Results of the Randomized I-BFM-SG Trial „Acute Lymphoblastic Leukemia Intercontinental-BFM 2002“ in 5060 Children Diagnosed in 15 Countries on 3 Continents
Authors: Stary Jan , Zimmermann Martin , Campbell Myriam , Castillo Luis , Dibar Eduardo , Donska Svetlana , Gonzalez Alejandro , Izraeli Shai , Janic Dragana , Jazbec Janez , Konja Josip , Kaiserova Emilia , Kowalczyk Jerzy , Kovacs Gabor , Li Chi-Kong , Magyarosy Edina , Popa Alexander , Stark Batia , Jabali Yahia , Trka Jan , Hrusak Ondrej , Janotova Iveta , Riehm Hansjörg , Masera Giuseppe , Schrappe Martin 
Published: October 2019

Abstract
Abstract 872

Introduction:
ALL IC-BFM 2002 is one of the most successful projects developed by the I-BFM-SG, which is one of the world largest societies involving national leukemia groups. The trial evaluated in a randomized manner the impact on outcome of intensified late reinduction in the context of a newly developed risk stratification. The main goal of the trial was improvement of outcome of children with ALL in each of the 3 risk groups (RG).

Patients & methods:
From Nov 2002-Nov 2007, 5060 eligible pts aged 0–18 yrs with newly diagnosed ALL from Argentina (1270), Chile (558), Croatia (122), Cuba (151), Czech Republic (291), Hong Kong (155), Hungary (259), Israel (292), Poland (908), Serbia (266), Slovakia (137), Slovenia (36), Ukraine (421), Uruguay (96), and Moscow (98) were enrolled in the trial (http:clinicaltrials.gov “NCT00764907”). Stratification into 3 RGs was based on early treatment response (evaluated in PB on day 8 and in BM on days 15 and 33), age, initial WBC, and presence/absence of BCR/ABL or MLL/AF4. Standard Risk (SR) criteria were: < 1,000 blasts/μL in PB day 8 after 7 days of oral prednisone with 1 intrathecal methotrexate (IT-MTX) and age ≥ 1 yr and < 6 yr and initial WBC < 20,000/μL and M1 or M2 marrow on day 15 and M1 marrow on day 33 (all criteria must be fulfilled). Intermediate Risk (IR) criteria were: < 1,000 blasts/μL in PB day 8 and age < 1 yr or ≥ 6 yr and/or WBC ≥ 20,000/μL and M1 or M2 marrow on day 15 and M1 marrow on day 33 (or SR criteria but M3 marrow on day 15 and M1 marrow on day 33). High Risk (HR) criteria were: IR and M3 marrow on day 15, PB on day 8 ≥ 1,000 blasts/μL, M2 or M3 marrow on day 33, translocation t(9;22) [BCR/ABL] or t(4;11) [MLL/AF4] (at least one criterion must be fulfilled). The majority of infants < 1 yr were treated in studies Interfant 99 and Interfant 06. Treatment consisted of protocol I‘/I, SR/IR consolidation with 6-MP and MD MTX 2g/m2 × 4 (with additional IT-MTX in maintenance) for BCP-ALL, 6-MP and HD MTX 5g/m2 × 4 for T-ALL, HR consolidation with 3 HR polychemotherapy blocks. A randomized question was asked in late intensification: SR: would 2 shorter elements (protocol III × 2) be more effective than 1 longer (protocol II × 1) even though the cumulative dose of most drugs is not increased? IR: could the risk of failure be reduced by a third reintensification element (protocol III × 3)? HR: could the use of 3 reintensification elements (protocol III × 3) achieve the same or better results than the HR approach applied in BFM (3 HR blocks + protocol II × 1) or AIEOP (protocol II × 2)? Chemotherapy was concluded by maintenance therapy (6-MP/MTX), making up a total of 2 yrs overall treatment. Prophylactic CNS radiotherapy 12 Gy was applied in T-ALL and HR pts.

Results:
With median follow-up 4.9 yr, the 5-yr EFS was 74 ± 1% and 5-yr OS 82 ± 1% for the whole group of 5060 pts. The CR rate was 97%, 255 (5%) children died in remission. The 5-yr EFS/OS was 81 ± 1%/90 ± 1% in 1564 SR pts (30.9% of all pts), 75 ± 1%/83 ± 1% in 2650 IR pts (52.4%) and 55 ± 2%/62 ± 2% in 846 HR pts (16.7%). Randomization rate was 79% of those patients who survived for at least 20 weeks (planned timepoint of randomization). None of the experimental arms achieved significantly better EFS compared to standard treatment.
CI of relapses at 5 yr was 18 ± 1% overall, CI for isolated BM relapse was 12 ± 1%, isolated and combined CNS relapse 4 ± 0.3%, isolated and combined testicular relapse 2 ± 0.2%. Secondary malignancy was diagnosed so far in 26 patients (5-yr CI 0.6 ± 0.1%). Significantly better EFS was achieved in BCP-ALL(75 ± 1%) in comparison with T-ALL (69 ± 1%), girls vs. boys (76 ± 1% vs 72 ± 1%), children aged < 10 yr vs ≥ 10 yr (77 ± 1% vs 65 ± 1%), M1/M2 BM D15 vs. M3(76 ± 1% vs 50 ± 3%). 140 pts with Ph+ALL achieved a EFS of 47 ± 4% Allogeneic HSCT in CR1 was done in 139 pts with 5 -yr DFS of 64 ± 4%.

Conclusions:
Although the experimental arm was no better than the traditional one across individual RGs, the majority of participating countries, many of them were new-comers to this intensive therapy, improved their treatment results against previous national studies. The trial confirmed the validity and feasibility of a simple risk stratification of ALL applied in a complex and heterogeneous multinational environment. Despite the great differences between individual countries, the trial set a firm stage for willing national leukemia groups to run collaborative clinical trials in ALL under the umbrella of I-BFM-SG.
Supported by MSM0021620813 and MZ0FNM2005.

Disclosures:
No relevant conflicts of interest to declare.