Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib

Abstract

BACKGROUND Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. METHODS We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. RESULTS We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell–receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. CONCLUSIONS Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell–receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.)

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

“…Additionally, in patients with del(17p) in PCYC‐1102/1103, cytogenetic complexity present at treatment initiation was associated with shorter PFS and OS despite similar rates of initial response; this analysis was limited by baseline imbalances and small sample size. Woyach et al (2014) described characteristic resistance mutations arising during ibrutinib treatment among patients with CLL progression, and a subsequent report detailing outcomes from a large single‐institution cohort of ibrutinib‐treated CLL patients found that the presence of a complex karyotype rather than del(17p) was associated with a 4‐fold increase in the risk for discontinuation due to disease progression during ibrutinib treatment (Maddocks et al , 2015). Findings from subsequent studies also suggest that cytogenetic complexity is a prognostic marker of poorer outcomes in the presence or absence of del(17p) (Thompson et al , 2015; Yu et al , 2017).…”

“…The extent of prior exposure to cytotoxic chemotherapy is associated with clonal evolution to genetically high‐risk disease, including del(17p) and cytogenetic complexity (Brejcha et al , 2014; Malcikova et al , 2015), further suggesting that precision therapeutics should be used earlier in the course of disease. Likewise, the likelihood that patients in this high‐risk group with R/R disease may develop resistance to a single‐agent targeted therapy provides a compelling rationale for combination treatment approaches (Woyach et al , 2014). Although combinations with anti‐CD20 monoclonal antibodies and chemoimmunotherapy appear unlikely to significantly improve outcomes in patients with del(17p), including CR rates, over those seen with ibrutinib alone, combinations with other novel agents appear more promising (Sharman et al , 2017).…”

Efficacy of cisplatin-based immunochemotherapy plus alloSCT in high-risk chronic lymphocytic leukemia: final results of a prospective multicenter phase 2 HOVON study

“…resistance to targeted therapy 50 are not expected to affect the response to cisplatin-based induction. …”

The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies

“…12 Acalabrutinib monotherapy has shown promising activity in animal models of CLL and lymphoma 13,14 and in CLL patients. 1,15 Like ibrutinib, acalabrutinib is already being tested in combination with anti-CD20 monoclonal antibodies, in particular in B-cell non-Hodgkin lymphoma (www.clinicaltrials.com). The data presented here suggest that acalabrutinib may be usefully combined with these antibodies.…”