Clin Cancer Res. 2023 May 9:CCR-22-3217. doi: 10.1158/1078-0432.CCR-22-3217. Online ahead of print.
ABSTRACT
PURPOSE: To determine the role of CD49d for response to Bruton’s tyrosine kinase inhibitors (BTKis) in patients with chronic lymphocytic leukemia (CLL).
METHODS: In patients treated with acalabrutinib (n=48), CD49d expression, VLA-4 integrin activation, and tumor transcriptomes of CLL cells were assessed. Clinical responses to BTKis were investigated in acalabrutinib (n=48; NCT02337829), and ibrutinib (n=73; NCT01500733) treated patients.
RESULTS: In patients treated with acalabrutinib, treatment induced lymphocytosis was comparable for both subgroups but resolved more rapidly for CD49d+ cases. Acalabrutinib inhibited constitutive VLA-4 activation but was insufficient to block BCR and CXCR4 mediated inside-out activation. Transcriptomes of CD49d+ and CD49d- cases were compared using RNA sequencing at baseline and at 1 and 6 months on treatment. Gene set enrichment analysis revealed increased constitutive NF-кB and JAK-STAT signaling, enhanced survival, adhesion, and migratory capacity in CD49d+ over CD49d- CLL that was maintained during therapy. In the combined cohorts of 121 BTKi treated patients, 48 (39.7%) progressed on treatment with BTK and/or PLCG2 mutations detected in 87% of CLL progressions. Consistent with a recent report, homogeneous and bimodal CD49d positive cases (the latter having concurrent CD49d+ and CD49d- CLL subpopulations, irrespective of the traditional 30% cutoff), had a shorter time to progression of 6.6 years, while 90% of cases homogenously CD49d negative were estimated progression-free at 8 years (P = .0004).
CONCLUSIONS: CD49d/VLA-4 emerges as a microenvironmental factor that contributes to BTKi resistance in CLL. The prognostic value of CD49d is improved by considering bimodal CD49d expression.
PMID:37159219 | DOI:10.1158/1078-0432.CCR-22-3217
