High Dose (HD-AraC) Vs Standard Dose Cytosine Arabinoside (SD-AraC) During Induction and IL-2 Vs Observation After Consolidation/Autologous Stem Cell Transplantation in Patients with Acute Myelogenous Leukemia (AML): Final Report of the AML-12 Trial of EORTC and GIMEMA Leukemia Groups on the Value of Low Dose IL-2 Maintenance,

Abstract 3612

The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) combined with the same drugs, in previously untreated AML < 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm/d for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability 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/d s.c. for 5 days per month) during one year. A total of 577 pts 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 in eligible pts. From 9/1999 till 1/2008, 2005 pts were randomized (891 by EORTC-LG and 1114 by GIMEMA). In addition 104 pts (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. Due to insufficient reporting, 3 centers, who recruited 63 pts, have been excluded from the analysis. After 1 or 2 courses of induction, CR was achieved in 1500 pts. Between 4/2000 and 5/2008 544 pts have been randomized for the IL-2 question, of whom 528 (222 EORTC, 306 GIMEMA) met the eligibility criteria and were included in the analysis: 263 in IL-2, 265 in Observation (Obs) arm; the remaining pts have not been randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The two groups were well balanced with respect to the above mentioned stratification factors. Due to prolonged pancytopenia after auto-SCT, severe organ damage or infection after auto-SCT, early relapse or patient refusal, 165 pts actually received IL-2 and 197 pts were adequately documented in the Obs arm. During the first 4 months 82% of the pts in the IL-2 arm received a mean daily dose of 6 × 10⁶ IU and 62% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (22%) or toxicity (16%). During the second 4 months, out of 103 pts 82% in the IL-2 arm received a mean daily dose of 6 × 10⁶ IU and 76% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (15%), toxicity/refusal (6%) or other reasons (2%). During the third 4 months, among 79 of the pts in the IL-2 arm 80% received a mean daily dose of 6 × 10⁶ IU and 85% of the pts received the maximally required 20 s.c. injections. Grade 3–4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (3% vs 0%), fatigue (7.9% vs 1%), rigor/chills (6.1% vs 0%), arthralgia/myalgia (3.6% vs 0%).

For the total of 528 pts, the median follow-up from the 2^nd randomization was 6 years. As of July 2011, a total of 308 events were reported: 150 (IL-2 arm) vs 158 (Obs arm); among them 277 relapses (137 vs 140) and 31 deaths without relapses (13 vs 18). The DFS from 2^nd randomization was similar in the 2 groups: the 5-yr DFS rate was 44.2% (IL-2) vs 40.4% (Obs), hazard ratio (HR)=0.95, 95% CI (0.76,1.19), p=0.66. A total of 259 pts died: 128 (IL-2 arm) vs 131 (Obs. arm). The 5-yr overall survival rate was 52.2% (IL-2) vs 50.9% (Obs), HR=0.98, 95% CI (0.77,1.26), p=0.9. The initial remission induction treatment (received/randomized) did not have impact on the results after the 2^nd randomization.