Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614)

Abstract

Event-free survival (EFS) is controversial as an end point for speeding approvals in newly diagnosed acute myeloid leukemia (AML). We aimed to examine the robustness of EFS, specifically timing of complete remission (CR) in defining induction failure and impact of hematopoietic cell transplantation (HCT). The study included 1884 untreated AML patients enrolled across 5 trials conducted through Alliance for Clinical Trials in Oncology using anthracycline and cytarabine induction chemotherapy. EFS was defined as time from randomization/registration to induction failure, relapse, or death. Three definitions of induction failure were evaluated: failure to achieve CR by 60 days after randomization/registration, failure to achieve CR by the end of all protocol-defined induction courses, and failure to achieve CR by the end of all protocol-defined treatment. We considered either censoring or no censoring at time of non-protocol-mandated HCT. Although relapse and death are firm end points, the determination of induction failure was not consistent across studies. There was minimal impact of censoring at HCT on EFS estimates; however, median EFS estimates differed considerably based on the timing of CR in defining induction failure, with the magnitude of difference being large enough in most cases to lead to incorrect conclusions about efficacy in a single-arm trial, if the trial definition was not consistent with the definition used for the historical control. Timing of CR should be carefully examined in the historical control data used to guide the design of single-arm trials using EFS as the primary end point. Trials were registered at www.clinicaltrials.gov as #NCT00085124, #NCT00416598, # NCT00651261, #NCT01238211, and #NCT01253070.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Kaplan-Meier (KM) curves of EFS by induction failure definition (fail def) D1 to D3, with and without censoring at HCT. KM curves of EFS in CALGB 10201 (A), CALGB 10503 (B), CALGB 10603 (C), CALGB 10801 (D), and CALGB 11001 (E). Green curves represent EFS estimates (est) by D1 (no CR by 60 days after registration/randomization), blue curves represent EFS estimates by D2 (no CR by the end of all protocol-defined induction courses), and red curves represent EFS estimates by D3 (no CR by the end of all protocol-defined treatment). Solid curves represent EFS analysis with censoring at non–protocol-specified HCT, and dashed curves represent EFS analysis without censoring at HCT.