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).

in British journal of haematology by Paolo Strati, Richy Agajanian, Izidore S Lossos, Morton Coleman, Robert Kridel, Andrew Wood, Robin Lesley, Chuan-Chuan Wun, Deborah M Stephens

TLDR

  • A phase 1b study evaluating acalabrutinib plus rituximab and lenalidomide (R) in patients with relapsed/refractory (R/R) follicular lymphoma (FL) found acceptable toxicity and preliminary efficacy, with a 75.9% overall response rate and a 35.1% complete response rate.

Abstract

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 (R). Acalabrutinib, a second-generation BTKi, has potential to improve Refficacy 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 Rin patients with R/R FL. Overall, 29 patients received acalabrutinib plus R(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.

Overview

  • The study evaluated the safety and efficacy of acalabrutinib combined with rituximab and lenalidomide (R) in patients with relapsed/refractory (R/R) follicular lymphoma (FL).
  • The study aimed to investigate the dosage and safety profile of the combination therapy, specifically the role of lenalidomide dose in determining treatment-related toxicity.
  • The study enrolled 29 patients and observed responses in 75.9% of patients, with a complete response rate of 35.1% overall.

Comparative Analysis & Findings

  • The study found that the incidence of grade ≥3 serious treatment-emergent adverse events (TEAEs) was higher in the 20-mg lenalidomide cohort (52.4%) compared to the 15-mg cohort (37.5%).
  • Earner treatment withholdings/reductions were observed in patients receiving the higher dose of lenalidomide (20-mg).
  • The study observed a higher complete response rate in patients receiving the higher dose of lenalidomide (42.9% vs 25.0%).

Implications and Future Directions

  • The study's findings suggest that the combination therapy with acalabrutinib, rituximab, and lenalidomide (R) is feasible and effective for patients with R/R FL, with acceptable toxicity.
  • The study highlights the importance of dose adjustment to balance efficacy and toxicity, particularly with lenalidomide, to achieve optimal treatment outcomes.
  • Future studies should investigate the optimal dosage and combination of agents to achieve the best balance between efficacy and toxicity, and to explore the potential benefits of this treatment strategy in other lymphoma subtypes.
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