Improved Outcome with Androgens as Maintenance Treatment in Elderly Patients with Acute Myeloid Leukemia after ICL Regimen as Induction Therapy: Results of the GOELAMS SA-2002 Multicenter Phase III Randomized Open Trial
Authors: Pigneux Arnaud , Himberlin Chantal , Hunault-Berger Mathilde , Witz Francis , Recher Christian , Harousseau Jean-Luc , Tournilhac Olivier , Berthou Christian , Escoffre-Barbe Martine , Guyotat Denis , Fegueux Nathalie , Delain Martine , Lioure Bruno , Jourdan Eric , Bouscary Didier , Legros Laurence , Milpied Noel , Bauduer Frederic , Perry Frederic , Luquet Isabelle , Bene Marie-Christine , Ifrah Norbert , Sotto Jean-Jacques , Guardiola Philippe 
Published: April 2020

Abstract
The French group, GOELAMS, performed a multicenter phase III randomized open trial to evaluate whether adding androgens to post-remission induction therapy was associated with an improved outcome in elderly pts with de novo AML. All patients received the ICL induction protocol (idarubicin 8mg/m2 day1–5, cytarabine 100mg/m2 day1–7 & lomustine 200mg/m2 day1). Patients in complete or partial remission received maintenance therapy consisting in 6 reinduction courses (idarubicin 8mg/m2 day1, cytarabine 100mg/m2 day1–5.), once every 3 months, with a continuous regimen of methotrexate and 6-mercaptopurine in-between these. At diagnosis, patients were randomized to receive (AndroG arm) or not (Control arm) norethandrolone 10 to 20 mg per day, according to body weight. Androgen was started after recovery from aplasia, between day-20 and day-30 following induction chemotherapy, and was to be continued during the 2-year maintenance therapy period if a complete or partial remission was achieved following induction chemotherapy. The two arms were well-balanced for known prognostic factors. Between June 2002 and January 2005, 330 patients with de novo AML and age 60 y (median 70, range 60–86) were included. Pts with acute promyelocytic leukemia were not included. At diagnosis, ECOG was 0–1, 2, 3–4 in 270, 55, and 5 cases; WBC count was &lt; 4 G/L, &gt; 30 G/L, &gt; 100 G/L in 141, 85, and 33 pts. Of note, 61% of the pts with a WBC count &lt; 4 G/L were males, and 52% of males had a low WBC count vs 33% of females (p&lt;0.001). Centrally reviewed cytogenetics was available in 308 cases (high-risk, 78; int-risk, 185; low-risk, 15; failures, 30). Median follow-up from induction chemotherapy was 1.1 y (1st quartile, 0.34 y; 3rd quartile, 2.91 y) for the overall group, and 3.6 y (1st quartile, 3.2 y; 3rd quartile, 4.3 y) for pts alive at last news. Complete remission, on days 40 and 80, was achieved by 56% vs 52%, and 83% vs 79% of the pts in Control and AndroG arms, respectively. Twelve pts from the AndroG arm did not receive norethandrolone. Fine & Gray competing-risk model was used to estimate 5-year relapse incidence and the effect of norethandrolone on this endpoint. As for relapse, the potential benefit of norethandrolone on 5-year leukemia-free survival (LFS), event-free survival (EFS), and overall survival (OS) was analyzed on an intention-to-treat basis, using univariate and multivariate adjusted models. S-Plus2000Pro software was used for all analyses.
Results: Crude univariate analyses regarding the effect of androgen randomization on 5-year relapse incidence, LFS, EFS and OS are listed in Table 1.
Table 1
Full time period from diagnosis HR, hazard ratio; CI, confidence interval; Cox p-val, p-value of Cox regression model. Endpoints Control AndroG Gray test p-val HR; 95%CI Cox p-val Relapse 66% 54% 0.21 -- -- LFS 23% 33% -- 0.79; 0.58–1.09 0.15 EFS 16% 22% -- 0.95; 0.75–1.22 0.69 OS 19% 26% -- 0.96; 0.74–1.23 0.72
Of note, the effect of norethandrolone on relapse incidence, LFS, EFS, and OS, was violating the proportional hazards assumption (scaled Schoenfeld residuals analysis). Since the 2 hazards rate functions crossed each other, which would result in ineffective comparisons if using log-rank tests, time-dependent models were considered. For all these endpoints, as estimates for the 2 arms were not significantly different during the first year, but diverged during the following years, favoring the AndroG arm (Table 2, Figure 1), a step-function at 1 year from diagnosis was considered.
Table 2
Time period starting 1 year from diagnosis Endpoints Control AndroG Gray test p-val HR; 95%CI Cox p-val Relapse 55% 33% &lt; 0.01 -- -- LFS 37% 54% -- 0.56; 0.33–0.94 0.028 EFS 32% 52% -- 0.57; 0.36–0.89 0.013 OS 37% 60% -- 0.63; 0.41–0.96 0.034
Figure Figure
Thus, for pts alive and in complete remission at 1 year from diagnosis, relapse incidence was lower, while LFS, EFS and OS were higher in the AndroG arm, even after adjusting for other significant covariates (p=0.029 Relapse; p=0.038 LFS; p=0.028 EFS; p=0.029 OS). Moreover, the beneficial effect of norethandrolone was more pronounced in males, and in pts having WBC count &lt; 4 G/L as shown in Figure 2 for the LFS.
Figure Figure
Conclusion: addition of low-dose norethandrolone to maintenance chemotherapy is associated with an improved outcome in elderly pts with AML; especially in those achieving CR and remaining in remission for at least a year. Improved outcome was observed with androgen in males and/or in pts with low proliferative disease.