Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): Toxicity and Efficacy Interim Results of the FRALLE 2000-A Protocol.

From December 2000 to May 2004, 433 children with SR-BCP-ALL (age: 1–9, WBC<50 G/L, CNS-, no MLL-R, no BCR-ABL) were included in the FRALLE 2000 -A multicenter protocol. 367 pts are evaluable at point date. Induction regimen consisted in prednisone prephase for 7 days (60 mg/m2/d) + IT MTX, dexamethasone 6 mg/m2 (D8–D28), vincristine 1.5mg/m2(D8, D15, D22, D29), L-asparaginase 6000 U/m2 (9 infusions). Good marrow responders at D21(M1: 346 pts) were randomized to receive or not daunorubicin (DNR) 40 mg /m2 at D22 and D29. D21 M2/M3 pts (n= 19) were not randomized and given DNR. Two pts died before D21. A 12 week-consolidation with VCR (2 monthly), DEX pulses and 6 MP/mtx was followed by a 1st delayed intensification (CCG mode for the first month then VP16-AraC-Lanvis instead of cyclophosphamide Ara-C),and interphase therapy with VCR (1 monthly, Dex pulses and 6 MP/mtx). A 2nd delayed intensification (DI°2) (modified Capizzi: VCR, MTX 100 mg/m2, ASPA; every 10 days for 4 cycles) was followed by maintenance(total duration 24 months) with 12 VCR DEX pulses during the first year. MRD at end of induction (EOI) was determined by DNA-based PCR for Ig/TCR rearrangements leading to intensification of consolidation therapy (3 blocks) and heavier DI°2 for bad reponders (MRD level > 1%).

RESULTS: 1. Efficacy : no leukemic induction failure and a low incidence of patients with D21 M2/M3 marrow have been observed (5 % versus 13% in the FRALLE 93 for the same population). Only 4 out 319 evaluable pts (1.3%) have a high EOI MRD (≥ 1%) at the end of induction therapy. Five relapses have only been observed yet even if MFU is still short (31 months). 2.Toxicity: Seven cases of non leukemic deaths have been observed. Main grade III-IV toxicities were attributable to L-Aspa (CNS thrombosis: 5pts, pancreatitis: 8 cases, allergic reaction during DI °2: 35 pts). One case of secondary AML was observed (UPN98: no DNR) (25 months of CR) with translocation t(9;11) and MLL rearrangement. 3.Randomization: at this FU no difference between the DNR+ and DNR- arms is obvious neither in terms of toxicity nor efficacy.

CONCLUSIONS: Most of the initial unusual toxicities mentioned where related to asparaginase even if potentially increased by the use of DEX during induction. Since most of the pancreatitis or CNS thrombosis episodes have been reported before July 2002, a potential hypothesis on the variation in the batches of the E.Coli asparaginase used in France can be made beside the classical ones (learning effect ....). Efficacy results, although preliminary, are very encouraging since at the same MFU 4 times more relapses (20 out of 410 pts) were observed in the FRALLE 93 for a comparable population.