From December 2000 to June 2010, 1201 children with SR-BCP-ALL (age: 1-9 years, WBC<50 G/L, CNS-, noMLL rearrangement, no BCR-ABL, no Down syndrome) were included in the FRALLE 2000-A multicenter protocol. At a MFU of 60 months, 1195 patients are evaluable. An ETV6-RUNX1 fusion transcript was documented in 28% of the pts (329 out of 1173 evaluable pts). Induction regimen: prednisone prephase +IT MTX, dexamethasone (DEX) 6 mg/m2/d, vincristine (VCR), native E.coli L-asparaginase ASPA: 6000 IU/m2x 9 infusions). Response was assessed at D8 (blood, good if < 1000 blasts/mm3), D21 (bone marrow morphology, good if less than 5% blasts, so-called M1) and end of induction D35 (bone marrow morphology and DNA-based PCR for Ig/TCR rearrangements MRD). A D21 M1 marrow was observed in 1132 pts (94.7%). Out of these, 1128 pts were randomized to receive daunorubicin (DNR; 40 mg/m2 at D22 and D29) [560 DNR(+) pts] or not [568 DNR(-) pts]. Pts with D21 M2/M3 marrow (n= 61; 5%) were not randomized and received two infusions of DNR. Two pts died before D21. Pts with D21 M1 marrow (A1 group) received after induction a 12 week-consolidation based on VCR, DEX, mercaptopurine (6-MP) and oral methotrexate (MTX), followed by a 1st delayed intensification (reduced “Protocol II”, including a total of 75 mg/m2 of doxorubicin), an interphase therapy (VCR, DEX, 6-MP, MTX), and a triple drug only-2nd delayed intensification (DI°2) (VCR, MTX 100 mg/m2, ASPA 20000 IU/m2; 4 cycles). A 24-month maintenance was then applied, including 12 VCR-DEX pulses the first year. A total of 18 intrathecal injections of MTX was given. Only the rare patients with D21 M3 marrow and/or EOI MRD level ≥1% (n= 47, 4%)(A3 group) received an intensified treatment after CR with 3 block-consolidation, intensified interphase with 6 cycles of MTX 5 g/m2  and a second DI (“reduced protocol II”). No pt received CNS irradiation.
 

       Results:
 

       1. Overall efficacy:  no leukemic induction failure was observed; 4 induction deaths (0.3%) occurred leading to a 99.7% CR rate. Only 30 out 1097 evaluable pts (2.7%) had a decisional EOI MRD ≥ 1%. Eighty-two relapses have been observed (BM: 47, CNS+: 24, BM+CNS: 9, testis: 2). For the whole population 5-year EFS is 91.5% (95%CI: 89.8-93.3), 5-year OS is 97.4% (95%CI: 96.4-98.4). 5-yr EFS and OS for the A1 and A3 groups are 93.1% vs. 61.2% (p<0.0001), and 98.3% vs. 84.2% respectively (p<0.0001). Five-year DFS of the 30 pts with MRD ≥1% is 58.8% (95%CI: 41.7-82.8). Five-year EFS of the children with ETV6-RUNX1 fusion transcript is 96.6% (95%CI: 94.4-98.8).
 

       2. Overall toxicity: 5 non leukemic deaths have been observed after CR (0.4%). Other main toxicities were attributable to ASPA (CNS thrombosis: 1.5%, grade 3-4 pancreatitis: 0.8%, allergic reaction-all grades- during DI °2: 70%). Six cases of secondary neoplasms were observed (AML: 5 pts, astrocytoma: 1 pt).
 

       3. Randomization: 5y EFS and OS from randomization was 92.9% and 97.2% for D21 M1 pts DNR(+) versus 93.3% and 98.2% for D21 M1 DNR(-) pts (p= 0.89 and p= 0.85, respectively). Interestingly EOI MRD levels in the two arms were not different at the sensitivity cut-off of 10-2 (p=0.93) or 10-3(p= 0.74).
 

       4. Prognostic factors: for the whole population, age < 6 years, WBC < 20.000/mm3, ETV6-RUNX1 positivity, as well as D21 marrow M1 and EOI MRD levels of 10-2 and 10-3 were all associated to EFS in univariate analysis. In multivariate analysis remain only WBC < 20.000/mm3 (p=.001), ETV6-RUNX1 positivity (p=.02), EOI MRD levels ≤ 10-3 (p=1.4x10-5). Considering only randomized pts (D21M1 pts) age <6 (p=.004), WBC < 20.000/mm3 (p=.04), ETV6-RUNX1 positivity (p=.01), EOI MRD levels ≤ 10-3(p=.002) remain as independent prognostic factors in multivariate analysis.
 

       Conclusions:
 

       Very good results were obtained with this VCR-DEX-ASPA oriented protocol. SR-BCP ALL pts which represents around 55 % of all children with ALL can be cured with a modest dose of anthracyclin (75 mg/m2). A further decrease in therapy based on the identified prognostic factors could be proposed. Intensification of the chemotherapy for the rare SR pts with a very high MRD has salvaged half of these pts but the addition of new drugs and/or HSCT is now to be evaluated.

Disclosures: No relevant conflicts of interest to declare.