Acalabrutinib in combination with rituximab and lenalidomide in patients with relapsed or refractory follicular lymphoma: Results of the phase 1b open-label study (ACE-LY-003).

Patients with relapsed/refractory (R/R) follicular lymphoma (FL) have limited effective treatment options. Bruton tyrosine kinase inhibitors (BTKis) increase the anti-tumoural phenotype of tumour-associated macrophages, providing rationale to combine them with rituximab and lenalidomide (R²). Acalabrutinib, a second-generation BTKi, has potential to improve R² efficacy without increasing T-cell-mediated toxicity due to its lack of interleukin-2-inducible T-cell kinase inhibition. Here, we report safety and efficacy from a phase 1b dose-finding study (NCT02180711) evaluating acalabrutinib plus R² in patients with R/R FL. Overall, 29 patients received acalabrutinib plus R² (lenalidomide 15 mg, n = 8; lenalidomide 20 mg, n = 21). At a median acalabrutinib exposure of 21 months, the most common grade ≥3 treatment-emergent adverse event (TEAE) was neutropenia (37.9%). The incidence of grade ≥3 serious TEAEs was 37.5% and 52.4% in the lenalidomide 15-mg and 20-mg cohorts, respectively; overall, the most common were COVID-19 pneumonia, COVID-19 infection and pneumonia. Earlier treatment withholdings/reductions were observed in the 20-mg cohort. With a median follow-up of 34.1 months, the overall response rate was 75.9%. The complete response rate was 25.0% and 42.9% in the lenalidomide 15- and 20-mg cohorts, respectively. Due to acceptable toxicity and preliminary efficacy, the lenalidomide 20-mg dose was selected for further investigation.