Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7–48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2–63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1–41.6). The general population IR was 31.0 (95% CI = 27.8–34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98–2.38) and rituximab (HR = 1.68, 95% CI = 1.00–2.84). Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings.

Baseline characteristics associated with NEDA-3 status in fingolimod-treated patients with relapsing-remitting multiple sclerosis

Fingolimod is an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) and there is class I evidence that it is superior to standard care in reducing relapse rate. However, real-world data investigating its effectiveness and potential predictors of response are still scarce. To estimate (i) the proportion of fingolimod-treated patients who achieved the no evidence of disease activity (NEDA-3) status; and (ii) to determine which baseline (i.e. at treatment start) clinical and magnetic resonance imaging (MRI) variables were associated with better outcomes. We collected clinical and MRI data of RRMS patients treated with fingolimod and followed-up for 24 months. The proportion of patients who had NEDA-3 - i.e. absence of relapses, sustained Expanded Disability Status Scale (EDSS) worsening and radiological activity on MRI - was estimated. A Cox proportional hazard model was carried out to investigate which baseline characteristics were associated with the NEDA status at follow-up. We collected data of 201 patients who started fingolimod. Of them, 24 (12%) were treatment-naïve, 115 (58%) were switched after failing a self-injectable drug, and 60 (30%) switching from natalizumab. Five patients who discontinued fingolimod early (within 3 months) (bradycardia, n = 2; leukopaenia, n = 2; macular oedema, n = 1) were removed from the analysis. At follow-up, 118 (60%) patients achieved the NEDA-3 status, while 78 experienced clinical and/or MRI activity. The risk of not achieving the NEDA-3 status was associated with higher baseline EDSS score (hazard ratio [HR] = 1.18, p = 0.024) and more relapses in the 12 months prior to fingolimod start (HR = 1.61, p = 0.014). Our findings suggest that fingolimod may lead to a better control of the disease if started in patients with a less aggressive disease (i.e. fewer pre-treatment relapses and milder disability level), thus supporting its possible role as an early treatment for MS