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Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312.

Original publication

DOI

10.1182/blood-2016-03-704973

Type

Journal article

Journal

Blood

Publication Date

08/2016

Volume

128

Pages

911 - 922

Addresses

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom;

Keywords

Humans, Chromosome Aberrations, Genetic Predisposition to Disease, Recurrence, Prognosis, Disease-Free Survival, Cytogenetic Analysis, Risk Factors, Cohort Studies, Demography, Mutation, Adolescent, Child, Child, Preschool, Infant, Female, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, DNA Copy Number Variations