Impact of Rituximab-Based Immunochemotherapy Induction and Maintenance on the Immunisation Rate Against Tetanus Toxin in Follicular Lymphoma Treated Patients : A Subanalysis of the PRIMA Study
Authors: Karlin Lionel , Bienvenu Jacques , Casasnovas Rene-Olivier , Delfau-Larue Marie-Helene , Feugier Pierre , Dupuis Jehan , Rabeony Tioka , Ferme Christophe , Sebban Catherine , Soubeyran Pierre , Cartron Guillaume , Delmer Alain , Bordessoule Dominique , Brice Pauline , Lamy Thierry , Bousseta Sami , Tilly Hervé , Salles Gilles Andre 
Published: October 2019

Abstract
Background
CD20 is a cell surface antigen commonly expressed on B-cell lineage, but is absent on hematopoïetic stem cells and plasma cells. Therefore, it has been postulated that its targeting should not significantly affect immunoglobulin serum concentrations. However, due to rapid and prolonged B-cell depletion, rituximab-based therapy has been shown to impair humoral response. In addition, protective serologic response to influenza vaccination in lymphoma patients in the 6 months following rituximab-containing regimen has been found to be particularly low1. Because the vast majority of adults individuals have been previously vaccinated against tetanus, we decided to analyse the impact of prolonged rituximab-based therapy on the immune protection rate against tetanus toxin in patients, and conducted in this aim a sub-analysis in follicular lymphoma (FL) patients treated into the PRIMA study.
Methods
The PRIMA study is a multicentre, phase III, randomized study in patients with advanced FL evaluating the benefit of maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy, whose results have been previously published2. In a subset of patients, serum samples were prospectively collected and antitetanus toxin antibodies were measured at baseline, end of immunochemotherapy induction and end of maintenance period. Protective titer was defined as > 0.1 UI/mL according to standards. Statistical analysis aimed to determine if serum antitetanus antibodies titers significantly changed over time according to different phases of treatment, and if rituximab maintenance arm had a significant impact as compared to observation arm.
Results
Overall, 104 patients were evaluable for this subanalysis. Fifty-five percent were male. Median age was 57 (range, 27-80), 88.5% had Ann-Arbor stage III-IV disease. All patients had received R-CHOP induction. Among those patients, 56 were randomised into rituximab arm, 48 into observation arm. At baseline, median serum antitetanus antibodies titers in the overall population was 0.8 UI/mL (range, 0–8) and 89.4% of patients had protective titers. At the end of induction, among the 70 evaluable subjects, 90% had still a protective titer with a median of 0.7 UI/mL (range, 0-4), and at the end of maintenance period, among the 62 evaluable patients, 93% had still protective titer with a median of 0.8 (range, 0-3). When comparing the two arms, at the end of maintenance period, median serum antitetanus antibodies titer was 0.8 UI/mL in the rituximab arm, not significantly different from that in the observation arm (0.6 UI/mL) (p=0.17). At the end of the maintenance period, 100% of subjects had still protective titer in the rituximab arm versus 84.6% in the observation arm.
Conclusion
In this subanalysis of 104 FL treated patients issued from the PRIMA study, rituximab-based induction and maintenance therapy did not significantly affect the immunisation rate against tetanus toxin in previously immunized patients. These results are in contrast with the poor serologic response rate obtained following rituximab-based therapy, emphasizing that common serum vaccinal titers should be controlled, and vaccination updated, when possible, before treatment initiation and the first rituximab administration.
References
1-Yri O, Torfoss D, Hungnes O, et al. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood 2011, 118 (6769 – 6771).
2-Salles G, Seymour J, Offner F, et al. Rituximab maintenance for 2 years in patient with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011, 377 (42-51).

Disclosures
Karlin: Sandoz: Consultancy; celgene: Consultancy, Honoraria; Janssen: Honoraria. Delmer:Roche: Honoraria. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.