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.).
Article: Transplant for CLL: still an option?Blood 12/2014; 124(26):3835-6. · 9.78 Impact Factor
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ABSTRACT: Ibrutinib (PCI-32765)-a potent, covalent inhibitor of Bruton tyrosine kinase (BTK), an important kinase in the B-cell receptor signaling pathway-was recently approved by the FDA for the treatment of relapsed or refractory mantle cell lymphoma (MCL). The drug was granted accelerated approval based on the findings of an international, multicenter, single-arm phase II study that enrolled patients with relapsed or refractory MCL. In the study, ibrutinib (560 mg daily) was well tolerated as a single agent and resulted in an overall response rate of 68% and an estimated median response duration of 17.5 months. Ibrutinib's response rate and duration of response compare favorably with those for other novel agents approved for the treatment of relapsed or refractory MCL, while being less toxic than most chemotherapy or chemoimmunotherapy regimens. Ibrutinib is currently being studied in combination with chemoimmunotherapy, monoclonal antibody therapy, and novel agents in both the initial and the relapsed/refractory treatment settings. We review the mechanism of action, preclinical and clinical development, and the role of ibrutinib in the context of other available treatments. Clin Cancer Res; 20(21); 5365-71. ©2014 AACR.Clinical Cancer Research 11/2014; 20(21):5365-71. · 8.19 Impact Factor
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ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (CLL) (i.e., refractory to purine analogues, short response (< 24 months) to chemoimmunotherapy, and/or presence of 17p-/TP53 mutations). Currently, treatment algorithms for HR-CLL are being challenged by the introduction of novel classes of drugs. Among them, BCR-signal inhibitors (BCRi) and BCL2 antagonists (BCL2a) appear particularly promising. As a result of the growing body of favourable outcome data reported for BCRi/BCL2a, uncertainty is emerging on how to advise patients with high-risk CLL about indication and timing of HSCT. This position paper provides an overview of currently available evidence and theoretical considerations to guide this difficult decision process. As long as the risks and benefits of different treatment strategies are not settled, all patients with high-risk CLL should be considered for treatment with BCRi/BCL2a. For those patients responding to these agents there are two treatment possibilities: (1) performing an HSCT, and (2) to continue on the novel drug. Individual disease-specific and transplant-related risk factors, along with patient's preferences, should be taken into account when advising one of these treatments over the other.Blood 10/2014; · 9.78 Impact Factor