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

Julie A.E. Irving, Amir Enshaei, Catriona A. Parker, Rosemary Sutton, Roland P. Kuiper, Amy Erhorn, Lynne Minto, Nicola C. Venn, Tamara Law, Jiangyan Yu, Claire Schwab, Rosanna Davies, Elizabeth Matheson, Alysia Davies, Edwin Sonneveld, Monique L. Den Boer, Sharon B. Love, Christine J. Harrison, Peter M. Hoogerbrugge, Tamas Revesz & 2 others Vaskar Saha, Anthony Moorman

Research output: Contribution to journalArticle

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 amarrow 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 5 .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 5 .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 languageEnglish (US)
Pages (from-to)911-922
Number of pages12
JournalBlood
Volume128
Issue number7
DOIs
StatePublished - Aug 18 2016
Externally publishedYes

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B-Lymphoid Precursor Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cells
Cytogenetics
Recurrence
Mutation
Polyploidy
Survival Rate
Hazards
Screening
Confidence Intervals

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. / Irving, Julie A.E.; Enshaei, Amir; Parker, Catriona A.; Sutton, Rosemary; Kuiper, Roland P.; Erhorn, Amy; Minto, Lynne; Venn, Nicola C.; Law, Tamara; Yu, Jiangyan; Schwab, Claire; Davies, Rosanna; Matheson, Elizabeth; Davies, Alysia; Sonneveld, Edwin; Den Boer, Monique L.; Love, Sharon B.; Harrison, Christine J.; Hoogerbrugge, Peter M.; Revesz, Tamas; Saha, Vaskar; Moorman, Anthony.

In: Blood, Vol. 128, No. 7, 18.08.2016, p. 911-922.

Research output: Contribution to journalArticle

Irving, JAE, Enshaei, A, Parker, CA, Sutton, R, Kuiper, RP, Erhorn, A, Minto, L, Venn, NC, Law, T, Yu, J, Schwab, C, Davies, R, Matheson, E, Davies, A, Sonneveld, E, Den Boer, ML, Love, SB, Harrison, CJ, Hoogerbrugge, PM, Revesz, T, Saha, V & Moorman, A 2016, 'Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia', Blood, vol. 128, no. 7, pp. 911-922. https://doi.org/10.1182/blood-2016-03-704973
Irving, Julie A.E. ; Enshaei, Amir ; Parker, Catriona A. ; Sutton, Rosemary ; Kuiper, Roland P. ; Erhorn, Amy ; Minto, Lynne ; Venn, Nicola C. ; Law, Tamara ; Yu, Jiangyan ; Schwab, Claire ; Davies, Rosanna ; Matheson, Elizabeth ; Davies, Alysia ; Sonneveld, Edwin ; Den Boer, Monique L. ; Love, Sharon B. ; Harrison, Christine J. ; Hoogerbrugge, Peter M. ; Revesz, Tamas ; Saha, Vaskar ; Moorman, Anthony. / Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. In: Blood. 2016 ; Vol. 128, No. 7. pp. 911-922.
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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 amarrow 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 5 .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 5 .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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AU - Irving, Julie A.E.

AU - Enshaei, Amir

AU - Parker, Catriona A.

AU - Sutton, Rosemary

AU - Kuiper, Roland P.

AU - Erhorn, Amy

AU - Minto, Lynne

AU - Venn, Nicola C.

AU - Law, Tamara

AU - Yu, Jiangyan

AU - Schwab, Claire

AU - Davies, Rosanna

AU - Matheson, Elizabeth

AU - Davies, Alysia

AU - Sonneveld, Edwin

AU - Den Boer, Monique L.

AU - Love, Sharon B.

AU - Harrison, Christine J.

AU - Hoogerbrugge, Peter M.

AU - Revesz, Tamas

AU - Saha, Vaskar

AU - Moorman, Anthony

PY - 2016/8/18

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N2 - 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 amarrow 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 5 .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 5 .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.

AB - 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 amarrow 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 5 .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 5 .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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