Acalabrutinib Plus Venetoclax and Obinutuzumab or Rituximab in Patients with Treatment-Naïve or Relapsed CLL

Acalabrutinib is approved for chronic lymphocytic leukemia (CLL), and although patients with CLL have presented durable responses to acalabrutinib monotherapy, they may have a better response with combination therapy. A study examined the safety and efficacy of acalabrutinib plus a CD20 antibody (obinutuzumab or rituximab) and the BCL-2 inhibitor venetoclax in treatment-naïve (TN) or relapsed/refractory (R/R) patients with CLL. The results were presented at the 62nd ASH Annual Meeting & Exposition.

Patients with intermediate or high-risk CLL and an Eastern Cooperative Oncology Group performance status (ECOG PS) score ≤2 were eligible for inclusion. R/R patients with a history of Bruton’s tyrosine kinase inhibitor treatment were eligible if they did not discontinue the treatment due to CLL progression. Patients with R/R CLL were given oral acalabrutinib 100 mg twice daily until progression, plus intravenous (IV) rituximab 375 mg/m2 for nine infusions, plus oral venetoclax per standing dosing cycles. TN patients were given oral acalabrutinib and venetoclax plus IV obinutuzumab per standing dosing cycles. The main outcome was safety; other outcomes included investigator-assessed overall response rate (ORR, defined as a partial response or better) at cycle 16, complete response (CR) rate, undetectable minimal residual disease (uMRD) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics.

There were 12 R/R patients (median age, 66 years; nine patients were male) and 12 TN patients (median age, 61 years; nine patients were male). The entire cohort had ECOG PS ≤1. Six R/R patients and eight TN patients had unmutated immunoglobulin heavy chain. In the R/R cohort, the median number of prior therapies was one.

The R/R group had a median follow-up of 23.2 months, and the TN group had 22 months, at which time 11 and 10 patients, respectively, were still on treatment. Each cohort had one patient discontinue treatment due to adverse events (AEs), and in the TN group, one patient withdrew from treatment.

In the R/R group, the median number of treatment cycles was: acalabrutinib, 23 (range, 14.9-27.5); rituximab, six (6-6); and venetoclax, 13 (10.0-13.7). In the TN group, the median number of treatment cycles was: acalabrutinib, 23 (range, 18-24.8); obinutuzumab, six (6-6); and venetoclax, 13 (13-13.5).

AEs of interested that occurred were cardiac (R/R, n=7; TN, n=4); one patient in the R/R group had atrial fibrillation (AF), and this patient had a prior AF history. There were no ventricular arrhythmias. Hypertension AEs were reported in three R/R patients and seven TN patients. The most common infection in the R/R group was upper respiratory tract infection (URTI; 50%); in the TN group, the most common infections were URTI (67%), sinusitis (42%), and nasopharyngitis (42%). Three TN patients had grade ≥3 infections.

The ORR was 92% in the R/R group (95% confidence interval [CI], 62-100) and 100% in the TN group (95% CI, 74-100) after 16 cycles. Half of the patients in each cohort, at the time of data cutoff, had attained CR or CR with incomplete marrow recovery (CRi); all patients with CR or CRi attained uMRD in peripheral blood by the time they attained CR/CRi. Neither cohort attained median DOR, PFS, and OS; both groups had an estimated 18-month PFS and OS rate of 100%.