CD49d Protein Contributes to BTKi Resistance in CLL

Expression of the adhesion protein CD49d identifies a biologically distinct subtype of chronic lymphocytic leukemia (CLL) with inferior progression-free survival (PFS) for patients on Bruton’s tyrosine kinase inhibitor (BTKi) therapy, according to a new study.

The study assessed CD49d expression, VLA-4 integrin activation, and tumor transcriptomes of CLL cells in patients treated with acalabrutinib (n=48). In addition, clinical responses to BTKis were investigated in patients treated with acalabrutinib (n=48) and ibrutinib (n=73).

In patients treated with acalabrutinib, treatment-induced lymphocytosis was comparable for both subgroups but resolved more rapidly for CD49d-positive cases. Acalabrutinib inhibited constitutive VLA-4 activation but was insufficient to block BCR and CXCR4-mediated inside-out activation, according to the researchers.

Transcriptomes of CD49d-positive and CD49d-negative cases were compared using RNA sequencing at baseline and at one and six months on treatment. Gene set enrichment analysis revealed increased constitutive NF-κB and JAK-STAT signaling, enhanced survival, adhesion, and migratory capacity in CD49d-positive over CD49d-negative CLL that was maintained during therapy.

In the combined cohorts of 121 BTKi-treated patients, 48 (39.7%) progressed on treatment with BTK or PLCG2 mutations detected in 87% of CLL progressions. Homogeneous and bimodal CD49d-positive cases had a shorter time to progression of 6.6 years, whereas 90% of homogenous CD49d-negative cases had an estimated progression-free survival of eight years (P=.0004).

“CD49d/VLA-4 emerges as a microenvironmental factor that contributes to BTKi resistance in CLL,” the authors wrote. “The prognostic value of CD49d is improved by considering bimodal CD49d expression.”

Reference

Alsadhan A, Chen J, Gaglione EM, et al. CD49d Expression identifies a biologically subtype of chronic lymphocytic leukemia with inferior progression-free survival on BTK inhibitor therapy [published online ahead of print, 2023 May 25]. Clin Cancer Res. 2023;OF1-OF10. doi:10.1158/1078-0432.CCR-22-3217