Bendamustine Versus Fludarabine/Cyclophosphamide for Lymphodepletion in CAR-T Therapy: a Randomized Trial

Chimeric antigen receptor (CAR) T-cell immunotherapy (CAR-T) has emerged as an effective treatment for relapsed/refractory aggressive B-cell lymphomas. Three products that demonstrate clinical activities in relapse/refractory large B-Cell Lymphoma (LBCL), axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are currently available. To ensure an optimal CAR-T cell expansion and proliferation inside the host once infused, lymphodepleting therapy is administered before CAR-T immunotherapy as it exerts its activities by generating the optimal cytokine and metabolites milieu to ensure engraftment and proliferation of CAR-T cells once infused, by removing anergic circulating lymphocytes responsible of the "cytokine sink effect", and by debulking immunosuppressive tumor masses by the time of CAR-T cell infusion. Nowadays, commercially approved CAR-T products use a combination of fludarabine (Flu) and cyclophosphamide (Cy), at different dosages, as the standard lymphodepletion regimen. After CAR-T cell infusion participants might experience several toxicities including hematological toxicities and resulting infective events, as a direct consequence of lymphodepleting chemotherapy infusion.

Furthermore, the participants can experience CAR-T specific toxicities such as cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS), which are the consequence of the CAR-T cell to tumor engagement activity. In fact, these toxicities are responsible for more than 60% of non-relapse mortalities after CAR-T cells and their treatment increase the hospitalization stay and overall costs of CAR-T cell immunotherapy.

Therefore, there is a great need to improve the current CAR-T cell immunotherapy treatment to reduce the risk of toxicity. A growing number of retrospective studies demonstrated that bendamustine lymphodepletion is an alternative lymphodepletion regimen. In all these studies, bendamustine lymphodepletion showed comparable response rate but drastically reduced toxicities, in terms of CRS, neurotoxicity, hematological toxicity and, in particular, infections. As a result, its use is steadily increasing across Swiss centers. There are no published and other randomized trials, currently ongoing, investigating this particular question. For these reasons, bendamustine should be tested against the current SoC lymphodepleting chemotherapy.

This trial aims to prospectively compare the safety and efficacy of bendamustine versus standard Flu/Cy lymphodepletion before CART cell therapy in participants with relapsed/refractory large B-cell lymphoma (LBCL).