The combination of ATRA and anthracycline based chemotherapy (CT) is established as the reference treatment of newly diagnosed APL. For CT, recent reports have suggested than an anthracycline alone may be as effective as anthracycline-AraC combinations, while being less myelosuppressive. We tried to confirm this hypothesis in a randomized trial.

Patients and methods: In APL 2000 trial (started in July 2000) newly diagnosed APL patients (pts) < 60 years with WBC < 10,000/mm3 were randomized between a standard group A (induction : ATRA 45mg/m2/d until CR with DNR 60 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3 ; first consolidation with the same CT course, second consolidation with DNR 45 mg/m2/dx3 and AraC 1g/m2/12h x4d ; maintenance : intermittent ATRA 15d every 3 months and continuous 6 MP + MTX, during two years) and Group B (same treatment as group A, but without AraC). Other pts were not randomized: pts aged < 60 with WBC > 10,000/mm3 (Group C) received the same treatment as Group A, but with AraC 2 g/m2/12h x4d during the second consolidation course. Pts aged > 60 with WBC < 10,000 (Group D) and >10,000/mm3 (Group E) received the same treatment as Group B and Group A, respectively. All pts with WBC > 10,000/mm3 received intrathecal MTX +AraC for CNS prophylaxis.

Results: the first interim analysis was made at the reference date of September 1st 2003, after inclusion of 300 patients. Overall 289 (96.3 %) patients achieved CR, 9 (3 %) had early death (ED) and 2 had resistant leukemia. 19 patients relapsed, including 15 hematological relapses (Hem Rel) and 4 purely molecular relapses (Mol Rel) (ie treated before Hem rel). The randomized groups (pts < 60 years, WBC < 10,000) i.e. Group A (AraC +, 80 pts) and Group B (AraC -, 87 pts) were well balanced for all pretreatment characteristics. In Group A, 79 patients (98 %) achieved CR and one had early death (ED), as compared to 82 (94 %) CR, 3 ED, and 2 resistant leukemias in Group B (p = NS). The 2 year incidence of relapse, event free survival and survival was 3.8% vs. 11.9% (p = 0.021), 93.6% vs. 83.4% (p = 0.019), and 97.4% vs. 89.9% (p = 0.085) in Group A and B, respectively. Of the 11 relapses in group B, 9 were Hem Rel and 2 were Mol Rel, as compared to 1 and 1, respectively, for the 2 relapses in group A. For non randomized groups, the CR rate, 2 year relapse rate, EFS and survival were 97 %, 2.6%, 88.4%, and 91% for Group C (< 60 years, > 10 000 WBC, n = 70), 98 %, 11%, 79.4%, and 90.3% for Group D (> 60 years < 10 000 WBC, n = 47) and 87 %, 0%, 78.3%, and 78.3% for Group E (> 60 years, > 10 000 WBC, n = 16).

Conclusion: Our results strongly support that, at least with the anthracycline used (DNR at a cumulative dose of 495mg/m2) AraC should not be omitted in consolidation chemotherapy of newly diagnosed APL, even in patients with WBC < 10,000/mm3. The low relapse rate in patients with WBC > 10 000/mm3 supports a role for high dose AraC (1 to 2 g/m2/12h) in this population at higher risk of relapse. Following this first interim analysis, Groups B and D (ie groups without AraC) were closed for inclusion. Updated results will be presented.

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