Introduction:

BTKis have become a standard of care in the management of CLL and are associated with excellent long-term outcomes. Patients are commonly treated with a BTKi on a continuous basis until disease progression or intolerance. Over time, particularly during disease progression, resistance may develop, primarily driven by mutations in BTK leading to impaired drug binding and ineffective kinase activity inhibition. Large-scale real-world investigations characterizing the prevalence and type of resistance mutations seen are lacking. The aim of this study is to characterize the most common BTK resistance mutations using real-world databases.

Methods:

This was a retrospective analysis of samples from patients with suspected CLL who had been receiving a BTKi that were sent for any reason for next-generation sequencing by NeoGenomics Laboratories between November 1, 2018 and October 31, 2023. Only patients who had been receiving a BTKi for more than a year were included because mutations are related to the duration of exposure. Bone marrow, peripheral blood, lymph node, or formalin-fixed paraffin-embedded tissue samples were sequenced for a minimum of 275 genes. The minimum overall mean coverage was > 1000×, and sequence coverage ≥ 100× was required for a specific mutation to be called. An analytical sensitivity was established at 5% allelic frequency for non-hot spots and at 3% allele frequency for hot spots. No mutations with a variant allele frequency of less than 3% are reported. Samples with a BTK mutation (exons 1-19) were linked with de-identified patient data from ConcertAI RWD360, a de-identified clinical electronic medical record (EMR) oncology database that is built from multiple oncology health care clinics and oncologists. The database aggregates longitudinal, patient-level structured data from multiple oncology EMR systems using standard variable coding algorithms and it has been used to conduct research in hematology (Mato et al. 2022).

Results:

In total, samples from 13 940 unique patients were processed, of which 238 patients had BTK mutations, indicating a low BTK mutation rate (1.7%). Data on BTKi use were available for 136 of the 238 patients, the majority of whom received first-line treatment (80.9%, 110 patients), with only 26 patients (19.1%) receiving a BTKi as second- or later-line treatment. The most common exons with mutations were exon 15 (198 patients; 83.2%), exon 8 (12 patients; 5.0%), exon 14 (10 patients; 4.2%), and exon 16 (9 patients; 3.8%). When looking at exon 15, the most common mutation was found at amino acid C481 (190 patients; 94.1% of patients with exon 15 mutations). Mutations in amino acid T474 occurred in only 8 patients (4.0% of patients with exon 15 mutations), and mutations in amino acids I443, E445, N451, and V463 occurred in 1 patient each (0.5% of patients with exon 15 mutations). Of the 9 patients with mutations in exon 16, none were in amino acid L528. Of the 10 patients with mutations in exon 14, 2 (20.0%) had mutations in amino acid A428. The most common co-mutations in patients with a BTK mutation were TP53 (106 patients; 44.5%), SF3B1 (62 patients; 26.1%), ATM (52 patients; 21.8%), NOTCH1 (47 patients; 19.7%), and PLCG2 (22 patients; 9.2%).

Conclusions:

This is the largest cohort of patients with CLL receiving BTKis who have been analyzed for BTK mutations. The rate of BTK mutations seen with BTKis was low and there were no patients with mutations in amino acid L528 (exon 16) in the cohort. Among patients with mutations, the incidence of mutations in amino acid T474 in exon 15 was very low (3.4%). BTK mutations commonly occurred alongside other mutations, in particular TP53 (44.5%), and were more common in patients with BTK mutations than they were in the overall population with CLL (Knisbacher et al. 2020; Landau et al. 2015). Future analyses will evaluate the association between BTK mutations and exposure to BTKis, the time to mutation, and the time from mutation to relapse, alongside other outcomes.

Disclosures

Skarbnik:ADC Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Kite: Consultancy, Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; SeaGen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Acerta Pharma: Research Funding; Novartis: Honoraria; Gilead Sciences: Honoraria. Danilov:BeiGene: Consultancy; Nurix: Consultancy, Research Funding; TG Therapeutics: Research Funding; Genentech: Consultancy; Cyclacel: Research Funding; Incyte: Consultancy; Janssen: Consultancy; Lilly Oncology: Consultancy, Research Funding; Morphosys: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy, Research Funding; Takeda Oncology: Research Funding; AstraZeneca: Consultancy, Research Funding; GenMab: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Bayer Oncology: Research Funding; ADCT: Consultancy; Abbvie: Consultancy, Research Funding; Prelude: Consultancy. Hoffmann:ADC, Janssen, Pharmacyclics, BeiGene, Novartis, Astra-Zeneca, Abbvie, Kite, TG: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Other: Travel. Awan:ADC Therapeutics: Consultancy; Incyte: Consultancy; BMS: Consultancy; Adaptive Biotechnologies: Consultancy; Genmab: Consultancy; Dava Oncology: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Loxo Oncology: Consultancy; AbbVie/Pharmacyclics: Consultancy, Research Funding. Scarpa:NeoGenomics Laboratories: Current Employment, Current equity holder in publicly-traded company. Davies:Guardant Health: Ended employment in the past 24 months; NeoGenomics Laboratories: Current Employment. Oakland:Concert AI: Current Employment, Current equity holder in private company; GNS Healthcare: Ended employment in the past 24 months. Kovach:ConcertAI: Current Employment, Current holder of stock options in a privately-held company; IBM: Patents & Royalties: no outstanding dividends; IBM owned. Lilyquist:ConcertAI: Current Employment. Munugalavadla:AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AZN: Current equity holder in publicly-traded company, Other: Stock in publicly-traded company; Gilead Sciences: Current equity holder in publicly-traded company, Other: A family member is an employee and stockholder of Gilead Sciences.. Yong:AZN: Current equity holder in publicly-traded company, Other: Stock in publicly-traded company; AstraZeneca PLC: Current Employment. Shetty:AstraZeneca: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Allan:ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Speakers Bureau; Epizyme: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Woyach:Loxo Lilly: Consultancy; Genentech, Inc.: Consultancy; Janssen: Research Funding; BeiGene: Consultancy; Newave: Consultancy; Merck: Consultancy; Pharmacyclics: Consultancy, Research Funding; Schrodinger: Research Funding; Morphosys: Research Funding; AstraZeneca: Consultancy; AbbVie: Research Funding.

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2024
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