COPENHAGEN — Rheumatoid arthritis patients can safely undergo multiple courses of retreatment with the anti-CD20 monoclonal antibody rituximab without increasing their risk of serious adverse events, Dr. Ronald F. van Vollenhoven reported at the annual European Congress of Rheumatology.
Presenting the results of a pooled analysis of safety data representing 5,964 patient-years of rituximab exposure from retreatment populations in RA clinical trials, Dr. van Vollenhoven reported that rituximab remains well tolerated with a stable safety profile after up to five treatment courses. Specifically, “the rates of adverse events, serious adverse events, and infections remained stable following each course of treatment,” he said. The findings are particularly important because multiple courses of treatment are often needed to sustain the efficacy of rituximab, which is often used as a treatment of last resort after the failure of other therapies.
The pooled analysis, which included safety data from phase IIA, IIB, and III studies, included 2,579 RA patients who received multiple courses of rituximab. Of these, 1,926 patients received two or more treatment courses, 1,228 patients received three or more courses, 794 patients received four or more, and 282 received at least five courses, said Dr. van Vollenhoven, a rheumatologist at the Karolinska University Hospital in Stockholm. Of the 2,579 patients, 2,417 were followed for more than 1 year from start of treatment, whereas 1,198, 743, 564, and 109, respectively, were followed for more than 2, 3, 4, and 5 years, and 138 withdrew from the trials because of adverse events.
Based on the pooled analysis, the rates of any adverse event (reported per 100 patient-years) after treatment courses one through five, respectively, were 379, 313, 319, 329, and 330, and the respective rates per 100 patient-years of any serious adverse events were 18.3, 17.4, 16.6, 12.0, and 13.4.
“The most frequent adverse events were infusion-related reactions, which occurred in 25% of the patients for the first infusion of the first course, and decreased for subsequent infusions,” Dr. van Vollenhoven said. In all, “15 events in 14 patients were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring in courses one through five, respectively.”
Although the proportion of patients with below-normal IgM or IgG levels increased with the number of treatment courses, there were no significant differences by course in the rates of infections or serious infections, said Dr. van Vollenhoven. The overall serious infection rate per 100 patient-years was 4.26, which is consistent with observations in other RA cohorts, and there were no cases of tuberculosis, he noted.
“There was one case of progressive multifocal leukoencephalopathy [PML] reported in a patient who had previously received chemotherapy for oropharyngeal cancer,” Dr. van Vollenhoven said, but like other cases of PML that have been reported in the RA treatment literature, it is unclear whether the occurrence of the fatal reactivation of the JC virus in the central nervous system was related to the rituximab, to other drugs, to the prior cancer treatment, or to the patient's existing impaired immune response.
With respect to malignancy, the analysis showed rates comparable to malignancy rates observed in the general RA population, and there was no increased risk of malignancy with additional courses of treatment, he said.
“These [data], showing the same basic safety profile with retreatment that has been shown in clinical treatment trials, are important. We pride ourselves on the use of biologics and the ability to reach specific targets with treatment, but B-cell therapies, for all their effectiveness, may have long-term consequences that are hard to predict,” said Dr. van Vollenhoven. “It's important to have a good long-term safety system to evaluate retreatment with these drugs.”
Dr. van Vollenhoven disclosed having received financial support for research from Roche.