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Title: 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
Authors: BUYSE, Marc 
Michiels, Stefan
Squifflet, Pierre
Lucchesi, Kathryn J.
Hellstrand, Kristoffer
Brune, Mats L.
Castaigne, Sylvie
Rowe, Jacob M.
Issue Date: 2011
Abstract: Background In 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 Methods Data 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. Results Kaplan-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). Conclusions The 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. ( Identifier: NCT00003991)
Notes: [Buyse, M; Squifflet, P] IDDI, B-1340 Louvain, Belgium [Buyse, M] Hasselt Univ, Ctr Stat, I BioStat, Diepenbeek, Belgium [Michiels, S] Inst Jules Bordet, B-1000 Brussels, Belgium [Lucchesi, KJ] MedVal Sci Informat Serv LLC, Skillman, NJ USA [Hellstrand, K; Brune, ML] Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden [Castaigne, S] Hop Andre Mignot, Le Chesnay, France [Rowe, JM] Rambam Med Ctr, Haifa, Israel [Rowe, JM] Technion Israel Inst Technol, Haifa, Israel
Keywords: leukemia-free survival; overall survival; immunotherapy; statistical analyses; clinical trial interpretation;leukemia-free survival; overall survival; immunotherapy; statistical analyses; clinical trial interpretation
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ISSN: 0390-6078
e-ISSN: ****-****
DOI: 10.3324/haematol.2010.039131
ISI #: 000294722700007
Category: A1
Type: Journal Contribution
Validations: ecoom 2012
Appears in Collections:Research publications

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