Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis

Abstract

Objective. To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). Methods. In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group) or with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. Results. Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. Conclusion. The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN. ClinicalTrials.gov identifier: NCT02260934.

Next stop in the treatment of refractory systemic lupus erythematosus: B-cell targeted combined therapy

“…Definite results have been published very recently. 21 From the mechanistic point of view, B cell depletion occurred in both groups, but B cells remained lower in those receiving belimumab. Moreover, the percentage of total and autoreactive naïve B cells decreased in the belimumab group, consistent with impaired maturation of naïve B cells and enhanced censoring of autoreactive B cells.…”

What's New in the Treatment of Systemic Lupus Erythematosus

“…The autoimmune B cell subpopulation might be more sensitive to belimumab-mediated BLyS inhibition. A phase II trial assessed the effect of induction therapy with RTX followed by maintenance therapy with belimumab in 43 patients with recurrent or refractory lupus nephritis (29). Of these, 21 patients received rituximab, cyclophosphamide and glucocorticoids and subsequently weekly belimumab infusions until week 48 and 22 patients received rituximab and cyclophosphamide without belimumab infusions.…”

Advances in Lupus Nephritis Pathogenesis: From Bench to Bedside

“…Belimumab, a recombinant human IgG1λ monoclonal antibody that inhibits B-cell activating factor, showed efficacy and safety as an add-on therapy to steroids plus either MMF or cyclophosphamide-azathioprine regimens when given intravenous monthly over a period of 104 months, with an effect size of 11% for a PIRR (primary efficacy renal response) [10,23]. In the phase II CALIBRATE trial, the addition of belimumab to a rituximab/cyclophosphamide/steroid regimen impaired the maturation of naïve B-cells and stimulated the negative selection of autoreactive B-cells [24]. However, this was more of a proof-of-concept trial to evaluate the effect of belimumab after B-cell depletion with rituximab and neither designed nor powered to evaluate the superiority in terms of enhancing clinical response rates [24].…”

“…In the phase II CALIBRATE trial, the addition of belimumab to a rituximab/cyclophosphamide/steroid regimen impaired the maturation of naïve B-cells and stimulated the negative selection of autoreactive B-cells [24]. However, this was more of a proof-of-concept trial to evaluate the effect of belimumab after B-cell depletion with rituximab and neither designed nor powered to evaluate the superiority in terms of enhancing clinical response rates [24]. Accordingly, the reduction in the percentage of naïve B-cells after belimumab addition supports the dependence on BAFF of the differentiation of transitional B-cells to naïve B-cells [24].…”