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. 2021 May;36(5):1175-1182.
doi: 10.1007/s00467-020-04811-0. Epub 2020 Oct 28.

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

Claire Dossier  1 , Benjamin Prim  1 , Christelle Moreau  2 , Thérésa Kwon  1 , Anne Maisin  1 , Sylvie Nathanson  3 , Christiane De Gennes  4 , Katia Barsotti  5 , Abdelmajid Bourrassi  6 , Julien Hogan  1 , Georges Deschênes  7
Affiliations

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

Claire Dossier et al. Pediatr Nephrol. 2021 May.

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 m2 obinutuzumab followed by 1000 mg/1.73 m2 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/mm3) 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.

Keywords: B cell recovery; Children; Daratumumab; Obinutuzumab; Relapse; Rituximab; Steroid-dependent nephrotic syndrome.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Probability of remission following anti CD20 monoclonal antibodies in 34 previous attempts of B cell depletion (red line) vs. after obinutuzumab injection in the 14 patients (blue line)
Fig. 2
Fig. 2
Time course of the plasma level of immunoglobulin G (IgG) (graph a; n = 101), immunoglobulin A (IgA) (graph b; n = 150), immunoglobulin M (IgM) (graph c; n = 150) from obinutuzumab injection. Obviously, 49 points of plasma IgG obtained within 10 weeks from intravenous polyclonal IgG infusion have been discarded in order to analyze the spontaneous course of the level of plasma IgG. The regression lines have been obtained by the weighted least squares method
See this image and copyright information in PMC

Comment in

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