Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib
- Author(s)
- Woyach, JA; Jones, D; Jurczak, W; Robak, T; Illés, Á; Kater, AP; Ghia, P; Byrd, JC; Seymour, JF; Long, S; Mohamed, N; Benrashid, S; Lai, TH; De Jesus, G; Lai, R; de Bruin, G; Rule, S; Munugalavadla, V;
- Details
- Publication Year 2024-09-05,Volume 144,Issue #10,Page 1061-1068
- Journal Title
- Blood
- Publication Type
- Research article
- Abstract
- Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF, 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and 1 ibrutinib-treated patient had emergent TP53/BTK comutations. Emergent PLCG2 mutations occurred in 3 acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696.
- Publisher
- American Society of Hematology
- Keywords
- Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; *Adenine/analogs & derivatives; *Agammaglobulinaemia Tyrosine Kinase/genetics/antagonists & inhibitors; *Benzamides/therapeutic use; Disease Progression; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/genetics; *Mutation; *Piperidines/therapeutic use; Protein Kinase Inhibitors/therapeutic use/adverse effects/administration & dosage; *Pyrazines/therapeutic use/administration & dosage; *Pyrazoles/therapeutic use; *Pyrimidines/therapeutic use/administration & dosage
- Department(s)
- Clinical Haematology
- Publisher's Version
- https://doi.org/10.1182/blood.2023023659
- Open Access at Publisher's Site
https://doi.org/10.1182/blood.2023023659- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-10-01 07:37:07
Last Modified: 2024-10-01 07:37:20