Impact of Perforin 1 A91V germ line background in patients with aggressive B-NHL treated with R-CHOP
Year: 2025
Type: article
Abstract: 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 deathinducing 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 eventfree, 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.
Source: Blood Advances
Authors: Onur Cetin, Igor Kos, Evi Regitz, Moritz Bewarder, Torben M. Rixecker, Eugen Tausch, Eva C. Schwarz, Johanna Jansky, Vadim Lesan, Claudia Schormann, Frank Neumann, Markus Loeffler, Michael Hallek, Kirsten Fischer, Sylvia Zöphel, Annette M. Staiger, German Ott, Konstantinos Christofyllakis, Joerg T. Bittenbring, Viola Poeschel, Dominic Kaddu-Mulindwa, Philipp B. Staber, Rudy Ligtvoet, Sandra Robrecht, Marita Ziepert, Norbert Schmitz, Markus Hoth, Christoph Kessel, Stephan Stilgenbauer, Bettina Altmann, Lorenz Thurner
Institutions: Saarland University, Universitätsklinikum des Saarlandes, Universität Ulm, University Hospital Ulm, Leipzig University, University of Cologne, University Hospital Cologne, Deutsche CLL Studiengruppe (DCLLSG), Robert Bosch Hospital, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, University Hospital Münster
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Award: G1275602140
OpenAlex ID: W4417119335