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Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia
Open accessAbstract
IMPORTANCE: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up. OBJECTIVE: To determine features associated with discontinuation of ibrutinib therapy and outcomes. DESIGN, SETTING, AND PARTICIPANTS: A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014. MAIN OUTCOMES AND MEASURES: Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse. RESULTS: With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient. CONCLUSIONS AND RELEVANCE: This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not. TRIAL REGISTRATIONS: clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.
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“In published studies of disease progression during BTKi therapy,approximately 35% of patients were found to have aBTK mutation alone, an additional 10% had a coexisting mutations in PLCG2, 5% of cases had a PLCG2mutation alone, and the remaining 50% were wild-type (WT) for BTK and PLCG2 (Figure 2)(12, 19, 21–31).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [27]
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“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 [128]
In the citing paper
“While the most common ibrutinib-resistant BTK mutant is C481S, other mutants observed in patients include C481R, C481F, C481Y, T474I, and T474S.33”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [33]
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Self-citationIdelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia
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Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia
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Self-citationResistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
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Self-citationStilgenbauer, S., Eichhorst, B. F., Schetelig, J., Coutre, S. E., Seymour, J. F., Munir, T., Puvvada, S. D., Wendtner, C., Roberts, A. W., Jurczak, W. J., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30019-5 · Cited by 809
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Metadata
- Authors
- Maddocks, K. J., Ruppert, A. S., Lozanski, G., Heerema, N. A., Zhao, W., Abruzzo, L., Lozanski, A., Davis, M., Gordon, A., Smith, L. L., Mantel, R., Jones, J. A., Flynn, J. M., Jaglowski, S. M., Andritsos, L. A., Awan, F., Blum, K. A., Grever, M. R., Johnson, A. J., Byrd, J. C., & Woyach, J. A.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Woyach, Jennifer A.
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-04-01
- Volume
- 1
- Issue
- 1
- Pages
- 80
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC4520535
- OpenAlex
- W1999128869
- Cited by
- 584
- References
- 21
- Citations by year
- 2026: 13 · 2025: 29 · 2024: 35 · 2023: 38 · 2022: 47 · 2021: 59 · 2020: 65 · 2019: 72 · 2018: 60 · 2017: 85 · 2016: 64 · 2015: 16
- FWCI
- 41.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (4p01ca081534-16)
- National Cancer Institute (P01CA095426, U10CA180861, P50CA140158, R01CA183444, P01CA95426, K23CA178183, R01CA177292, P01-CA-081534)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Keywords
- chronic lymphocytic leukemia, BTK inhibitors, treatment discontinuation, Richter transformation, BTK mutations, PLCG2 mutations, relapse, deep sequencing, prognostic factors, sequential clinical trials, targeted therapy resistance
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Adult, Aged, Aged, 80 and over, Clinical Trials as Topic, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Mutation, Ohio, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Recurrence, Risk Factors, Time Factors, Biomarkers, Tumor, Leukemia, Lymphocytic, Chronic, B-Cell, Treatment Outcome, Disease Progression, Protein Kinase Inhibitors, Phospholipase C gamma, Kaplan-Meier Estimate, Molecular Targeted Therapy, High-Throughput Nucleotide Sequencing
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