慢性粒单核细胞白血病诊治进展ppt课件

1、1 1CMML诊治进展2 23 34 4 1Definition 2Diagnosis 3Risk stratification 4Therapeutic options Contents5 5Definition6 6WHO Classification of MDS/MPN 1CMML 2Atipical CML, BCR-ABL1 negative 3JMML 4MDS/MPN, U (RARS-T, refractory anemia with ringed sideroblasts associated with thrombocytosis)7 7Definition A clon

2、al 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)8 8Diagnosis9 9Clinical manifestationM

3、DS-type Fatigue and dyspnea due to anemia susceptibility to infections rarely bleedingMPN-type significant weight loss drenching nigh sweats left upper quadrant pain from significant splenomegaly1010Morphology (PB)PB monocytes usually range from 2 to 5 PB monocytes usually range from 2 to 5 10109 9/

4、L, but /L, but may exceed 80 may exceed 80 10109 9/L./L.The monocytes generally are mature, but can The monocytes generally are mature, but can exhibit abnormal granulation or unusual nuclear exhibit abnormal granulation or unusual nuclear lobation or chromatin patten. (abnormal lobation or chromati

5、n patten. (abnormal monocytes)monocytes)Dysgranulopoiesis is present in most cases.Dysgranulopoiesis is present in most cases.1111Morphology (BM) in over 75% of cases in over 75% of casesnormalcellular and hypocellular also occurnormalcellular and hypocellular also occurdysgranulopoiesis, dyderythro

6、poiesis, dysgranulopoiesis, dyderythropoiesis, micromegakaryocytes and megakaryocytesmicromegakaryocytes and megakaryocytes with with abnormally lobated nuclei (in up to 80% of patients)abnormally lobated nuclei (in up to 80% of patients)monocytic proliferation can be difficult to monocytic prolifer

7、ation can be difficult to appreciate (cytochemistry and appreciate (cytochemistry and immunohistochemistry)immunohistochemistry)1212Monocytosis with morphologicallynormal monocytes (PB)Monocytes with nuclear andCytoplasmic abnormalities (PB)CMML-1 (BM)CMML-2(BM)Representative peripheral blood and BM

8、 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 cytoplas

9、m.1313ImmunophenotypeThe 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

10、has been 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 expression of CD2, and decreased express

11、ion of HLA-DR, CD13, CD15, and CD36 may be observed.HLA-DR, CD13, CD15, and CD36 may be observed.1414grnulocytic proliferation grnulocytic proliferation an increase in erythroid precursorsan increase in erythroid precursorsmild to moderate increase in the amount of reticulin mild to moderate increas

12、e in the amount of reticulin fibres (30%)fibres (30%)Histopathology1515Immunohistochemistry on tissue sectionsthe most reliable markers : CD168R, CD163the most reliable markers : CD168R, CD163 monocytic cells : lysozym (+) CAE (-)monocytic cells : lysozym (+) CAE (-)granulocytic cells : lysozym (+)

13、CAE (+)granulocytic cells : lysozym (+) CAE (+)relatively insensitive as compared with relatively insensitive as compared with cytochemistry or flow cytometrycytochemistry or flow cytometry1616Chromosomal abnormalities No specific cytogenetic alterations have been identified in patients with CMML.So

14、me 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%)1717Chromosomal abnormalities 1818 Chromosomal abnormalities 110/4

15、14 (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

16、years : 4%Such E, Cervera J, Costa D, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011; 96(3):375-383. 1919MyelomonocyticClonal proliferationDiseaseprogressionSomatic mutations2020Spliceosomal mutations Yoshida, et al. Frequent pathway Yoshida, et al. Fr

17、equent pathway mutations of splicing machinery mutations 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

18、 CMML were more frequent in CMML casescases2121SRSF2 mutations in CMML(a new diagnostic marker?)129/275 (47%) had SRSF2mut 129/275 (47%) had SRSF2mut SRSF2mut were correlated with higher age, less SRSF2mut were correlated with higher age, less pronounced anemia and a normal karyotypepronounced anemi

19、a and a normal karyotype.SRSF2mut and EZH2mut were mutually 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

20、subcohort.Meggendorfer M, Meggendorfer M, 2222WHO diagnostic criteria for CMML Persistent peripheral blood monocytosisPersistent peripheral blood monocytosisPh chromosome or BCR-ABL1Ph chromosome or BCR-ABL1Arrangement of PDGFRA or PDGFRB (specially Arrangement of PDGFRA or PDGFRB (specially exclude

21、d in cases with eosinophilia)excluded in cases with eosinophilia)3 months1109/L2323Less 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)Dysplasia in one or more cell lines(b)(b)An acquired clonal cytogenetic abnormality or

22、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 predomi

23、nantly represent MPN rather than MDS.The IPSS classification scheme therefore cannot be used for patients with CMML.3030Risk stratificationMDAPS (M. D. Anderson Prognostic Score) 3131One 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 blas

24、ts 10%BM blasts 10%ALC : absolute lympcyte count IMC : immature myeloid cellsALC : absolute lympcyte count IMC : immature myeloid cells3232subgroupsscoreMedian survival(months)low0-124Intermediate-1215Intermediate-238high45Risk model3333New MDS model applied in CMML with leukocytosis (WBC 12 109 /L)

25、3434Score3535lowInt-1Int-2highLevels of risk3636Therapeutic options3737Therapeutic optionsBest supportive careBest supportive careHypomethylating agents (azacitidine and Hypomethylating agents (azacitidine and decitabine)decitabine)Cytotoxic chemotherapyCytotoxic chemotherapyAllogeneic stem cell tra

26、nsplantationAllogeneic stem cell transplantation3838Cytotoxic 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/

27、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 to

28、lerated3939Hypomethylating 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

29、(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 months4040Allogeneic stem cell transplantation(retrospective registry from large transplant centers)EGBMT283 patients245 patients (93%) successfully engrafted.III/IV acute