https://orcid.org/0009-0007-3441-7743
Key Points
PRF1 A91V carriers have a better prognosis than wild-type patients in treatments without rituximab.
PRF1 A91V carriers show no additional benefit from rituximab in first-line chemotherapy for DLBCL.
Rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) is a critical mechanism in the treatment of B-cell malignancies. The effectiveness of ADCC depends on multiple factors, including rituximab binding, granule release, perforin/granzyme concentration, and the expression of death-inducing ligands. This study aimed to determine whether genetic variants in key effector molecules influence treatment outcomes in aggressive B-cell non-Hodgkin lymphoma (B-NHL).We genotyped variants of PRF A91V (rs35947132), GZMB Q48R (rs8192917), and FASL (rs5030772 and rs763110) in 501 patients from the RICOVER-60 trial (NCT0052936/EU-20243), which compared 6 versus 8 cycles of chemotherapy containing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without rituximab in elderly patients with untreated aggressive B-NHL. Associations with event-free, progression-free, and overall survival were analyzed. Validation cohorts included the NHL-B2 trial for the CHOP-only arm and the OPTIMAL>60 trial for the R-CHOP arm. Additionally, samples from patients with chronic lymphocytic leukemia (CLL) of the CLL-8 trial were analyzed.In the RICOVER-60 trial, 13% (63/501) of patients carried the PRF1 A91V variant. Carriers showed significantly better outcomes with CHOP alone but no additional benefit from rituximab. These findings were validated in independent cohorts of aggressive B-NHL but not in CLL, where the PRF1 A91V variant was overrepresented (119/589; 20%) compared to aggressive B-NHL and general population.Our results suggest that PRF A91V is a negative predictive marker for rituximab-mediated cellular cytotoxicity in aggressive B-NHL and may have broader implications for immune effector cell-based therapies.
