Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia
Open accessAbstract
Key Points: Most cases of ibrutinib-resistant CLL were due to mutations in BTK and/or PLCG2 and often composed of multiple independent subclones. High sensitivity testing identified resistance mutations up to 15 months before manifestation of clinical progression.
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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 [12]
In “Resistance mutations at disease progression” (page unavailable), the paper reports BTK and/or PLCG2 mutations in 8 of 10 patients with progressive CLL, leaving 2 of 10 without detectable mutations—not the claimed 50% wild-type. Table 3 shows 5 of those 10 had both mutations, 1 had BTK alone, and 2 had PLCG2 alone. These proportions differ substantially from the percentages attributed to this source. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPrimary resistance, where a cBTKi fails to provide benefit, is uncommon and most often associated with Richter transformation.
“Primary resistance,where a cBTKi fails to provide benefit, is uncommon and most often associated with Richter transformation(12, 13).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [12]
The Discussion says transformation accounted for most early progression, and the Abstract reports transformation in 5 of 84 patients (6.0%). But the paper studies ibrutinib, not all covalent BTK inhibitors, and does not establish that these early progressions were primary resistance—failure to obtain benefit from treatment. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDuration of response with a BTKi is longer in settings where clonal complexity and evolutionary potential are lower, such as in treatment-naïve cases.
“Duration of response with a BTKi is longer in settings where clonal complexity and evolutionary potential are lower, such as in treatment-naïve cases(12, 14, 17).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [12]
The Progression-free survival section reports significantly shorter time to progression on ibrutinib in relapsed/refractory CLL than in treatment-naïve CLL, supporting longer disease control in the latter group. The paper does not establish that treatment-naïve cases have lower clonal complexity or evolutionary potential, or that those factors explain the difference. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCo-occurrence of BTK mutations within the same cell has not been demonstrated in patient samples.
“However, co-occurrence of BTK mutations within the same cell has not been demonstrated in patient samples(12, 23).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [12]
The Results and Discussion identify the distinct BTK mutations in patient PD9 as arising in separate subclones, not the same cell. The Discussion says the authors cannot exclude multiple mutations coexisting in a cell in other patients; it does not establish the broader claim that within-cell co-occurrence has never been demonstrated in patient samples. (LLM, conf=0.81)
Experimental — accuracy not yet measuredIn a study of 15 patients treated with ibrutinib, the VAF of BTK C481S ranged from 0.02 to 0.78.
“For example, in astudy of 15 patients treated with ibrutinib,the VAF of BTK C481S ranged from 0.02 to 0.78(12).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [12]
The Incidence and biology of progressive disease section reports that 15 of 84 ibrutinib-treated patients progressed; the study was not limited to 15 patients. Table 3 lists BTK C481S VAFs from 1.6% to 78.2%, approximately 0.02 to 0.78 when expressed as fractions and rounded. (LLM, conf=0.90)
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 [12]
The Discussion (page unavailable) lists C481R, C481F, and C481Y and explains that replacing C481 removes the residue to which ibrutinib binds covalently, leading to loss of sustained inhibition. It does not identify C481A or establish the claimed relative rarity of other C481 substitutions; it also does not directly describe the resulting bond as unstable. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMutations in PLCγ2 and/or Btk have been reported in 11 to 90% of cases of Ibrutinib-refractory CLL.
“Mutations in PLCγ2 and/or Btk have been reported in 11 to 90% cases of Ibrutinib-refractory CLL, further underscoring the importance of better understanding the process by which the partnership of Btk and PLCγ2 drives CLL disease progression (122, 123, 124, 125, 126).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [122]
The Discussion reports BTK and/or PLCG2 mutations in 80.0% of patients progressing with CLL, supporting their prevalence in ibrutinib-resistant disease. The cited paper does not establish the stated 11%–90% range; it supplies one figure within that range. (LLM, conf=0.83)
Experimental — accuracy not yet measuredA subset of patients with CLL become refractory to Ibrutinib treatment over time and relapse, with PLCγ2 as a primary driver of the recurrent disease.
“However, a subset of patients become refractory to this treatment over time and relapse, with PLCγ2 as a primary driver of the recurrent disease (122, 123).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [122]
The Abstract reports that 15 of 84 patients progressed during ibrutinib treatment, including 10 with progressive CLL. The Discussion identifies BTK and/or PLCG2 mutations in 80% of patients progressing with CLL, but does not establish PLCγ2 alone as the primary driver of recurrence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIbrutinib-resistant CLL often harbors several subclones with BTK C481 and PLCG2 mutations; different growth rates of these subclones are most consistent with each mutation arising in an independent ancestor.
“Ibrutinib-resistant CLL often harbors several subclones with BTK C481 and PLCG2mutations; different growth rates of these subclones aremost consistent with each mutation arising in an independent ancestor (12).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [12]
Continuous BTKi therapy exerts a strong selective pressure, with resistant subclones often emerging after years of treatment.
“Likewise, continuous BTKi therapy exerts a strong selective pressure, with resistant subclones often emerging after years of treatment(12, 17, 18).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [12]
Most BTK mutations are single base pair substitutions affecting C481.
“Most BTK mutations are single base pair substitutions affecting C481(Figure 3) (12, 34).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [12]
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 [12]
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Cites
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275 · cited 9× · see citing works
“Resistance mutations at disease progression Mutations previously identified in CLL patients who progressed on ibrutinib affect exon 15 of BTK (C481S) and exons 19 (R665W), 20 (S707F, P or Y), and 24 (L845F) of PLCG2.”
BackgroundResultInfluentialMaddocks, K. J., Ruppert, A. S., Lozanski, G., Heerema, N. A., Zhao, W., Abruzzo, L., Lozanski, A., Davis, M., Gordon, A., Smith, L. L., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2014.218 · Cited by 584 · see citing works
Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)
Komarova, N. L., Burger, J. A., & Wodarz, D. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409362111 · Cited by 98 · see citing works
Walliser, C., Hermkes, E., Schade, A., Wiese, S., Deinzer, J., Zapatka, M., Désiré, L., Mertens, D., Stilgenbauer, S., & Gierschik, P. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.746842 · Cited by 51 · cited 1× · see citing works
“Further, R665W and L845F mutations were shown to increase sensitivity of PLCγ2 to Rac2 and reconstitute downstream BCR signaling independent of BTK activation.(37) Ibrutinib resistant CLL often harbored several subclonal mutations.”
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“However, a subset of patients become refractory to this treatment over time and relapse, with PLCγ2 as a primary driver of the recurrent disease (122, 123).”
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Self-citationResistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy
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“Most BTK mutations are single base pair substitutions affecting c481 (Figure 2) [12,33]. the first reported BTK mutation in cll patients with progressive disease on ibrutinib [19,34] was a missense mutation changing c481 to serine (c481S) [19]. the c481S mutation disrupts the covalent binding of…”
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- Authors
- Ahn, I. E., Underbayev, C., Albitar, A., Herman, S. E. M., Tian, X., Maric, I., Arthur, D. C., Wake, L., Pittaluga, S., Yuan, C. M., Stetler-Stevenson, M., Soto, S., Valdez, J., Nierman, P., Lotter, J., Xi, L., Raffeld, M., Farooqui, M., Albitar, M., & Wiestner, A.
- Affiliations
- National Cancer Institute (MY)
- National Institutes of Health (US)
- NeoGenomics (United States) (US)
- National Heart, Lung, and Blood Institute (US)
- Department of Laboratory Medicine, Clinical Center, and
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Corresponding author
- Ahn, Inhye E.
- Underbayev, Chingiz
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2017-03-16
- Volume
- 129
- Issue
- 11
- Pages
- 1469-1479
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC5356450
- OpenAlex
- W2566053885
- Cited by
- 341
- References
- 4
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 36 · 2023: 40 · 2022: 27 · 2021: 58 · 2020: 40 · 2019: 53 · 2018: 35 · 2017: 23
- FWCI
- 23.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Pharmacyclics
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- ibrutinib resistance, chronic lymphocytic leukemia, clonal evolution, Bruton's tyrosine kinase, subclonal heterogeneity, disease progression, salvage therapy
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Adenine, Aged, Cell Transformation, Neoplastic, Follow-Up Studies, Humans, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Disease Progression, Disease-Free Survival, Drug Resistance, Neoplasm, Phospholipase C gamma, Clonal Evolution
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