Post-Consolidation Immunotherapy with Histamine Dihydrochloride and Interleukin-2 in AML: Assessment of Consistency and Robustness of Treatment Benefit for Patients in First Complete Remission.

Background: Data from a randomized multinational trial of 320 adults with 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) for all patients in complete remission (CR) (n=320; hazard ratio [HR]=1.38; P=0.008) and for patients in first CR (CR1; n=261; HR=1.39; P=0.011) over standard-of-care (no treatment) (Brune et al, Blood, 2006). Our objective was to critically assess these trial data to verify:

1. the consistency of treatment benefit across subsets of patients, taking into account the prognostic groups and baseline characteristics;

2. the robustness across study centers and trial endpoints (LFS and overall survival [OS]); and

3. the utility of LFS as a surrogate for OS in AML.

Methods: Forest plots were constructed with HRs of HDC/IL-2 treatment effects versus controls for subsets of CR1 patients based on prospectively defined baseline characteristics: age > or ≤60, gender, treatment initiated at > or ≤6 months from CR to randomization, performance status, white blood cells at diagnosis, Southwest Oncology Group karyotypes, AML subtypes, intensive induction/consolidation with autologous stem cell transplant or high dose cytarabine, extramedullary leukemia, and country. Inconsistency coefficients and interaction tests were used to detect any differences in benefit among subsets. A “leave-one-out” analysis was carried out to assess robustness of the results to the elimination of individual study centers. Correlations were estimated between LFS and OS using a bivariate copula model, and between the HRs for LFS and OS using weighted linear regression.

Results: The benefit of HDC/IL-2 over no treatment was statistically consistent across all subsets of CR1 patients regardless of baseline prognostic variables. Inconsistency coefficients and P-values of interaction tests ranged from 0% to 44% and 0.18 to 0.84, respectively. The treatment effect was robust, with statistical significance in 13 of 33 subsets analyzed. In site-specific leave-one-out analyses, P-values for the treatment benefit ranged from 0.006 to 0.031 (mean 0.013), confirming that no single site dominated the results. With regard to the surrogacy of LFS for OS, LFS and OS were correlated at the individual patient level (Kendall’s τ =0.70). More importantly, at the country level, the HRs for the effects of HDC/IL-2 on LFS and on OS were strongly correlated (R²=0.88).

Conclusions: These analyses confirm the consistency and robustness of the HDC/IL-2 effect over no treatment to prolong LFS in AML patients in CR1. There was no notable heterogeneity in the HDC/IL-2 treatment benefit across baseline characteristics or country. No single study center dominated the effect. In this trial, LFS was found to be a strong surrogate for OS and may be an acceptable surrogate for OS in future AML trials.