Acalabrutinib Offers Less Wear and Tear on the Heart in CLL Patients

In a head-to-head trial of Bruton’s tyrosine kinase inhibitors, acalabrutinib (Calquence) demonstrated similar efficacy to ibrutinib (Imbruvica), but with less cardiotoxicity, in patients with previously treated chronic lymphocytic leukemia (CLL), a researcher reported.

The ELEVATE-R/R trial showed that at a median of 40.9 months, progression-free survival (PFS) was the same in both the acalabrutinib and ibrutinib groups, but that the incidence of cardiac events, including atrial fibrillation (Afib) and hypertension, was significantly lower with acalabrutinib, reported John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“These results demonstrate that acalabrutinib is better tolerated and has similar efficacy to ibrutinib in patients with previously treated CLL,” Byrd said in a presentation at the American Society of Clinical Oncology (ASCO) virtual meeting.

Bruton’s tyrosine kinase (BTK) is part of the B-cell receptor signaling pathway critical in CLL pathogenesis. While ibrutinib was the first irreversible BTK inhibitor FDA approved for patients with CLL/small lymphocytic leukemia (CLL/SLL), Byrd noted that it has been associated with adverse events (AEs), such as cardiovascular toxicities, leading to treatment discontinuation.

Acalabrutinib is a next-generation, more selective, irreversible BTK approved for CLL/SLL, which has produced fewer AEs when compared across trials, Byrd pointed out. The agent was FDA approved in 2019 for use in adults with CLL or SLL based on results from the ELEVATE-TN and ASCEND trials.

The current phase III, randomized, non-inferiority, open-label trial was designed to compare the two drugs in patients with previously treated CLL.

The trial included 533 patients (median age of 66) who had received one or more prior therapies, and had the presence of del (17p) or del (11q). Byrd and colleagues randomized 268 patients to receive acalabrutinib 100 mg dosed twice daily, and 265 patients to receive ibrutinib 420 mg dosed once daily .

The primary endpoint of the trial was PFS, while secondary endpoints included any grade of Afib, incidence of grade ≥3 infections and Richter transformation, and overall survival (OS).

Median PFS was 38.4% in both trial arms, with a HR of 1.00 (95% CI 0.79-1.27), “suggesting an equivalence of efficacy,” Byrd reported.

Not only was the incidence of Afib of any grade significantly lower with acalabrutinib (9.4% vs 16.0%), but when considering just patients who had never had the condition before, the incidence of Afib was more than double in patients taking ibrutinib (14.9% vs 6.2%).

Additionally, the time to development of Afib was longer in the acalabrutinib arm (28.8 months vs 16.0 months), while treatment discontinuation among patients developing Afib was greater in the ibrutinib arm (16.7% vs none in the acalabrutinib arm).

“By reducing and/or delaying the onset of these cardiac toxicities, acalabrutinib may improve the long-term adherence to BTK inhibitor therapy,” observed ASCO discussant Jacqueline C. Barrientos, MD, of Northwell Health Cancer Institute in Manhasset, New York.

As for other secondary endpoints, the incidence of grade ≥3 AEs was comparable between the two arms, as was the incidence of Richter transformation. Median OS was not reached in either arm, with a hazard ratio of 0.82 favoring acalabrutinib, Byrd reported, with 63 deaths in the acalabrutinib arm and 73 in the ibrutinib arm.

The incidence of AEs leading to discontinuation of treatment was 14.7% in the acalabrutinib group and 21.3% in the ibrutinib group. Diarrhea, arthralgia, hypertension, contusion, and Afib occurred more frequently with ibrutinib, while headache and cough occurred more frequently with acalabrutinib.

Overall, the rate of cardiac events was higher with ibrutinib (30.0% vs 24.1%). In addition to a lower incidence of Afib and hypertension, Byrd and colleagues found lower rates of pneumonitis and infections with acalabrutinib.

“Based on the data presented, acalabrutinib use will have an impact on patients’ quality of life,” Barrientos commented. “Although this was a high-risk cohort of patients with relapsed disease, this data confirms prior reports of tolerability of the drug, and would likely be extrapolated to non-risk patients and into earlier lines of therapy.”

During a Q&A session, Byrd was asked how clinicians should decide which of these drugs to use.

“With the similar efficacy and diminished toxicity with acalabrutinib, that would likely be the first choice,” said Byrd, adding that since they are different chemical structures, if a patient develops a rash “or some untoward event,” ibrutinib could be considered. “And in younger patients there is less data with acalabrutinib, and using ibrutinib based on the ECOG study with rituximab may be a consideration, as well, based upon established data.”