title: Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232.
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 × 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.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA;
authors.forename: Brent L
authors.initials: BL
authors.lastname: Wood
authors.affiliation: Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, FL;
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA;
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.affiliation: US Army Medical Research and Materiel Command, Fort Detrick, MD;
authors.forename: Wanda L
authors.initials: WL
authors.lastname: Salzer
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL;
authors.forename: James B
authors.initials: JB
authors.lastname: Nachman
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: Department of Pathology, The Ohio State University School of Medicine, Columbus, OH;
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.affiliation: Nationwide Children's Hospital, Columbus, OH;
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: Cancer Center and Departments of Internal Medicine and Pathology, University of New Mexico, Albuquerque, NM;
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.affiliation: Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, FL;
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Dai
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX;
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.affiliation: Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Pediatrics and The New York University Cancer Institute, New York University Medical Center, New York, NY; and.
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Maine Children's Cancer Program, Scarborough, ME.
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001215:Asparaginase / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D060046:Maintenance Chemotherapy; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D018365:Neoplasm, Residual / Q000473:pathology*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C042705:pegaspargase; D003907:Dexamethasone; D001215:Asparaginase; D002955:Leucovorin; D011241:Prednisone; D008727:Methotrexate