A global antiB cell strategy combining obinutuzumab and daratumumab in severe pediatric nephrotic syndrome

Abstract

Background Steroid-sensitive nephrotic syndrome (SSNS) is, in most patients, a chronic disease with 80% experiencing at least one relapse after first flare. B cell depletion using rituximab is effective in preventing relapse in steroid-dependent (SDNS) patients but fails to maintain long-term remission following B cell recovery, possibly due to development of autoreactive long-lived plasma cells. We investigated sequential combination of antiCD20 antibody targeting all B cell subsets, and antiCD38 antibody with high plasma cell cytotoxicity in patients with uncontrolled SDNS after failure of one or several attempts at B cell depletion. Methods Fourteen patients with median disease duration 7.8 years received 1000 mg/1.73 m 2 obinutuzumab followed by 1000 mg/1.73 m 2 daratumumab 2 weeks later. Oral immunosuppression was discontinued within 6 weeks, and biological monitoring performed monthly until B cell recovery. Results Median age at treatment was 11.0 [IQR 10.4–14.4] years. B cell depletion was achieved in all patients, and B cell reconstitution occurred in all at median 9.5 months after obinutuzumab injection. After median follow-up 20.3 months (IQR 11.5–22.6), 5/14 patients relapsed including 4 within 100 days following B cell repletion. Relapse-free survival was 60% at 24 months from obinutuzumab infusion. Mild infusion reactions were reported in 3/14 patients during obinutuzumab and 4/14 during daratumumab infusions. Mild transient neutropenia (500–1000/mm 3 ) occurred in 2/14 patients. Intravenous immunoglobulins were given to 12/14 patients due to hypogammaglobulinemia. Low IgA and IgM levels were noted in 8 and 14 patients, respectively. No severe infection was reported. Conclusion Global antiB cell strategy combining obinutuzumab and daratumumab induces prolonged peripheral B cell depletion and remission in children with difficult-to-treat SDNS. Electronic supplementary material The online version of this article (10.1007/s00467-020-04811-0) contains supplementary material, which is available to authorized users.

B Lymphocyte Subsets in Children With Steroid-Sensitive Nephrotic Syndrome: A Longitudinal Study

“…In recent years, the administration of monoclonal antibodies against CD20, a specific surface marker of B cells, has achieved remarkable results in the treatment of children with frequent relapses and steroid dependence. For example, a global anti-B cell strategy combining obinutuzumab and daratumumab was shown to induce prolonged peripheral B cell depletion and remission in children with difficult-to-treat SDNS, suggesting that B cells and their subgroups are involved in the pathogenesis of SSNS (3,4). There is also evidence that supports this role of B cells, with IgG levels shown to decrease in the acute and remission phases of children with INS.…”

New and Old Anti-CD20 Monoclonal Antibodies for Nephrotic Syndrome. Where We Are?

“…Only one study used obinutuzumab (single dose 1,000 mg 1.73m 2 ) in nephrotic syndrome in combination with sequential administration of the anti-CD38 (plasma cell) monoclonal antibody daratumumab (1,000 mg 1.73m 2 ) after 14 days (55). Fourteen patients who relapsed after conventional treatments with prednisone, rituximab and CNI and developed dependency with combination of more drugs (MDNS) were treated with the above association of obinutuzumab and daratumumab and were included in a retrospective analysis: 5 presented recurrence of proteinuria after about 10 months, 9 were in stable remission after 20 months of follow up.…”

On the road to eliminating long‐lived plasma cells—“are we there yet?”

“…Although interpretation is often complicated by potentially confounding effects of concomitant immunomodulating therapy, the timing and rate of antibody reduction relative to daratumumab treatment suggest its impact. In a recent relatively large prospective study of immunosuppression using daratumumab, 14 children with autoimmune nephrotic syndrome were treated with the combination of anti‐CD20 and anti‐CD38 with the hope of targeting both B and PC compartments 107 . The disease is thought to be cause by autoimmunity, and patients were previously responsive to immunosuppression including B‐cell depletion with anti‐CD20.…”