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Cited by 484Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

BTK C481S -Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia

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Woyach, Jennifer A., Ruppert, Amy S., Guinn, Daphne, Lehman, Amy, Blachly, James S., Lozanski, Arletta, Heerema, Nyla A., Zhao, Weiqiang +24 more·2017·Journal of Clinical Oncology
DOI 10.1200/jco.2016.70.2282PMC PMC5455463
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Abstract

Purpose: Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods: Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results: With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion: Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

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  • In published studies of disease progression during BTKi therapy, approximately 35% of patients were found to have a BTK mutation alone, an additional 10% had coexisting mutations in PLCG2, 5% had a PLCG2 mutation alone, and the remaining 50% were wild-type for BTK and PLCG2.

    “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 [24]

    The Results section reports mutations in both BTK and PLCG2 in 6 of 46 patients (13%) and PLCG2 alone in 3 of 46 (7%), roughly consistent with two of the claimed proportions. But it reports BTK alone in 31 of 46 (67%), leaving 6 of 46 (13%) with neither mutation—not the claimed 35% and 50%. These are findings from this paper's ibrutinib cohort, not an aggregate of published BTKi studies. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Additional missense mutations of C481 have been identified which make the BTK-ibrutinib bond reversible and unstable, including C481A, C481R, C481F, and C481Y, among others at C481 which are less common.

    “Subsequently, additional missense mutations of C481 have been identified which make the BTK-ibrutinib bond reversible and unstable, including C481A, C481R, C481F, and C481Y, among others at C481 which are less common (12, 24, 36).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [24]

    The Introduction (page not provided) says BTK C481S makes ibrutinib binding reversible and reduces its affinity, and the Results report C481 mutations in patients with progressive CLL. Our copy does not identify C481A, C481R, C481F, or C481Y, establish that those variants have the same effect, or describe their relative frequency. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Mutations of PLCG have been observed to co-occur with BTK mutations in the same patient.

    “Mutations of PLCG have been observed to co-occur with BTK mutations in the same patient (12, 19, 24).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [24]

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Research works printed but not linked: 12

  1. [1]Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287–6296. doi: 10.1182/blood-2011-01-328484. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  2. [2]Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123:3286–3295. doi: 10.1182/blood-2014-02-548610. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  3. [3]Woyach JA, Bojnik E, Ruppert AS, et al. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL) Blood. 2014;123:1207–1213. doi: 10.1182/blood-2013-07-515361. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  4. [5]Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213–223. doi: 10.1056/NEJMoa1400376. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  5. [6]Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437. doi: 10.1056/NEJMoa1509388. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  6. [9]Cheng S, Guo A, Lu P, et al: Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: Exploration of alternative kinase inhibitors. Leukemia 29:895-900, 2015 [DOI] [PubMed]
  7. [10]Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352–2354. doi: 10.1056/NEJMc1402716. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  8. [11]Liu TM, Woyach JA, Zhong Y, et al: Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood 126:61-68, 2015 [DOI] [PMC free article] [PubMed]
  9. [13]Thompson PA, O’Brien SM, Wierda WG, et al. Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens. Cancer. 2015;121:3612–3621. doi: 10.1002/cncr.29566. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  10. [14]Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42. doi: 10.1056/NEJMoa1215637. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  11. [15]Maddocks K, Flynn JM, Andritsos L, et al: A phase II study of the BTK inhibitor ibrutinib in genetic risk-stratified relapsed and refractory patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). European Hematology Association Annual Meeting, Milan, Italy, June 12-15, 2014 (abstr S1343) [Google Scholar]
  12. [16]Jaglowski SM, Jones JA, Nagar V, et al. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: A phase 1b/2 study. Blood. 2015;126:842–850. doi: 10.1182/blood-2014-12-617522. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI

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Authors
Woyach, J. A., Ruppert, A. S., Guinn, D., Lehman, A., Blachly, J. S., Lozanski, A., Heerema, N. A., Zhao, W., Coleman, J., Jones, D., Abruzzo, L., Gordon, A., Mantel, R., Smith, L. L., McWhorter, S., Davis, M., Doong, T.-J., Ny, F., Lucas, M., Chase, W., Jones, J. A., Flynn, J. M., Maddocks, K., Rogers, K., Jaglowski, S., Andritsos, L. A., Awan, F. T., Blum, K. A., Grever, M. R., Lozanski, G., Johnson, A. J., & Byrd, J. C.
Affiliations
The Ohio State University (US)
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2017-05-01
Volume
35
Issue
13
Pages
1437-1443
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.2016.70.2282
PMC
PMC5455463
OpenAlex
W2589238872
Cited by
484
References
2
Citations by year
2026: 27 · 2025: 35 · 2024: 62 · 2023: 58 · 2022: 49 · 2021: 80 · 2020: 60 · 2019: 52 · 2018: 37 · 2017: 23
FWCI
27.02
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Oncology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (P01CA095426, R35CA197734, P50CA140158, R01CA183444, K23CA178183, R01CA197870, P30CA016058, R01CA177292, P30CA014236)
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, ibrutinib, Bruton's tyrosine kinase, BTK C481S mutation, PLCG2 mutations, acquired resistance mutations, relapse, relapse biomarkers
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Humans, Male, Middle Aged, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Drug Resistance, Neoplasm, Phospholipase C gamma, Antibodies, Monoclonal, Humanized

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