High Dose Cytosine Arabinoside (HD-AraC) vs Standard Dose AraC (SD-AraC) during Induction, and Stem Cell Transplantation Followed by IL-2 or No Maintenance in Acute Myelogenous Leukemia (AML): First Report on the AML-12 Phase III Trial of the EORTC-Leukemia Group (LG) and GIMEMA.

The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/m² q 12 hrs for 4 days) in combination with daunorubicin (50 mg/m² for 3 days) and etoposide (50 mg/m² for 5 days) vs SD-AraC (100 mg/m² for 10 days) combined with the same drugs. All patients (pts) who reached complete remission (CR) received one consolidation course consisting of ID-AraC (500 mg/m² q 12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or an autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A second randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by maintenance with low dose IL-2 (4–8 x 10⁶ IU s.c. for 5 days per month) during one year. From 1999 till July 2005, 1359 AML pts (APL excluded), age < 61 years, from 65 centers (23 EORTC-LG and 42 GIMEMA) entered the trial. Currently 1235 pts have been randomized for induction and 355 pts post-consolidation. During the induction course toxicity profiles were similar in the 2 arms; however in the HD-AraC group the incidence of grade 3–4 liver transaminase abnormalities (9% vs 5%) and conjunctivitis (16% vs 1%) was higher, and time to neutrophil and platelet recovery shorter. HD-AraC in the induction cycle had no impact on the organ toxicity during the consolidation course, but the platelet recovery (> 50 x 10⁹/l) was significantly longer (median 4.4 vs 3.1 weeks). The IL-2 schedule was well tolerated in most pts with fatigue (20%), rigor/chills (6.5%), arthralgia/myalgia (4%) as the main grade 3–4 toxicities. Among 613 pts randomized until July 2004 by EORTC centers and 6 large GIMEMA centers, with a median follow-up of 2.2 years, 465 reached CR. Among 428 pts who received a consolidation course, 67 have a CR status still “too early” and 361 were still CR after consolidation: 156 had no donor, 136 had a donor and 69 were too old to be HLA typed. In these 3 groups the present estimates of the transplantation rates are: 60% (auto-SCT), 74% (allo-SCT) and 65% (auto-SCT), respectively. The 2-yr DFS rates (SE%) were 51.8% (4.4%), 66.5% (4.3%), and 52.3% (6.7%), respectively. Among 337 pts with information on cytogenetics, 41 (13%) had good risk, 167 (53%) normal, 70 (22%) other and 39 (12%) poor risk cytogenetics (−5/5q-, −7/7q-, complex). The 2-year EFS (time to no CR, relapse, death) rates (SE%) were 74.2% (5.7%), 43.7% (4.1%), 36.3% (6.2%) and 17.4% (7.1%), respectively.

So far:

1. the toxicity of HD-Ara-C is acceptable in induction of de novo AML pts < 61 years old, but better prevention of conjunctivitis should be stressed;

2. platelet recovery after consolidation is longer in those who received HD-Ara-C in induction;

3. transplantation rates are high after consolidation;

4. IL-2 toxicity is acceptable;

5. pts with a donor have a better outcome,

6. those with good/poor risk cytogenetics have an excellent/poor outcome, respectively.