BTK Inhibitor Synergizes With CD19-Targeted Chimeric Antigen Receptor-T Cells in Patients With Relapsed or Refractory B-Cell Lymphoma: An Open-Label Pragmatic Clinical Trial.

BACKGROUND

CD19-targeted chimeric antigen receptor-T cell (CART19) therapy is clinically effective in patients with relapsed or refractory B-cell lymphoma (BCL), but treatment failure and recurrence need to be overcome. Preclinical studies demonstrated that Bruton tyrosine kinase inhibitor (BTKi) improved the efficacy of CART19 therapy.

METHODS

We designed this open-label, non-randomized pragmatic clinical trial. The primary end point was safety, and the secondary end point was clinical response.

RESULTS

Thirty-seven patients included were assigned to CART19 monotherapy (n = 24) or CART19 combined with BTKi (n = 13) group on their own accord. Grade 1-2 and grade 3 cytokine release syndrome occurred in 43.2% and 2.7% of patients, respectively. One patient experienced grade 3 neurotoxicity. The most common severe adverse events were hematological toxicities, including neutropenia (in 97.3% of patients), thrombocytopenia (in 40.5%), and anemia (in 43.2%). The adverse effects were comparable between the two groups. The best objective response rates were 84.6% vs. 66.7% (p > 0.05) in patients with and without BTKi, and the best complete response rates were 61.5% vs. 25.0% (p < 0.05). The combination of BTKi significantly prolonged the overall survival but did not affect the progression-free survival or the duration of response. T cells of patients treated with BTKi were predisposed to early differentiation and less exhaustion 3 months after CART19 infusion. Single-cell RNA sequencing analysis demonstrated that T cells were dysfunctional at relapse.

CONCLUSION

BTKi combined with CART19 induced better outcomes with good safety profiles in patients with BCL.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05020392.