Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia

Abstract

Background Irreversible inhibition of Bruton tyrosine kinase (Btk) by ibrutinib represents a significant therapeutic advance for chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromise its therapeutic index. Acalabrutinib (ACP-196) is a more selective irreversible Btk inhibitor specifically designed to improve upon the safety and efficacy of first generation Btk inhibitors. Methods Sixty-one patients with relapsed CLL were treated in a phase 1–2 multicenter study designed to assess the safety, efficacy, pharmacokinetics and pharmacodynamics of oral acalabrutinib. Patients were continuously treated with acalabrutinib 100 to 400 mg once daily in the dose-escalation portion of the study, and 100 mg twice daily in the expansion portion. Results Patient demographics include a median age of 62 years; median of 3 prior therapies; 31% del(17)(p13.1) and 75% unmutated immunoglobulin heavy chain variable genes. No dose-limiting toxicities occurred. The most common adverse events observed were headache (43%), diarrhea (39%) and increased weight (26%). Most adverse events were Grade 1–2. At a median follow-up of 14.3 months, the best overall response rate was 95%, including 85% partial response, 10% partial response with lymphocytosis and 5% stable disease. In patients with del(17)(p13.1), the best overall response was 100%. No cases of Richter’s transformation and only 1 CLL progression have occurred. Conclusions Acalabrutinib is a highly selective Btk inhibitor that provides effective and well tolerated treatment for patients with relapsed CLL, including those with del(17)(p13.1).

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

“…Finally acalabrutinib has little toxicity on platelets which is an off-target effect of ibrutinib potentially leading to platelet dysfunction and bleeding. 1 It should be noted that we did not investigate in detail the direct effects of acalabrutinib on CLL cells, including apoptosis induction, alone and in combination with anti-CD20 monoclonal antibodes. This should be done in future work, using samples from a large panel of CLL patients sensitive or resistant to ibrutinib.…”

“…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.…”

“…[1][2][3] BTK inhibitors are often combined with anti-CD20 antibodies in the clinic, but ibrutinib interferes with some of the cell-mediated mechanisms of action of anti-CD20 antibodies, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis, perhaps due to inhibition of other BTK family kinases such as ITK or TEC. [4][5][6] The aim of this work was to verify whether acalabrutinib differs from ibrutinib with respect to inhibition of ADCC and antibody-dependent phagocytosis, induced by anti-CD20 rituximab and obinutuzumab.…”

Phase I study of single-agent CC-292, a highly selective Brutons tyrosine kinase inhibitor, in relapsed/refractory chronic lymphocytic leukemia

“…However, its clinical activity (in particular, durability of response) was inferior to that of ibrutinib or acalabrutinib. 3,13 Although the reasons are not completely clear, given reasonably high BTK occupancy in most patients on BID dosing, it seems likely that highly variable PK and PD limited the ability of CC-292 to consistently reach its target in vivo. As the importance of BCR signaling is now well established in the treatment of CLL, the suboptimal efficacy of CC-292 represents a valuable cautionary clinical experience in the development of next generation BTK inhibitors.…”

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

“…Most common side effects were headache, diarrhea, and weight gain and there were no cases of atrial fibrillation have been reported to date. 36 Ongoing phase III trials include acalabrutinib in isolation or combination in the first-line (NCT02475681) and in R/R CLL (NCT02029443; NCT02477696).…”