Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used have been reported in a new observational study.
“We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona, Spain. “But adverse effects — particularly frequency of infection — were increased in the high-dose group.”
Midaglia presented the findings at the recent 8th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
“There haven’t been large studies of rituximab in MS as the company (Genentech/Roche) prioritized development of ocrelizumab over rituximab,” she explained.
Rituximab has therefore never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.
“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Midaglia noted.
The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.
In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group).
In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).
Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.
Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.
The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group vs 72% of the lower-dose group (P = .09).
Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group; and by 81% and 100%, respectively, in the lower-dose group.
New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose grope; and in 16% and 0%, respectively, in the lower-dose group.
Reductions in B cell levels were similar with both doses.
However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.
Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% vs 0% in the second year, and in 9.7% vs 0% in the third year.
Urinary tract infections followed by respiratory infections were the most prevalent.
A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.
Midaglia told Medscape Medical News that most centers are using higher doses of rituximab — similar to the Barcelona cohort in this study.
“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.
She reported that her hospital has been using rituximab extensively in MS.
“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”
While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”
Now that ocrelizumab is approved, Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.
“For example, in progressive MS, ocrelizumab has quite a narrow indication — it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.
“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Midaglia concluded. “And now we have better data on the optimal dosage.”
Commenting for Medscape Medical News, Daniel Ontaneda, MD, co-moderator of the session at which the study was presented, said: “Rituximab is not an FDA-approved medication for MS, but it has been used in clinical practice quite extensively in the US and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”
Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”
Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec and Novartis, and personal fees for lectures from Roche.
8th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020: Session PS01.05. Presented September 11, 2020.