Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study

Abstract

Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m on days 1 to 5, cytarabine 100 mg/m on days 1 to 7, and lomustine 200 mg/m on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m on day 1, cytarabine 100 mg/m on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 10/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.

Acute Myeloid Leukemia, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology

“…107 A multicenter, phase III randomized study investigated the survival benefit of adding androgens to maintenance therapy in patients with AML aged ≥60 years (n=330). 108 In this study, induction therapy included cytarabine (100 mg/m 2 on days 1-7), idarubicin (8 mg/m 2 on days 1-5), and lomustine (200 mg/m 2 on day 1). Patients in CR or PR (n=247) were treated with 6 reinduction courses, alternating idarubicin on day 1, cytarabine on days 1 to 5, and a regimen of methotrexate and mercaptopurine, and randomized to receive androgen, norethandrolone (10 or 20 mg/d) according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen.…”

“…Compared with the arm that received no androgens, norethandrolone improved rates of 5-year DFS (31.2% vs 16.2%, respectively), EFS (21.5% vs 12.9%, respectively), and OS (26.3% vs 17.2%, respectively). 108 For patients who previously received lower-intensity therapy, a marrow evaluation to document remission status on hematologic recovery should be performed after 8 to 12 weeks. If a response is observed, a clinical trial, reduced-intensity HCT, or continuation with hypomethylating regimens (every 4-6 weeks until progression) may be appropriate.…”

New drugs creating new challenges in acute myeloid leukemia

“…Interestingly, the OS curve for norethandrolone only crossed into superior territory after~2.5 years. 44 Azacitidine has been evaluated in several phase 3 studies in the elderly patients with AML as a postremission maintenance therapy.…”

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

“…15 Absence of benefit of decitabine maintenance in younger AML patients in CR over historical controls has also been recently reported. 13 An alternate schedule or association with other drugs might show a more favorable outcome (tested currently in NCT01041703 (decitabine after clofarabine) and NCT01757535 (oral azacytidine maintenance after daunorubicin-based induction)).…”

“…15 ) including the same ICL induction but 2 years chemotherapy maintenance included 78 poor-risk cytogenetics patients, 9 with previous cancer but none with previous MDS, with a CR rate of 59%. Characteristics of these patients were similar to our population except for less cancer antecedents (11.5 vs 27.3%, P =0.02).…”