November 2021 Clinical practice Jolien Blokken
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In childhood acute lymphoblastic leukaemia (ALL), high hyperdiploidy accounts for a large proportion of all relapses. However, thus far there was no consensus regarding the optimal risk factors in patients with high hyperdiploid ALL. A retrospective analysis of data from the UKALL97/99 and UKALL2003 clinical trials now identified and validated a clinically useful profile, based on four constituent trisomies, to identify low-risk patients with high hyperdiploid ALL.

High hyperdiploidy is the most common genetic subtype of childhood acute lymphoblastic leukaemia (ALL) and is associated with a good outcome (survival >90%). However, given the high frequency of patients with high hyperdiploid ALL, this subgroup accounts for up to 25% of all relapses. Although many studies have sought to define a smaller subgroup of these patients that is associated with a uniform very low risk of relapse, to date there is no consensus definition of low-risk high hyperdiploidy. A recent analysis by Enshaei et al. now evaluated all previously published high hyperdiploid ALL data from the UKALL97/99 and UKALL2003 trials to identify new risk profiles by investigating all possible combinations of gained chromosomes.


The study was designed as a retrospective analysis of the data collected from the consecutive trials UKALL97/99 and UKALL2003. These trials enrolled 456 patients between 1-18 years (UKALL97/99) and 725 patients between 1-24 years (UKALL2003) who were newly diagnosed with B-cell precursor ALL. Cytogenetics and fluorescence in-situ hybridisation testing was performed on pre-treatment bone marrow samples. Patients with high hyperdiploidy and concomitant BCR–ABL1, ETV6–RUNX1, KMT2A, or TCF3–PBX1 fusions, or masked hypodiploidy were excluded from the analysis. Further, only chromosomal abnormalities and trisomies visible by conventional G-banded karyotyping were included in the analysis. The UKALL97/99 dataset was used as a discovery cohort, while the UKALL2003 cohort was used as a validation cohort. Survival analysis considered three endpoints: event-free survival (EFS), relapse rate and overall survival (OS). The median follow-up time for UKALL97/99 and UKALL2003 were 10.59 years and 9.40 years, respectively.


Using the UKALL2003 cohort, the prognostic effect of previously proposed cytogenetic risk factors was examined. However, no significant correlation was observed between any of the three survival endpoints examined and the modal chromosome number. Six trisomies (+3, +5, +7, +17, +18, +20) were associated with outcomes. Double and triple trisomies were associated with a significantly better relapse rate but not EFS and OS, compared with other patients with high hyperdiploidy (HR[95%CI]: 0.51[0.28-0.91]; p = 0.024; and HR[95%CI]: 0.38[0.19-0.77]; p = 0.0070, respectively).  Using the discovery cohort (UKALL97/99), all possible combinations of up to six gained chromosomes were created and compared using the C-index as a measure of the prediction power of the profile. The optimal set of chromosomes for predicting relapse was 5, 17, 18, and 20. The good risk profile comprised karyotypes with both +17 and +18 together, 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% vs. 16% (p< 0.0001), event-free survival 92% vs. 81% (p< 0.0001) and overall survival 96% vs. 86% (p< 0.0001). The outcome for high hyperdiploid poor-risk patients was similar to that of patients with an intermediate cytogenetic profile. This novel profile outperformed previously published risk profiles in terms of prediction accuracy and prognostic impact, and although statistically independent of minimal residual disease (MRD), it could be further refined by its integration.


The study validated a robust and clinically useful profile to define high hyperdiploid ALL patients with low relapse rate and good overall survival. The study reassured that the constituent trisomies (+5, +17, +18, and +20) are risk factors in high hyperdiploidy and provide a framework to further investigate which specific genes are determining treatment response. The prognostic effect of this profile is independent of MRD but can be refined by its integration. This novel UKALL high hyperdiploid good risk profile is superior in defining good risk high hyperdiploidy compared with counting chromosomes and can be used in future clinical trials and treatment protocols.


Enshaei A, Vora A, Harrison CJ, et al. 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;8(11):e828–39.