Impact of Perforin 1 A91V germ line background in patients with aggressive B-NHL treated with R-CHOP

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.

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Publication Details

Journal
Blood Advances
Published
2025-12-08
DOI
https://doi.org/10.1182/bloodadvances.2025016931
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
Field-Weighted Citation Impact
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article

Impact of Perforin 1 A91V germ line background in patients with aggressive B-NHL treated with R-CHOP

Norbert Schmitz, Igor Age Kos, Stephan Stilgenbauer, Sylvia Zöphel et al.
Blood Advances
Chronic Lymphocytic Leukemia Research
article

Impact of Perforin 1 A91V germ line background in patients with aggressive B-NHL treated with R-CHOP

Norbert Schmitz, Igor Age Kos, Stephan Stilgenbauer, Sylvia Zöphel, Rudy Ligtvoet, Joerg Thomas Bittenbring, Konstantinos Christofyllakis, Viola Poeschel, Evi Regitz, Markus Loeffler, Eugen Tausch, Philipp Bernhard Staber, Annette M. Staiger, Marita Ziepert, Torben Rixecker, Markus Hoth, Bettina Altmann, Onur Cetin, Dominic Kaddu‐Mulindwa, Vadim Lesan, Kirsten Fischer, Claudia Schormann, Christoph Kessel, Sandra Robrecht, Lorenz Thurner, Moritz Bewarder, German Ott, Michael J. Hallek, Eva C. Schwarz, Frank Neumann, Johanna Jansky
article en

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.

Blood AdvancesVol. 10(4)
University of Cologne (DE), Universität Ulm (DE), Robert Bosch Hospital (DE), Düsseldorf University Hospital (DE), University Hospital Münster (DE), Hôpital Nord (FR), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE), STZ eyetrial (DE), University Hospital Cologne (DE), University Hospital Ulm (DE), Heinrich Heine University Düsseldorf (DE), University of Tübingen (DE), Saarland University (DE), Leipzig University (DE)
Deutsche Forschungsgemeinschaft, Universität des Saarlandes, Deutsche Krebshilfe
Openalex Percentile: Top 40%
Chronic Lymphocytic Leukemia Research
DOIOpen Access PDFOpenAlex
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