《慢性粒单核细胞白血病诊治进展ppt课件》由会员分享，可在线阅读，更多相关《慢性粒单核细胞白血病诊治进展ppt课件（43页珍藏版）》请在金锄头文库上搜索。
1、CMML诊治进展1 12 23 31Definition 2Diagnosis3Riskstratification4Therapeuticoptions Contents4 4Definition5 5WHOClassificationofMDS/MPN1CMML 2Atipical CML, BCR-ABL1 negative3JMML4MDS/MPN, U (RARS-T, refractory anemia with ringed sideroblasts associated with thrombocytosis)6 6DefinitionAclonalhematopoietics
2、temcelldisorderthatischaracterizedbythepresenceofanabsolutemonocytosis(1109/L)intheperipheralbloodandthepresenceofmyelodysplasticandmyeloproliferativefeaturesinthebonemarrow.(WHO classification of myeloid neoplasms)7 7Diagnosis8 8ClinicalmanifestationMDS-typeFatigue and dyspnea due to anemiasuscepti
3、bility to infectionsrarely bleedingMPN-typesignificant weight lossdrenching nigh sweatsleft upper quadrant pain from significant splenomegaly9 9Morphology(PB)PB monocytes usually range from 2 to 5 PB monocytes usually range from 2 to 5 10109 9/L, but /L, but may exceed 80 may exceed 80 10109 9/L./L.
4、The monocytes generally are mature, but can exhibit The monocytes generally are mature, but can exhibit abnormal granulation or unusual nuclear lobation abnormal granulation or unusual nuclear lobation or chromatin patten. (abnormal monocytes)or chromatin patten. (abnormal monocytes)Dysgranulopoiesi
5、s is present in most cases.Dysgranulopoiesis is present in most cases.1010Morphology(BM)hypercellularhypercellularhypercellularhypercellular in over 75% of cases in over 75% of casesnormalcellular and hypocellular also occurnormalcellular and hypocellular also occurdysgranulopoiesis, dyderythropoies
6、is, dysgranulopoiesis, dyderythropoiesis, micromegakaryocytes and megakaryocytesmicromegakaryocytes and megakaryocytes with with abnormally lobated nuclei (in up to 80% of abnormally lobated nuclei (in up to 80% of patients)patients)monocytic proliferation can be difficult to monocytic proliferation
7、 can be difficult to appreciate (cytochemistry and immunohistochemistry)appreciate (cytochemistry and immunohistochemistry)1111Monocytosis with morphologicallynormal monocytes (PB)Monocytes with nuclear andCytoplasmic abnormalities (PB)CMML-1 (BM)CMML-2(BM)Representative peripheral blood and BM smea
8、rs 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.121
9、2ImmunophenotypeThe PB and BM cells usually express CD33 and CD13, The PB and BM cells usually express CD33 and CD13, with variable expression of CD14, CD68, CD64.with variable expression of CD14, CD68, CD64.An increased percentage of CD34+ cells has been An increased percentage of CD34+ cells has b
10、een associated with early transformation to acute associated with early transformation to acute leukemia.leukemia.Occasionally, overexpression of CD56, aberrant Occasionally, overexpression of CD56, aberrant expression of CD2, and decreased expression of HLA-expression of CD2, and decreased expressi
11、on of HLA-DR, CD13, CD15, and CD36 may be observed.DR, CD13, CD15, and CD36 may be observed.1313grnulocytic proliferation grnulocytic proliferation an increase in erythroid precursorsan increase in erythroid precursorsmild to moderate increase in the amount of mild to moderate increase in the amount
12、 of reticulin fibres (30%)reticulin fibres (30%)Histopathology1414Immunohistochemistryontissuesectionsthe most reliable markers : CD168R, CD163the most reliable markers : CD168R, CD163 monocytic cells : lysozym (+) CAE (-)monocytic cells : lysozym (+) CAE (-)granulocytic cells : lysozym (+) CAE (+)g
13、ranulocytic cells : lysozym (+) CAE (+)relatively insensitive as compared with relatively insensitive as compared with cytochemistry or flow cytometrycytochemistry or flow cytometry1515Chromosomal abnormalities No specific cytogenetic alterations have been identified in patients with CMML.Some of th
14、e 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%)1616Chromosomal abnormalities 1717 Chromosomal abnormalities 110/414(27%)p
15、atientshadcytogeneticabnormalitiesMultivariableanalysisSurvivalandProgressiontoAMLLow-risk:normalor-YasasingleanomalyOSat5years:35%Intermediate-risk:allotherabnormalitiesOSat5years:26%high-risk:trisomy8orabnormalitiesofchromosome7orcomplexkaryotypeOSat5years:4%Such E, Cervera J, Costa D, et al. Cyto
16、genetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011; 96(3):375-383. 1818MyelomonocyticClonal proliferationDiseaseprogressionSomatic mutations1919Spliceosomalmutations Yoshida, et al. Frequent pathway Yoshida, et al. Frequent pathway mutations of splicing machinery mut
17、ations of splicing machinery in myelodysplasia. in myelodysplasia. Nature 2011;478(7367):64-9.Nature 2011;478(7367):64-9.Less conspicuously but Less conspicuously but significantly, SRSF2 mutations significantly, SRSF2 mutations were more frequent in CMML caseswere more frequent in CMML cases2020SRS
18、F2mutationsinCMML(anewdiagnosticmarker?)129/275 (47%) had SRSF2mut 129/275 (47%) had SRSF2mut SRSF2mut were correlated with higher age, less pronounced SRSF2mut were correlated with higher age, less pronounced anemia and a normal karyotypeanemia and a normal karyotype.SRSF2mut and EZH2mut were mutua
19、lly exclusive but SRSF2mut and EZH2mut were mutually exclusive but associated with TET2mut.associated with TET2mut.SRSF2SRSF2 Pro95His had a favorable impact on OS in the Pro95His had a favorable impact on OS in the RUNX1RUNX1mut subcohort.mut subcohort.Meggendorfer M, Meggendorfer M, et al. et al.
20、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 leukemi
21、a (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):3080-8.2121WHOdiagnosticcriteriaforCMMLPersistent peripheral blood monocytosisPersistent peripheral blood monocytosisPh chromosome or BCR-ABL1Ph chromosome or BC
22、R-ABL1Arrangement of PDGFRA or PDGFRB (specially excluded Arrangement of PDGFRA or PDGFRB (specially excluded in cases with eosinophilia)in cases with eosinophilia)3months1109/L2222Less than 20% blasts in PB and BMLess than 20% blasts in PB and BMAt least one of the followingAt least one of the foll
23、owing(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 PBa
24、nd 12109/L)wereexcludedfromthisanalysis,becausetheseindividualswerebelievedtopredominantlyrepresentMPNratherthanMDS.TheIPSSclassificationschemethereforecannotbeusedforpatientswithCMML.2929Risk stratificationMDAPS (M. D. Anderson Prognostic Score) 3030OnepointforeachofthefollowingvariablesHb Hb 120g/
25、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 cells3131subgroupsscoreMedian survival(months)low0-124Intermediate-1215Intermediate-238high45Riskmodel3232NewM
26、DSmodelappliedinCMMLwithleukocytosis(WBC12109/L)3333Score3434lowInt-1Int-2highLevelsofrisk3535Therapeuticoptions3636TherapeuticoptionsBest supportive careBest supportive careHypomethylating agents (azacitidine and Hypomethylating agents (azacitidine and decitabine)decitabine)Cytotoxic chemotherapyCy
27、totoxic chemotherapyAllogeneic stem cell transplantationAllogeneic stem cell transplantation3737CytotoxicchemotherapyWatteletal.Blood1996;88:24802487.1,000mg/dayoforalhydroxyureato150mg/weekoforaletoposidein105patientsRR:60%vs36%OS:20monthsvs9monthsBeranetal.JClinOncol1999;17:28192830topotecanatados
28、eof1.25mg/m2asacontinuousinfusionandcytarabine1.0g/m2over2hr,bothfor5days,27patientsCR:44%OS:9.4monthsInductionmortality:7%Quintas-Cardamaetal.Cancer2006;107:15251529.9-nitro-campothecin,atadoseof2mg/m2orallydailyfor5daysaweekin32patientsCR:11%PR:16%OS:12monthsWelltolerated3838HypomethylatingagentsA
29、ribietal.Cancer2007;109:713717.decitabineatasametotaldoseof100mg/m2percoursein3differentschedulesin19patientsCR:58%PR:0%HI:11%OS:19monthsWijermansetal.LeukRes2008;32:587591.decitabineadministeredas15mg/m2over4hrIV3timesaday(totaldoseof135mg/m2percourse)in31patientsCR:10%PR:16%HI:19%OS:15monthsCostae
30、tal.Cancer2011;117:26902696.azacitidine75mg/m2/dayfor7daysor100mg/m2/dayfor5days,every4weeksin38patients.CR:11%PR:3%HI:25%OS:12months3939Allogeneicstemcelltransplantation(retrospectiveregistryfromlargetransplantcenters)EGBMT283patients245patients(93%)successfullyengrafted.III/IVacuteGVHD:85/258(30%)
31、chronicGVHD:58/102(57%)NRM(nonrelapsemortality):37%Eissaetal.BiolBloodMarrowTransplant2011;17:908915.85patientsbetween1986and2008attheirinstitutionIII/IVacuteGVHD:21/81(26%)chronicGVHD:37(44%)Ten-yearRFS:40%4040RecommendationscytotoxicchemotherapyHydroxyurearemainsthecornerstoneoftherapyPatientswith
32、elevatedWBCcount(13109/L)Hypomethylat-ingagentsORRsvaryfrom40to70%inselectedgroupsofpatientsApprovedbyFDAClinicaltrials.thebestoptionforpatientswhoarewillingtoparticipate4141Allo-SCTRRshaverangedfrom17to50%andtreatment-relatedmortalityfrom12to52%.Patientsuptotheageof65-70withacompatibledonorRIChasbeenshowntoimproveNRM,OS,andRFSNovelagentsaloneorincombinationwithhypomethylatingagentsnucleosideanalog,immunomodul-atoryagent,andhistonedeacetylaseinhibitorsBeingactivelyinvestigatedRecommendations4242Thanks for your Thanks for your AttentionAttention！4343
