High hyperdiploid risk profile for childhood acute lymphoblastic leukaemia

November 2021 Science Nalinee Pathak

Childhood acute lymphoblastic leukemia (ALL) is a cancer of blood and bone marrow with characteristic cytogenetic abnormality referred to as higher hyperdiploidy (HH). It is defined as the non-random gain of chromosomes from 46 to a range of 51-67. Interestingly, several studies have shown that HH is associated with favourable outcomes. However, HH is observed in almost 25% of relapse cases of childhood ALL. Thus, it is important to identify risk factors associated with this clinical subgroup. Numerous studies have evaluated specific cytogenetic risk factors such as higher modal chromosome number, specific trisomies, or triple trisomies as potential risk factors for childhood ALL. Still, there is a lack of knowledge about optimal risk factors associated with the disease. Researchers from Newcastle university (UK) have addressed this question, and recently reported their findings in the journal Lancet Haematology.

Retrospective analysis of clinical trials

A retrospective analysis of patient data from clinical trials UKALL97/99 and UKALL2003 was performed. Between Jan 1, 1997, and June 15, 2002, a total of 456 patients aged 1-18 were enrolled in UKALL97/99 trial, and UKALL2003 enrolled 725 patients (aged 1-24) between Oct 1, 2003, and June 30, 2011, who were newly diagnosed with ALL. Towards the prognostic profile of HH, two trial data sets (UKALL97/99) were used as discovery sets and UKALL2003 as a validation cohort. A combination of Bayesian information criterion, targeted projection pursuit, and multivariate analysis was performed for identifying an optimal number of trisomies, along with best subset regression and multivariate analysis for optimal combination. Event free survival (EFS), relapse rate (RR), and overall survival (OS) were set as endpoints of survival analysis.

Main findings

Median follow-up time was 10.59 (IQR 9·25–12·06) and 9.40 years (8·00–11·55) for UKALL97/99 and UKALL97/99 cohorts, respectively. The risk profile of the patients was predicted on the trisomic status of four chromosomes. The cases with Karyotype with +17 and +18 or +17 or +18 in the absence of +5 and +20 were classified as good risk profile, whereas all other cases were marked as poor risk profile. Patients with good and poor risk were in 82:18 and 80:20 ratio in the discovery and validation cohorts, respectively.

The good risk profile patients responded better to treatment in comparison to poor risk profile patients 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). However, the outcome in patients with intermediate and poor risk remained similar. Importantly, the HH risk profile prognostic effect was independent of minimal residual disease and outperformed all other existing HH risk profiles.

Conclusion

Based on the findings of the study, UKALL HH risk profile should be incorporated with standard genetic analysis when assessing HH as a risk factor.

Reference

Enshaei A, Vora A, Harrison CJ, Moppett J, Moorman A 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. Lancet Haematol. 2021 Nov;8(11):e828–39.

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