慢性粒單核細胞白血病診治進展

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 CMMLCMML診治進展診治進展 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 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慢性粒單核細胞白血病診治進展 1 1DefinitionDefinition 2 2DiagnosisDiagnosis 3 3Risk stratificationRisk stratification 4 4Therapeutic optionsTherapeutic options Contents Contents 慢性粒單核細胞白血病診治進展慢性粒單核

2、細胞白血病診治進展 DefinitionDefinition 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 WHO Classification of MDS/MPNWHO Classification of MDS/MPN 1 1CMMLCMML 2 2Atipical CML, BCR-ABL1 negative 3 3JMML 4 4MDS/MPN, U (RARS-T, refractory anemia with ringed sideroblasts associated with thrombocytosis) 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

3、 Definition 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 in the bone marrow. (WHO classification of myeloid neoplasms)(WHO cla

4、ssification of myeloid neoplasms) 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 DiagnosisDiagnosis 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 Clinical manifestationClinical manifestation MDS-typeMDS-type Fatigue and dyspnea due to anemia susceptibility to infections rarely bleeding MPN-typeMPN-type significant weight loss drenchi

5、ng nigh sweats left upper quadrant pain from significant splenomegaly 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 Morphology (PB)Morphology (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

6、 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 chromatin patten. (abnormal monocytes)monocytes) Dysgranulopoiesis is present in most cases

7、.Dysgranulopoiesis is present in most cases. 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 Morphology (BM)Morphology (BM) in over 75% of casesin over 75% of cases normalcellular and hypocellular also occurnormalcellular and hypocellular also occur dysgranulopoiesis, dyderythropoiesis, dysgranulopoiesis, dyderythropo

8、iesis, 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 can be difficult to appreciate (c

9、ytochemistry and appreciate (cytochemistry and immunohistochemistry)immunohistochemistry) 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 Monocytosis with morphologicallyMonocytosis with morphologically normal monocytes (PB)normal monocytes (PB) Monocytes with nuclear andMonocytes with nuclear and Cytoplasmic abnormal

10、ities (PB)Cytoplasmic abnormalities (PB) CMML-1 (BM)CMML-1 (BM) CMML-2(BM)CMML-2(BM) Representative peripheral blood and BM smears Representative peripheral blood and BM smears distinction between promonocytes and abnormal monocytes may be problematicdistinction between promonocytes and abnormal mon

11、ocytes may be problematic Promonocytes typically have a Promonocytes typically have a light-gray cytoplasm with a few light-gray cytoplasm with a few lilac-colored granules and a stippled lilac-colored granules and a stippled nuclear chromatin.nuclear chromatin. Abnormal monocytes have denser Abnorm

12、al monocytes have denser chromatin, nuclear convolutions chromatin, nuclear convolutions and folds and a more greyish and folds and a more greyish cytoplasm.cytoplasm. 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 ImmunophenotypeImmunophenotype The PB and BM cells usually express CD33 and The PB and BM cells usually

13、 express CD33 and CD13, with variable expression of CD14, CD68, CD13, with variable expression of CD14, CD68, CD64.CD64. An increased percentage of CD34+ cells has An increased percentage of CD34+ cells has been associated with early transformation to been associated with early transformation to acu

14、te leukemia.acute leukemia. Occasionally, overexpression of CD56, aberrant Occasionally, overexpression of CD56, aberrant expression of CD2, and decreased expression of expression of CD2, and decreased expression of HLA-DR, CD13, CD15, and CD36 may be HLA-DR, CD13, CD15, and CD36 may be observed.obs

15、erved. 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 grnulocytic proliferation grnulocytic proliferation an increase in erythroid precursorsan increase in erythroid precursors mild to moderate increase in the amount of mild to moderate increase in the amount of reticulin fibres (30%)reticulin fibres (30%) Histopatho

16、logyHistopathology 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 Immunohistochemistry on tissue Immunohistochemistry on tissue sectionssections the most reliable markers : CD168R, CD163the most reliable markers : CD168R, CD163 monocytic cells : lysozym (+) CAE (-)monocytic cells : lysozym (+) CAE (-) granulocytic ce

17、lls : lysozym (+) CAE (+)granulocytic cells : lysozym (+) CAE (+) relatively insensitive as compared with relatively insensitive as compared with cytochemistry or flow cytometrycytochemistry or flow cytometry 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 Chromosomal abnormalities Chromosomal abnormalities No specifi

18、c cytogenetic alterations have been identified No specific cytogenetic alterations have been identified in patients with CMML.in patients with CMML. Some of the more frequently reported recurring Some of the more frequently reported recurring abnormalities include:abnormalities include: Monosomy 7 (

19、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%) 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 Chromosomal abnormalities Chromosomal abnormalities 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 Chromosomal abnormalities C

20、hromosomal abnormalities 110/414 (27%)110/414 (27%) patients had patients had cytogeneticcytogenetic abnormalitiesabnormalities MultivariableMultivariable analysisanalysis Survival and Survival and ProgressionProgression to AMLto AML Low-riskLow-risk: normal or : normal or -Y as a single anomaly-Y a

21、s a single anomaly OS at 5 years : 35%OS at 5 years : 35% Intermediate-riskIntermediate-risk: : all other abnormalitiesall other abnormalities OS at 5 years : 26%OS at 5 years : 26% high-riskhigh-risk: trisomy 8 : trisomy 8 or abnormalities ofor abnormalities of chromosome 7 or chromosome 7 or compl

22、ex karyotype complex karyotype OS at 5 years : 4%OS at 5 years : 4% Such E, Cervera J, Costa D, et al.Such E, Cervera J, Costa D, et al. Cytogenetic risk stratification in chronic Cytogenetic risk stratification in chronic myelomonocytic leukemia.myelomonocytic leukemia. HaematologicaHaematologica.

23、2011; 96(3):375-383. . 2011; 96(3):375-383. 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 MyelomonocyticMyelomonocytic Clonal proliferationClonal proliferation DiseaseDisease progressionprogression Somatic mutationsSomatic mutations 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 Spliceosomal mutationsSpliceosomal mutations Yoshida, e

24、t 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 but Less conspicuously but significantly, SRSF2 significantly, SRSF

25、2 mutations were more mutations were more frequent in CMML casesfrequent in CMML cases 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 SRSF2 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 hi

26、gher age, less pronounced anemia and a normal karyotypepronounced anemia 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 th

27、e Pro95His had a favorable impact on OS in the RUNX1RUNX1mut subcohort.mut subcohort. Meggendorfer M, Meggendorfer M, 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 WHO diagnostic criteria for CMML WHO diagnostic criteria for CMML Persistent peripheral blood monocytosisPersistent peripheral blood monocytosis Ph chrom

28、osome or BCR-ABL1Ph chromosome or BCR-ABL1 Arrangement of PDGFRA or PDGFRB Arrangement of PDGFRA or PDGFRB (specially excluded in cases with eosinophilia)(specially excluded in cases with eosinophilia) 3 months3 months1 110109 9/L/L 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 Less than 20% blasts in PB and BMLess

29、than 20% blasts in PB and BM At 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 molecular genetic abnormality present in hematopoietic cells (c)(c) No evidence of other causes of monocytosis (infect

30、ion, inflammation or malignancy) CMML-1CMML-1: blast (including promonocytes) 5% in PB and 12 “Proliferative-type CMML”(WBC 12 10 109 9 /L) were /L) were excluded from this analysis, because these individuals were excluded from this analysis, because these individuals were believed to predominantly

31、represent MPN rather than believed to predominantly represent MPN rather than MDS.MDS. The IPSS classification scheme therefore cannot be used The IPSS classification scheme therefore cannot be used for patients with CMML.for patients with CMML. 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 Risk stratificationRisk s

32、tratification MDAPS (M. D. Anderson Prognostic Score)MDAPS (M. D. Anderson Prognostic Score) 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 One point for each of the followingOne point for each of the following variablesvariables Hb Hb 120g/L 120g/L ALC ALC 2.5 2.5 10 109 9/L/L PB IMC PB IMC 0%0% BM blasts 10%BM blas

33、ts 10% ALC : absolute lympcyte count IMC : immature myeloid cellsALC : absolute lympcyte count IMC : immature myeloid cells 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 subgroupssubgroupsscorescoreMedian survivalMedian survival (months)(months) lowlow0-10-12424 Intermediate-1Intermediate-12 21515 Intermediate-2Inte

34、rmediate-23 38 8 highhigh4 45 5 Risk modelRisk model 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 New MDS model applied in CMML withNew MDS model applied in CMML with leukocytosis leukocytosis (WBC (WBC 12 12 10 109 9 /L)/L) 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 ScoreScore 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 lowlow Int-1Int-1 Int-

35、2Int-2 highhigh Levels of riskLevels of risk 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 Therapeutic optionsTherapeutic options 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 Therapeutic optionsTherapeutic options Best supportive careBest supportive care Hypomethylating agents (azacitidine Hypomethylating agents (azacitidine and de

36、citabine)and decitabine) Cytotoxic chemotherapyCytotoxic chemotherapy Allogeneic stem cell transplantationAllogeneic stem cell transplantation 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 Cytotoxic chemotherapyCytotoxic chemotherapy Wattel et al.Wattel et al. Blood Blood 1996;88:2480241996;88:248024 87.87. 1,000 mg

37、/day of oral1,000 mg/day of oral hydroxyurea to 150 mg/week of hydroxyurea to 150 mg/week of oral etoposide in 105oral etoposide in 105 patientspatients RR: 60% vs 36%RR: 60% vs 36% OS: 20 months vs 9 OS: 20 months vs 9 monthsmonths Beran et al.Beran et al. J Clin Oncol J Clin Oncol 1999;17:28192819

38、99;17:281928 3030 topotecan at a dose of 1.25 topotecan at a dose of 1.25 mg/m2 as a continuousmg/m2 as a continuous infusion and cytarabine 1.0g/m2 infusion and cytarabine 1.0g/m2 over 2 hr,both for5 days, 27 over 2 hr,both for5 days, 27 patientspatients CR: 44% CR: 44% OS: 9.4 monthsOS: 9.4 months

39、 Induction mortality: 7%Induction mortality: 7% Quintas-Cardama Quintas-Cardama et al.et al. Cancer Cancer 2006;107:152512006;107:15251 529.529. 9-nitro-campothecin, at a dose of 9-nitro-campothecin, at a dose of 2mg/m2 orally daily for 5 days a 2mg/m2 orally daily for 5 days a week in 32 patientswe

40、ek in 32 patients CR: 11% CR: 11% PR: 16%PR: 16% OS: 12 monthsOS: 12 months Well toleratedWell tolerated 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 Hypomethylating agentsHypomethylating agents Aribi et al.Aribi et al. Cancer Cancer 2007;109:713717.2007;109:713717. decitabine at a same total dose of 100 decitabine

41、 at a same total dose of 100 mg/mmg/m2 2 per course in 3 different per course in 3 different schedules in 19 patientsschedules in 19 patients CR: 58% CR: 58% PR: 0%PR: 0% HI: 11%HI: 11% OS: 19 monthsOS: 19 months Wijermans Wijermans et al.et al. Leuk Res Leuk Res 2008;32:587591.2008;32:587591. decit

42、abine administered as 15 mg/m2 decitabine administered as 15 mg/m2 over 4 hr IV 3 times a day (total dose over 4 hr IV 3 times a day (total dose of 135 mg/mof 135 mg/m2 2 per course) in 31 per course) in 31 patientspatients CR: 10% CR: 10% PR: 16%PR: 16% HI: 19%HI: 19% OS: 15 monthsOS: 15 months Cos

43、ta et al. Cancer Costa et al. Cancer 2011;117:2690262011;117:269026 96.96. azacitidine 75 mg/m2/day for 7 days azacitidine 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days, every 4 or 100 mg/m2/day for 5 days, every 4 weeks in 38 patients.weeks in 38 patients. CR: 11% CR: 11% PR: 3%PR: 3% HI: 25%HI: 25% OS: 12 monthsOS: 12 months 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 Allogeneic stem cell transplan