SEOUL, SOUTH KOREA – B cell–depleting therapies in patients with lupus nephritis have a higher likelihood of complete response if B cells are almost completely depleted, and strategies for achieving more complete B-cell depletion continue to be tested, according to evidence presented by Richard A. Furie, MD, at an international congress on systemic lupus erythematosus (SLE).
“If you go back about 20 years ago or so, when we designed the LUNAR and EXPLORER trials, we were scared to death of rituximab [Rituxan and biosimilars], about what would happen when you deplete B cells,” said Dr. Furie, chief of the division of rheumatology at Northwell Health in New York.
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Dr. Richard A. Furie
The LUNAR trial, which compared rituximab with placebo in patients with lupus nephritis, did not show a statistically significant difference in renal outcomes at 1 year. However, a post hoc analysis done several years later told a different story. It looked at patients who achieved complete peripheral depletion of B cells, defined as zero cells per microliter in peripheral blood. “You can see about a fourfold increase in complete response rates in those who were complete B-cell depleters at 1 year,” Dr. Furie told the conference.
It therefore raises the question of how to achieve greater B-cell depletion rates in patients. Dr. Furie said one strategy might be to first mobilize memory B cells and neutralize B cell–activating factor using belimumab (Benlysta), and then treat with rituximab to eliminate B cells. This strategy of sequential belimumab-rituximab treatment has been taken in several clinical trials.
More potent B-cell depletion with obinutuzumab
Another approach is to choose more potent B cell–depleting therapies, such as obinutuzumab (Gazyva), which is an anti-CD20 monoclonal antibody that was approved in 2013 for the treatment of chronic lymphocytic leukemia.
The NOBILITY trial compared obinutuzumab with placebo in 125 patients with lupus nephritis who were on background treatment with mycophenolate and corticosteroids. At 1 year, significantly more patients achieved B-cell thresholds either below 5 cells per microliter or even zero cells per microliter than had been seen previously with rituximab.
That also translated into clinical benefit, Dr. Furie said. By week 76, half the patients who had sustained depletion of B cells below 0.4 cells per microliter had a complete response, compared with 35% of those who still had detectable B cells and 18% of the placebo group. Treatment with obinutuzumab did not show any link to higher rates of serious adverse events, serious infections, or deaths.
“I think we’re all pretty much convinced more is better, without introducing safety issues,” Dr. Furie said in an interview.
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Dr. Joan Merrill
Joan Merrill, MD, professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, said the data did suggest that renal outcomes were better with more complete depletion, but raised the question of whether this might increase the risk of infections or infectious severity.
Dr. Furie noted that complete response not only required improvement in proteinuria, complement levels, and anti–double-stranded DNA antibodies, but also in serum creatinine, “because maintenance of eGFR [estimated glomerular filtration rate] is the name of the game with lupus nephritis.”
However, he also pointed out that there may be a ceiling for response rates in patients with lupus nephritis when using stricter endpoints for serum creatinine. The NOBILITY trial required patients to achieve a serum creatinine that did not increase by more than 15% from baseline. But when researchers did an analysis that instead only required patients to achieve a reduction in proteinuria and maintain normal creatinine, the complete response rate in complete B-cell depleters increased to 72%, compared with 50% in partial depleters and 37% in the placebo group.