Low-dose rituximab—about half the standard treatment—appears to be as protective against multiple sclerosis (MS) progression as higher doses, researchers reported at MS Virtual 2020, the joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis.
The annualized relapse rate among patients who were treated with low-dose rituximab was 0.05 compared with an annualized relapse rate of 0.03 among patients receiving the standard dose of the disease-modifying therapy, reported Luciana Midaglia, MD, a clinical neurologist and PhD candidate at the Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron of the Universitat Autònoma de Barcelona in Spain.
Despite clinical trials and widespread use of rituximab in treating MS, Dr. Midaglia noted that a standardized treatment schedule for rituximab has yet to be established, and, hence the researchers tried to find that therapeutic sweet spot.
"We were able to achieve with low doses of rituximab treatment the same effectiveness with a better safety profile," she told Neurology Today At the Meetings. "I think our work will change clinical practice."
The study was conducted at two centers—in Barcelona, where 249 patients were given high-dose therapy, and Girona, where 54 received low-dose rituximab. After two intravenous infusions of 1000 mg of rituximab at baseline, patients in the Barcelona clinic received two more infusions every six months for the first year, and then 1000 mg every six months. At Girona, following the two infusions of 1000 mg at baseline, patients were treated with 500 mg every six months.
The study was continued for three years, and patient outcomes were analyzed in February 2020. Patients were clinically followed every six months with lab tests, and brain MRI scans were performed at baseline and yearly thereafter.
More than half the patients were diagnosed with secondary progressive multiple sclerosis; about 25 percent were diagnosed with relapsing-remitting disease, about 20 percent had primary progressive multiple sclerosis.
Dr. Midaglia and colleagues also reported improvement in Extended Disability Status Scale (EDSS) scores—a measure of disability. After treatment, 82 percent of the Barcelona cohort improved or were stable, compared with 72 percent of those in Girona (p=0.09). When considering only those patients who entered the trial with progressive forms of the disease, 79 percent were improved or stable in the Barcelona cohort compared with 71 percent of those in Girona (p=0.23).
The researchers reported fewer infections among patients on low-dose treatment. In the first year of treatment, approximately 7.2 percent of high dose patients experienced infections compared with 3.7 percent of the low dose patients. In year two, 9.7 percent of the patients on high-dose rituximab were diagnosed with infections compared with no infections in the patients on the low dose treatment. The same percentages were recorded in the third year.
"Urinary tract infections and respiratory infections were most prevalent," Dr. Midaglia said. Grade 1 infections were not counted.
Discussing the study, Lauren B. Krupp, MD, FAAN, the Nancy Glickenhouse Pier professor of neurology and director of the MS Comprehensive Care Center at New York University, told Neurology Today At the Meetings, "Anti-CD20 therapies are becoming increasingly used for the treatment of MS and multiple options for this treatment mechanism will soon be available."
"While this class of disease-modifying therapy is highly effective and additionally offers convenience for many with either relapsing-remitting multiple sclerosis or progressive multiple sclerosis, prolonged use is associated with an increased risk of adverse events and particularly infections," Dr. Krupp noted.
"The possibility that a lower dose of rituximab, the first anti-CD20 therapy to become available and one widely used throughout the world to treat MS, could have a similar efficacy but lower adverse event risk than what has been more conventionally used is a major advance for those with multiple sclerosis."
While there was no statistical difference in effectiveness, Dr. Krupp said she had some concerns. "The lower dose among progressive patients was associated with lower rates of maintaining stability. Additional studies with larger cohorts will be necessary to confirm whether the advantages of the lower dose for those with relapsing-remitting MS are also applicable to those with progressive MS."
"Further, attention to the long term effects of higher versus lower dosing will be an important consideration as additional anti-CD 20 agents become available," she said. "Unfortunately, current clinical trials used to register MS therapies are relatively brief (one to two years) so that the long term risks and benefits of various doses are not routinely evaluated until longitudinal studies such as reported here are completed."
Dr. Krupp noted that rituximab is widely used in the USA, although perhaps not as frequently prescribed in other countries such as Italy or Sweden.
"That a lower dose is safer and equally effective than the conventional dose will have direct implications for the use of this agent among MS centers in the US," she said. "At our center in NYU, many of us have already begun to use lower doses on our patients for the reasons demonstrated in this study."
Dr. Midaglia had no relevant disclosures. Lauren Krupp has received advisory board/consulting fees, travel and meal allowances, and/or research funding from Sanofi-Aventis, Biogen, Novartis, Janssen, and Roche. She is also a non-compensated consultant and/or advisory board member with Novartis and Celgene. Dr. Krupp receives royalties for use of the Fatigue Severity Scale by various biopharmaceutical entities.
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MS Virtual 2020 Abstract PS01.05: Midaglia L, Alverez Bravo G, Robles Cedeno R, et al. Rituximab treatment for MS: An observational multicentric dose comparison.
Zecca C, Bovis F, Novi G, et al. Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience. Mult Scler 2019; Epub 2019 Oct 1.