Acalabrutinib Poses Low Cardiac Risk in CLL, Analysis Shows

Jennifer R. Brown, MD, PhD

Patients with chronic lymphocytic leukemia (CLL) who received treatment with single-agent acalabrutinib (Calquence) experienced a low incidence of cardiac toxicities leading to treatment discontinuation, according to data from a pooled analysis across 4 clinical trials presented during the 2020 ASH Annual Meeting & Exposition.¹

Results showed that 17% (n = 129) of 762 patients with CLL who received treatment with the second-generation BTK inhibitor as a monotherapy experienced cardiac toxicity of any grade at a median follow-up of 25.9 months, which led to treatment discontinuation in 7 patients (0.9%). Notably, 91% of patients who had cardiac AEs had 1 or more pre-existing risk factors prior to acalabrutinib treatment. The most common cardiovascular risk factors in patients with or without cardiac AEs included hypertension (67% vs 68%, respectively), hyperlipidemia (29% vs 36%), and arrhythmias (22% vs 17%).

Five percent (n = 37) of patients experienced cardiac events that were grade 3 or higher. Of these patients, 49% (n = 18) continued to receive acalabrutinib at the time of data cutoff. Sixteen percent (n = 6) of the 37 patients discontinued treatment due to acute myocardial infarction (n = 2), congestive cardiac failure (n = 2), cardiac failure (n =1), and cardiac tamponade (n = 1). Four patients discontinued due to other toxicities, 5 because of progressive disease, 3 patients due to death, and 1 due to other reasons.

Moreover, among 51 grade 3 or higher cardiac events, 31% led to dose delay (n = 16) and 12% (n = 6) resulted in acalabrutinib discontinuation. Thirty-seven of these events were grade 3, 12 were grade 4, and 2 were grade 5. Seventy-one percent (n = 36) of these cardiac AEs were managed with the use of concomitant medications and 84% (n = 43) of them resolved. A total of 25% of patients experienced cardiac AEs of grade 3 or higher within the first 6 months on acalabrutinib.

"In this analysis, cardiac events occurred in 17% of patients with CLL who were treated acalabrutinib monotherapy and rarely resulted in discontinuation. [The majority] of patients with cardiac AEs had pre-existing risk factors,” Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and a professor of Medicine at Harvard Medical School, said in a presentation of the data during the meeting. “Overall, these data suggest a low risk of cardiac AEs with acalabrutinib in patients with CLL.”

Data included in the pooled analysis were collected from 4 studies2-5 in which patients with CLL were treated with 1 or more dose of acalabrutinib monotherapy (n = 762):

- A phase 1/2 study (NCT02029443) of acalabrutinib in patients with CLL

- ELEVATE-TN study (NCT02475681) of acalabrutinib with or without obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil in treatment-naïve CLL

- ASCEND study (NCT02970318) of acalabrutinib versus idelalisib (Zydelig) plus rituximab (Rituxan) or bendamustine plus rituximab in relapsed/refractory CLL

- A phase 2 study NCT02337829 of acalabrutinib in patients with treatment-naïve relapsed/refractory CLL with 17p deletions (del)

On these trials, acalabrutinib was given at total daily doses of 100 mg to 400 mg. Seventy-eight patients were given 100 mg of acalabrutinib twice daily, while 14% started on another dose and later switched to a 100-mg twice-daily dose. Treatment with acalabrutinib was continued until either disease progression or death.

Cardiovascular toxicities have been linked with the first-generation BTK inhibitor ibrutinib, possibly because of off-target kinase inhibition.6 Data from an analysis of 562 patients with lymphoid malignancies indicated that patients who were treated with ibrutinib experienced an increased incidence of hypertension (78%) and atrial fibrillation (13%) at a median follow-up of 30 months.7 Investigators theorized that because acalabrutinib has greater selectivity for BTK in vitro compared with ibrutinib, the agent may have a more favorable toxicity profile.⁸

To examine this further, investigators set out to learn more about the cardiovascular toxicities with acalabrutinib in patients who received the agent as a monotherapy in clinical trials. Specifically, they evaluated the incidence, seriousness, and severity of cardiac events in this patient population and the association between these toxicities and the drug.

Moreover, they looked at the time to onset of cardiac events and event duration, event management and resolution for toxicities that were grade 3 and higher, and incidence of these events within the first 6 months of treatment. Incidence and time to onset of hypertension AEs were also examined, as well as cardiovascular and hypertension risk factors.

The median age of all patients evaluated was 67.0 years compared with 69.0 years in the subset of patients with cardiac events. In both groups, the majority of participants were male, at 67 years and 64 years, respectively. Moreover, 93% and 95% of patients, respectively had an ECOG performance status of 1 or less. In both groups, patients had a median of 1 prior regimen received. Forty-six percent of all patients were treatment naïve, while 54% had relapsed/refractory disease; these rates were 45% and 55%, respectively in the cardiac-event subgroup.

The median follow-up duration was 25.9 months (range, 0.0-58.5) among all patients included in the analysis, with 72% of patients remaining on treatment at the time of data cutoff. Twenty-seven percent (n = 208) of patients discontinued treatment with acalabrutinib, mostly because of either disease progression (11%) or toxicities (9%).

Additional results showed that the median time to onset of cardiac events was 10.1 months (range, 0.1-49.7) with a median event duration of 0.2 months (range, 0-24.6). Moreover, the median time to onset of atrial fibrillation/flutter was 17.1 months (range, 0.3-42.1) and lasted for a median duration of 0.1 months (range, 0-12.4). The median time to hypertension events was 6.5 months (range, 0.1-44.2), which lasted for a median duration 1.0 months (range, 0-36.8). Of 38 patients who experienced atrial fibrillation/flutter while on treatment, 18% (n = 7) had a prior history of arrhythmia or atrial fibrillation/flutter. Of 67 patients who experienced hypertension events while on acalabrutinib, 69% (n = 46) had prior hypertension and 27% (n = 18) had risk factors.

“The rate of cardiac onset was generally constant over time on the study,” Brown noted.

The most common any-grade cardiac AEs that occurred in patients who were treated with acalabrutinib included atrial fibrillation (4%; n = 32; events, 44), palpitations (3%; n = 23; events, 27), and tachycardia (2%; n = 17; events, 8). The most common grade 3 or higher cardiac AEs were atrial fibrillation (1%; n = 10; events, 11), acute myocardial infarction (0.7%; n = 5; event, 6), and cardiac failure (0.4%; n = 3; events, 3). No grade 3 or higher palpitations or tachycardia were reported.

The safety of acalabrutinib will be compared with ibrutinib in patients with CLL and del(17p) or del(11q) in the phase 3 randomized ACE-CL-006 trial (NCT02477696).⁹

References

1. Brown JR, Byrd JC, Ghia G, et al. Pooled analysis of cardiovascular events from clinical trials evaluating acalabrutinib monotherapy in patients with chronic lymphocytic leukemia (CLL) Poster presented at: 2020 ASH Annual Meeting and Exposition; resented at: 2020 ASH Annual Meeting & Exposition; December 4-8, 2020; Virtual. Poster 3146.

2. Byrd JC, Harrington B, O'Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332. doi:10.1056/NEJMoa1509981

3. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone Vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl_1):31. doi:10.1182/blood-2019-128404

4. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or Refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

5. Sun C, Nierman P, Kendall EK, et al. Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib. Blood 2020;136(1):93-105. doi:10.1182/blood.2019003715

6. Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton's tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57. doi:10.1186/s12943-018-0779-z

7. Dickerson T, Wiczer T, Waller A, et al. Hypertension and incident cardiovascular events following ibrutinib initiation. Blood. 2019;134(22):1919-1928. doi:10.1182/blood.2019000840

8. Barf T, Covey, T, Izumi R, et al. Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile. J Pharmacol Exp Ther. 2017;363(2):240-252. doi:10.1124/jpet.117.242909

9. Study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk CLL. ClinicalTrials.gov. Updated December 5, 2019. Accessed December 7, 2020. https://clinicaltrials.gov/ct2/show/NCT02477696.