Prognostic significance of minimal residual disease in high risk B-ALL: A report from Children's Oncology Group study AALL0232

Michael J. Borowitz, Brent L. Wood, Meenakshi Devidas, Mignon L. Loh, Elizabeth A. Raetz, Wanda L. Salzer, James B. Nachman, Andrew J. Carroll, Nyla A. Heerema, Julie M. Gastier-Foster, Cheryl L. Willman, Yunfeng Dai, Naomi J. Winick, Stephen P. Hunger, William L. Carroll, Eric Larsen

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124 Scopus citations

Abstract

Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 x 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

Original languageEnglish (US)
Pages (from-to)964-971
Number of pages8
JournalBlood
Volume126
Issue number8
DOIs
StatePublished - Aug 20 2015

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Borowitz, M. J., Wood, B. L., Devidas, M., Loh, M. L., Raetz, E. A., Salzer, W. L., Nachman, J. B., Carroll, A. J., Heerema, N. A., Gastier-Foster, J. M., Willman, C. L., Dai, Y., Winick, N. J., Hunger, S. P., Carroll, W. L., & Larsen, E. (2015). Prognostic significance of minimal residual disease in high risk B-ALL: A report from Children's Oncology Group study AALL0232. Blood, 126(8), 964-971. https://doi.org/10.1182/blood-2015-03-633685