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

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 × 2 factorial design to receive either high-dose methotrexate (HD-MTX...

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Published in:Blood Vol. 126; no. 8; pp. 964 - 971
Main Authors: Borowitz, Michael J, Wood, Brent L, Devidas, Meenakshi, Loh, Mignon L, Raetz, Elizabeth A, Salzer, Wanda L, Nachman, James B, Carroll, Andrew J, Heerema, Nyla A, Gastier-Foster, Julie M, Willman, Cheryl L, Dai, Yunfeng, Winick, Naomi J, Hunger, Stephen P, Carroll, William L, Larsen, Eric
Format: Journal Article
Language:English
Published: United States 20.08.2015
Subjects:
Antineoplastic Agents - administration & dosage
Asparaginase - administration & dosage
Child
Child, Preschool
Dexamethasone - administration & dosage
Disease-Free Survival
Dose-Response Relationship, Drug
Female
Flow Cytometry
Humans
Induction Chemotherapy
Kaplan-Meier Estimate
Leucovorin - administration & dosage
Maintenance Chemotherapy
Male
Methotrexate - administration & dosage
Neoplasm, Residual - pathology
Polyethylene Glycols - administration & dosage
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - mortality
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology
Prednisone - administration & dosage
Prognosis
Proportional Hazards Models
Risk Factors
ISSN:1528-0020
Online Access:Get more information
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Summary: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 × 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.
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ISSN:1528-0020
DOI:10.1182/blood-2015-03-633685