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.
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.
  
  
  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.
authors.affiliation: International Drug Development Institute, 30 Avenue Provinciale, Louvain-la-Neuve, Belgium. marc.buyse@iddi.com
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Pierre
authors.initials: P
authors.lastname: Squifflet
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Lucchesi
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Hellstrand
authors.forename: Mats L
authors.initials: ML
authors.lastname: Brune
authors.forename: Sylvie
authors.initials: S
authors.lastname: Castaigne
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers; D018572:Disease-Free Survival; D006632:Histamine / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D060046:Maintenance Chemotherapy; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007376:Interleukin-2; D006632:Histamine