Feasibility and efficacy of CD19-targeted CAR-T cells with concurrent ibrutinib for CLL after ibrutinib failure.

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered T (CD19 CAR-T) cell immunotherapy after ibrutinib failure. Since pre-clinical studies showed that ibrutinib could improve CAR-T cell antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR-T cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was planned to begin at least 2 weeks before leukapheresis and continue at least 3 months after CAR-T cell infusion. CD19 CAR-T cell immunotherapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate by iwCLL criteria was 83%, and 61% achieved minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year OS and PFS probabilities were 86% and 59%, respectively. Compared to CLL patients treated with CAR-T cells without ibrutinib, CAR-T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines despite equivalent in vivo CAR-T cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR-T therapy with and without concurrent ibrutinib, respectively (p=0.91). CD19 CAR-T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.