TY - JOUR
T1 - 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
AU - Buyse, Marc
AU - Michiels, Stefan
AU - Squifflet, Pierre
AU - Lucchesi, Kathryn J.
AU - Hellstrand, Kristoffer
AU - Brune, Mats L.
AU - Castaigne, Sylvie
AU - Rowe, Jacob M.
PY - 2011/8/1
Y1 - 2011/8/1
N2 - 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.
AB - 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.
KW - Clinical trial interpretation
KW - Immunotherapy
KW - Leukemia-free survival
KW - Overall survival
KW - Statistical analyses
UR - http://www.scopus.com/inward/record.url?scp=79961097283&partnerID=8YFLogxK
U2 - 10.3324/haematol.2010.039131
DO - 10.3324/haematol.2010.039131
M3 - Article
C2 - 21546500
AN - SCOPUS:79961097283
SN - 0390-6078
VL - 96
SP - 1106
EP - 1112
JO - Haematologica
JF - Haematologica
IS - 8
ER -