#1649 Obinutuzumab is effective for the treatment of rituximab-resistant membranous nephropathy

Abstract Background and Aims Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in nondiabetic adults. Rituximab has become the first-line therapy for patients with MN after the recognition of MN as an autoimmune disease. However, 40% of patients with MN do not respond to rituximab. Obinutuzumab is a humanized and glycoengineered type II anti-CD20 monoclonal antibody that has superior in vitro B-cell cytotoxicity compared with rituximab which might provide an attractive option for rituximab-resistant MN. We presented our single-center experience of treating MN with obinutuzumab. Method Fourteen patients with rituximab-resistant PLA2R-associated MN who received obinutuzumab at the First affiliated hospital of Xi'an Jiaotong university between January 2022 and June 2023 were included in this retrospective study. Resistance to rituximab was defined as the failure to achieve complete (urinary protein excretion <0.3 g/d along with normal serum albumin concentration and stable renal function) or partial (urinary protein excretion <3.5 g/d or with ≥50% reduction vs baseline, accompanied by improvement or normalization of serum albumin concentration and stable GFR) remission of NS in 3-6 months after 2 doses of rituximab administration. Clinical and laboratory parameters were evaluated at presentation, before and after obinutuzumab administration. Results Of all patients with an average age of 50.0 ± 13.6 years, 10 (71.4%) patients were men, 8 (57.1%) patients had hypertension and 4 (28.6%) patients had diabetes. The median disease duration was 1.3 (1.0, 4.8) years. At presentation, the proteinuria and albumin levels were 7.94 ± 4.23 g/d and 21.5 ± 3.6 g/L, respectively. The mean serum creatinine level was 70.5 ± 10.7 µmol/L and the patients had a median baseline anti-PLA2R level of 193.5 (104.5,299.2) RU/mL. Six patients had been previously exposed to steroids, alkylating agents, calcineurin inhibitors in different combinations in addition to rituximab. Both patients received 1 g of obinutuzumab on day 0 and day 15. At obinutuzumab administration, the proteinuria and albumin levels were 8.43 ± 3.36 g/d and 22.4 ± 4.0 g/L, respectively. The mean serum creatinine level was 85.1 ± 28.5 µmol/L and median anti-PLA2R level decreased to 32.7 (10.7,178.) RU/mL compared with that at presentation. After a median follow-up of 5.4 (4.0, 9.7) months after obinutuzumab therapy, complete remission was achieved in 4 (28.6%) and partial remission was achieved in 8 (57.1%) of patients. Of the remaining two patients who did not achieve complete or partial remission, 1 patient had a follow-up of 4 months and had a 33% decline in proteinuria accompanied by improvement in serum albumin. The other patient had an anti-PLA2R level higher than 1500 RU/mL (exceeding detection upper limit) at obinutuzumab administration and an inadequate follow-up of 3 months without proteinuria decline. Whereas, anti-PLA2R level decreased to 18.17 RU/ml accompanied by B-lymphocyte depletion (absolute CD19 count <5 cells/ml) at that time. Of the 12 patients who achieved complete or partial remission, the median time from treatment to remission was 4.7 ± 2.3 months. Two patients with longer follow-up maintained complete remission at 1 year. At first complete or partial remission, the proteinuria and albumin levels were 3.47 ± 1.99 g/d and 32.5 ± 3.3 g/L, respectively. The mean serum creatinine level was 74.8 ± 24.1 µmol/L and anti-PLA2R levels of 11 patients had a decline in the titer to <2 RU/ml (negative result for our immunology laboratory). B-lymphocyte depletion was achieved in all these patients. Conclusion Obinutuzumab may represent an attractive alternative therapy in patients with resistance to rituximab. Larger prospective studies are needed to validate these findings.