Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies

Abstract

Bruton tyrosine kinase (BTK) is a validated target for treatment of B-cell malignancies, and oral inhibitors of BTK have emerged as a standard of care for these diseases. Acalabrutinib is a second generation, highly selective, potent, covalent BTK inhibitor that exhibits minimal off-target activity in in vitro assays, providing the potential to improve tolerability over the first-in-class BTK inhibitor, ibrutinib. Acalabrutinib was approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in the US in 2017 and 2019, respectively. Acalabrutinib is also undergoing trials for other B-cell malignancies, both as monotherapy and in combinations. In this review, we discuss results from clinical trials evaluating the efficacy and safety of acalabrutinib in patients with CLL, MCL, and Waldenstrom’s macroglobulinemia. Recent phase 3 data showed that acalabrutinib improved progression-free survival (PFS) compared with rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL, and acalabrutinib with or without obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL. Overall, acalabrutinib had a tolerable safety profile, with most adverse events being grade 1/2 severity (most commonly headache and diarrhea) and a low rate of discontinuation due to adverse events.

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

“…Diarrhea is commonly observed AE in patients treated with BTKi. It is observed mainly in the first six months from beginning therapy, with a frequently observed self-limited course [148,149]. Similar incidence is observed between patients treated with ibrutinib and acalabrutinib [148,149].…”

“…It is observed mainly in the first six months from beginning therapy, with a frequently observed self-limited course [148,149]. Similar incidence is observed between patients treated with ibrutinib and acalabrutinib [148,149]. Temporary drug holds should be considered in the case of grade ≥3 diarrhea.…”

“…Headaches are noted approximately in 40% of patients treated with acalabrutinib and are rarely observed in patients receiving ibrutinib [148]. Usually, headaches occur early after treatment initiation and the incidence decreases over time.…”

Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

“…Three phase 3 randomised controlled trials of acalabrutinib or zanubritinib, compared to ibrutinib in various lymphoma subtypes, have each demonstrated an improved safety profile of the second generation agents, and, particularly, lower rates of atrial fibrillation, which was observed in 2–2.5% with zanubrutinib and 9% acalabrutinib, compared to approximately 15% with ibrutinib [ 28 , 33 , 34 ]. Acalabrutinib has predominantly been developed in CLL and MCL, and is FDA approved for both indications [ 35 ]. A phase 2 study in treatment naïve and relapsed refractory WM showed high levels of efficacy in both settings, including ORR of 93% and PFS of 82% in relapsed disease at a median follow up of 27.4 months [ 27 ].…”

Targeted Treatment of Chronic Lymphocytic Leukemia: Clinical Utility of Acalabrutinib

“…A pooled analysis of 610 patients on acalabrutinib revealed atrial fibrillation episodes of any grade at a rate of 2.3%. 47 In patients with relapsed/refractory CLL receiving therapy with acalabrutinib in the ASCEND trial, there was a 6% frequency of atrial fibrillation (9 of 154), reported at a median follow-up of 22 months. 29 In patients receiving frontline therapy with acalabrutinib in the ELEVATE-TN trial, the incidence of atrial fibrillation was 4% (7 of 179) in patients receiving treatment with acalabrutinib as monotherapy, 3% (6 of 178) in patients receiving acalabrutinib-obinutuzumab and 1% (1 of 169) in patients receiving obinutuzumab-chlorambucil, at a median follow-up of 28.3 months.…”