Francis Witz

Autologous stem cell transplantation in adults with acute lymphoblastic leukemia in first complete remission: analysis of the LALA-85, -87 and -94 trials

To evaluate the results of autologous stem cell transplantation (ASCT) in a large population of adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR), we performed an individual data-based overview of the last three trials from the LALA group. Overall, 349 patients with ALL prospectively randomized in the consecutive LALA-85, -87, and -94 trials to receive either ASCT or chemotherapy as post-CR treatment were analyzed. Eligibility criteria were 15–50-year-old patients without sibling donors in both LALA-85/87 trials and 15–55-year-old patients with high-risk ALL and no sibling donors in the LALA-94 trial. Intent-to-treat analysis, which compared 175 patients from the ASCT arm to 174 patients from the chemotherapy arm, showed that ASCT was associated with a lower cumulative incidence of relapse (66 vs 78% at 10 years; P=0.05), without significant gain in disease-free or overall survival. Despite a possible lack of statistical power, a nested case–control analysis performed in 85 patient pairs adjusted for time to transplant and prognostic covariates confirmed these intent-to-treat results in patients actually transplanted. Of interest, the reduced relapse risk after ASCT translated in better disease-free survival in the 300 rapid responders who reached CR after the first induction course.

Successful treatment of adult acute lymphoblastic leukemia after relapse with prednisone, intermediate-dose cytarabine,mitoxantrone, and etoposide (PAME) chemotherapy

Thirty‐nine patients with relapsed acute lymphoblastic leukemia (ALL) and four with primarily refractory ALL were treated with a regimen that included cytarabine 1 gm/m2 (2‐hour infusion) twice daily days 1 to 5, mitoxantrone 12 mg/m2 daily days 1 to 5, prednisone 0.5 mg/kg daily days 1 to 5, and etoposide 200 mg/m2/day daily days 6 to 8. Of the 43 patients, 30 achieved a complete remission (CR), 28 out of the 39 relapsed patients and two among the four with refractory disease. Five patients died in aplasia. Eight patients were nonresponders. Nonhematologic side effects consisted predominantly of nausea, vomiting, and mucositis. One patient had transient cerebellar dysfunction. Recovery of blood counts occurred at a median of 24 days. The median time to CR was 38 days. As this regimen is highly effective in relapsed or refractory ALL, its use during earlier stage of the disease is warranted.

Comparison of Chemotherapy and Autologous and Allogeneic Transplantation as Postinduction Regimen in Adult Acute Lymphoblastic Leukemia: a Preliminary Multicentric Study

The results of chemotherapy in adults with acute lymphoblastic leukemia (ALL) have improved in recent years but have lagged behind those in children with ALL [1, 2]. The overall probability of achieving complete remission (CR) exceeds 75%, and it now appears that approximately 35% of patients achieving CR can be cured using chemotherapy alone [2, 3]. It is therefore appropriate to study alternative forms of treatment such as allogeneic or autologous bone marrow transplantation (BMT) in adult ALL.

Treatment of Adult Acute Lymphoblastic Leukemia. Preliminary Results of a Trial from the French Group

We present here the results of a cooperative trial in 244 adult patients with acute lymphoblastic leukemia. Induction therapy with vincristine, cytoxan, and prednisone (VCP) gave the same complete remission rate after one course as more aggressive induction with vincristine, rubidazone, araC, and prednisone (VRAP) due to increased toxic death in the aggressive arm. Because of high efficacy of salvage therapy with VRAP regimen in patients failing to achieve CR with VCP regimen, patients initially randomized to receive VCP had a significantly higher CR rate than patients initially receiving VRAP (87% vs. 73%, p = 0.01). Patients randomized to receive postremission consolidation using adriamycin, araC, and asparaginase (AAA) prior to maintenance had a significantly longer remission than patients not receiving consolidation (p less than 0.005). At the time of analysis allogeneic bone marrow transplantation does not significantly increase disease-free survival when compared with intensive consolidation chemotherapy.

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

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.