Randomized Phase III Study of Decitabine +/- Hydroxyurea (HY) Versus HY in Advanced Proliferative CMML

Overview

This is a phase III, two-arm, randomized, stratified, multicenter, open-label study with individual therapeutic benefit aim: Decitabine (DAC) with or without Hydroxyurea (HY) versus HY in patients with advanced proliferative Chronic Myelomonocytic Leukemia (CMML) The primary objective of the study is to compare between the two arms Event-free Survival (EFS). Secondary objectives are to compare between both arms: Overall Survival (OS) Cumulative incidence of AML Overall and Complete Response Rates at 3 and 6 cycles according to IWG 2006 criteria modified for CMML Response duration Toxicity (hematological and non hematological) Prognostic factors

ARM A: DECITABINE (DAC) Decitabine (DAC) will be administered at 20 mg/m2 intravenously daily for 5 days every 28 days. Treatment will be delayed at the discretion of the investigator (up to D56) for febrile neutropenia (≥ 38.5°C; absolute neutrophil count \[ANC\], \< 1,000/μL), clinical and/or microbiologic infection with grade 3 to 4 neutropenia (ANC \< 1,000/μL), or hemorrhage with grade 4 thrombocytopenia (\< 25,000 platelets/μL). If renal or hepatic dysfunction occurs, treatment will be stopped until resolution or withheld if dysfunction persists more than 4 days. Persistent grade 4 thrombocytopenia or neutropenia beyond D49 will mandate bone marrow evaluation. Treatment will be continued until an event is reached. Events and thus study exit will be acknowledged only after agreement between the investigator and a Trial Committee. Allopurinol, 300mg/d, will be started at the time of inclusion; hydration during treatment will be administered to all patients. In (the rare) case of necessity, prophylactic anti-emetics could be given. Hydroxyurea may be added during the first 3 cycles if WBC counts \> 30 G/L, and mandatory if WBC \> 50 G/L. The daily dose will be adapted to maintain WBC below 15 to 20 G/L. ARM B: HYDROXYUREA (HY) Hydroxyurea (HY) 1g/d once daily, with dose adjustments (up to 4g/d) to maintain a WBC count between 5 and 10 G/L. Allopurinol, 300mg/d started at the time of inclusion will be administered to all patients. Treatment will be continued until an event is reached. Events and thus study exit will be acknowledged only after agreement between the investigator and a Trial Committee. This is intended to prevent early dropout, notably in the HY arm. Dose escalation will be performed by steps of 0.5 g/d, up to 4 g/d, if the WBC has been reduced by less than 20% and remains \> 15 G/L. HY will then be adapted to maintain a WBC count between 5 and 10 G/L. HY will be lowered if platelets decrease by \> 30 X 109/L (if initially below 100 X 109L). HY will be discontinued in cases of grade 4 thrombocytopenia or neutropenia, and reintroduced at a lower dose after recovery to grade ≤ 3. Persistent grade 4 thrombocytopenia or neutropenia after a 4 week discontinuation will mandate bone marrow evaluation.