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Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials

BACKGROUND: High hyperdiploidy is the most common genetic subtype of childhood acute lymphoblastic leukaemia and is associated with a good outcome. However, some patients relapse and, given its prevalence, patients with high hyperdiploidy account for a large proportion of all relapses. We aimed to e...

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Autores principales: Enshaei, Amir, Vora, Ajay, Harrison, Christine J, Moppett, John, Moorman, Anthony V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567211/
https://www.ncbi.nlm.nih.gov/pubmed/34715050
http://dx.doi.org/10.1016/S2352-3026(21)00304-5
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author Enshaei, Amir
Vora, Ajay
Harrison, Christine J
Moppett, John
Moorman, Anthony V
author_facet Enshaei, Amir
Vora, Ajay
Harrison, Christine J
Moppett, John
Moorman, Anthony V
author_sort Enshaei, Amir
collection PubMed
description BACKGROUND: High hyperdiploidy is the most common genetic subtype of childhood acute lymphoblastic leukaemia and is associated with a good outcome. However, some patients relapse and, given its prevalence, patients with high hyperdiploidy account for a large proportion of all relapses. We aimed to evaluate putative risk factors and determine the optimal pattern of trisomies for predicting outcome. METHODS: We used discovery and validation cohorts from consecutive trials—UKALL97/99 (n=456) and UKALL2003 (n=725)—to develop the prognostic profile. UKALL97/99 recruited patients aged 1–18 years between Jan 1, 1997, and June 15, 2002, and UKALL2003 recruited children and young adults aged 1–24 years between Oct 1, 2003, and June 30, 2001, from the UK and Ireland who were newly diagnosed with acute lymphoblastic leukaemia. Cytogenetic and fluorescence in-situ hybridisation testing was performed on pre-treatment bone marrow samples by regional UK National Health Service genetic laboratories or centrally by the Leukaemia Research Cytogenetics Group, and results were reported using established nomenclature and definitions. We examined the prognostic effect of previously proposed genetic and non-genetic risk factors among patients with high hyperdiploid acute lymphoblastic leukaemia treated on UKALL2003. We used Bayesian information criterion, targeted projection pursuit, and multivariate analysis to identify the optimal number of trisomies, and best subset regression and multivariate analysis to identify the optimal combination. Survival analysis considered three endpoints, as follows: event-free survival, defined as time to relapse, second tumour, or death, censored at last contact; relapse rate, defined as time to relapse for those reaching complete remission, censored at death in remission or last contact; and overall survival, defined as time to death, censored at last contact. FINDINGS: The median follow-up time for UKALL97/99 was 10·59 years (IQR 9·25–12·06) and 9·40 years (8·00–11·55) for UKALL2003. UKALL97/99 included 208 female patients and 248 male patients, and UKALL2003 included 345 female patients and 380 male patients. We deduced that the trisomic status of four chromosomes provided the optimal information for predicting outcome. The good risk profile comprised karyotypes with +17 and +18 or +17 or +18 in the absence of +5 and +20. All remaining cases were classified in the poor risk profile. The ratio of patients with good risk and poor risk was 82:18 and 80:20 in the discovery and validation cohorts, respectively. In the validation cohort, patients with the high hyperdiploid good risk profile had an improved response to treatment compared with other patients with high hyperdiploidy at 10 years (relapse rate 5% [95% CI 3–7] vs 16% [10–23]; p<0·0001; event-free survival 92% [90–94] vs 81% [73–86]; p<0·0001; and overall survival 96% [94–97] vs 86% [79–91]; p<0·0001). The outcome for high hyperdiploid poor risk patients was similar to that of patients with an intermediate cytogenetic profile. The prognostic effect of the UKALL high hyperdiploid profile was independent of minimal residual disease and the profile outperformed other high hyperdiploid risk profiles. INTERPRETATION: Future clinical trials and treatment protocols using high hyperdiploidy as a risk stratification factor should consider modifying the definition beyond chromosome count to incorporate this novel UKALL high hyperdiploid profile. FUNDING: Blood Cancer UK.
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spelling pubmed-85672112021-11-09 Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials Enshaei, Amir Vora, Ajay Harrison, Christine J Moppett, John Moorman, Anthony V Lancet Haematol Articles BACKGROUND: High hyperdiploidy is the most common genetic subtype of childhood acute lymphoblastic leukaemia and is associated with a good outcome. However, some patients relapse and, given its prevalence, patients with high hyperdiploidy account for a large proportion of all relapses. We aimed to evaluate putative risk factors and determine the optimal pattern of trisomies for predicting outcome. METHODS: We used discovery and validation cohorts from consecutive trials—UKALL97/99 (n=456) and UKALL2003 (n=725)—to develop the prognostic profile. UKALL97/99 recruited patients aged 1–18 years between Jan 1, 1997, and June 15, 2002, and UKALL2003 recruited children and young adults aged 1–24 years between Oct 1, 2003, and June 30, 2001, from the UK and Ireland who were newly diagnosed with acute lymphoblastic leukaemia. Cytogenetic and fluorescence in-situ hybridisation testing was performed on pre-treatment bone marrow samples by regional UK National Health Service genetic laboratories or centrally by the Leukaemia Research Cytogenetics Group, and results were reported using established nomenclature and definitions. We examined the prognostic effect of previously proposed genetic and non-genetic risk factors among patients with high hyperdiploid acute lymphoblastic leukaemia treated on UKALL2003. We used Bayesian information criterion, targeted projection pursuit, and multivariate analysis to identify the optimal number of trisomies, and best subset regression and multivariate analysis to identify the optimal combination. Survival analysis considered three endpoints, as follows: event-free survival, defined as time to relapse, second tumour, or death, censored at last contact; relapse rate, defined as time to relapse for those reaching complete remission, censored at death in remission or last contact; and overall survival, defined as time to death, censored at last contact. FINDINGS: The median follow-up time for UKALL97/99 was 10·59 years (IQR 9·25–12·06) and 9·40 years (8·00–11·55) for UKALL2003. UKALL97/99 included 208 female patients and 248 male patients, and UKALL2003 included 345 female patients and 380 male patients. We deduced that the trisomic status of four chromosomes provided the optimal information for predicting outcome. The good risk profile comprised karyotypes with +17 and +18 or +17 or +18 in the absence of +5 and +20. All remaining cases were classified in the poor risk profile. The ratio of patients with good risk and poor risk was 82:18 and 80:20 in the discovery and validation cohorts, respectively. In the validation cohort, patients with the high hyperdiploid good risk profile had an improved response to treatment compared with other patients with high hyperdiploidy at 10 years (relapse rate 5% [95% CI 3–7] vs 16% [10–23]; p<0·0001; event-free survival 92% [90–94] vs 81% [73–86]; p<0·0001; and overall survival 96% [94–97] vs 86% [79–91]; p<0·0001). The outcome for high hyperdiploid poor risk patients was similar to that of patients with an intermediate cytogenetic profile. The prognostic effect of the UKALL high hyperdiploid profile was independent of minimal residual disease and the profile outperformed other high hyperdiploid risk profiles. INTERPRETATION: Future clinical trials and treatment protocols using high hyperdiploidy as a risk stratification factor should consider modifying the definition beyond chromosome count to incorporate this novel UKALL high hyperdiploid profile. FUNDING: Blood Cancer UK. Elsevier Ltd 2021-10-26 /pmc/articles/PMC8567211/ /pubmed/34715050 http://dx.doi.org/10.1016/S2352-3026(21)00304-5 Text en © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Articles
Enshaei, Amir
Vora, Ajay
Harrison, Christine J
Moppett, John
Moorman, Anthony V
Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
title Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
title_full Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
title_fullStr Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
title_full_unstemmed Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
title_short Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
title_sort defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia: a retrospective analysis of data from the ukall97/99 and ukall2003 clinical trials
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567211/
https://www.ncbi.nlm.nih.gov/pubmed/34715050
http://dx.doi.org/10.1016/S2352-3026(21)00304-5
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