Molecular Profiling Identifies CD49d and CD79b as Predictive Markers for Acquired Acalabrutinib Resistance in...

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Bruton tyrosine kinase inhibitors (BTKi) are effective for chronic lymphocytic leukemia (CLL).
• Mechanisms of acquired resistance to BTKi, particularly second-generation inhibitors like acalabrutinib, are not fully understood.
• Identifying novel predictive markers for BTKi resistance is crucial for optimizing CLL treatment strategies.

Purpose of the Study:

• To identify novel predictive markers of acquired resistance to acalabrutinib in patients with CLL.
• To investigate alternative mechanisms of resistance beyond the B-cell receptor (BCR) pathway.
• To evaluate the utility of specific cell surface markers as predictors of treatment response.

Main Methods:

• Analysis of clinical samples from 41 patients with CLL receiving acalabrutinib (NCT02029443).
• Profiling of peripheral blood mononuclear cells (PBMCs) at baseline and a second timepoint using RNA-seq and flow cytometry.
• Comparison of patients who responded to treatment versus those who developed progressive disease.

Main Results:

• Acquired resistance to acalabrutinib correlated with upregulation of integrin alpha-4 (ITGA4; CD49d), CD79B, MYC, LAG3, and MCL1.
• High baseline surface expression of CD49d and CD79b predicted increased risk of disease progression on acalabrutinib.
• Patients with high CD49d expression showed reduced acalabrutinib-induced lymphocytosis and higher tumor proliferation markers (CD38, Ki-67).

Conclusions:

• CD49d and CD79b are significant predictive markers for CLL progression during acalabrutinib therapy.
• These markers may help identify patients at higher risk of resistance, enabling personalized treatment approaches.
• The findings expand the understanding of resistance mechanisms to BTKi in CLL beyond BCR pathway mutations.