- Note that this randomized trial of norethandrolone maintenance therapy among older individuals treated with chemotherapy for acute myeloid leukemia (AML) found that the androgenic agent successfully prolonged disease-free survival.
- There were no cases of prostate cancer reported in either arm of the study.
Androgen maintenance therapy for acute myeloid leukemia (AML) led to significantly longer survival in older patients, a randomized trial showed.
Among patients in complete remission 1 year after chemotherapy induction, those assigned to androgen maintenance therapy had a twofold improvement in disease-free survival (DFS) at 5 years as compared with no maintenance therapy (P=0.002). The 5-year overall survival also was significantly higher in patients who received either of two doses of norethandrolone for 2 years after achieving remission (P=0.008).
All outcomes relevant to prognosis favored the patient group that received androgen maintenance therapy, Norbert Ifrah, MD, of University Hospital Center in Angers, France, and coauthors reported online in the Journal of Clinical Oncology.
“In choosing to add androgens to post-remission therapy, we expected to improve DFS, which was achieved, yet a beneficial effect was finally observed for EFS and OS. This beneficial effect was intriguingly time-dependent and became significant only among patients who had failed to relapse during the first year of therapy.”
A time-dependent analysis of covariates identified hyperleukocytosis (WBC count >30 x 109/L at diagnosis) as an additional prognostic factor.
“These data suggest that for the non-negligible population of elderly patients with AML with a WBC count <30 x 109/L at diagnosis, the addition of androgens could become a valid cost-effective maintenance therapy,” the authors concluded.
In an accompanying editorial, however, Joseph G. Jurcic, MD, director of the Hematologic Malignancies Department of Columbia University Medical Center in New York City, said that although intriguing, the data must be considered in the context of uncertainty surrounding the role of maintenance therapy in AML. Chemotherapy-based approaches to maintenance have yielded limited benefit, but studies of molecularly targeted agents have been more promising, he explained. Moreover, the lomustine-based induction chemotherapy is not favored by many experts in the field, the intensive postremission therapy may be difficult for many older patients to tolerate, and the androgen preparation used in the study is not widely available.
“Before [the approach is] 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,” Jurcic wrote.
“Future studies must also include careful correlative studies to elucidate the effects of androgens on normal and leukemic progenitors. These data provide proof of principle that maintenance strategies can improve outcomes in AML and support further investigation of this approach.”
AML is a disease of older individuals, as more than 70% of patients are over 60 at diagnosis. Older patients with AML have a poor prognosis, owing in part to low tolerance to intensive chemotherapy regimens. Additionally, Ifrah and co-authors noted, older patients with AML often have unfavorable prognostic features, such as poor-risk cytogenetics and multidrug resistance phenotype.
Older patients have a higher treatment-related mortality, lower rate of complete remission after induction therapy, and briefer duration of remission, as compared with younger patients with AML. The 5-year overall survival for older patients with AML is 15% or less, the researchers continued.
The rationale for androgen maintenance therapy in AML came from a long successful clinical experience in the treatment of aplastic anemia, which led to small, single-center preliminary clinical trials in AML. Subsequent in vitro studies showed that androgens inhibited proliferation of leukemia cell lines, providing additional rationale to evaluate the agents in AML.
Ifrah and his co-investigators in the French GOELAMS (Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang) cooperative group performed the multicenter clinical trial to evaluate two weight-based doses of norethandrolone (10 or 20 mg) as maintenance therapy in older patients with AML. The trial involved 330 patients ≥60 with newly diagnosed AML.
All patients received induction therapy with idarubicin, cytarabine, and lomustine, and those who attained complete or partial remission received additional treatment with alternating courses of idarubicin-cytarabine and methotrexate-mercaptopurine. Patients who remained in complete remission at 1 year (N=247) were randomized to 2 years of norethandrolone maintenance therapy or no maintenance.
The primary endpoint was DFS. Secondary endpoints included EFS, overall survival, and safety.
The authors reported that 52 patients (16%) died during induction therapy, most often as a result of sepsis (N=23).
After a median follow-up of 1.2 years from the start of induction therapy (4.6 years among patients alive at last follow-up), the patients assigned to androgen maintenance had a 5-year DFS rate of 31.2% versus 16.2% for patients who received no maintenance therapy.
Relapses occurred in 146 patients (64 in the maintenance arm and 82 without maintenance), and 32 patients died in complete remission — 16 in each arm.
Patients assigned to androgen maintenance therapy had 5-year EFS and overall survival rates of 21.5% and 26.3%, respectively, compared with 12.9% and 17.2% in the group that received no maintenance therapy.
Analysis of postremission toxicity showed no difference between the treatment groups with respect to rehospitalization, need for transfusion, or grade 3/4 toxicities. The authors reported that secondary cancers occurred in 11 patients on androgen maintenance and 16 in the no-maintenance arm, and no patient in either arm developed prostate cancer.
The study was supported by University Hospital Center of Grenoble in France.
Ifrah disclosed relationships with Celgene, Sanofi, Novartis, Pfizer, Chugai, and Alexion Pharmaceuticals. One or more coauthors disclosed relationships with Novartis, Amgen, Merck Sharp & Dohme, Celgene, Pfizer, Chugai, Sunesis Pharmaceuticals, Mundipharma, Roche, Janssen-Cilag, GlaxoSmithKline, Cell Therapeutics, Sanofi, Alexion, and Celgene.
Jurcic disclosed relationships with Novartis, Bayer, Amgen, Alexion Pharmaceuticals, Seattle Genetics, Sunesis Pharmaceuticals, Celgene, Astellas, Actinium Pharemaceuticals, Daiichi Sankyo, Forma Therapeutics, Kura, and Syros Pharmaceuticals.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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