Extremely Long-lasting B-cell Depletion and BAFFling Effects Following Obinutuzumab-based Regimen in Lupus Nephritis

A 47-year-old man diagnosed with class V Lupus nephritis in 1993 has been treated over the years with cyclophosphamide, azathioprine, mycophenolate and Rituximab (RTX). In 2017, 2 years after the last (effective) RTX infusion, a renal relapse occurred (proteinuria up to 11 g/24 h with Class III nephritis at repeat biopsy). He received Obinotuzumab (Obi) (1Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, Sondermann P, Jäger C, Strein P, Fertig G, Friess T, Schüll C, Bauer S, Dal Porto J, Del Nagro C, Dabbagh K, Dyer MJ, Poppema S, Klein C, Umaña P. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 3;115(22):4393-4402.Google Scholar) 1000 mg on day 1 and weeks 2, 24 and 26 as an add-on therapy to mycophenolate and corticosteroids (2Furie R.A. Aroca G. Cascino M.D. Garg J.P. Rovin B.H. Alvarez A. Fragoso-Loyo H. Zuta-Santillan E. Schindler T. Brunetta P. Looney C.M. Hassan I. Malvar A. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial.Ann Rheum Dis. 2022 Jan; 81: 100-107Crossref PubMed Scopus (166) Google Scholar). He has been on complete peripheral B-Cell Depletion (BCD) (< 0.4 cells /mcL ) for over 72 months with stable clinical response (SLEDAI-2k=29 to SLEDAI-2k=4) (Figure 1) despite the occurrence of a severe SARS-CoV2-infection. Three bone marrow biopsies from 2021 and 2023 were unremarkable. Circulating levels of B cell activating factor (BAFF) progressively increased during the follow-up (Figure 1) (2Furie R.A. Aroca G. Cascino M.D. Garg J.P. Rovin B.H. Alvarez A. Fragoso-Loyo H. Zuta-Santillan E. Schindler T. Brunetta P. Looney C.M. Hassan I. Malvar A. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial.Ann Rheum Dis. 2022 Jan; 81: 100-107Crossref PubMed Scopus (166) Google Scholar, 3Carter L.M. Isenberg D.A. Ehrenstein M.R. Elevated serum BAFF levels are associated with rising anti-double-stranded DNA antibody levels and disease flare following B cell depletion therapy in systemic lupus erythematosus.Arthritis Rheum. 2013 Oct; 65: 2672-2679Crossref PubMed Scopus (141) Google Scholar, 4Scholz J.L. Cancro M.P. Resolve, revise, and relax: the 3 Rs of B cell repertoire adjustment.Immunol Lett. 2012 Mar 30; 143: 2-8Crossref PubMed Scopus (14) Google Scholar). Figure 1S, Table 1S and 2S provide a comparison of the BCD duration with Obi- and RTX in different randomized controlled trials in SLE. In a post-hoc analysis of the NOBILITY study (5Roccatello D, Vital E, Black, Jacob-Moffatt, Looney CM, Martins E, Mao HA, Schindler T, Garg HSJ, Terres JR, Furie RA. NDT Abstract 60th ERA Congress 2023, B-Cell Recovery in a Randomized Controlled Trial of B-Cell Depletion With Obinutuzumab for the Treatment of Proliferative Lupus Nephritis (NOBILITY) last access 7 April 7, 2024Google Scholar), of 63 patients who received two 1000 mg infusions of Obi at baseline and week 2, 59 (93.7%) achieved BCD by Week 24, i.e., before obi redosing. Of the 51 patients who had sufficient follow-up data, 37 (72.5%) attained B-cell recovery within 93 weeks after last dose of Obi. At Week 104, 23 of 37 (62.2%) achieved an overall renal response. In the 11 patients requiring more than 93 weeks to achieve B-cell recovery it occurred within a median time of 114 weeks. Two of these 11 cases, including our patient, had not yet achieved B-cell recovery at the time of that last evaluation. The results of the NOBILITY trial (2Furie R.A. Aroca G. Cascino M.D. Garg J.P. Rovin B.H. Alvarez A. Fragoso-Loyo H. Zuta-Santillan E. Schindler T. Brunetta P. Looney C.M. Hassan I. Malvar A. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial.Ann Rheum Dis. 2022 Jan; 81: 100-107Crossref PubMed Scopus (166) Google Scholar) strongly support the concept that Obi is superior to rituximab at inducing BCD, leading to a higher rate of remissions (Table S1 and S2 for comparison, as supplementary material). Adverse effects were mild and unrelated to duration of BCD (5-S1). While concerns may arise about the long-term effects of lack of B cell repopulation over years, data show that clinical remission persists as long as BCD lasts despite increases in peripheral BAFF levels. Disclosures - No conflict of interest to declare Download .pdf (.13 MB) Help with pdf files