Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

Abstract

Background:Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus–positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0–3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months.Objective:We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts.Methods:From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6–8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment.Results:Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4–32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity.Interpretation:A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus–positive patients remains uncertain.

Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy

“…To increase our ability to detect disease reactivation, we obtained monthly brain MRIs for the first 6 months, a time interval that has a high risk of post-natalizumab relapse. 6–11 Initiating teriflunomide at the time patients were due for their next natalizumab infusion was associated with low 12-month relapse risk (proportion of relapse-free patients 0.94), and only two patients (4%) experienced SDW, in contrast to some post-natalizumab outcomes previously reported. 6–9,12,13 While direct comparisons to other reported studies of post-natalizumab DMT cannot be made, the low risks of relapse and SDW we observed may provide potential guidelines for transitioning patients off natalizumab.…”

“…7 In a prospective study of patients switching from natalizumab to fingolimod, 11.5% of patients relapsed within 6 months. 10 The odds ratio of relapse was 7.2 for patients with washout of 8–12 weeks versus those with 4 or fewer weeks’ washout. A placebo controlled prospective study of fingolimod demonstrated a 9–12% and 16% relapse risk with natalizumab washout of up to 12 and 16 weeks, respectively, but a 61% relapse risk after a 3-month natalizumab washout.…”

“…5 PML risk has prompted the discontinuation of natalizumab in a large percentage of patients. However, studies have reported heightened MS disease activity after natalizumab withdrawal, including increased relapse frequency, [6][7][8][9][10][11][12][13][14] increased disease activity on magnetic resonance imaging (MRI), [8][9][10]14,15 increased relapse severity, 6,7 and relapse-related fatalities. 12,13 Several studies have not substantiated these observations.…”

Switching from natalizumab to alemtuzumab in patients with relapsing multiple sclerosis

“…6 Previous studies examining washout periods when switching from natalizumab suggest that the risk of breakthrough disease activity increases with washout periods greater than 8-12 weeks. 7,8 In our cohort, the high proportion of cases with breakthrough disease activity in those switching due to lack of efficacy is only partly explained by the duration of the washout. Recent work has also shed light on lymphocyte depletion following alemtuzumab administration, its potential link to anti-alemtuzumab antibodies and the impact this may have on breakthrough disease activity at an individual level.…”

“…Fingolimod has been commonly used as an option in those making the switch from natalizumab, but is associated with high rates of breakthrough clinical and/or radiological disease activity, although the risks may be lower with shorter washout periods. 2 Rituximab has been suggested as an alternative to fingolimod in patients discontinuing natalizumab due to high PML risk, however, rituximab is not licenced for the treatment of RRMS and is not available in some countries for this indication. 3 Alemtuzumab is a monoclonal antibody that binds to the CD52 surface protein on T and B lymphocytes, resulting in their depletion with subsequent re-population, with comparable efficacy to natalizumab.…”