Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia

Marc Buyse,Kathryn J Lucchesi,Jacob M Rowe,Pierre Squifflet,Mats L Brune,Sylvie Castaigne

doi:10.1186/1745-6215-12-86

Abstract

BackgroundData from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.PurposeTo assess the consistency of treatment benefit across patient subsets and the robustness of data with respect to trial centers and endpoints.MethodsForest plots were constructed with hazard ratios (HRs) of HDC/IL-2 treatment effects versus no treatment (control) for prospectively defined patient subsets. Inconsistency coefficients (I2) and interaction tests (X2) were used to detect any differences in benefit among subsets. Robustness of results to the elimination of individual study centers was performed using "leave-one-center-out" analyses. Associations between treatment effects on the endpoints were evaluated using weighted linear regression between HRs for LFS and OS estimated within countries.ResultsThe benefit of HDC/IL-2 over controls was statistically consistent across all subsets defined by baseline prognostic variables. I2 and P-values of X2 ranged from 0.00 to 0.51 and 0.14 to 0.91, respectively. Treatment effects were statistically significant in 14 of 28 subsets analyzed. The "leave-one-center-out" analysis confirmed that no single center dominated (P-values ranged from 0.004 to 0.020 [mean 0.009]). The HRs representing the HDC/IL-2 effects on LFS and OS were strongly correlated at the country level (R2 = 0.84).LimitationsSmall sample sizes in some of the subsets analyzed.ConclusionsThese analyses confirm the consistency and robustness of the HDC/IL-2 effect as compared with no treatment. LFS may be an acceptable surrogate for OS in future AML trials. Analyses of consistency and robustness may aid interpretation of data from multicenter trials, especially in populations with rare diseases, when the size of randomized clinical trials is limited.Trial RegistrationClinicalTrials.gov: NCT00003991

Highlights

The results of a clinical trial should not be assessed solely in terms of statistical significance
leukemia-free survival (LFS) may be an acceptable surrogate for overall survival (OS) in future acute myeloid leukemia (AML) trials
If an overall treatment effect is detected in a multicenter trial, what assurance can be made that the effect is not heavily influenced by a single center or very few centers? In a multinational trial, are the efficacy outcomes and the treatment effects on these outcomes broadly comparable between countries? A study of the robustness of the treatment effects with respect to centers, and of the consistency of these effects with respect to countries, can provide assurance that the trial results are broadly representative and, as such, more likely to be generalizable. This paper addresses these issues in the context of a randomized multinational phase 3 trial of histamine dihydrochloride, used in conjunction with low-dose interleukin-2 (HDC/IL-2) as remission maintenance therapy in AML patients [13]

Summary

Introduction

The results of a clinical trial should not be assessed solely in terms of statistical significance In their Statistical Principles for Clinical Trials (ICH E9), the International Conference on Harmonization recommends evaluating “the robustness of the results and primary active therapies are lacking, protection against false positive results with >95% confidence may be too stringent [2]. This point is clearly illustrated by acute myeloid leukemia (AML), a disease with incidence ranging from 2 to 4 per 100,000 persons in Europe and the United States [3]. Data from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.

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