Impact of PRF 1 A91V germline carrier status in patients with aggressive b-NHL treated with rituximab
Year: 2025
Type: conference-abstract
Abstract: INTRODUCTION Rituximab mediated antibody-dependent cellular cytotoxicity (ADCC) is an essential component of therapy in B-cell malignancies. The efficiency of cellular cytotoxicity depends on many factors including rituximab binding, lytic granule release and perforin/granzyme concentration, or expression of death-inducing ligands. Here we analysed whether selected variants in key effector molecules affect outcomes in B-cell non-Hodgkin lymphoma (B-NHL). METHODS PRF1 A91V (rs35947132) was genotyped in 501 patients enrolled in the RICOVER-60 trial (NCT0052936), comparing 6 versus 8 cycles of CHOP chemotherapy with or without rituximab in untreated elderly patients with aggressive B-NHL (Pfreundschuh et al., Lancet Oncol 2008). We evaluated associations with event-free, progression-free, and overall survival. The NHL-B2 (Pfreunschuh et al. Blood 2004) trial served as validation cohort for the CHOP-only arm and the interim analysis of the OPTIMAL>60 (NCT01478542) (Pfreundschuh et al., J Clin Oncol 2017) trial as validation cohort for the R-CHOP arm of the discovery RICOVER-60-cohort. RESULTS Within the RICOVER-60 trial 63 of 501 patients (13%) were carriers of the PRF1 A91V. Carriers showed significant better outcomes, with a 36-month overall survival of 81% [95% CI: 68%-95%] compared to 64% [95% CI: 57%-71%] in wildtype patients treated with CHOP alone. However, no additional benefit was observed for these carriers of PRF1 A91V by the addition of rituximab: 36-month EFS 61% [95% CI: 44%-77%] with CHOP and 63% [95% CI: 46%-81%] with R-CHOP; 36-month OS 81% [95% CI: 68%-95%] with CHOP and 73% [95% CI: 57%-89%] with R-CHOP, respectively. These results were validated in independent cohorts in aggressive B-NHL. In NHL-B2 trial the positive prognostic impact of PRF1 A91V was confirmed for CHOP-only therapy with a significantly higher 36-month OS of 87% [95% CI: 73%-100%] in PRF1 A91V carriers compared to 60% [95% CI: 54%-66%] (p=0.030) in wildtype carriers. In the interim analysis of OPTIMAL>60, where all patients received rituximab with chemotherapy, there were no significant differences between PRF1 A91V carriers and wildtype carriers in PFS (HR: 0.8 [95% CI: 0.3 - 1.9], p=0.635) or OS (HR: 0.7 [95% CI: 0.2 - 2.2], p=0.526). CONCLUSION Patients with aggressive B-NHL carrying the PRF1 A91V germline variant had a favourable outcome with CHOP only chemotherapy, but no benefit from the addition of rituximab. These results suggest PRF1 A91V as a negative predictive marker for rituximab-mediated cellular cytotoxicity in aggressive B-NHL, and it may have potential implications for other immune effector cell-based therapies.
Source: Blood
Authors: Onur Cetin, Igor Age Kos, Evi Regitz, Moritz Bewarder, Torben Rixecker, Eugen Tausch, Eva Schwarz, Johanna Jansky, Vadim Lesan, Claudia Schormann, Frank Neumann, Markus Loeffler, Michael Hallek, Kirsten Fischer, Sylvia Zöphel, Annete Staiger, German Ott, Konstantinos Christofyllakis, Jörg Bittenbring, Viola Poeschel, Dominic Kaddu-Mulindwa, Philipp Staber, Rudy Ligtvoet, Sandra Robrecht, Marita Ziepert, Norbert Schmitz, Markus Hoth, Christoph Kessel, Stephan Stilgenbauer, Bettina Altmann, Lorenz Thurner
Institutions: Saarland University, 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 of Münster, University Hospital Münster
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417008389
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