Impact of Post-Remission Treatments in Patients Aged 65–70 Years with De Novo AML: A Comparison of Two Concomitant Randomized ALFA Trials with Overlapping Age Inclusion Criteria
Authors: Itzykson Raphael , Gardin Claude , Pautas Cécile , Thomas Xavier , Turlure Pascal , Raffoux Emmanuel , Terré Christine , Castaigne Sylvie , Dombret Hervé , Boissel Nicolas 
Published: April 2020

Abstract
Background: The outcome of older patients with AML treated with intensive chemotherapy remains poor. No standard of treatment for post-remission therapy been demonstrated in these patients, and repeated high-dose cytarabine (AraC) post-remission courses have only been shown of benefit in patients aged of 50 years or less.
Objective: To compare the overall outcome and the impact of post-remission strategies in patients with newly-diagnosed AML aged 65 to 70 years and enrolled during the same period (12/1999 to 10/2006) in two concomitant randomized ALFA trials with overlapping age inclusion criteria. The ALFA-9803 study (Gardin et al, Blood, 2007) was designed for elderly patients (65y+ with de novo or post-MDS AML) while the ALFA-9801 trial was designed for middle-aged patients (50–70y with de novo AML) (Pautas et al. ASH 2007 #162). All other inclusion criteria were similar among the two trials.
Patients and Treatments: Analysis was restricted to the 211 patients aged 65–70y with de novo AML. A frontline randomization between idarubicin (IDA) and daunorubicin (DNR) was included in the two trials, with a total IDA/DNR dose of 36/180 mg and 36–48/240 mg during induction, for the 9803 and 9801 trial respectively. After induction, both trials essentially differed by the post-remission chemotherapy, which comprised two intermediate-dose cytarabine (IDAC) cycles in the 9801 trial and a second randomization between one repeated 3+7 like cycle and six 1+5 anthracycline-based ambulatory consolidations in the 9803 trial. Only two patients received a stem cell transplantation in first CR (1 allogeneic, 1 autologous). In both studies, the initial randomization between IDA and DNR had no impact on OS. Nevertheless, all analyses were stratified on IDA/DNR randomization arm.
Results: Seventy-six patients were treated in the 9801 trial and 135 in the 9803 trial. Median age was 67 years and M/F sex ratio was 110/101. Median WBC was 7.4 G/L. Cytogenetic risk was favorable in 9 (4%), intermediate in 118 (56%) and unfavorable in 54 (26%) patients, respectively. Ninety-five and 116 patients were randomized to receive DNR and IDA, respectively. Aside from median age (67 vs 68 years in 9801 and 9803, respectively; P&lt;.001), patient characteristics were similar between the two protocol subgroups, in terms of inclusion date, sex, PS, FAB, cytogenetics, and WBC. The overall CR rate was 62%. In univariate analysis, there was a trend for a higher CR rate in the younger 9801 trial (70 vs 57%; p=.17). As expected, cytogenetics was identified as the sole significant risk factor for CR achievement (89% in favorable, 68% in intermediate, and 44% in unfavorable-risk; p=0.03). Median follow-up, OS, RFS, and EFS were 35, 14, 12 and 6.5 months, respectively. In univariate analysis, the trial did not influence OS (3-year OS, 20 vs 17% in the 9801 and 9803 trial, respectively; p=.71), RFS or EFS. Again, the only identified risk factor for OS and EFS was high-risk cytogenetics. After CR achievement, 44 9801-patients (58%) received the planned IDAC consolidation, while 30 (22%) and 33 (24%) 9803-patients received the planned 3+7 like or ambulatory consolidation, respectively. In these patients, no significant differences in CR duration (median CR duration: 12.4, 14.8 and 11.9 months with IDAC, 3+7 like, and ambulatory consolidation, respectively; p=0.57) was observed among these three different post-remission strategies. In multivariate analysis, only unfavorable cytogenetics affected OS (HR=1.8 [95% CI 1.3–2.6], p=10-3) and EFS (HR=2.0 [1.4–2.8], p&lt;10-4), with a trend for adverse RFS (HR=1.6 [.99–2.7], p=.055).
Conclusion: In patients aged 65–70 years with de novo AML, more intensive post-remission therapy containing IDAC does not appear to significantly improve EFS, RFS, or OS, as compared to less intensive consolidation or even repeated anthracyclin-based ambulatory treatment. The poor early outcome of those with unfavorable cytogenetics justifies the evaluation of new global therapeutic approaches in this patient subset.