE(-)monocytic cells:lysozym(+)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 cytometryChromosomal abnormalities Chromosoma

18、l 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

19、(1.5%)deletion 20q(0.71%)Chromosomal abnormalities Chromosomal 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-r

20、isk: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 proliferationDi

21、seaseprogressionSomatic 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):64-9.Less conspicuously Less consp

22、icuously but significantly,but significantly,SRSF2 mutations were SRSF2 mutations 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 with higher age,SRSF2mut were corre

23、lated 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 favorable impac

24、t on Pro95His had a favorable impact on OS in the OS in the RUNX1RUNX1mut subcohort.mut subcohort.Meggendorfer M,Meggendorfer M,chronic GVHD:37(44%)Hypomethylat-ing agentsLeuk Res 2008;32:587591.all other abnormalitiesCytotoxic chemotherapyApproved by FDA慢性粒单核细胞白血病诊治进展Less conspicuously but signific

25、antly,SRSF2 mutations were more frequent 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 trialsImmunoph

26、enotype(b)An acquired clonal cytogenetic 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 granula

27、tion or unusual nuclear lobation 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 Persistent peripheral blood monocytosismonocytosisPh chromosome or BCR-ABL1Ph chromosome or BCR-ABL1Ar

28、rangement 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 20%blasts in PB and BMLess than 20%blasts in PB and BMAt least one of the followingAt least one of the following(a)(a)Dysp

29、lasia 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 exclu

30、ded 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)O

31、ne point for each of the following 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

32、-1215Intermediate-238high45Risk modelNew MDS model applied in CMML with leukocytosis(WBC 12 109/L)Risk stratificationnormalcellular and hypocellular also occurRepresentative peripheral blood and BM smearsMonosomy 7(3.Abnormal monocytes have denser chromatin,nuclear convolutions and folds and a more

33、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 times a day(total dose of 135 mg/m2 per course)in 31 patientsSRSF2 mutations in 275 casesthe best op

34、tion 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 chromatin,nuclear convolutions and folds and a more greyish cytoplasm.An increased percentage of CD34+ce

35、lls has been associated with early transformation to acute leukemia.Clonal proliferationFrequent pathwayMonosomy 7(3.ScorelowInt-1Int-2highLevels of riskTherapeutic optionsTherapeutic optionsBest supportive careBest supportive careHypomethylating agents Hypomethylating agents(azacitidine and decitab

36、ine)(azacitidine and decitabine)Cytotoxic chemotherapyCytotoxic 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:

37、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

38、2mg/m2 orally daily for 5 days a week in 32 patientsCR: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

39、;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%

40、OS:12 monthsAllogeneic 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 p

41、atients between 1986 and 2008 at their institutionIII/IV acute GVHD:21/81(26%)chronic GVHD:37(44%)Ten-year RFS:40%RRs 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 a

42、nd immunohistochemistry)Immunophenotypehigh-risk:trisomy 8At least one of the followingchronic 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 typica

43、lly have a light-gray cytoplasm with a few lilac-colored granules and a stippled 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 identi

44、fied in patients with CMML.Risk stratificationNRM(nonrelapse mortality):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 f

45、rom 40 to 70%in selected groups of patientsApproved by FDAClinical trials.the best option for patients who are willing to participatehigh-risk:trisomy 8Chromosomal abnormalitiesMonosomy 7(3.The PB and BM cells usually express CD33 and CD13,with variable expression of CD14,CD68,CD64.Histopathology245

46、 patients(93%)successfully engrafted.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 cytarabi

47、ne 1.BM blasts 10%Patients 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 o

48、f PDGFRA or PDGFRB(specially 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 occurSuc

49、h E,Cervera J,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 monocy

50、tosisalone 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 recur