Augmented Early Intensification and Higher Consolidation Methotrexate Dosing Show No Benefit in Childhood ALL

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Results of the Intercontinental-Berlin-Frankfurt-Münster 2009 trial in childhood acute lymphoblastic leukemia (ALL) were reported in the Journal of Clinical Oncology by Campbell et al. Findings included no benefit of augmented early intensification in intermediate-risk or high-risk patients and no benefit of a higher dose of consolidation methotrexate in patients with intermediate-risk precursor B-cell ALL.  

As stated by the investigators, “The International Berlin-Frankfurt-Münster study group conducted a study on pediatric ALL. [Measurable] residual disease (MRD) was assessed using flow cytometry, and the impact of early intensification and methotrexate dose on survival was evaluated.”

Study Details

The study included 6,187 patients aged younger than 19 years. MRD by flow cytometry refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, white blood cell count, unfavorable genetic aberrations, and treatment response measured morphologically. In open-label fashion, intermediate-risk and high-risk groups were randomly assigned to receive standard early intensification protocol I phase B (IB; cyclophosphamide, cytarabine, mercaptopurine, and methotrexate) or an augmented IB regimen (cyclophosphamide, cytarabine, mercaptopurine, methotrexate, vincristine, and L-asparaginase) during induction. Patients with intermediate-risk precursor B-cell ALL were randomly assigned to methotrexate at 2 or 5 g/m2 during consolidation.  

Key Findings

Among all patients, 5-year event-free survival and overall survival were 75.2% and 82.6%, including 90.7% and 94.7% in the standard-risk group (n = 624), 77.9% and 85.7% in the intermediate-risk group (n = 4,111), and 60.8% and 68.4% in the high-risk group (n = 1,452).

MRD by flow cytometry was available for 82.6% of patients. Event-free survival at 5 years was 86.6% in patients with MRD levels < 0.1% (30.8% of patients), 76.2% among those with MRD between ≥ 0.1% and < 10% (52.8%), and 59.2% among those with MRD ≥ 10% (16.4%). Event-free survival at 5 years among patients in the intermediate-risk and high-risk groups with MRD < 0.1% was 85.0% and 79.6%, respectively.

Among 1,699 intermediate-risk and high-risk patients receiving the standard IB regimen vs 1,620 receiving the augmented IB regimen, 5-year event-free survival was 73.6% vs 72.8% (P = .55). Among 1,056 patients with intermediate-risk precursor B-cell ALL who received methotrexate at 2 g/m2 vs 1,027 receiving methotrexate at 5 g/m2, 5-year event-free survival was 78.8% vs 78.9% (P = .84).

The investigators concluded, “The MRDs were successfully assessed using flow cytometry. A methotrexate dose of 2 g/m2 was effective in preventing relapse in non­–high-risk precursor B-cell ALL. Augmented IB showed no advantages over the standard IB.”

Myriam Campbell, MD, PhD, of Hospital Roberto del Rio, Universidad de Chile, Chilean National Pediatric Oncology Group, Santiago, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by a University Medical Center Ljubljana Research Grant (Slovenia), Foundation from Children with Leukemia (Hungary), Hellenic Society of Pediatric Hematology-Oncology, National Pediatric Cancer Program (Chile), and others. For full disclosures of the study authors, visit

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