Research Summary
Bruton tyrosine kinase (BTK) inhibitors are often used to treat chronic lymphocytic leukemia (CLL). Ibrutinib is a covalent BTK inhibitor associated with adverse events (AEs), including cardiovascular toxicities; the incidence of AEs might be in part due to the inhibition of off-target receptor and nonreceptor tyrosine kinases. Acalabrutinib is also a covalent BTK inhibitor, but it is more selective than ibrutinib, demonstrating lower off-target activity. The Phase III ELEVATE-RR trial showed that patients with previously treated CLL with del17p and del11q who received acalabrutinib experienced noninferior progression-free survival (PFS) and lower incidence of atrial fibrillation/flutter, compared to those treated with ibrutinib. In this study, Seymour et al1 conducted a post hoc analysis to compare safety outcomes associated with acalabrutinib and ibrutinib in patients with CLL.
To be eligible for the international, multicenter, open-label ELEVATE-RR trial, patients had to receive at least one prior line of therapy, harbor del17p13.1 and/or del11q22.3, and have an Eastern Cooperative Oncology Group (ECOG) of 2 or less. Patients with significant cardiovascular disease, concurrent warfarin/vitamin K antagonist equivalent treatment, and prior treatment with a BTK or B-cell lymphoma 2 inhibitor were excluded.
Patients were randomized to receive either twice-daily oral acalabrutinib 100mg (n=268) or once-daily ibrutinib 420mg (n=265), stratified by del17p status, ECOG score, and number of previous treatments. Median patient age was 66 years, and median number of previous therapies was two. Forty-five and 64 percent of patients had del17p and del11q, respectively, while 51 percent had del17p and/or TP53 mutation.
Patients had a median time on the study of 40.9 months. A greater percentage of patients treated with ibrutinib, compared to those treated with acalabrutinib, discontinued treatment due to AEs (22% vs. 15%). The ibrutinib group had a median time to treatment discontinuation of 37.8 months, compared to 44 months in the acalabrutinib group. The acalabrutinib arm had a slightly longer median exposure to treatment, at 38.3 months, compared to 35.5 months for the ibrutinib arm.
Safety data from 266 and 263 patients in the acalabrutinib and ibrutinib groups, respectively, were analyzed. Significantly more patients treated with ibrutinib experienced any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia, with exposure-adjusted incidence rates (EAIRs) ranging from 1.5- to 4.1-fold higher for the ibrutinib group compared to the acalabrutinib group. The rate of any-grade cough and headache were higher among those who received acalabrutinib, with EAIRs 1.2- and 1.6-fold higher, compared to those treated with ibrutinib.
The incidence of any-grade hypertension, atrial fibrillation/flutter, and bleeding events were significantly higher among the ibrutinib arm, compared to the acalabrutinib arm (23 vs. 9 patients,16 vs. 9 patients, and 51 vs. 38 patients, respectively); EAIRs were 2.8-, 2.0-, and 1.6-fold higher, respectively, in patients who received ibrutinib, compared to those treated with acalabrutinib. Furthermore, the incidence of Grade 3 or higher hypertension was significantly higher in the ibrutinib arm, compared to the acalabrutinib arm.Â
Median time to atrial fibrillation/flutter onset was about double the length in the acalabrutinib arm, compared to the ibrutinib arm. Compared to the ibrutinib group, the acalabrutinib arm had a significantly lower cumulative incidence of atrial fibrillation/flutter and hypertension; at 36 months, the absolute difference in incidence was 7.5 percent for atrial fibrillation/flutter and 18.2 percent for hypertension. Seven patients in the ibrutinib arm discontinued treatment due to atrial fibrillation/flutter, compared to no patients in the acalabrutinib arm. The prevalence of hypertension was lower with acalabrutinib treatment across all patient subgroups, and the incidence of atrial fibrillation/flutter was lower with acalabrutinib across all subgroups, except patients with a prior history of atrial fibrillation/flutter.
At all time points, the cumulative incidence of bleeding events was lower in the acalabrutinib arm, compared to the ibrutinib arm; at 36 months, the absolute difference was 14.6 percent. The incidence of bleeding events was consistently lower in patients treated with acalabrutinib, compared to those treated with ibrutinib, regardless of age or prior treatment with 1 to 3 previous lines of therapy.
The ibrutinib arm had a higher mean overall adverse event (AE) burden score (Grade 1–4 analysis: 5.14; Grade 1–5 analysis: 5.28), compared to the acalabrutinib arm (Grade 1–4 analysis: 3.86; Grade 1–5 analysis: 4.00). Mean overall AE burden score was also significantly higher with ibrutinib among patients younger than 65 years, those aged 65 years or older, and those who received 1 to 3 prior treatments. AE burden was numerically higher with ibrutinib in patients who received four or more prior treatments. Additionally, patients with and without polypharmacy at baseline had significantly increased AE burden with ibrutinib treatment, compared to acalabrutinib treatment. Ibrutinib treatment also led to significantly higher AE burden scores for atrial fibrillation/flutter, hypertension, and hemorrhage.
The authors concluded that acalabrutinib had a lesser AE burden, including for key cardiovascular events, with noninferior efficacy to ibrutinib among patients with previously treated CLL.
Reference
- Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142(8):687–699.