title: Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To assess the consistency of treatment benefit across patient subsets and the robustness of data with respect to trial centers and endpoints.
  
  
  METHODS
  Forest 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.
  
  
  RESULTS
  The 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).
  
  
  CONCLUSIONS
  Small sample sizes in some of the subsets analyzed.
  
  
  CONCLUSIONS
  These 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.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00003991.
authors.affiliation: International Drug Development Institute, Department of Biostatistics, Louvain-la-Neuve, Belgium. marc.buyse@iddi.com
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Pierre
authors.initials: P
authors.lastname: Squifflet
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Lucchesi
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: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D005260:Female; D006632:Histamine / Q000008:administration & dosage; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012074:Remission Induction; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007376:Interleukin-2; D006632:Histamine