Molecular associations of response to the new-generation BTK inhibitor zanubrutinib in marginal zone lymphoma.

Abstract

Using tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group translational study sought to characterize primary and acquired molecular determinants of response and resistance of marginal zone lymphoma (MZL) to zanubrutinib for patients treated in the MAGNOLIA clinical trial. WES was performed on baseline tumor samples obtained from 18 patients. For 7 patients, ctDNA sequence was interrogated using a bespoke hybrid-capture next-generation sequencing assay for 48 targeted genes. Somatic mutations were correlated with objective response data and survival analysis using Fisher exact test and Kaplan-Meier (log-rank) method, respectively. Baseline WES identified mutations in 33 of 48 (69%) prioritized genes. NF-κB, NOTCH, or B-cell receptor (BCR) pathway genes were implicated in samples from 16 of 18 patients (89%). KMT2D mutations (n = 11) were most common, followed by FAT1 (n = 9), NOTCH1, NOTCH2, TNFAIP3 (n = 5), and MYD88 (n = 4) mutations. MYD88 or TNFAIP3 mutations correlated with improved progression-free survival (PFS). KMT2D mutations trended to worse PFS. Acquired resistance mutations PLCG2 (R665W/R742P) and BTK (C481Y/C481F) were detected in 2 patients whose disease progressed. A BTK E41K noncatalytic activating mutation was identified before treatment in 1 patient who was zanubrutinib-refractory. MYD88, TNFAIP3, and KMT2D mutations correlate with PFS in patients with relapsed/refractory MZL treated with zanubrutinib. Detection of acquired BTK and PLCG2 mutations in ctDNA while on therapy is feasible and may herald clinical disease progression. This trial was registered at https://anzctr.org.au/ as #ACTRN12619000024145.

• Authors: Maciej Tatarczuch, Mark Waltham, Jake Shortt, Galina Polekhina, Eliza A Hawkes, Shir-Jing Ho, Judith Trotman, Daniella Brasacchio, Melannie Co, Jessica Li, Vanitha Ramakrishnan, Karin Dunne, Stephen S Opat, Gareth P Gregory
• Journal: Blood advances (Blood Adv) Vol. 7 Issue 14 Pg. 3531-3539 (07 25 2023) ISSN: 2473-9537 [Electronic] United States
• PMID: 36947202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• zanubrutinib
• Myeloid Differentiation Factor 88
• NF-kappa B
• Protein Kinase Inhibitors

Topics

• Humans
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Mutation
• NF-kappa B (metabolism)
• Lymphoma, B-Cell, Marginal Zone (drug therapy, genetics, pathology)
• Protein Kinase Inhibitors