Molecular characterization and clinical outcome of B-cell precursor acute lymphoblastic leukemia with IG-MYC rearrangement
Simon Bomken, Amir Enshaei, Ed C. Schwalbe, Aneta Mikulášová, Yunfeng Dai, Masood Zaka, Kent Fung, Matthew Bashton, Huezin Lim, Lisa Jones, Nefeli Karataraki, Emily Winterman, Cody Ashby, Andishe Attarbaschi, Yves Bertrand, Jutta Bradtke, Barbara Buldini, G. A. Amos Burke, Giovanni Cazzaniga, Gudrun Göhring, Hesta A. De Groot-Kruseman, Claudia Haferlach, Luca Lo Nigro, Mayur Parihar, Adriana Pleșa, Emma Seaford, Edwin Sonneveld, Sabine Strehl, Vincent H.J. van der Velden, Vikki Rand, Stephen P. Hunger, Christine J. Harrison, Chris M. Bacon, Frederik W. van Delft, Mignon L. Loh, John Moppett, Josef Vormoor, Brian A. Walker, Anthony V. Moorman, Lisa J. Russell
Abstract
Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukemia (BCP-ALL) carries an immunoglobulin- MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukemia and use of individualized treatment schedules of unproven efficacy. Here we compare the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered in a national BCP-ALL clinical trial/registry. When present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analyses. The outcomes analyzed were 3-year event-free survival and overall survival. IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either established BCP-ALL-specific abnormalities (high hyperdiploidy, n=3; KMT2A-rearrangement, n=6; iAMP21, n=1; BCR-ABL1, n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J-rearranged cases, clearly distinct from Burkitt leukemia/lymphoma. Children with IG-MYC-r within that subgroup had a 3-year event-free survival of 47% and overall survival of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this group of patients must be allowed access to contemporary, minimal residual disease-adapted, prospective clinical trial protocols.