The Acute Lymphoblastic Leukemia (ALL) Intercontinental-Berlin-Frankfurt-Münster (BFM) 2009 Trial has demonstrated that inclusion of minimal residual disease (MRD) assessment improved risk-based treatment in patients with pediatric ALL and validated the use of a lower dose of methotrexate in patients with precursor B-cell intermediate-risk ALL (pcB-ALL). The findings were published in the Journal of Clinical Oncology.

The investigators examined whether incorporating the assessment of MRD using flow cytometry improved risk stratification and evaluated the impact of early intensification in pediatric ALL. They also evaluated methotrexate doses of 2 versus 5 g/m2 every 2 weeks, 4 times, on survival in intermediate-risk pcB-ALL. The primary endpoint was event-free survival (EFS) and the main secondary endpoint was overall survival (OS).

The study enrolled patients from June 2010 to March 2018. A total of 6187 patients (56.1% male and 43.9% female) younger than 19 years from 13 resource-limited countries were included in the analysis. Most patients were between 1 and <6 years of age (54.6%). Patients at intermediate risk (n=4111) and high risk (n=1452) were randomized to receive the standard early intensification protocol I phase B (IB) or augmented IB regimens. Patients at standard risk (n=624) were assigned to the standard early intensification protocol IB regimen.

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Among all patients, the 5-year EFS and OS rates were 75.2% and 82.6%, respectively. By risk group, the 5-year EFS and OS rates were 90.7% and 94.7% for standard risk, 77.9% and 85.7% for intermediate risk, and 60.8% and 68.4% for high risk, respectively.

The 5-year EFS rates in patients who underwent protocol IB (n=1669) and augmented IB (n=1620) were 73.6% and 72.8%, respectively (P =.55), and 78.8% and 78.9% in patients receiving methotrexate doses of 2 g/m2 (n=1056) and 5 g/m2 (n=1027), respectively (P =.84).

Results for MRD assessed by flow cytometry on day 15 were available for 82.6% of patients. The 5-year EFS and cumulative incidence of relapse rates were 86.6% and 9.9% in patients with MRD levels <0.1% (30.8%), 76.2% and 18.2% in patients with MRD ≥0.1 and <10% (52.8%), and 59.2% and 26.3% in patients with MRD ≥10% (16.4%), respectively (P <.0001 for both). In patients with MRD <0.1%, the 5-year EFS rate was 85.0% for patients in the intermediate-risk group and 79.7% for patients in the intermediate-risk group.

“Early treatment intensification, as tested in this study, is disadvantageous, because it leads to more toxicity and no improvement in the outcomes. In patients with [intermediate-risk] pcB-ALL, the same outcome may be achieved with a lower dose of [methotrexate] than that reported in AEIOP-BFM and other trials, without measuring serum levels, making the treatment less expensive and complex,” the investigators explained in their report.

A limitation noted by the authors was that pegylated and Erwinia asparaginase were not uniformly available, meaning patients with allergies did not always receive complete treatment.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 


Campbell M, Kiss C, Zimmermann M, et al. Childhood acute lymphoblastic leukemia: results of the randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial. J Clin Oncol. Published online May 4, 2023. doi:10.1200/JCO.22.01760