Comparative Effectiveness of Rituximab Dosed Every 6 and 12 Months in Relapsing Multiple Sclerosis

Abstract

Background and objectives: Rituximab (RTX) dosed every 6 months is an affordable and highly effective treatment for relapsing multiple sclerosis (RMS). However, higher cumulative doses are associated with greater risks of infections. Whether extending dosing intervals at a low dose (500 mg) increases the risk of return of disease activity, particularly in those with only 1 year of stability or with significant return of B cells, is uncertain. Our objective was to compare whether extending RTX dosing to every 12 months (q12mo) vs continuing every 6 months (q6mo) dosing in patients with RMS increased the risk of return of disease activity.

Methods: We emulated a target trial comparing the effectiveness of RTX 500 mg q12mo to q6mo starting in year 2 (baseline) among patients with RMS who had active disease at RTX start and no evidence of disease activity (NEDA) during the first year on RTX. Eligible patients were identified from the retrospective cohort of patients with MS treated with RTX between 2008 and 2023 in Kaiser Permanente Southern California. The absence of relapses, MRI disease activity, and disability progression (NEDA-3) were analyzed by intention-to-treat (ITT) and per-protocol (PP) with inverse probability of treatment weighting of receiving q6mo or q12mo dosing.

Results: We identified 140 patients (mean age 40.4 years, 73.6% female) who received q12mo dosing and 468 patients (mean age 38.4, 70.9% female) on q6mo dosing after baseline with a median ITT follow-up of 2.6 (interquartile range [IQR] 1.9-3.3) and 3.9 years (IQR 2.4-4.8), respectively. Relapses and/or MRI disease activity (3.5%) and failing NEDA-3 (3.8%) up to 4 years later were uncommon. Extending dosing to q12mo was associated with significant B-cell repopulation (70.5% with ≥80 cells/μL PP, 75.7% ITT) compared with q6mo intervals (23.3% with ≥80 cells/μL PP, 60.2% ITT) but not with an increased risk of failing NEDA-3 up to 4 years after baseline in propensity score-adjusted ITT (hazard ratio [HR] 1.60, 95% CI 0.69-3.68) or PP analyses (HR 1.44, 95% CI 0.45-4.61).

Discussion: Extending low-dose RTX treatment intervals after 1 year of stability to q12mo was highly effective and did not result in an increased risk of disease activity despite high B-cell counts compared with continuing q6mo dosing over 2 or more years of follow-up.

Classification of evidence: This study provides Class IV evidence that in persons with RMS with NEDA-3 in the 12 months following RTX, extending the dosing interval to 12 months did not increase the risk of disease activity compared with continuing q6mo dosing.

Figure 1. Selection of People With Relapsing Multiple Sclerosis for the Emulation of a Target Trial Comparing the Effectiveness of Rituximab 500 mg Dosed Every 12 Months and Every 6 Months After 1 Year of Stability on Rituximab

ICD = International Classification of Diseases; MS = multiple sclerosis; NEDA-3 = no evidence of disease activity-3; PPMS = primary progressive multiple sclerosis; q12 months = every 12 months; q6 months = every 6 months; RMS = relapsing multiple sclerosis; RTX = rituximab; SPMS = secondary progressive multiple sclerosis.

Figure 2. Comparative Risk of Failing NEDA-3 With Rituximab 500 mg Every 12 and 6 Months

This figure shows the Kaplan-Meier curves depicting the probability of failing NEDA-3 (relapse, MRI disease activity and/or disability progression, NEDA-3) in pwRMS treated with rituximab 500 mg every 12 months (aqua-colored line) and every 6 months (red line) after 1 year of NEDA-3 on rituximab. Panel A shows the results from intention-to-treat analyses and panel B, per-protocol analyses. The overall risk of failing NEDA-3 was low in both groups and there was no significant difference between groups over the first 4 years of follow-up in either intention-to-treat or per-protocol analyses. NEDA-3 = no evidence of disease activity-3; pwRMS = people with relapsing multiple sclerosis; q6mo = every 6 months; q12mo = every 12 months.

Figure 3. Individual- and Group-Level Absolute CD19⁺ B-Cell Counts in the Target Trial Population

Depicted are the average absolute CD19⁺ B-cell counts per microliter (μL) among those treated with rituximab 500 mg q12mo after the first year on rituximab are in red and those treated q6mo in blue. Shaded areas represent 95% CIs. Panel A depicts the intention-to-treat results and panel B, per-protocol results. Time zero (baseline) is the start of year 2 after the first rituximab infusion. B-cell counts at baseline are not significantly different between groups indicating that low B-cell counts were not a major determinant in the decision to extend dosing. As expected, B-cell counts increased after dose extension in the q12mo group and most patients routinely had counts above 80 cells/μL in both analyses. In per-protocol analyses, the q6mo group maintained significantly lower B-cell counts compared with the q12mo group with only 23.3% patients reaching B-cell counts at least once >80 cells/μL. In intention-to-treat analyses, where 66.9% in the q6mo group was switched to either lower doses or extended intervals, counts rose in the q6mo group as well. Values above 300 cells/μL are not depicted. Only 4 patients had no B-cell counts measured throughout the study period. q6mo = every 6 months; q12mo = every 12 months.