Value of Low Dose IL-2 as Maintenance Following Consolidation Treatment or Autologous Transplantation in Acute Myelogenous Leukemia (AML) Patients Aged 15-60 Years Who Reached CR After High Dose (HD-AraC) Vs Standard Dose (SD-AraC) Cytosine Arabinoside During Induction: Results of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups.

Abstract 791

The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m²/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2^nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 10⁶ IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2^nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2^nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age<61 years, were randomized (891 by EORTC-LG and 1114 by GIMEMA) and 104 (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. After 1 or 2 courses of induction, CR was achieved in 1377 patients. Between 4/2000 and 5/2008 550 (230 EORTC, 320 GIMEMA) were randomized for the IL-2 question: 276 in IL-2, 274 Observation (Obs) arm; the remaining patients were not randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The 2 groups were well balanced with respect to the stratification factors, age, sex, WBC counts and history of the disease. Currently, maintenance/observation period has been documented for 144 IL-2 and 144 Obs patients. The patients received a median of 30 s.c. injections (range 3-60) of IL-2. In more than 75% of patients, the mean dose was 6 × 10⁶ IU per injection. Grade 3-4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (4.2% vs 0%), fatigue (9% vs 1.4%), rigor/chills (4.2% vs 0%), arthralgia/myalgia (3.5% vs 0%). A total of 32 patients (22.2%) out of 144 stopped IL-2 prematurely based on patient refusal or medical decision due to toxicity. In the Obs arm, 4 (2.8%) patients out of 144 went off study due to toxicity. Maintenance/observation period has not yet been documented for 132 IL-2 and 130 Obs patients. Among them 28 (21.2%) vs 13 (10%) respectively went off-study due to toxicity of the previous treatment (autoSCT or consolidation), 41 vs 45 due to early relapse, 9 vs 11 due to protocol violation, 9 vs 5 due to other reason. For the total of 550 patients, the median follow-up from the 2^nd randomization was 3.6 years. As of July 2009, a total of 269 DFS events were reported: 132 (IL-2 arm) vs 137 (Obs arm); among them 242 relapses (121 vs 121) and 27 deaths without relapses (11 vs 16). The DFS from 2^nd randomization was similar in the 2 groups: the 3-yr DFS rate was 44.1% (IL-2) vs 42.0% (Obs), hazard ratio (HR)=0.93 (95% CI 0.74-1.19), p=0.57. A total of 106 patients died in each treatment group. The 3-yr overall survival rate was 54.1% (IL-2) vs 55.9% (Obs), HR=1.01 (95% CI 0.77-1.32), p=0.94. The initial treatment received/randomized did not impact the treatment outcome after the 2^nd randomization. This evaluation of the second randomization (IL-2 vs Obs) of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 3.6 years, low dose IL-2 maintenance does not lead to a higher DFS and overall survival.