Ofatumumab in Rituximab-Resistant and RituximabIntolerant Patients With Primary Membranous Nephropathy: A Case Series

Rationale & Objective: Rituximab is the first- choice therapy for patients with primary membranous nephropathy (MN) and nephrotic syndrome. However, approximately 30% of patients are treatment-resistant or become treatment-intolerant with hypersensitivity reactions upon repeated drug exposures. We aimed to assess whether ofatumumab, a fully human second-generation anti-CD20 antibody, could be a valuable alternative to rituximab in this population. Study Design: Case series. Setting & Participants: 7 rituximab-intolerant and 10 rituximab-resistant patients with MN who consented to receive ofatumumab (50-300 mg, single intravenous infusion) and were followed at the nephrology unit of Azienda SocioSanitaria Territoriale Papa Giovanni XXIII (Bergamo, Italy) between September 2015 and January 2019. Findings: Over a median (IQR) follow-up of 5.0 (3.0-9.8) months, all 7 rituximab-intolerant and 3 of the 10 rituximab-resistant patients exhibited complete (proteinuria <0.3 g/d) or partial (proteinuria <3.5 g/d with >= 50% reduction vs baseline) remission of nephrotic syndrome. Circulating B cells were similarly depleted in all patients by 1 week, and serum anti-phospholipase A2 receptor antibody concentrations decreased to <2.7 relative units/ mL in 3 of 4 rituximab-intolerant and 4 of 8 rituximab-resistant patients with phospholipase A2 receptor-related disease. Ofatumumab significantly reduced 24-hour urinary protein and immunoglobulin G excretion and increased serum albumin and immunoglobulin G levels. These effects were greater in rituximabintolerant than in rituximab-resistant patients. Measured glomerular filtration rate significantly increased by an average of 13.4% at 24 months compared with baseline (P= 0.036) among all patients in the series. There were 14 nonserious infusion-related adverse events in 9 patients that recovered with temporary infusion interruption. Limitations: Retrospective design, limited number of patients. Conclusions: Ofatumumab may represent an effective and safe treatment for rituximabintolerant cases of MN. Larger prospective studies will be needed to validate these preliminary findings and explore the effectiveness of other second-generation antiCD20 antibodies in this clinical setting.