Background/Purpose: Patients with LN who received obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, with standard-of-care (MMF) immunosuppression (Phase II NOBILITY; NCT02550652; PMID 34615636) showed improved clinical responses through Week 104 versus those who received MMF alone. Sustained depletion up to Week 52 was associated with a better initial clinical response.¹ This analysis aims to characterize subsequent B-cell recovery after the last dose of obinutuzumab in NOBILITY and its impact on later response and safety.

Methods: 125 patients with active Class III/IV LN receiving MMF and corticosteroids were randomized and received either obinutuzumab 1000 mg (n=63) or placebo (n=62) on Day 1 and Weeks 2, 24 and 26, and followed through Week 104 or to B-cell recovery, whichever was longer. Blood B cells were measured using both a TBNK cell assay with a LLoQ of 10 CD19⁺ cells/µL and a high-sensitivity minimal residual B-cell 1.1 assay with an LLoQ of 0.4 cells/µL. B-cell depletion was defined as ≤0.4 cells/µL, and recovery was defined as ≥20 cells/µL or the patient’s predose baseline, whichever was lower. Time to peripheral B-cell recovery after the last dose of obinutuzumab, the relationship between time to recovery and efficacy at Week 104, and safety throughout the main study and follow-up period were evaluated (SAE and infectious SAE rates, adjusted for patient-years [PY] at risk).

Results: Of 63 patients who received obinutuzumab, 4 did not achieve full B-cell depletion during the study. By Week 24, 59 patients (93.7%) achieved B-cell depletion (before obinutuzumab redosing); of those, 4 discontinued prior to B-cell recovery, and 4 completed the study at or after Week 104 but before achieving B-cell recovery. The remaining 51 patients comprised the analysis population, which was grouped based on the time to B-cell recovery distribution (Figures 1 and 2). Of the 51 patients, 3 (5.9%) recovered B cells before redosing at Week 26; 1/3 achieved CRR at Week 104. 37 patients (72.5%) attained B-cell recovery ≤93 weeks of their last dose of obinutuzumab (median, 78.1 weeks). 18/ 37 (48.6%) and 23/37 (62.2%) achieved CRR and overall renal response (ORR), respectively, at Week 104. In these 37 patients, SAE and infectious SAE rates per 100 PY were 13 and 8. 11 patients (21.6%) did not recover B cells by Week 93 after their last dose of obinutuzumab. 9/11 patients achieved B-cell recovery at a median of 102 weeks, and 2/11 had not yet achieved B-cell recovery at the time of writing. 5/11 patients (45.5%) achieved CRR, and 8/ 11 (72.7%) achieved ORR at Week 104. In these 11 patients, SAE and infectious SAE rates per 100 PY were 10 and 0, respectively.

Conclusion: Most patients recovered peripheral B cells ≤93 weeks after the last obinutuzumab dose. Renal response rates at Week 104 were similar among patients who recovered B cells within 2 years of their final obinutuzumab infusion and those who recovered later or were still depleted, suggesting a greater clinical effect of early sustained depletion vs duration of depletion on clinical response.¹ Within the limitation of small sample size, the SAE and infectious SAE rates appeared similar regardless of the duration of B-cell depletion. 1. Vital E, et al. Arthritis Rheumatol. 2020;72 (suppl 10).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-recovery-in-a-randomized-controlled-trial-of-b-cell-depletion-with-obinutuzumab-for-the-treatment-of-proliferative-lupus-nephritis/