In patients with refractory lupus nephritis, the addition of belimumab to a treatment regimen of rituximab and cyclophosphamide was found to be safe, according to study results published in Arthritis & Rheumatology. Researchers noted that the treatment regimen demonstrated diminished maturation of translational naive B cells during B-cell reconstitution and enhanced the negative selection of autoreactive B cells.

In a phase 2, multicenter, open-label, randomized, controlled trial (Combination of Antibodies in Lupus Nephritis: Belimumab and Rituximab Assessment of Tolerance and Efficacy [CALIBRATE; ClinicalTrials.gov Identifier: NCT02260934]), the investigators sought to evaluate the safety, mechanism of action, and preliminary efficacy of rituximab plus cyclophosphamide followed by belimumab for the treatment of patients with lupus nephritis.

During the treatment phase, participants received methylprednisolone 100 mg, rituximab 1000 mg, and cyclophosphamide 750 mg administered intravenously (IV) at weeks 0 and 2. At week 4, the participants were randomly assigned to receive rituximab plus cyclophosphamide, followed by weekly belimumab infusions (RCB group) or rituximab plus cyclophosphamide, but no belimumab infusions (RC group). Patients in the RCB group received 10 mg/kg of IV belimumab at weeks 4, 6, and 8, then every 4 weeks through week 48. Patients in the RC group did not receive any additional treatment or placebo infusion. Hydroxychloroquine therapy was permitted throughout the study period. All participants were followed up until week 96.


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The primary study endpoint was the safety of the treatment regimen, which was the percentage of patients who experienced 1 or more infectious adverse events (AEs) of grade 3 or greater at or prior to week 48. Severity of AEs was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints included the percentage of participants with evidence of B-cell reconstitution and those with grade 4 hypogammaglobulinemia (an immunoglobulin G [IgG] level of <300 mg/dL associated with an infectious AE of CTCAE grade ≥3).

Eligible participants were aged18 years or over, had a diagnosis that met the American College of Rheumatology (ACR) or Systemic Lupus International Collaborating Clinics (SLICC) criteria for systemic lupus erythematosus (SLE), and had serum positivity for antinuclear antibodies and/or antidouble-stranded DNA at the time of screening. All of the participants had recurrent or refractory lupus nephritis.

Results of the study showed that treatment with belimumab was not associated with an increase in the incidence of AEs in patients with refractory lupus nephritis. At week 48, the researchers reported a complete or partial response in 52% (n=11/21) of participants in the RCB group and 41% (n=9/22) of those in the RC group (P =.452). The main reason for treatment failure was attributed to a lack of improvement in or worsening of lupus nephritis.

Although B-cell depletion was reported in both groups, the percentage of B cells remained significantly lower in the group that received belimumab (geometric mean number of B cells at week 60, 53 cells/µL in the RBC group vs 11 cells/µL in the RC group; P =.0012). Percentages of total and autoreactive translational 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 RBC vs RC group (P =.0349) — a finding that was consistent with impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. 

Investigators concluded that clinical efficacy was not improved with rituximab plus cyclophosphamide in combination with belimumab compared with use of a therapeutic strategy of B-cell depletion alone in patients with lupus nephritis. “The CALIBRATE trial is an important step in understanding the mechanisms of action of combination therapy with rituximab and belimumab for the treatment of LN in SLE. These findings may lay the foundation for larger trials designed to assess efficacy,” they added.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis. Arthritis Rheumatol. 2020;73(1):121-131. doi:10.1002/art.41466