Molecular Profiling Identifies CD49d and CD79b as Predictive Markers for Acquired Acalabrutinib Resistance in Patients With Chronic Lymphocytic Leukemia

• DOI: 10.1002/hon.70008
• Publication Date: 2024-12-24T05:42:23Z
• Authors: Elena Bibikova; Sara Parsa; Muskan Floren; Brian Law; Tracy Clevenger; Jean Cheung; Gary De Jesus; Kathleen Burke; Michael Gulrajani; Kyoko Yamaguchi; Phuong Do; Brian Dougherty; David Whitston; Graham Brock; Veerendra Munugal...; Melanie M. Frigault; Tanja N. Hartmann; John C. Byrd; Richard R. Furman; Jennifer R. Brown; Todd Covey; Andrew Mortlock
• Keywords: 0303 health sciences; 03 medical and health sciences; 610

ABSTRACT Contemporary studies of Bruton tyrosine kinase inhibitor (BTKi) resistance focus on mutations in the B‐cell receptor (BCR) pathway, but alternative mechanisms remain undefined. Here, we sought to identify novel predictive markers acquired acalabrutinib, a second‐generation BTKi, patients with chronic lymphocytic leukemia (CLL). Clinical samples from 41 relapsed/refractory or treatment‐naive CLL receiving acalabrutinib as part clinical trial (NCT02029443) were divided into two groups: those who continued respond treatment (NP, n = 23) and developed progressive disease therapy (PD, 18). Peripheral blood mononuclear cells (PBMCs) groups profiled at baseline (BL) second timepoint (T2) by RNA‐seq flow cytometry. Our findings show correlation between upregulation integrin alpha‐4 ( ITGA4 ; CD49d), BCR surface CD79B , oncogenes such MYC LAG3 MCL1 cells. High expression CD49d CD79b prior was associated increased risk progression CLL. When stratified pretreatment expression, hi group (defined ≥ 30% CD49d+ baseline) showed reduced acalabrutinib‐induced lymphocytosis higher levels tumor proliferation CD38 Ki‐67 compared lo < baseline). In summary, are useful for acalabrutinib. Trial Registration: ClinicalTrials.gov identifier: NCT02029443