Journal article

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia

Piers Blombery, Mary Ann Anderson, Jia-nan Gong, Rachel Thijssen, Richard W Birkinshaw, Ella R Thompson, Charis E Teh, Tamia Nguyen, Zhen Xu, Christoffer Flensburg, Thomas E Lew, Ian J Majewski, Daniel HD Gray, David A Westerman, Constantine S Tam, John F Seymour, Peter E Czabotar, David CS Huang, Andrew W Roberts

CANCER DISCOVERY | AMER ASSOC CANCER RESEARCH | Published : 2019

Abstract

The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for veneto..

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Grants

Awarded by Leukemia and Lymphoma Society


Awarded by Cancer Council of Victoria


Awarded by National Health and Medical Research Council (NHMRC) of Australia



Funding Acknowledgements

The authors are grateful to the patients who enrolled on the venetoclax clinical trials, and for assistance from Naomi Sprigg with collection and curation of samples, Dr. Andrew Mitchell for mass cytometry maintenance/operation, and Tania Tan for sample preparation for mass cytometry. The mass cytometry was performed in part at the Materials Characterisation and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility. This research was supported by grants from the Snowdome Foundation (P. Blombery and M.A. Anderson), Vision Super and the Wilson Centre of Lymphoma Genomics (P. Blombery), the Leukemia and Lymphoma Society [fellowship to R. Thijssen (5467-18); SCOR (7015-18) to D.C.S. Huang and A.W. Roberts], the Cancer Council of Victoria (grants 1146518 and 1102104 to D.H.D. Gray; 1124178 to I. J. Majewski), the Victorian Cancer Agency (fellowship to I. J. Majewski), the CLL Global Foundation (C.S. Tam), the National Health and Medical Research Council (NHMRC) of Australia [fellowships to C.E. Teh (1089072), D.H.D. Gray (1090236), P.E. Czabotar (1079700), D.C.S. Huang (1043149), and A.W. Roberts (1079560)], and grants to P.E. Czabotar (project 1141874), D.C.S. Huang (program 1113133), and A.W. Roberts (program 1113577). This work was made possible through Victorian State Government Operational Infrastructure Support, Australian Government NHMRC IRIISS, and financial support for mass cytometry by the Victorian Comprehensive Cancer Centre.