(1) Background: CAR-T-cell therapy is a novel therapeutic option for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The parameters that predict a favorable outcome after CAR-T-cell treatment are a matter of ongoing exploration. (2) Methods: We analyzed 36 consecutive patients with r/r DLBCL receiving tisagenlecleucel or axicabtagene ciloleucel at a single academic institution. We hypothesized that lymphoma subtypes (transformed versus de novo DLBCL) are of prognostic importance. We also assessed age, previous treatment, bridging therapy, remission status at the time of CAR-T treatment and at six months, LDH, the occurrence of CRS or ICANS, and CAR-T-DNA ddPCR kinetics for their prognostic impact. (3) Results: CRS was observed in 24 (67%) patients, and ICANS was observed in 14 (39%) patients. CR was achieved in 20 (56%) patients. Achievement of CR within six months after CAR-T was associated with better PFS (p < 0.0001) and OS (p < 0.0001). Remarkably, transformed (=secondary) lymphoma was associated with a better outcome than de novo disease for PFS (p = 0.0093) and OS (p = 0.0209), and the CR rate was 78% versus 33% (p = 0.0176). Mortality in patients with transformed DLBCL was 23% compared with 56% in de novo patients (p = 0.0209). (4) Conclusion: The presence of transformed DLBCL seems to be associated with a more favorable course after CAR-T treatment than that observed in the de novo DLBCL patients.
