Publication Date:
2019-11-13
Description:
Background: Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase (BTK) inhibitor developed to minimize off-target activity. Acalabrutinib monotherapy shows promising safety and efficacy in CLL (Ghia et al 2019). However, a few patients (pts) develop resistance to acalabrutinib. A known mechanism of covalent BTK inhibitor resistance is acquired mutations in BTK (particularly Cys481) and its downstream target PLCg2. Alternate mechanisms and the contribution of the CLL microenvironment to acquired resistance remain to be elucidated. In this study, we performed cell surface phenotyping, intracellular signaling, and RNA-seq analyses on samples from 39 pts with relapsed/refractory or treatment-naive CLL from the ACE-CL-001 clinical trial (NCT02029443) to identify novel mechanisms of acalabrutinib resistance with focus on the CLL microenvironment. Methods : Pts were divided into 2 groups: those who continued to respond to treatment (non-progressed, NP, n=23) and those who developed progressive disease (progressed, PD, n=16) within 36 months of starting acalabrutinib. Blood mononuclear cells (PBMCs) were analyzed after 6 months of acalabrutinib therapy (100 mg twice a day) for the first (NP) group of patients, or at the time of progression for the second (PD) group of patients and compared with pre-treatment baseline. Expression of cell surface markers, including CD49d, CD38, and CD79b, was evaluated by flow cytometry. A 30% positive cut-off was used to identify pts that express high levels of CD49d, an α-chain of the VLA-4 integrin (Tissino, et al 2018), CD38, and CD79b. Intracellular flow cytometry was used to measure cell proliferation via Ki-67 staining. RNA-seq was used to measure changes in gene expression. Results: Cell surface phenotyping showed higher expression of CD49d (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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