Prospective Comparison of Allogeneic Bone Marrow Transplantation, Intensive Consolidation Chemotherapy, and Unpurged Autologous Bone Marrow Transplantation as Post-Remission Therapy in Adult Acute Myeloid Leukemia

Abstract

From November 1987 to April 1994, 522 adult (15-50 years) patients with de novo acute myeloblastic leukemia (AML) were included in the GOELAM 1 protocol comparing allogeneic bone marrow transplantation (BMT), intensive consolidation chemotherapy (ICC) and autologous BMT (ABMT). For induction treatment, patients were randomized to receive a combination of cytosine-arabinoside (ara-C) (200 mg/m2 per day continuous infusion on days 1-7) and either idarubicin (IDR) (8 mg/m2 per day on days 1-5) or rubidazone (RBA) (200 mg/m2 per day on days 1-4). After achievement, of complete remission (CR) an allogeneic BMT was proposed to patients up to the age of 40 with an HLA-identical sibling. Other patients in CR had to receive a first course of ICC (ICC1) with highdose ara-C (3 g/m2 every 12 by 3-h infusion on days 1-4, eight doses) and either IDR (10 mg/m2 per day on days 5-6) or RBZ (200 mg/m2 per day on days 5-6). Bone marrow was collected after ICC1 and cryopreserved without any in vitro manipulation. If the hematopoietic quality of the collected marrow was adequate, patients were then randomly assigned to receive a second course of ICC (ICC2) with m amsacrine (AMSA); (150 mg/m2 per day on days 1-5) and etoposide (VP-16) (100 mg/m2 per day on days 1-5) or an ABMT after a preparative regimen with busulfan (4 mg/kg per day for 4 days) and cyclophosphamide (50 mg/kg per day for 4 days). As of July 1, 1994 490 patients were evaluable and 361 (74%) achieved CR with no significant difference between IDR and RBZ. An allogeneic BMT was planned in 83 cases and was actually performed in 67. Out of the 278 other patients 227 did receive ICC1. The median duration of neutropenia after ICC1 was 19 days and there were nine toxic deaths (4%). A total of 171 patients were randomized between ICC2 (84) and ABMT (87), and 128 have currently been analyzed (61 ICC2, 67 ABMT). The main reasons for exclusion were toxicity, refusal, poor hematologic reconstituion post ICC1, and relapse. With a median follow up of 44 months, the overall survival of the entire cohort of patients is 37% at 6 years (median 22 months) with no difference between the two induction treatment arms. The 4-year disease-free survival (DFS) of the patients in CR who actually received the assigned treatment was 45% for allogeneic BMT, 53% for ICC2, and 47% for ABMT. When considering intention to treat there was no significant difference in DFS between allogeneic BMT and other forms of post-remission therapy or between ICC2 and ABMT. We conclude that (a) a significant improvement of survival can be obtained for patients with de novo AML up 50 years of age with three different modalities of intensive consolidation; (b) the three approaches give comparable results—after ICC1, ICC2 appears to be as effective as unpurged ABMT and is easier to perform; (c) new strategies are needed to reduce the exclusion rate.