Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children's oncology group studies: a report from the children's oncology group.
OBJECTIVE
Five-year overall survival (OS) for children with B-cell precursor acute lymphoblastic leukemia (B-ALL) exceeds 90% with risk-adapted therapy. Age, initial WBC count, genetic aberrations, and minimal residual disease (MRD) are used for risk stratification. Intrachromosomal amplification of a region of chromosome 21 (iAMP21; three or more extra copies of RUNX1 on an abnormal chromosome 21) is a recently identified recurrent genomic lesion associated with inferior outcome in some studies. We investigated the impact of iAMP21 in a large cohort treated in contemporary Children's Oncology Group (COG) ALL trials.


METHODS
Fluorescent in situ hybridization for specific genetic aberrations was required at diagnosis. MRD was measured by flow cytometry at end induction. Outcome was measured as event-free survival (EFS) and OS.


RESULTS
iAMP21 was found in 158 (2%) of 7,793 patients with B-ALL age ≥ 1 year; 74 (1.5%) of 5,057 standard-risk (SR) patients, and 84 (3.1%) of 2,736 high-risk (HR) patients. iAMP21 was associated with age ≥ 10 years, WBC less than 50,000/μL, female sex, and detectable MRD at day 29. Four-year EFS and OS were significantly worse for patients with iAMP21 and SR B-ALL, but iAMP21 was not a statistically significant prognostic factor in HR patients. There was no interaction between MRD and iAMP21. Among SR patients, day 29 MRD ≥ 0.01% and iAMP21 were associated with the poorest EFS and OS; absence of both was associated with the best outcome.


CONCLUSIONS
iAMP21 is associated with inferior outcome in pediatric B-ALL, particularly SR patients who require more intensive therapy and are now treated on HR COG ALL protocols.
Nyla A. Heerema and Julie M. Gastier-Foster, The Ohio State University Wexner Medical Center; Julie M. Gastier-Foster, The Ohio State University College of Medicine and Nationwide Children's Hospital, Columbus, OH; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Meenakshi Devidas, University of Florida, Gainesville, FL; Mignon L. Loh, University of California at San Francisco, San Francisco, CA; Michael J. Borowitz, Johns Hopkins Medical Institutions, Baltimore, MD; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Leonard A. Mattano Jr, Michigan State University College of Human Medicine, Kalamazoo, MI; Kelly W. Maloney and Stephen P. Hunger, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO; Cheryl L. Willman, University of New Mexico, Albuquerque, NM; Brent L. Wood, University of Washington, Seattle, WA; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; and William L. Carroll and Elizabeth A. Raetz, The New York University Cancer Institute, New York University Langone Medical Center, New York, NY.
Nyla A
NA
Heerema
Andrew J
AJ
Carroll
Meenakshi
M
Devidas
Mignon L
ML
Loh
Michael J
MJ
Borowitz
Julie M
JM
Gastier-Foster
Eric C
EC
Larsen
Leonard A
LA
Mattano
Kelly W
KW
Maloney
Cheryl L
CL
Willman
Brent L
BL
Wood
Naomi J
NJ
Winick
William L
WL
Carroll
Stephen P
SP
Hunger
Elizabeth A
EA
Raetz
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002891:Chromosomes, Human, Pair 21; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011379:Prognosis; D016019:Survival Analysis; D014178:Translocation, Genetic; D016896:Treatment Outcome