Discussion
We present an exceptional case of durable remission despite lacking on-target loss of B cells following reinfusion, as well as a case series of seven other pediatric patients who received tisagenlecleucel reinfusion for treatment of post-CAR-T relapse or early loss of BCA. Approximately 40-50% of pediatric patients with B-ALL relapse post-CAR-T, and consolidative HSCT is currently the standard of care. The feasibility of reinfusion with the same product depends on the availability of additional CAR-T cells, as well the presence of CD19+ blasts if in relapse.17,18 Our institutional experience has suggested that tisagenlecleucel reinfusion has a limited, albeit non-zero, likelihood of being a definitive therapy. There is a subset of patients for whom it is successful, though the identification of these patients remains unclear. For some, reinfusion can provide temporary benefit with remission and/or BCA reintroduction.
Our institutional experience has shown mixed success. CAR-T reinfusion remained the definitive therapy for 25% of patients, who are alive without evidence of disease. Prior studies have reported similar experiences with CAR-T reinfusion for either loss of BCA or disease relapse, where reinfusion was the definitive therapy for 20-25% of patients.6,19-22 Five of the remaining six patients reinfused are alive, following additional therapy after tisagenlecleucel reinfusion including HSCT, humanized CAR-T, and/or immunotherapy. In our cohort CAR-T reinfusion was safe and generally well tolerated, with only one patient requiring tocilizumab for CRS.
For our patient who remains in remission seven years following third CAR-T infusion, his second CAR-T infusion, which was not preceded by lymphodepleting chemotherapy, failed with disease progression 28 days post-infusion. Gardner et al. reported a similar experience: of eight patients reinfused for loss of CAR-T cells, only the two that received lymphodepleting chemotherapy had CAR-T re-expansion.2For our patient we hypothesized that the third infusion irradicated the remaining leukemic clone, as the lack of BCA argues against the presence of persistent, active CAR-T cells for surveillance against recurrence. While monitoring BCA allowed for the early detection of MRD by flow cytometry prior to a morphologic relapse following his initial CAR-T infusion, our current institutional practice includes measuring MRD by next generation sequencing. This allows for significantly higher sensitivity and earlier relapse detection but was not commercially available when our patient was treated.15
Our experience suggests that tisagenlecleucel reinfusion is safe and can induce remissions in patients with CD19+ relapse, possibly as an alternative to HSCT or other therapies for post-CAR-T relapse. However, the subset of patients for whom this is definitive therapy is small. Our study is limited by sample size, and pooling experiences among pediatric institutions is needed to make conclusions about tisagenlecleucel reinfusion. Clinical trials of humanized CAR-T products may also offer a pathway to durable remission.9 Other potential strategies to deepen remission include increasing lymphodepleting chemotherapy dosing, using PD-1 inhibitors to augment T cell response, and empirically reinfusing as a “boost” while in remission with ongoing BCA.23,24 CAR-T cell dose has been associated with improved event-free and overall survival, and multiple CAR-T infusions improved survival in preclinical mouse studies.25,26 Such studies suggest that reinfusion may reduce the rate of B cell recovery, allowing for prolonged CAR-T cell persistence, and a pediatric phase II study of scheduled reinfusion is ongoing (NCT05460533).27