Ofatumumab for Rituximab-Resistant Nephrotic Syndrome

Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m(2) intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, -12% [95% confidence interval, -73% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.

Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. The best outcomes are seen in patients with steroid-dependent nephrotic syndrome who have failed to respond to multiple therapies. By contrast, the benefits of rituximab therapy are limited in patients with steroid-resistant nephrotic syndrome, particularly those with focal segmental glomerulosclerosis (FSGS). Therapy with plasma exchange and one or two doses of rituximab has shown success in patients with recurrent FSGS. Young patients and those with normal serum albumin at recurrence of nephrotic syndrome are most likely to respond to rituximab therapy. A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A(2) receptor autoantibodies, which are implicated in the pathogenesis of this disorder. Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. However, the available evidence of efficacy of rituximab therapy is derived chiefly from small case series and requires confirmation in prospective, randomized, controlled studies that define the indications for use and predictors of response to this therapy.

The availability of safe and effective monoclonal antibodies (mAbs) has dramatically altered treatment strategies for B-cell malignancies. Rituximab, a type I chimeric anti-CD20 mAb, not only has activity against a broad range of CD20-positive B-cell malignancies but also, when combined with chemotherapy or other biologic agents, has improved response rates; in addition, in certain situations, progression-free survival and even overall survival may be prolonged. Recently, other anti-CD20 mAbs have been developed to improve on the activity achieved with rituximab or to demonstrate efficacy in patients whose diseases are resistant to rituximab. The most extensively studied of these is ofatumumab, a type I human antibody that binds to a different epitope of CD20 than rituximab. Preclinical data suggest improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity compared with rituximab. In early clinical trials, ofatumumab demonstrated single-agent activity against chronic lymphocytic leukemia (CLL) and a number of histologies of B-cell non-Hodgkin's lymphomas. This antibody was recently approved by the US Food and Drug Administration for the treatment of CLL that is resistant to both fludarabine and alemtuzumab. Additional study is ongoing with ofatumumab in combination with chemotherapy and biologic agents to further enhance its efficacy. Ofatumumab offers another effective agent with which to improve the outcome of patients with B-cell malignancies.