Elderly patients with Acute Myeloid Leukemia (AML) have a poor prognosis and investigations into new maintenance therapies could improve the outcomes in this group of patients.
Arnaud Pigneux from the Centre Hospital University of Bordeaux, France, and colleagues recently published results of the GOELAMS study: a randomized, phase III multicenter trial, which evaluated whether norethandrolone given during maintenance could improve the survival outcome of elderly AML patients. The primary endpoint of the study was Disease Free Survival (DFS) by intention to treat and the secondary end points of the study were Event Free Survival (EFS), Overall Survival (OS), and safety. The findings were published ahead of print in the Journal of Clinical Oncology in October 2016.
In this study, patients received an induction therapy containing idarubicin, cytarabine, and lomustine. Patients that achieved Complete Remission (CR) or Partial Remission (PR) received an additional treatment with alternating six courses of idarubicin-cytarabine and methotrexate-mercaptopurine. Patients who remained in CR at 1 year were then randomized to 2 years of norethandrolone maintenance therapy (arm A) or no maintenance (arm B).
- Enrolled 330 patients (median age > 60)
- CR or PR was achieved by 76%; CR = 70.7%
- 5-year DFS in arm A & arm B; 31.2% vs 16.2%, P = 0.002
- 5-year OS in arm A & arm B; 26.3% vs 17.2%, P = 0.008
- 5-year EFS in arm A & arm B; 21.5% vs 12.9%
- Death occurred in 52 patients
- Patients with White Blood Count (WBC) > 30 x 109 did not benefit from norethandrolone maintenance
It was concluded by the authors that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML regardless of prognostic factors and without increasing toxicity.
In a corresponding editorial, Joseph Jurcic from the Columbia University Medical Center, commented on the key findings of this study as well as describing some of the limitations. Firstly, he commented that the study by Pigneux et al. lacked correlative studies, which makes the mechanism of androgen in AML maintenance speculative. Secondly, the backbone chemotherapy regimen, which included lomustine, used in this study is not considered standard by many groups. Additionally, the intensive post-remission therapy used for the elderly patients in this study were of concern as it might be difficult for these group of patients to cope with. Furthermore, the androgen used in this study is not widely available and can cause severe toxicities. Joseph Jurcic further commented on the approach used by Pigneux et al. by stating that “before considered standard of care, the generalizability of the findings should be demonstrated with a more commonly used chemotherapy backbone and more readily available androgen formulations, particularly because other preparations have not produced clinical benefit”. Joseph Jurcic further concluded that the data by Pigneux et al. provides proof that maintenance strategies can improve outcomes in AML and thus requires further investigation.
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/m2 on days 1 to 5, cytarabine 100 mg/m2 on days 1 to 7, and lomustine 200 mg/m2 on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m2 on day 1, cytarabine 100 mg/m2 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.
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 × 109/L did not benefit from norethandrolone.
This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.