Background Richter transformation (RT) of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma has an estimated median OS of only 8-12 mo. Tisagenlecleucel CAR-T cell therapy is approved for treatment of r/r LBCL after ≥2 lines of prior therapy. Here, we describe the efficacy and safety of tisagenlecleucel in patients (pts) with RT in a real-world setting with a median follow-up (infusion to data cutoff) of 31 mo. Methods Data were part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. Pts were treated in the US, Canada, or Israel. Efficacy outcomes included ORR, PFS, and OS. Safety outcomes included incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results As of May 4, 2023, 48 pts with RT received a single tisagenlecleucel infusion. Median age at infusion was 68 y (range, 39-83); 58% were ≥65 y old. Median number of all prior lines of therapy was 3 (range, 1-8); 42% received prior ibrutinib therapy. No information confirming clonal relation of LBCL to CLL was available. Fifty percent of pts had primary refractory disease. Prior to infusion, 46% of pts had elevated lactate dehydrogenase. Two pts who had not yet reached 100 d post-infusion at data cutoff were not evaluable for efficacy and safety. Among the 46 pts evaluated for efficacy and safety, the ORR (CR + PR) was 63% (95% CI, 47.5-76.8) and CR rate was 50% (n=23). In total, 23 pts (23/46, 50%) experienced disease relapse, 17 within 6 mo of infusion (Fig.). Twelve- and 24-mo PFS were 43% and 39%, respectively; 12- and 24-mo OS rates were 51% and 44%, respectively. Among 23 pts with a BOR of CR, 57% remained in remission at data cutoff. The most common AEs of any grade were CRS (78%), hypogammaglobinemia (46%), and ICANS (35%). Grade 3/4 CRS was reported in 11% of pts. No pt experienced grade 5 CRS. CRS was managed with tocilizumab in 81% of cases. Grade 3 ICANS was reported in 9% of pts. No grade 4/5 ICANS events were observed. Two pts went on to receive a stem cell transplant following tisagenlecleucel infusion. In total, 25 deaths were reported. Most common cause of death was progressive disease (13/48, 27%); 12/48 (25%) died without disease progression. Causes of non-relapse-related mortality included infection (including COVID-19, n=5), respiratory failure (n=2), malignant neoplasm (n=2), prior malignancy (n=1), multiorgan dysfunction (n=1), and severe veno-occlusive disease (n=1). Conclusions In the largest cohort of pts with RT receiving treatment in a real-world setting, tisagenlecleucel resulted in a high ORR and durable survival. The incidences of CRS and ICANS were similar to other real-world reports of tisagenlecleucel for pts with LBCL. Overall, these findings demonstrate that tisagenlecleucel could be considered a potential treatment option for pts with RT who have a high unmet medical need.