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

Lina Hamadeh, Amir Enshaei, Claire Schwab, Cristina N. Alonso, Andishe Attarbaschi, Gisela Barbany, Monique L. den Boer, Judith M. Boer, Marcin Braun, Luciano Dalla Pozza, Sarah Elitzur, Mariana Emerenciano, Larisa Fechina, Maria Sara Felice, Eva Fronkova, Irén Haltrich, Mats M. Heyman, Keizo Horibe, Toshihiko Imamura, Marta Jeison, Gábor Kovács, Roland P. Kuiper, Wojciech Mlynarski, Karin Nebral, Ingegerd Ivanov Öfverholm, Agata Pastorczak, Rob Pieters, Henriett Piko, Maria S. Pombo-de-Oliveira, Patricia Rubio, Sabine Strehl, Jan Stary, Rosemary Sutton, Jan Trka, Grigory Tsaur, Nicola Venn, Ajay Vora, Mio Yano, Christine J. Harrison and Anthony V. Moorman on behalf of the International BFM Study Group

Key Points

  • The UKALL-CNA classifier is a validated and robust prognostic tool that can be deployed in a variety of clinical trial settings.

  • The UKALL-CNA classifier can be used to refine risk stratification for patients with intermediate-risk cytogenetics.

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.

  • Submitted September 5, 2018.
  • Accepted December 6, 2018.
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