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.