Event-Free Survival Is a Surrogate for Overall Survival in Patients Treated for Acute Myeloid Leukemia
Authors: Schlenk Richard F. , Döhner Hartmut , Döhner Konstanze , Ganser Arnold , Heuser Michael , Benner Axel , Buyse Marc E. , Burzykowski Tomasz 
Published: October 2019

Abstract
Purpose: We evaluated whether event-free survival (EFS) can be used as a surrogate for overall survival (OS) in patients treated for acute myeloid leukemia.
Material: We carried out a meta-analysis of individual patient data from four randomized clinical trials carried out under the auspices of the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG): AMLHD 98B (Schlenk et al. Leukemia 2004 18:1798-803; n=254), AMLSG 06-04 (NCT00151255, n=189), AMLSG 07-04 (NCT00151242, n=1,100) and AMLSG 12-09 (NCT01180322, n=268). Some of these trials addressed multiple therapeutic questions, which resulted in a total of 7 independent treatment comparisons.
Methods: A two-level modelling approach was used to estimate the association between EFS and OS, and between the treatment effects on EFS and on OS. At the individual level, a copula was fitted to model the joint distribution of EFS and OS, and Spearman's rank correlation coefficient (rho) was used to quantify the association between the endpoints. At the trial-level, a linear regression was fitted through the estimated treatment effects (Weibull-model-based log hazard ratios) on EFS and OS, taking into account the estimation error. The coefficient of determination (R²) was used to quantify the association between the treatment effects. The surrogate threshold effect (STE) was estimated as the treatment effect on EFS that would predict a significant treatment effect on OS.
Results: A total of n=1,811 patients were included in the analysis. Spearman's correlation coefficient was equal to 0.76 (standard error, SE, 0.015). The coefficient of determination (R²) of the linear regression between log hazard ratios on EFS and on OS was equal to 0.97 (SE 0.13). The intercept of the regression line was equal to -0.04 (SE 0.04) and the slope was equal to 0.80 (SE 0.21). The surrogate threshold effect was equal to 0.90. Using an alternative method of estimation of treatment effects, marginal proportional hazards models for EFS and OS, the R² was equal to 0.98 (SE 0.21), the intercept of the regression line was equal to -0.02 (SE 0.05), the slope was equal to 0.82 (SE 0.28), and the surrogate threshold effect was equal to 0.89. Further results for different subsets of patients, for example, those with activating FLT3 mutations, will be presented at the meeting.
Interpretation: In this population of intensively-treated AML patients, there was a tight association between the treatment effect on EFS and OS, suggesting that the former can be used as a surrogate for the latter in clinical trials assessing the efficacy of new treatments. The surrogate threshold effect of about 0.90 and the regression analysis suggest that a reduction of at least 10% in the risk of an event would reliably predict a reduction of approximately 8% in the risk of death.

Disclosures
Schlenk: Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Teva: Honoraria, Research Funding; AROG: Honoraria, Research Funding; Amgen: Research Funding; Böhringer Ingelheim: Honoraria; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Buyse:IDDI: Employment; Novartis: Research Funding. Burzykowski:IDDI: Employment; Novartis: Research Funding.