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
Observational Study
. 2023 Jun 27;7(12):2794-2806.
doi: 10.1182/bloodadvances.2022008821.

BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib

Silvia Bonfiglio  1   2 , Lesley-Ann Sutton  3 , Viktor Ljungström  3   4 , Antonella Capasso  5 , Tatjana Pandzic  4 , Simone Weström  4 , Hassan Foroughi-Asl  3 , Aron Skaftason  3 , Anna Gellerbring  6   7 , Anna Lyander  6   7   8 , Francesca Gandini  2   9 , Gianluca Gaidano  10 , Livio Trentin  11 , Lisa Bonello  12   13 , Gianluigi Reda  14 , Csaba Bödör  15   16 , Niki Stavroyianni  17 , Constantine S Tam  18   19 , Roberto Marasca  20 , Francesco Forconi  21   22 , Panayiotis Panayiotidis  23 , Ingo Ringshausen  24 , Ozren Jaksic  25 , Anna Maria Frustaci  26 , Sunil Iyengar  27 , Marta Coscia  13   28 , Stephen P Mulligan  29 , Loïc Ysebaert  30 , Vladimir Strugov  31 , Carolina Pavlovsky  32 , Renata Walewska  33 , Anders Österborg  34 , Diego Cortese  3 , Pamela Ranghetti  2 , Panagiotis Baliakas  4 , Kostas Stamatopoulos  35 , Lydia Scarfò  2   5   9 , Richard Rosenquist  3   36 , Paolo Ghia  2   5   9
Affiliations
Observational Study

BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib

Silvia Bonfiglio et al. Blood Adv. .

Abstract

Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: G.G. is on the advisory board/speaker’s bureau of Janssen, AbbVie, AstraZeneca, and BeiGene. F.F. received honoraria and/or is on the advisory board of AbbVie, Acerta/AstraZeneca, Janssen-Cilag, and BC platforms. O.J. reports consultancy for AstraZeneca and Eli Lilly, and is on the speaker’s bureau of AbbVie, AstraZeneca, and Johnson & Johnson. R.W. reports meeting sponsorship from AbbVie and Janssen; is on the advisory board of AstraZeneca, Janssen, SecuraBio, and AbbVie; and is on the speaker's bureau of AbbVie, AstraZeneca, Janssen, and BeiGene. A.O. receives research funding from BeiGene, Janssen, AstraZeneca and Gilead. P.B. received honoraria from AbbVie, Gilead, and Janssen, and received research funding from Gilead. K.S. received honoraria and/or is on the advisory board of AbbVie, Acerta/AstraZeneca, Gilead, and Janssen, and received research funding from AbbVie, Gilead, and Janssen. L.S. is on the advisory board of AbbVie, AstraZeneca, and Janssen. R.R. received honoraria and/or is an advisory board member in AbbVie, AstraZeneca, Janssen, Illumina and Roche. P.G. received honoraria and/or is on the advisory board of AbbVie, Acerta/AstraZeneca, Adaptive, ArQule/MSD, BeiGene, CelGene/Juno, Gilead, Janssen, Loxo/Lilly, and Sunesis, and received research funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Oncoplot displaying the somatic variants detected in the 13 genes analyzed by a HaloPlex high sensitivity custom panel in the relapsed and responding cohorts. Illustrated are the distribution of the somatic variants, IGHV mutational status, cytogenetic profile determined by fluorescence in situ hybridization or lymphoid panel (del[8p]), and the mutation frequency of each gene in the relapsed and responding cohorts, respectively. Patient identifiers are indicated across the top row.
Figure 2.
Figure 2.
TP53 clonal dynamics in the relapsed and responsive cohorts. (A) TP53 clonal dynamics in 10 mutated patients of the relapsed cohort. Each patient is represented by a different color. The vertical axis displays the mutation VAF%, corrected according to the % of CD19+ cells in the sample. Two patients were not included in the chart because of missing CD19+ purity data. (B) TP53 clonal dynamics in 18 mutated patients of the responsive cohort. Each patient is represented by a different color. The vertical axis displays the mutation VAF%, corrected according to the % of CD19+ cells in the sample. Three patients were not included in the chart because of the missing CD19+ purity data.
See this image and copyright information in PMC

References

    1. Schiattone L, Ghia P, Scarfo L. The evolving treatment landscape of chronic lymphocytic leukemia. Curr Opin Oncol. 2019;31(6):568–573. - PubMed
    1. Herman SEM, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123(21):3286–3295. - PMC - PubMed
    1. Herman SEM, Niemann CU, Farooqui M, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014;28(11):2188–2196. - PMC - PubMed
    1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42. - PMC - PubMed
    1. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223. - PMC - PubMed

Publication types

MeSH terms