Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor–resistant chronic lymphocytic leukemia with disease progression and Richter transformation
Open accessAbstract
Background: In a proportion of patients with chronic lymphocytic leukemia (CLL), resistance to Bruton tyrosine kinase (BTK) inhibitors (BTKi) is attributed to acquired BTK/ phospholipase C gamma 2 ( PLCG2 ) mutations. However, knowledge regarding additional genetic lesions associated with BTK/PLCG2 mutations, and gene mutations in patients lacking BTK/PLCG2 mutations, is limited. Methods: Using targeted deep sequencing, mutations in 29 genes associated with CLL and/or the BCR signaling pathway were assessed in patients with CLL who developed resistance to BTK inhibition with ibrutinib/acalabrutinib at a single institution. Results: The study group included 29 patients with BTKi‐resistant CLL, 23 patients with disease progression, and 6 patients with Richter transformation (RT). The median times to disease progression and RT were 33.3 months and 13.3 months, respectively. In 11 patients, sequencing was possible at both baseline (prior to treatment with BTKi) and at time of disease progression/RT. Of these patients, 4 demonstrated BTK mutations at the time of disease progression/RT; patients without BTK mutations frequently acquired mutations associated with disease progression/RT in TP53 , SF3B1 , and CARD11 , whereas additional mutations were rare in patients with BTK ‐mutated CLL. Sequencing of all 29 patients at the time of disease progression/RT identified BTK mutations at a frequency of 66%, including a novel V537I mutation. Among patients with disease progression, BTK mutations were observed in 16 patients (70%). The median time to disease progression was shorter in patients without BTK mutations compared with those with BTK ‐mutated CLL. Among patients with RT, SF3B1 mutations were more frequent than BTK mutations (67% vs 50%). Following BTKi discontinuation, we sequential mutation analysis was performed in 2 patients with RT and 3 patients with disease progression in the setting of persistent disease. Both patients with RT demonstrated disappearance of BTK and expansion of TP53 mutations. All 3 patients with disease progression received venetoclax and demonstrated suppression of BTK mutations. Conclusions: Longitudinal, targeted, multigene deep sequencing is informative for the clinical monitoring of mutational evolution in patients with CLL who are receiving BTKi.
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Two separate studies observed no PLCγ2 or BTK mutations detected in patients with CLL before Ibrutinib treatment.
“Interestingly, two separate studies observed that there were no PLCγ2 or BTK mutations detected in patients with CLL before Ibrutinib treatment (127, 128).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [127]
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- Authors
- Kanagal‐Shamanna, R., Jain, P., Patel, K. P., Routbort, M., Bueso‐Ramos, C., Alhalouli, T., Khoury, J. D., Luthra, R., Ferrajoli, A., Keating, M., Jain, N., Burger, J., Estrov, Z., Wierda, W., Kantarjian, H. M., & Medeiros, L. J.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Department of Hematopathology The University of Texas MD Anderson Cancer Center Houston Texas
- Corresponding author
- Kanagal‐Shamanna, Rashmi
- Medeiros, L. Jeffrey
- ORCID
- Venue
- Cancer
- Publisher
- Wiley
- Published
- 2018-12-03
- Volume
- 125
- Issue
- 4
- Pages
- 559-574
- ISSN
- 0008-543X (ISSN-L)
- 1097-0142
- OpenAlex
- W2903504864
- Cited by
- 98
- References
- 38
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 16 · 2023: 7 · 2022: 14 · 2021: 22 · 2020: 13 · 2019: 11
- FWCI
- 6.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- chronic lymphocytic leukemia, BTK inhibitors, ibrutinib, acalabrutinib, BTK mutations, PLCG2 mutations, Richter transformation, disease progression, TP53 mutation, SF3B1 mutation, CARD11 mutation, venetoclax
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Cell Transformation, Neoplastic, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Mutation, Piperidines, Prognosis, Pyrazines, Pyrazoles, Pyrimidines, Biomarkers, Tumor, Cohort Studies, Leukemia, Lymphocytic, Chronic, B-Cell, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse, Disease Progression, Drug Resistance, Neoplasm, High-Throughput Nucleotide Sequencing
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