- Acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared to idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), reducing the risk of disease progression or death by 69% after 16.1 months.
- Acalabrutinib had a more tolerable safety profile than standard combination therapies.
Why this matters
- There is a need for effective but also well-tolerated agents to treat CLL.
- Acalabrutinib previously demonstrated less off-target kinase inhibition compared with ibrutinib in vitro and substantial activity in CLL patients.
- Acalabrutinib monotherapy may represent an effective and well-tolerated treatment option for R/R CLL.
- The phase 3 ASCEND Study enrolled 301 patients with R/R CLL.
- Patients were randomly assigned (1:1) to receive acalabrutinib vs IdR or BR at investigator’s choice.
- Crossover from IdR/BR arm was allowed after confirmed disease progression.
- The primary endpoint was progression-free survival (PFS) assessed by independent review committee.
- Interim analysis was planned after occurrence of about 79 events (2/3 of the primary event goal).
- At a median follow-up of 16.1 months (range 0.5-22.1), acalabrutinib significantly prolonged PFS compared to IdR/BR (median not reached vs 16.5 months; HR 0.31 [95% CI 0.20-0.49]; P
- PFS benefit with acalabrutinib was consistent across subgroups.
- Discontinuation due to adverse events (AEs) occurred in 11% of patients on acalabrutinib vs 49% of patients on IdR and 17% on BR.
- Grade ≥3 AEs with acalabrutinib were neutropenia (16%), anaemia (12%) and pneumonia (5%); with IdR, neutropenia (40%) and diarrhea (24%); and with BR, neutropenia (31%), anemia (9%) and constipation (6%).
- Events of clinical interest were atrial fibrillation (5.2% acalabrutinib vs 3.3% IdR/BR), bleeding (26% vs 7.2%), Grade ≥3 infections (15% vs 24%), and secondary primary malignancies (excluding nonmelanoma skin cancer; 6.5% vs 2.6%).
“There are no clear signals that the toxicity is being less important with acalabrutinib. If you compare with what emerged from a trial with ibrutinib at 16 months, it was almost the same. Maybe some mild side effects, like bruising, are a little less frequent, but I think that this is the only thing that we can say about it at the moment. We are really waiting for the head-to-head comparison that will not be out before one or one year and a half.” Florence Cymbalista, MD at Hôpital Avicenne and Professor at Université Paris 13 (France).