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Characterization of Mechanisms of Resistance in Previously Treated Chronic Lymphocytic Leukemia (CLL) From a Head‐to‐Head Trial of Acalabrutinib Versus Ibrutinib
Open accessAbstract
Introduction: Acalabrutinib (Acala) is a highly selective, next-generation covalent Bruton tyrosine kinase inhibitor (BTKi) approved for CLL. In ELEVATE-RR (NCT02477696) at a median follow-up of 41 mo, Acala demonstrated noninferior progression-free survival with fewer cardiovascular adverse events versus ibrutinib (Ibr) in patients (pts) with relapsed/refractory (R/R) CLL. Disease progression on covalent BTKis is often characterized by acquisition of B-cell receptor pathway mutations, but no data have compared mutational profiles of Acala versus Ibr. We report clonal evolution data in pts with CLL progressing on Acala versus Ibr in ELEVATE-RR. Methods: Peripheral blood samples at baseline and relapse from pts in ELEVATE-RR were used. DNA was extracted from enriched CD19+ cells (RoboSep) and subjected to a 50-gene sequencing assay panel with a sensitivity cutoff for BTK and PLCG2 resistance–associated mutations at 0.5% variant allele fraction (VAF). Forty-eight other CLL-associated genes were assessed at 1%–2% VAF. Results: Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) and 30 (excluding 6 Richter) pts in the Acala and Ibr groups, respectively. At progression, emergent BTK mutations were seen in 31 (66%) Acala versus 11 (37%) Ibr pts (P = 0.02) (Figure 1; median VAF: 5.7 vs. 5.8). Emergent PLCG2 mutations occurred in 3 (6%) Acala vs. 6 (20%) Ibr pts (P = 0.14). Only 1 Acala pt had co-occurrence of BTK and PLCG2 mutations versus 4 Ibr pts. BTK C481S, C481Y, and C481R mutations occurred at similar frequency in both groups; a novel E41V mutation within the pleckstrin homology domain of BTK (median VAF: 16%) was seen in 1 Acala pt. L528W and A428D co-mutations were observed in 1 Ibr pt. Six Acala pts had TP53 and BTK co-mutations. Emergent TP53 mutations were seen in both groups (13% [Acala] vs. 7% [Ibr], P = 0.47; median VAF: 5% [Acala] versus 37% [Ibr]). Only 2 Ibr pts had TP53 mutations (1 had TP53/BTK co-mutation). No statistical difference was seen in the proportions of Acala versus Ibr pts who acquired BTK mutations among pts with del(17p) (39% vs. 64%; P = 0.18), del(11q) (77% vs. 46%; P = 0.07), complex karyotype (58% vs. 73%; P = 0.48), unmutated IGHV (90% vs. 100%; P = 0.55), or trisomy 12 positivity (3% vs. 18%; P = 0.16). Additional mutations (Acala vs. Ibr) included DNMT3A (5 vs. 1 pts), TET2 (1 pt for each), and NRAS (1 pt; Acala only). The research was funded by: AstraZeneca Keywords: Chronic Lymphocytic Leukemia (CLL), Genomics, Epigenomics, and Other -Omics, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. J. A. Woyach Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Genentech, Janssen, Merck, Loxo/Lilly, Newave, Pharmacyclics Research funding: Abbvie, Janssen, Karyopharm Therapeutics, Loxo/Lilly, Pharmacyclics, Schrodinger D. Jones Research funding: Abbvie, Acerta/AstraZeneca, Pharmacyclics, Novartis, MingSight, Other remuneration: The Ohio State University: High sensitivity BTK mutation profiling W. Jurczak Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Lilly, Roche, Takeda Research funding: Abbvie, AstraZeneca, BeiGene, Janssen, Lilly, Roche, Takeda T. Robak Consultant or advisory role: AstraZeneca, BeiGene, Janssen Oncology Honoraria: AstraZeneca, BeiGene, Janssen Research funding: AstraZeneca, BeiGene, Janssen A. Illés Employment or leadership position: University of Debrecen Honoraria: Janssen, Celgene, Novartis, Pfizer, Takeda, Roche Research funding: Takeda, Seattle Genetics A. P. Kater Consultant or advisory role: AstraZeneca, BMS, Roche/Genentech, Janssen, AbbVie, LAVA Research funding: AstraZeneca, BMS, Roche/Genentech, Janssen, AbbVie Other remuneration: Janssen, LAVA, AbbVie, AstraZeneca P. Ghia Honoraria: AbbVie, AstraZeneca, Janssen, BMS, MSD, Loxo Oncology/Lilly, and Roche Research funding: AbbVie, AstraZeneca, Janssen, and BMS J. C. Byrd Consultant or advisory role: Janssen, Novartis, Syndax, Newave, AstraZeneca, Kura, Vincerx, Trilrom, Abbvie Stock ownership: Vincerx Research funding: Zencor, Pharmacyclics Educational grants: Janssen, Novartis Other remuneration: Ohio State University J. F. Seymour Consultant or advisory role: AbbVie, AstraZeneca, Celgene, Genentech, Genor Bio, Gilead, Janssen, Morphosys, Roche, Sunesis, TG Therapeutics Research funding: Abbvie, Celgene, Janssen, Roche Other remuneration: Abbvie, Celgene, Roche, TG Therapetics G. De Jesus Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca R. Lai Employment or leadership position: AstraZeneca G. de Bruin Employment or leadership position: Acerta Pharma B.V. A. Butturini Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca, Amgen, Roche S. Rule Employment or leadership position: AstraZeneca V. Munugalavadla Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca; Gilead Sciences
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There is a tendency for T747I mutations with acalabrutinib and L528W mutations with zanubrutinib among others.
“There is a tendency for T747I mutations with acalabrutinib and L528W mutations with zanubrutinib among others (Figure 3)(20–22).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [21]
The results in section 63 report L528W and A428D co-mutations in one ibrutinib-treated patient, not a tendency with zanubrutinib. The paper compares acalabrutinib with ibrutinib and does not report T747I with acalabrutinib. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIbrutinib, acalabrutinib, and zanubrutinib bind covalently to residue C481 of BTK, and thus are susceptible to mutations changing C481 to another amino acid, most commonly C481S.
“Ibrutinib, acalabrutinib, and zanubrutinib bind covalently to residue C481 of BTK, and thus are susceptible to mutations changing C481 to another amino acid, most commonly C481S(19–21).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [21]
In section 63 (page not given), the Introduction describes acalabrutinib as a covalent BTK inhibitor, and the Results report BTK C481S, C481Y, and C481R mutations in both the acalabrutinib and ibrutinib groups at progression. The copy does not discuss zanubrutinib, explicitly identify C481 as the binding residue, or establish that C481S is the most common substitution. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn 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 [21]
The Results (section 63; page not provided) report BTK and PLCG2 mutations, including co-occurrence, among 77 patients whose CLL progressed on acalabrutinib or ibrutinib. The reported counts imply about 5% had PLCG2 mutations alone, but they do not support the claimed 35% BTK-only, 10% co-mutated, and 50% wild-type breakdown; the paper also does not present those figures as a summary of published studies. (LLM, conf=0.86)
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Cited by 12
Metadata
- Authors
- Woyach, J. A., Jones, D., Jurczak, W., Robak, T., Illés, A., Kater, A. P., Ghia, P., Byrd, J. C., Seymour, J. F., Long, S., Mohamed, N., De Jesus, G., Lai, R., de Bruin, G., Butturini, A., Rule, S., & Munugalavadla, V.
- Affiliations
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- The Ohio State University (US)
- The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
- Medical University of Lodz (PL)
- University of Debrecen Debrecen Hungary
- Hovon (NL)
- Vita-Salute San Raffaele University (IT)
- University of Cincinnati (US)
- The Royal Melbourne Hospital (AU)
- The Ohio State University Wexner Medical Center (US)
- AstraZeneca South San Francisco California USA
- AstraZeneca (United States) (US)
- Acerta Pharma BV (Netherlands) (NL)
- AstraZeneca (Canada) (CA)
- ORCID
- Venue
- Hematological Oncology
- Publisher
- Wiley
- Published
- 2023-06
- Volume
- 41
- Issue
- S2
- Pages
- 249-250
- ISSN
- 0278-0232 (ISSN-L)
- 1099-1069
- OpenAlex
- W4379981441
- Cited by
- 12
- References
- 0
- Citations by year
- 2025: 4 · 2024: 7 · 2023: 1
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hematological Oncology (publishedVersion)
- Funders
- AstraZeneca
- 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
- acalabrutinib, ibrutinib, chronic lymphocytic leukemia, relapsed/refractory CLL, BTK inhibitors, PLCG2 mutations, clonal evolution, B cell receptor signaling
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