Validation of response assessment according to international consortium for MDS/MPN criteria in chronic myelomonocytic leukemia treated with hypomethylating agents

The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) are active in Chronic Myelomonocytic Leukemia (CMML) with overall response rates (ORR) of 40–70%, translating into median overall survivals (OS) of 12–22 months. Response to HMA in these CMML cohorts was mostly evaluated according to IWG-2006 criteria, which do not assess improvement of myeloproliferative features nor quality of life. In myelodysplastic syndroms (MDS) patients treated with HMA, these criteria have limited impact in predicting OS. Normalization of WBC and monocyte counts, regression of splenomegaly or other extramedullary disease, and improvement of quality of life have been reported in CMML patients treated with HMA and studies in MDS and primary myelofibrosis have shown that symptom improvement could be correlated to a prolonged OS. To capture both MDS and myeloproliferative neoplasm (MPN) features in a singly response scale in CMML, an international expert panel, the MDS/MPN International Working Group, proposed new response criteria for MDS/MPN, hereafter referred to as overlap-MDS/MPN criteria. These new criteria take in consideration bone marrow and peripheral blood blast reduction and improvement of cytopenias, but also account for correction of WBC, monocyte and peripheral immature myeloid cell counts (IMC), regression of splenomegaly and other extra-medullary disease. These criteria also assess correction of myelofibrosis, generally moderate in CMML, and propose a provisional entity of ‘clinical benefit’ solely based on improvement assessed with the MPN-SAF scoring system, which has been developed in primary myelofibrosis and has never been validated in MDS/MPN. These new criteria remain to be validated. To validate these overlap-MDS/MPN criteria in the most frequent entity amongst MDS/MPN, namely CMML, we updated clinical data from 79 CMML patients treated by AZA or DAC included in GFM CMML clinical trials (EudraCT No. 2008-00047021) or registry (PHRC MAD-06). The cohort included 56 males and 23 females, with a median age of 72 years. At HMA onset, 57% of patients had CMML-1 and 43% had CMML-2. Splenomegaly was present in 40% of cases. Median Hb, WBC, ANC and platelets were 9.7 g/dl, 14.5 × 10/l, 7.1 × 10/l and 101× 10/l, respectively. CPSS prognosis score was low in 12%, intermediate-1 in 20%, intermediate-2 in 51% and high in 17%. The GFM prognostic risk was low in 32%, intermediate in 36% and high in 32% assessable patients respectively. Forty-eight patients (61%) received AZA and 31 (39%) received DAC, with a median interval between diagnosis and HMA onset of 5 months (inter-quartile range (IQR) 1.1–26.3). The median number of cycles was 9 [IQR 5-17]. Detailed baseline characteristics of patients are provided as Supplementary Data. Median follow-up was 59 months, during which 33 patients (42%) had AML transformation and 11 (14%) received an