Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL): A Comparison between French -Belgian-Swiss and Spanish Results.

Abstract

ATRA combined to anthracycline based chemotherapy is the reference treatment of newly diagnosed APL and a role for maintenance treatment is supported by many studies, but some controversies remain, like the role of AraC. Methods: We performed a joint analysis of pts < 65 yrs included in studies LPA99 (Spanish PETHEMA) and APL 2000 (French -Belgian-Swiss APL group) to address some of those issues. In LPA99, pts received ATRA combined to Idarubicin (IDA) for induction, followed by 3 consolidation courses, 2 with IDA and 1 with mitoxantrone (MTZ, at cumulative dose of 50 mg/m2), and maintenance with intermittent ATRA and continuous 6MP + MTX during 2 years. Pts with high (WBC > 10000/mm3) and intermediate (WBC < 10000/mm3, platelets < 40000/mm3) Sanz score also received ATRA during consolidation courses and higher cumulative dose of IDA (100 mg/m2), vs low risk pts (no consolidation ATRA, cumulative IDA: 80 mg/m2). No AraC was administered in LPA99 trial. For APL 2000, we restricted the analysis to treatment groups that received AraC: pts with low or intermediate Sanz score received induction with ATRA and DNR (60 mg/m2/d x 3) + AraC (200 mg/m2/d x 7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d x 3) + AraC (1 g/m2/12h x 8) course and the same maintenance as in LPA99. High risk patients received the same treatment, but with intrathecal CNS prophylaxis and, in pts < 60 years, AraC 2g/m2/12h x 8 during the last course. Median follow up was 30 and 22 months in LPA99 (412 pts) and APL 2000 (180 pts), respectively. Comparisons were adjusted on age, gender, WBC and platelet counts. Results: In low and intermediate risk patients (308 LPA99 pts, 97 APL 2000 pts), the CR rates, 2 year cumulative incidence of relapse (CIR), EFS and survival were 96% and 99% (p = 0.2), 2.5% and 6.9% (p = 0.05), 93% and 91% (p = 0.6), 95% and 97% (p = 0.3) in LPA99 and APL 2000 trials, respectively. In high risk patients (104 LPA99 pts, 83 APL 2000 pts), the CR rate, 2 year CIR, EFS and survival were 84% and 95% (p = 0.02), 16.0% and 3.3% (p = 0.06), 69.2% and 88.0% (p = 0.01), 82.4% and 91.2% (p = 0.04) in LPA 99 and APL 2000, respectively. Four relapses in high risk pts involved the CNS in LPA99, vs. none in APL 2000. Three and 5 pts in LPA99 and APL 2000 respectively, died in CR, from treatment toxicity. Conclusion: This analysis suggests than in pts with WBC < 10000/mm3, the current PETHEMA approach yields even fewer relapses than a classical ATRA + DNR + AraC regimen, while being less myelosuppressive. This may be due to the anthracyclines used (IDA and MTZ instead of DNR) and/or to the higher cumulative dose of anthracyclines used in LPA99 trial, and possibly also to consolidation ATRA for intermediate risk pts. On the other hand, in pts with high WBC counts, APL 2000 results yielded better EFS and survival and a strong trend for fewer relapses (including relapses involving the CNS), suggesting a beneficial role for AraC, possibly at high dose, in this subset of patients