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More relapses with reduced intensity delayed intensification in standard-risk children with acute lymphoblastic leukemia

Results of the large international AIEOP-BFM-ALL 2000 study in childhood acute lymphoblastic leukemia (ALL) patients with a favourable prognosis (i.e. a complete minimal residual disease [MRD] response by day 33), demonstrated that an attempt to reduce the burden of chemotherapy by lower intensity delayed intensification, resulted in a higher rate of relapses. In fact, in this study, the 4-year disease free survival (DFS) and the 4-year cumulative incidence of relapse (CIR) were shown to be inferior when the less intensive BFM protocol III was used instead of the traditional BFM protocol II.1

The AIEOP-BFM-ALL 2000 study enrolled 4,741 ALL patients, aged 1 to 17 years. In total, the 1,164 patients with the best treatment response and the lowest risk of relapse were randomised between a treatment with protocol III (P-III) (N=584) or standard protocol II (P-II) (N=579). The aim of this delayed re-intensification was to reduce the treatment burden. Compared to the standard BFM P-II, P-III is shorter (duration 29 vs. 49 days) and includes a 30% lower dose of dexamethasone and a 50% lower dose of vincristine, doxorubicin, and cyclophosphamide. The study was designed to demonstrate non-inferiority of the reduced intensity treatment as compared to standard treatment.1

Only patients who were defined as MRD standard risk, defined as being MRD negative at both days 33 and 78 after the start of induction therapy, were eligible for the randomisation. The main analysis was planned as a per protocol analysis of the 4-year disease free survival. With a median follow-up of 8.6 years, the 4-year DFS rate was shown to be 91.8% with P-III as compared to 95.8% for patients who received P-II (log-rank p=0.04). The lower limit of the one-sided 95% confidence interval for the DFS rates was -6.4%, which is far below the pre-defined non-inferiority range of -4%, (p-value on difference of the 4-year DFS estimates: 0.005). The 4-year CIR rate was 6.3% with P-III and 3.2% for P-II (Gray p=0.09). After 8 years, the DFS rates were 89.2% and 92.3% for P-III and P-II, respectively. The 8-year CIR rates were shown to be 8.7% with P-III and 6.4% with P-II. The 8-year overall survival (OS) was 96.1% in the P-III arm and 98.0% in the group of patients treated with P-II. Finally, the 8-year cumulative incidence of secondary malignancies was 1.3% and 0.6% for patients who received P-III and P-II, respectively. An intent-to-treat analysis revealed almost identical results.1

There were no major differences of the treatment effect in clinical and biological subgroups and in the subgroups of the two induction regimens (DEXA vs. PRED), with the exception of age at diagnosis. For patients below 10 years of age, the 4-year DFS rate was 90.7% if treated with P-III compared to 92.5% with P-II (p=0.26). For patients who were 10 years of age or older, the 4-year DFS rate was 81.6% with P-III compared to 90.3% with P-II (p=0.04). The pattern of relapse was similar after P-III and P-II. The incidence of death in remission was also comparable at 0.9% for P-III and 0.7% with P-II. The rate of grade 3/4 infections, which was used as an indicator for relevant toxicity, was essentially the same in P-III and P-II.1

In conclusion, in children with ALL who achieved an early complete MRD response, an attempt to reduce the burden of chemotherapy by lower intensity delayed intensification was not successful. In fact, this study demonstrated more relapses in patients treated less intensively. Interestingly, the 5-year DFS and CIR rates reported in this study were almost identical to what was previously reported in the DCOG 11 study (93% and 6% respectively). Based on these findings, the DCOG authors considered the result of their non-randomised study sufficient to prove that therapy reduction is safe and feasible in MRD-negative ALL patients.2


  1. Schrappe M, Zimmermann M, Möricke A, et al. Reduced Intensity Delayed Intensification in Standard-Risk Patients Defined By Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: Results of an International Randomized Trial in 1164 Patients (Trial AIEOP-BFM ALL 2000). Presented at ASH 2016; Abstract 4.
  2. Pieters R, de Groot-Kruseman H, Van der Velden V, et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 2016;34:2591-601.

Speaker Martin Schrappe


Martin Schrappe, MD,
Department of General Paediatrics, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Centre Schleswig-Holstein, Kiel, Germany


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