Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukaemia

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 is less well understood and has not been studied comprehensively. We analysed 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 (CNA) and mutations. Cytogenetic risk groups were predictive of outcome post-relapse and survival rates at 5 years for patients with good, intermediate and high risk cytogenetics were 68%, 47% and 26%, p<0.001. TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% CI 1.51-3.70), p<0.001 and 2.15 (1.32-3.48), p=0.002. NRAS mutations were associated with an increased risk of progression among standard risk patients with high hyperdiploidy: 3.17 (1.15-8.71), p=0.026. 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. Clinicaltrials.org: ISCRTN45724312.