La leucemia mielomonocitica cronica
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La leucemia mielomonocitica cronica
Sessione 1: Approccio terapeutico alle sindromi mielodisplastiche e alla leucemia mieloide cronica La leucemia mielomonocitica cronica Francesco Onida Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università Degli Studi di Milano 2008 WHO classification of the Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs) • Chronic Myelomonocytic Leukemia (CMML) • Atypical Chronic Myeloid Leukemia (aCML) • Juvenile Myelomonocytic Leukemia (JMML) • MDS/MPN, Unclassifiable (MDS/MPN-U), including refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) as a provisional entity Vardiman et al., Blood 2009;114:937-951 Diagnostic criteria for CMML 1. Persistent peripheral blood monocytosis >1x109/L 2. No Philadelphia chromosome or BCR-ABL1 fusion gene 3. No rearrangement of PDGFRB (cases with eosinophilia and PDGFRB abnormalities should be classified as “myeloid neoplasm with eosinophilia associated with PDGFRB rearrangement”) 4. Fewer than 20% blasts* in the blood and in the bone marrow 5. Dysplasia in one or more myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML may still be made if the other requirements are met, and: • an acquired, clonal cytogenetic or molecular genetic abnormality is present in the haemopoietic cells, or • the monocytosis has persisted for at least 3 months and • all other causes of monocytosis have been excluded *Blasts include myeloblasts, monoblasts and promonocytes. Orazi A et al. Myelodysplastic/Myeloproliferative Neoplasms, Chapter 4, in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4° Edition, IARC Press, 2008, pp. 76-86. CMML • Well-defined diagnostic criteria • Heterogeneity of clinical features • Extreme heterogeneity of natural course Subclassification of CMML 1994 (FAB): − Myelodysplastic (MD)-CMML WBC ≤13x109/L − Myeloproliferative (MP)-CMML WBC >13x109/L 2001-2008 (WHO): − CMML-1 PB-blasts <5% BM-blasts <10% − CMML-2 PB-blasts 5-19% or Auer rods BM-blasts 10-19% or Auer rods Life expectation in CMML (127 pts) Onida F - Unpublished data Management recommendations for CMML: consensus statements from the SIE, SIES, GITMO groups Prognosis and risk classification Because life expectancy in CMML is highly heterogeneous, risk assessment is recommended for clinical decision making in individual patients CMML-1 and CMML-2 WHO classification is recommended for prognostic implications but it should not be considered sufficient on its own to discriminate between low- and highrisk patients. Haematologica. 2013 Sep;98(9):1344-52 Management recommendations for CMML: consensus statements from the SIE, SIES, GITMO groups Prognosis and risk classification Although not included in the WHO classification, the distinction between MD- and MP-CMML is highly recommended due to its clinical implications The use of CMML specific risk-oriented systems* for individual patient risk assessment is recommended, in particular for patients who are candidates for allogeneic HSCT or enrolled in clinical trials * At present, there is no universally used validated CMML-specific risk classification system Haematologica. 2013 Sep;98(9):1344-52 Prognostic Scoring Systems Cytogenetic risk stratification in CMML Abnormal karyotype: 110/414 (27%) • Trisomy 8 • -Y • Complex • Monosomy 7 Low risk: • normal or –Y (single) High risk: • abn chr 7, complex, +8 (n=30; 27%) (n=18; 16%) (n=12; 11%) (n=6; 5%) Overall Survival CMML-specific IPSS CGs Intermediate risk: • all others Such et al. Haematologica 2011; 96(3): 375 CMML-specific prognostic scoring system (CPSS) Training cohort: 558 pts (Spanish Group of Myelodysplastic Syndromes) Validation cohort: 274 pts (Düsseldorf, Pavia) Risk Groups: Low = 0 Interm-1 = 1 Interm-2 = 2-3 High = 4-5 Such et al. Blood 2013; 121(15): 3005-3015 CMML-specific prognostic scoring system (CPSS) Training cohort Validation cohort An alternative CPSS with Hb instead of RBC transfusion dependency offered identical prognostic capacity Such et al. Blood 2013; 121(15): 3005-3015 Prognostic score including gene mutations in CMML (GFM) Training cohort: 312 pts (GFM) Validation cohort: 165 pts (Munich Leukemia Laboratory cohort) Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36 Prognostic score including gene mutations in CMML (GFM) • Age > 65 yrs = 2 points • Anemia (M < 10 g/dL, F < 11 d/dL) = 2 points • WBC > 15 x 109/L = 3 points • Platelet < 100 x 109/L = 2 points • ASXL1 status = 2 points Risk Groups: Low = 0-4 Interm = 5-7 High ≥ 8 Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36 Prognostic score including gene mutations in CMML (GFM) Training cohort Validation cohort Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36 International CMML Consortium International CMML Consortium International CMML Consortium International CMML Consortium Baseline characteristics Padron E et al. ASH 2014 International CMML Consortium Baseline characteristics - BM Padron E et al. ASH 2014 International CMML Consortium Baseline characteristics - blood Padron E et al. ASH 2014 International CMML Consortium Padron E et al. ASH 2014 International CMML Consortium Padron E et al. ASH 2014 International CMML Consortium Padron E et al. ASH 2014 Molecular analysis in CMML (42 pts) Onida F - Unpublished data SRSF2 TET2 100% 100% P = 0.0418 80% 80% 87% 60% 40% 60% 53% 47% Patients with gene20%mutations 33% 20% 40% 38% 8% 100% 0% MD 0% P = 0.4134 MP 80% mut TET2 2 mut TET2 60% 85% 1 mut TET2 MD MP 73% 40% ASXL1 20% Proliferation-associated genes 100% 100% 0% P = 0.0123 P = 0.0296 80% MD 60% 80% MP 60% 60% 40% 45% 20% 40% 20% 9% 9% 0% 0% MD MP MD MP Onida F - Unpublished data Prognostic impact of gene mutation Onida F - Unpublished data Prognostic impact of gene mutation Onida F - Unpublished data Management recommendations for CMML: SIE, SIES, GITMO consensus statements Determinants of therapeutic intervention Therapy should be started when the disease is symptomatic or progressive, and, in particular, when one of these events occurs: • a) severe anemia (Hb less than 10 g/dL); • b) percentage of blasts in peripheral blood >5% (including myeloblasts, monoblasts and promonocytes;) • • • • • c) platelet count ≤ 50x109/L; d) WBC count ≥ 30x109/L; e) immature granulocytes ≥ 10% in peripheral blood; f) extramedullary manifestations of the disease g) symptomatic splenomegaly Haematologica. 2013 Sep;98(9):1344-52 Response rate: 60% vs 36% Median Survival: 20 vs 9 months Blood 1996, 88;7: 2480-2487 Intensive CT in CMML Topotecan 1.25 mg/m2 c.i. x 5 d + Ara-C 1 g/m2 x 5 d Response rate: CR 12/27 (44%) Response duration: median 33 wks Beran M at al. JCO 1999, 17: 2819-2830. Further intensification of treatment increases toxicity and mortality and does not appear to significantly benefit response and survival. Beran et al. Blood 2001, 98:624a FTIs in CMML CRs: CMML-1 (1 of 8; 12.5%) CMML-2 (2 of 9; 22.2%) Median survival: 14.5 months Leukemia 2008;22:1707–1711; Blood 2007;109:4158-4163 In CMML, tipifarnib and lonafarnib as single agents were associated with low and short-lasting response rates independent of RAS mutational status and inhibition of farnesyltransferase. Azacitidine in CMML Azacitidine in CMML Pleyer L et al. Leukemia Research (2014) 38, 475-483 Azacitidine in CMML: A UK multi-centre phase 2 prospective controlled study Drummond MW et al. Leukemia (2014) 28, 1570–1572 Decitabine in CMML European trial: 66 high-risk MDS patients. 45 mg/m2/d for 3 dq 6 wks 9 CMML pts 1 CR, 1 PR, 2 HI (overall RR of 44%) Wijermans P et al. J Clin Oncol 2000, 18:956–962 MDACC trial: Number of patients 19 CMML/95 MDS 13 (68%) WBC >12 x 109/L Schedule 20 mg/m2 i.v. x 5 d q28 20 mg/m2 s.c. x 5 d q28 10 mg/m2 i.v. x 10 d q28 16 1 2 Median number of courses 9 (range 1-18) Complete response Hematologic improvement 11 (58%) 2 (11%) Aribi A et al. Cancer 2007. 109;13:713-717 Decitabine in CMML – GFM Trial 39 patients (Nov 2008 – Jun 2009) – 32/39 MP-CMML • Inclusion criteria: - CMML dx according to WHO 2008, except BM blasts up to 29% - Poor prognosis (Int-2/High in MD, additional criteria in MP) • Treatment schedule: 20 mg/m2 i.v. x 5 d q28 Braun T et al. Blood 2011 118 (14) : 3824-3831 Decitabine in CMML – GFM Trial • Median number of cycles = 10 (range 1-24) • ORR 38% (15 pts) • 10% CR (4 pts) • 20% marrow CR (8 pts) • 8% HI (3 pts) RBC-transfusion independence in 36% (8/22) • 46% SD (18 pts) • 15% progression to AML (6 pts) Braun T et al. Blood 2011 118 (14) : 3824-3831 Decitabine in CMML – Italian Trial Titolo dello studio Studio clinico di fase II, aperto, multicentico che valuta l’efficacia di decitabina nel trattamento della leucemia mielomonocitica cronica nell’adulto Tipo di studio Studio aperto multicentrico Dose 6 cicli di decitabina 20 mg/m2 ev in infusione continua per 5 gg ogni 28 gg Obiettivo principale Efficacia di decitabina : percentuale di risposta secondo IWG 2000/2006 Obiettivi secondari Durata di risposta, sopravvivenza , Qualità di vita, studio biologico (midollo e s. periferico) della metilazione e espressione genica Arruolamento 12 mesi , 43 pazienti Durata dello studio 2 anni By courtesy of V. Santini Italian Trial - Criteri di inclusione 1. Età > 18 anni 2. Diagnosi di LMMC secondo criteri WHO 2008 3. Se leucociti ≤ 12 000/mm3: IPSS alto o INT-2 Se leucociti > 12 000/mm3: almeno 2 dei criteri seguenti: - Blasti midollari > 5 % - Tutte le anomalie citogenetiche clonali, esclusa t(5;12) (q33; p13) - Anemia < 10 g/dL - Piastrinopenia < 100 x 109/L - Splenomegalia > 5 cm sotto il margine costale - Localizzazione extra midollare dimostrata Decitabine in CMML – Risultati preliminari • N ° pazienti arruolati = 44 (variante proliferativa > 80%) • Età mediana = 72 anni (range 46-84) • Mediana cicli somministrati = 14 (range 1-34) • 2 pazienti ancora in trattamento (08/2014) • Risposta completa = 36% (16/44). • Buona tolleranza globale. Tossicità prevalentemente ematologica. • Metiloma alla diagnosi predittivo di risposta V. Santini, comunicazione personale Lenalidomide//Melphalan in CMML Lenalidomide Buckstein R et al. Leukemia Research (2014) 38, 756-763 Lenalidomide//Melphalan in CMML Lenalidomide CMML pts number = 12 (9 MP-CMML). Median age 73 (range 52-87) Lenalidomide 10 mg + Melphalan 2 mg x 21 days (q28) up to 12 cycles 3 responses, all in MP-CMML: 1 CR (68 d), 1 HI-PLT (63 d), 1 HI-E (147 d) Buckstein R et al. Leukemia Research (2014) 38, 756-763 Management recommendations for CMML: SIE, SIES, GITMO consensus statements First-line therapy - 1 The treatment strategy should be decided first according to the disease hematologic phenotype (MD vs MP) and to the number of blasts Patients with MD-CMML and less than 10% blasts in BM should be managed with supportive therapy aimed at correcting cytopenias. Patients with severe anemia and with serum EPO ≤ 500 mU/dL) should be treated with ESA. G-CSF may be considered in febrile neutropenia. In MD-CMML with high number of blasts (≥10% in BM, ≥5% in the blood), supportive therapy should be integrated with the use of hypomethylating agents. Haematologica. 2013 Sep;98(9):1344-52 Management recommendations for CMML: SIE, SIES, GITMO consensus statements First-line therapy - 2 In selected patients with MD-CMML, allo-SCT may be offered within clinical trials Patients with MP-CMML with a low number of blasts should be treated with cytoreductive therapy. HU is the drug of choice to control proliferative myelomonocytic cells and to reduce organomegaly. Patients with MP-CMML and a high number of blasts should receive blastolytic therapy with polychemotherapy followed, when possible, by allo-SCT (within clinical trial). Haematologica. 2013 Sep;98(9):1344-52 Allo--SCT in CMML Allo FHCRC (1990-2004) Pts number = 43. Median age 48 yrs (range 1-66) MD-CMML 16 (37%) / MP-CMML 27 (63%) WHO CMML-1: 32 /CMML-2: 11 Related donors in 21/ 22 UD Various conditioning regimens (mostly Bu-Cy or Bu-Cy-TBI) RFS 41% at 4 yrs, Cum. relapse 21%, NRM 35% Kerbauy et al. Biol BMT 11:713-720 (2005) EBMT (1988-2000) Pts number = 50. Median age 44 yrs (range 19-61) Related donors in 43 / 7 MUD Various conditioning regimens RFS 18% at 5 yrs, Cum. relapse 49%, NRM 52% Graft versus CMML effect? Kröger et al. Br J Haematol 2002, 118:67–73. Allo--SCT in CMML Allo Pts number = 85 Median age 52 yrs (range 1-69) CMML: de novo in 84%, secondary in 16% Donors: related in 38 (45%); unrelated in 47 (55%) Major causes of death: relapse and infections ± GvHD Outcomes at 10 yrs: • Progression-free Survival 38% • Cumulative relapse 27% (correlated with MDAPS) • Mortality associated with: lower Hct, HR CGs, High C.I., Older age • Outcome not affected by WHO classification Eissa H et al. BBMT 2010 Allo--SCT in CMML (SFGM Allo (SFGM--TC) Pts number = 73 (1992-2009). Median age 53 yrs (range 27-66) MD-CMML 57 (78%) / MP-CMML 16 (22%) WHO CMML-1: 24 /CMML-2: 26 Related donors in 41/ 32 UD MAC 41%, RIC 59% OS 42 % at 2 yrs, 32% at 3 yrs RFS 29% at 3 yrs, Cum. relapse 35% at 3 yrs, NRM 36% at 3 yrs Park et al. Eur J Haematol. 2013 May;90(5):355-64 Open questions Criteri diagnostici: Definizione di monocitosi. Relativa o assoluta? • AMC >1000/mcL, >10%? • WBC? Stable vs unstable count? • IMC? Eterogeneità clinica sottoclassificazioni: • MD- vs MP-CMML (what should be really considered MP?) • CMML-1 vs CMML-2 • Different molecular aberrations/signature (pathways) A proposal for a possible solution to the MD vs MP classification dilemma A new MDS subcategory: • RCUD/RCMD with monocytosis (monocyte >10%, WBC <10.000/mcL, IMC 0%, no splenomegaly) Within the MDS/MPN: • CMML with WBC 10.000 to 20.000/mcL (monocyte >10%) • CMML with WBC <10.000/mcL (monocyte >10%) if IMC >0% and/or splenomegaly and or organ infiltration (e.g. skin) A new Ph-negative MPN subcategory: • MP-CMML with WBC >20.000/mcL (monocyte >10%), or requiring cytoreductive treatment to maintain WBC <20.000/mcL Myeloid Disorders RCUD/RCMD with monocytosis MDS MDS/MPN CMML MPN MP-CMML AML