Evaluation of dose intensification of cytarabine in postremission therapy in older AML patients within the prospective phase II AMLSG 06-04 study

Abstract

Background: Progress in the treatment of acute myeloid leukemia (AML) in older patients (pts) is still limited. In the randomized part of the AMLSG 06‐04 trial, valproic acid (VPA) was evaluated in combination with intensive therapy plus all‐trans retinoic acid (ATRA) in older pts (>60 years) with newly diagnosed AML. The randomized part of the study (cohort‐1) was terminated due to excessive VPA‐induced toxicity (Tassara et al, Blood 2014;123:4027‐36.). The study was amended thereafter (cohort‐2) to evaluate a cytarabine dose‐intensifcation in first consolidation therapy. Here we report on the comparison of the two cohorts. Methods: Between 2004 and 2008, patients were treated in cohort‐1 (n=186) and cohort‐2 (n=376). 2 cycles of induction therapy (ATRA, idarubicin, cytarabine, n=93 with VPA) were followed by consolidation‐1 (mitoxantrone, ATRA, cytarabine [cohort‐1, 0.5g/m2; cohort‐2, 1g/m2] bid, days 1‐3) and consoldation‐2 (idarubicin, etoposide, ATRA). Results: Median age was 68 (range, 60‐84) years without difference between the cohorts (p=0.49). Complete remission (CR) rates after induction therapy were 45% and 48% (p=0.59) in cohort‐1 and ‐2, respectively. There were no significant differences in the cumulative incidences of relapse (CIR, p=0.26) and death (p=0.51) between cohort‐ 1 and ‐2 with CIR of 63% (SE, 4.8%) in cohort‐1 compared to 51% (SE, 6.3%) in cohort‐2. A Cox regression model on overall survival revealed older age (hazard ratio (HR) for a 10 years difference, 1.97, p<0.0001), 2010 European LeukemiaNet (ELN) unfavorable risk (HR, 1.57, p=0.0003) as well as cohort‐1 (HR, 1.31, p=0.02) as unfavorable parameters and ELN favorable risk (HR 0.55, p<0.0001) as favorable prognostic parameter. Survival was inferior (p=0.03) in cohort‐1 with 21% (95%‐CI, 16‐ 28%) compared to cohort‐2 with 28% (95%‐CI, 23‐33%) at 2 years. In an age‐adjusted analysis the molecular marker FLT3‐ITD was associated with an unfavorable prognosis. Conclusions: Although evaluated in a cohort‐ rather than a randomized study, intensification of cytarabine dosage in consolidation therapy seems to improve survival.