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. 2016 Aug 18;128(7):911-22.
doi: 10.1182/blood-2016-03-704973. Epub 2016 May 26.

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

Julie A E Irving  1 , Amir Enshaei  1 , Catriona A Parker  2 , Rosemary Sutton  3 , Roland P Kuiper  4 , Amy Erhorn  1 , Lynne Minto  1 , Nicola C Venn  3 , Tamara Law  3 , Jiangyan Yu  4 , Claire Schwab  1 , Rosanna Davies  1 , Elizabeth Matheson  1 , Alysia Davies  1 , Edwin Sonneveld  5 , Monique L den Boer  6 , Sharon B Love  7 , Christine J Harrison  1 , Peter M Hoogerbrugge  8 , Tamas Revesz  9 , Vaskar Saha  10 , Anthony V Moorman  1
Affiliations

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

Julie A E Irving et al. Blood. .

Abstract

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.

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Figures

Figure 1
Figure 1
CONSORT diagram depicting the patient cohorts used in this study with their key demographic and clinical features. “Age” refers to the mean age at relapse in years. *Material not available. E, early; F, female; HR, clinical high risk; L, late; M, male; VE, very early.
Figure 2
Figure 2
Progression-free and overall survival of relapsed B-cell precursor ALL patients stratified by cytogenetic risk and clinical risk group. Kaplan-Meier survival graphs depicting the PFS and OS of relapsed childhood. Patients with ALL treated on ALLR3 and stratified by cytogenetic risk group.
Figure 3
Figure 3
Cytogenetic, copy number, and mutational profile of relapsed acute lymphoblastic leukemia patients stratified by clinical risk group. Frequency of individual chromosomal abnormalities, copy number alterations and sequence mutations among clinical standard and high-risk B-cell precursor ALL patients treated in ALLR3. *P < .05; **P < .01.
See this image and copyright information in PMC

References

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