No Benefit of Adding High-Dose Melphalan (HDM) Suppported by Autologous Stem Cell Transplantation (SCT) over Treatment with Conventional Induction, HD ARAC Consolidation, and Auto SCT (Busulfan + HDM) for Acute Myelogenous Leukemia (AML) under 60: First Results of the Randomized AML 2001 Trial.

From 11/2001 until 04/2005, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were 1^st randomized to received induction with continuous IV ARAC (200 mg/m², x 7d) and Daunorubicin (D: 60 mg/m² x 3d) OR Idarubicin (I: 8 mg/m² x 5d). If marrow blasts > 5% on D15, 2^nd induction course was applied (D: 35 mg/m² x 2d OR I: 8 mg/m² x 2d plus ARAC 1 g/m² x 4 doses over 2d). After achieving CR, all patients received low dose consolidation (D: 60 mg/m² x 2d OR I: 12 mg/m² x 2d plus SC ARAC 100 mg/m² x 7d). Patients with HLA-identical sibling receive a T-replete alloSCT: either conventional (bone marrow graft, TBI-cyclophosphamide, ciclosporin-methotrexate) if age ≤ 50 = arm M; or non myeloablative (NST: peripheral blood, Busulfan (Bu)-Fludarabin-Thymoglobulin^®, ciclosporin alone), AFTER intensive consolidation (idem below) if age 51–60 = arm m. A small subgroup of patients (3 % patients in CR) with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction) did not receive 1^st line alloSCT but intensive consolidation then a 2^nd HD ARAC course; alloSCT was therefore considered for relapse = arm C. Other patients proceed to 2^nd randomization: intensive consolidation (D: 60 mg/m² x 2d OR I: 12 mg/m² x 2d plus ARAC 3 g/m² x 8 doses over 4d) PLUS 1 autoSCT (Bu 16 mg/kg over 4d + HDM 140 mg/m²) = arm A; or intensive consolidation PLUS 2 autoSCT (HDM 200 mg/m² THEN Bu 16 mg/kg over 4d + HDM 140 mg/m²) = arm B.

After 1^st randomization (D vs I), no difference was observed between 2 arms regarding age, leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: D = I 13%), intermediate (D 66%, I 59%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; D 21%, I 28%). Use of both anthracyclins results in same CR rate (D 83% vs I 85%); early death (3%); projected EFS (D 46% vs I 50%, p = 0,28) and OS (D 61% vs I 64%) at 2 years. Noteworthy was the more frequent use of 2^nd induction course to obtain CR with D (30%) as compared with I (22%).

78% of all patients in CR proceeded to 2^nd randomization or were assigned to alloSCT arms (33 % of them). Actual results concern 550 patients with 15 months follow-up. No benefit was observed with addition of HDM 200 for 2y projected DFS (A 53% vs B 49%) or OS (A = B 68%). Toxic death rate was higher in arm B, accounting for 18% total deaths vs 6% in arm A. Conventional alloSCT results in better 2y DFS than combined arms A+B (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06). No significant difference was observed between conventional and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50 : 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). In conclusion:

1. conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1;

2. NST after intensive consolidation seems promising for older patients and may extend use of alternative sources of alloSCT;

3. HDM course adds no benefit for these patients. Data with more than 2 years follow-up will be presented.