Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL

Abstract

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.

Graphical abstract

Figure 1.

Definition of the cytogenetic, copy number alteration and integrated classifications used in this study. Definition of the classifiers used in the current study: cytogenetic (A), UKALL-CNA (B), and original genetic risk (C). CYTO, cytogenetic; GEN, genetics; GR, good risk; IR, intermediate risk; PR, poor risk.

Figure 2.

Outcome of 3239 patients in the iBFM cohort stratified by the UKALL-CNA classifier. (A-B) Kaplan-Meier survival curves (A) and forest plots depicting the hazard ratio and 95% CI from univariate Cox regression models comparing the EFS for CNA-GR or CNA-PR against CNA-IR (B). Patients in the Israeli National Study were excluded from the forest plot, as no event occurred in the CNA-GR or CNA-IR groups. DCOG, Dutch Childhood Oncology Group.

Figure 3.

Outcome of 3239 patients in the iBFM cohort stratified by the original genetic risk group. (A-B) Kaplan-Meier survival curves (A) and forest plot (B) depicting the hazard ratio and 95% confidence interval from univariate Cox regression models comparing the EFS for GEN-PR vs GEN-GR. Patients in the Israeli National Study were excluded from the forest plot, as no event occurred in the GEN-GR group.

Figure 4.

Integration of cytogenetic and CNA subgroups using the 3239 patients in the iBFM cohort reveals a new genetic risk classification. (A) EFS of the 9 subgroups derived from cross-tabulating the 3 cytogenetic and 3 CNA risk groups. (B) Visualized inspection of these curves reveals 4 overall genetic risk groups. (C) EFS of the revised genetic risk groups, which are significantly different from one another.

Figure 5.

Outcome of 1405 patients in the iBFM cohort with IR cytogenetics classified according to their CNA profile. (A-B) Kaplan-Meier survival curves (A) and forest plot (B) depicting the hazard ratio and 95% confidence interval from univariate Cox regression models comparing the EFS for group B (CYTO-IR/CNA-IR and CYTO-IR/CNA-PR) vs group A (CYTO-IR/CNA-GR). Patients in the Israeli National and Sweden studies were excluded from the forest plot, as no event occurred in group B.