Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial

For patients with acute myeloid leukemia (AML), aged over 60 years old presenting with poor prognosis factors such as, adverse cytogenetics, previous myelodysplastic syndrome (MDS) or therapyrelated AML (t-AML), the outcome remains particularly dismal. It is generally accepted that these patients are candidates for palliative care or investigational therapy only. In such poor prognosis patients, although complete remission (CR) rates around 60% have been reported after induction chemotherapy, no standard postremission schedule has consistently improved survival. The relapse rate is still over 60%, leading to an overall median disease-free survival (DFS) of o1 year (range: 4–11 months). Both azacitidine and lenalidomide have single-agent activity in patients older than 60 years with untreated AML through non-overlapping mechanisms that could even be synergistic. Sequential or concomitant administration of these two drugs in high-risk MDS or AML unfit patients led in most reports to higher and earlier hematological response rates than after treatment with either of those drugs as singleagent. However, these cohorts were small, CR rates usually o20% and the duration of responses short. Maintenance with hypomethylating agents or in combination with lenalidomide following chemotherapy-induced CR has been reported in a few patients. We hypothesized that the above-described drugs, used alternately as maintenance therapy, could be more effective on the residual disease of patients in CR, especially in patients at high risk of relapse, with limited toxicity. The FILO (French Innovative Leukemia Organization, previously Goelams), tested this hypothesis in a phase II trial. Fit patients (performance status (PS) 0–2), 60 years of age or older, with poor-risk AML, were included. Poor-risk AML was defined by centrally reviewed poor-risk cytogenetics defined according to the European LeukemiaNet, previous MDS or therapy-related AML (t-AML). Patients with prior myeloproliferative neoplasm or MDS treated with azacitidine, decitabine or lenalidomide were excluded. The study was approved by an ethical committee (ID 2010/23 CPP Ouest II, Angers) and registered by clinicaltrials.gov as NCT01301820. All patients provided written informed consent. All patients received a classical FILO induction protocol ICL including lomustine 200 mg/m day 1, idarubicin 8 mg/m days 1–5, cytarabine 100 mg/m days 1–7 continuous infusion and granulocyte colony-stimulating factor from day 15 until hematological recovery. Only patients who reached CR after one induction cycle received maintenance therapy. Patients in CR without platelets reconstitution (o5% bone marrow blasts on day 35 but platelet count o100× 10/l), or failure were subsequently treated according to their physician’s choice. Maintenance included 12 cycles of alternating azacitidine (sc 75 mg/m/day, days 1–7) and lenalidomide (10 mg/day, days 1–21) every 28 days. Maintenance began after centralized randomization with either azacitidine (arm A) or lenalidomide (arm B). Maintenance cycles could be initiated at day 28 of the previous course if neutrophils and platelets were above 1 × 10 9 and 100× 10 /l, respectively. If these levels were not reached at day 42, the next cycle was initiated at a reduced dose of 50 mg/m/day or 5 mg/day for azacitidine and lenalidomide, respectively. Granulocyte colony-stimulating factor was allowed in case of severe neutropenia (o0.5 × 10 /l) over 7 days or if febrile neutropenia occurred. Red blood cells or platelets transfusions thresholds were 8 g/dl hemoglobin and 20 × 10 − /l platelets respectively. The NCICTCAEv4 was used to report toxicities. The primary endpoint was a 2-year DFS improvement of at least 20% compared to historical data (increment from 15 2) to 35%). Assuming a CR rate of 55% in this population following ICL induction, a type 1 error of 5% and a power of 80%, 117 patients had to be included. Between March 2011 and February 2013, 117 fit elderly patients (55% males, median age 69 years, range: 60–80) from 27 FILO centers received induction therapy. Eighty-three patients had poor cytogenetics, including complex karyotype (N= 65), monosomal karyotype (N= 54), chromosome 5 anomaly (N= 61), chromosome 7 anomaly (N= 44), chromosome 3q anomaly (N= 9), del(17p) (N= 33), tri(8) (N= 15) or involvement of 11(q23) (N= 5). Among them, 33 also had an antecedent of MDS and 27 therapy-related