TY - JOUR
T1 - Defining low-risk high hyperdiploidy in patients with paediatric acute lymphoblastic leukaemia
T2 - a retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials
AU - Enshaei, Amir
AU - Vora, Ajay
AU - Harrison, Christine J.
AU - Moppett, John
AU - Moorman, Anthony V.
N1 - Funding Information:
AE and AVM conceived and designed the study. AE, AVM, and CJH collected and assembled the data. AE and AVM analysed and interpreted the data. AE, CJH, and AVM provided financial support. CJH and AVM provided administrative support. CJH, AVM, AV, and JM provided study materials or patients. AE and AVM wrote the manuscript. All authors approved the final manuscript, were responsible for the decision to submit for publication, and had full access to all the data in the study. AE and AVM accessed and verified the data.
Funding Information:
We thank Blood Cancer UK (formerly Bloodwise and Leukemia & Lymphoma Research) for financial support and member laboratories of the UK Cancer Cytogenetic Group for providing cytogenetic data and material. We thank the Blood Cancer UK Childhood Leukaemia Cell Bank for providing material used in this study. We thank all clinicians who entered patients into the trial and the children and families who agreed to take part. The UK Medical Research Council funded the data management and statistical input into both trials and supported the working parties, which oversaw recruitment to the trial. Finally, we thank past and present members of the Leukaemia Research Cytogenetics Group for their work characterising these datasets.
Funding Information:
We thank Blood Cancer UK (formerly Bloodwise and Leukemia & Lymphoma Research) for financial support and member laboratories of the UK Cancer Cytogenetic Group for providing cytogenetic data and material. We thank the Blood Cancer UK Childhood Leukaemia Cell Bank for providing material used in this study. We thank all clinicians who entered patients into the trial and the children and families who agreed to take part. The UK Medical Research Council funded the data management and statistical input into both trials and supported the working parties, which oversaw recruitment to the trial. Finally, we thank past and present members of the Leukaemia Research Cytogenetics Group for their work characterising these datasets.
Publisher Copyright:
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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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U2 - 10.1016/S2352-3026(21)00304-5
DO - 10.1016/S2352-3026(21)00304-5
M3 - Article
C2 - 34715050
AN - SCOPUS:85117850686
SN - 2352-3026
VL - 8
SP - e828-e839
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 11
ER -