Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission

Abstract

BackgroundIn trials designed to evaluate new therapies for hematologic malignancies, end points such as leukemia-free survival are often used as surrogates for overall survival in acute leukemia. We aimed to assess whether leukemia-free survival is an acceptable statistical surrogate for overall survival when applied to remission maintenance therapy for acute myeloid leukemia. Design and MethodsData were analyzed from a randomized Phase III trial of remission maintenance immunotherapy with histamine dihydrochloride plus low-dose interleukin-2 versus no treatment in adults with acute myeloid leukemia. A two-stage surrogate validation model was applied in which correlations between Kaplan-Meier estimates of leukemia-free survival and overall survival, and between log hazard ratios reflecting treatment effects were analyzed. Country of patient enrollment was the unit of analysis. ResultsKaplan-Meier estimates of overall survival at 36, 48, and 60 months and leukemia-free survival at 24 months were reasonably correlated (R 2 ranging from 0.44 to 0.84) both for the overall (n=320) and first complete remission (n=261) populations. The effects of histamine dihydrochloride/interleukin-2 on log hazard ratios for leukemia-free survival and overall survival were well correlated (R 2 =0.88-0.93). ConclusionsThe significant correlations between overall survival and the surrogate end point (leukemia-free survival) and between the effect of histamine dihydrochloride/interleukin-2 on leukemia-free survival and overall survival satisfy the two-stage surrogate validation model.

Mixed-phenotype acute leukemia: suboptimal treatment when the 2008/2016 WHO classification is used

“…CR was assessed according to the criteria proposed by Cheson et al [12]. DFS was defined as the interval between CR and relapse, while OS was defined as the length of time from the date of diagnosis to the last follow-up or date of death from any cause [1314]. …”

Center-within-trial versus trial-level evaluation of surrogate endpoints

“…Published examples estimating trial-level surrogacy using trial sub-units for analysis include: evaluation of time to progression and progression-free survival as surrogates for overall survival in advanced ovarian cancer, where centers within trials are treated as the trial unit (Buyse et al, 2000; Burzykowski et al, 2001; Molenberghs et al, 2002; Tibaldi et al, 2003; Burzykowski and Buyse, 2006); change in visual acuity at 6 months after treatment as a surrogate for change in visual acuity at 12 months in age-related macular degeneration, where centers are treated as trial units (Buyse et al, 2000; Molenberghs, Geys, and Buyse, 2001; Molenberghs et al, 2002; Tibaldi et al, 2003; Alonso et al, 2004, 2006; Pryseley et al, 2007; Abrahantes, Shkedy, and Molenberghs, 2008; Molenberghs et al, 2008); progression-free survival as a surrogate for overall survival in advanced colorectal cancer, with centers as trial units (Burzykowski et al, 2001; Molenberghs et al, 2002; Tibaldi et al, 2003; Burzykowski and Buyse, 2006; Abrahantes, Shkedy, and Molenberghs, 2008); outcomes of the Positive and Negative Syndrome Scale (PANSS) as a surrogates for the Clinician’s Global Impression (CGI) scale in schizophrenia, where treating physicians, main investigators, or countries were considered as trial-level replicates (Molenberghs et al, 2002; Renard et al, 2002; Alonso et al, 2002, 2003, 2004b, 2006; Tilahun et al, 2007; Alonso and Molenberghs, 2007; Abrahantes, Shkedy, and Molenberghs, 2008; Molenberghs et al, 2008, 2010); prostate specific antigen (PSA) as a surrogate for overall survival in advanced prostate cancer, where country was used as the trial unit (Renard et al, 2003; Molenberghs et al, 2004); recurrence-free survival as a surrogate for overall survival in colon cancer, with grouped centers treated as the trial unit(Sertdemir and Burgut, 2009); leukemia-free survival as a surrogate for overall survival in maintenance therapy trials for patients with acute myeloid leukemia in complete remission, where countries within a single trial were treated similarly to trials Buyse et al (2011); pathologic complete response and local control as surrogates for overall survival in advanced rectal cancer, where grouped centers were treated as trial units Bonnetain et al (2012);and progression-free survival as a surrogate for overall survival in advanced non-small-cell lung cancer, where centers within trials was the unit of assessment of trial-level surrogacy Laporte et al (2013).…”

Current Knowledge and Perspectives on Histamine H1and H2Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

“…By inhibiting ROS production, H 2 R ligands allow agents that stimulate the immune system (e.g., interleukin-2) to effectively activate cytotoxic cells, improving tumor cell death (Hellstrand, 2002). As a result, combined histamine and interleukin-2 postremission therapy was shown to significantly prevent AML relapse (Buyse et al, 2011;Aurelius et al, 2012). …”