Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul 25;7(14):3531-3539.
doi: 10.1182/bloodadvances.2022009412.

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

Maciej Tatarczuch  1   2 , Mark Waltham  1   2 , Jake Shortt  1   2 , Galina Polekhina  3 , Eliza A Hawkes  3   4   5 , Shir-Jing Ho  6   7 , Judith Trotman  8   9 , Daniella Brasacchio  1   2 , Melannie Co  10 , Jessica Li  10 , Vanitha Ramakrishnan  10 , Karin Dunne  11 , Stephen S Opat  1   2 , Gareth P Gregory  1   2
Affiliations

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

Maciej Tatarczuch et al. Blood Adv. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: J.S. has received research funding from Amgen, Astex, and Bristol Myers Squibb/Celgene; served on advisory board or received consultancy fees from Astellas, Bristol Myers Squibb, Novartis, Mundipharma and Otsuka; and speakers bureau from Mundipharma. E.A.H. has served on advisory boards for Roche, Gilead, Antengene, LINK, Novartis, BeiGene, and Merck Sharp & Dohme and speaker bureau for AstraZeneca, Roche, and Merck, Sharp & Dohme; and received research funding from Roche, Bristol Myers Squibb, Merck KgA, AstraZeneca, Janssen, BeiGene, AbbVie, and Takeda. E.A.H. also reports personal support (Bristol Myers Squibb). J.T. has received research funding from BeiGene, Janssen, Pharmacyclics, Roche, Takeda, and Cellectar. V.R., M.C., and J.L. are employees of and own stock in BeiGene. S.S.O. has received research funding, served as a member of advisory boards, and received honoraria from BeiGene. G.P.G. has received research funding from BeiGene, AbbVie, Janssen, and Merck; advisory board/consultancy fees from Roche, Janssen, Gilead, Bristol Myers Squibb, Merck, Novartis, and Clinigen LINK; and serves on the speakers bureau of Roche. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Comutation plot for variants detected in primary tumor at study entry. (Left) Clustered according to best clinical response: CR Complete response, PR Partial response, SD Stable disease, PD Progressive disease. Unique sample identifier and MZL subtype also represented. Mutation burden is expressed relative to sample with highest number of mutations detected. Only one mutation per gene per tumor sample is represented. (Right) Ribbon diagram of BTK structure showing location of the non-catalytic E41K mutation distant from zanubrutinib binding site.
Figure 2.
Figure 2.
Molecular predictors of response to zanubrutinib. Kaplan-Meier survival curves showing progression-free survival according to presence or absence of somatic mutations of (A) MYD88 or TNFAIP3 (B) KMT2D, (C) NOTCH1 or NOTCH2. Median follow-up: 11.1 months (2.76-16.80). ∗includes one COVID-19-related death.
Figure 3.
Figure 3.
Detection of ctDNA mutations and evolution during zanubrutinib therapy for 5 patients. Represented is the relative abundance for each detected mutation (plotted as hGE/mL plasma, calculated from AF and plasma cfDNA concentration) and variation over time (x-axis: days). Numbers indicated above the plot at the sample time-points are the calculated total ctDNA (hGE/mL plasma). Associated tables present values for all BTK, PLCG2, TNFAIP3, KMT2D, MYD88, NOTCH2 and TP53 mutations. MZ04 not shown as only one time point (D254) was available for analysis. BD = below detection.
See this image and copyright information in PMC

References

    1. Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov. 2013;12(3):229–243. - PMC - PubMed
    1. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720–1748. - PMC - PubMed
    1. Rossi D, Trifonov V, Fangazio M, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012;209(9):1537–1551. - PMC - PubMed
    1. Spina V, Khiabanian H, Messina M, et al. The genetics of nodal marginal zone lymphoma. Blood. 2016;128(10):1362–1373. - PMC - PubMed
    1. Braggio E, Dogan A, Keats JJ, et al. Genomic analysis of marginal zone and lymphoplasmacytic lymphomas identified common and disease-specific abnormalities. Mod Pathol. 2012;25(5):651–660. - PMC - PubMed

Publication types

MeSH terms