After natalizumab: what are the options?


REPORT FROM THE 67TH AMERICAN ACADEMY OF NEUROLOGY (AAN) ANNUAL MEETING – WASHINGTON DC, APRIL 18-25, 2015 – It is well established that the risk of progressive multifocal leukoencephalopathy (PML) is substantially increased after 24 infusions of natalizumab. What is less well known is how best to manage patients following natalizumab discontinuation, and several studies at AAN have examined different switching options. 

A retrospective chart review found that 14 of 42 patients (33%) switching from natalizumab to fingolimod experienced a relapse in the first eight months, and five relapsing patients had new MRI lesions (Vu et al. AAN 2015; abstract P3.290). EDSS was slightly improved (from EDSS 2.7 to 2.4) and timed 25-foot walk (T25FW) was unchanged (7.5 to 7.4 seconds) after switching. Among those switching from natalizumab to DMF, 9 of 22 patients (41%) had a relapse, EDSS was slightly improved (2.7 to 2.4), and T25FW worsened by 26% (from 6.2 to 7.8 seconds). In the group switching to teriflunomide, 4 of 14 (28%) had a relapse, EDSS improved (from 3.0 to 2.6) and T25FW worsened by 7% (from 7.2 to 7.7 seconds).

A survey of 66 patients switched from natalizumab to DMF found that 71% of patients remained clinically stable (Amjad et al. AAN 2015; abstract P3.289). Those at higher risk of clinical instability were females (risk ratio 2.9), patients younger than age 60 years (RR 1.8), and those on natalizumab for less than two years (RR 2.4). The duration of the washout period (less than vs. more than 8 weeks) did not appear to influence the risk of clinical worsening.

A longer washout period has been reported to associated with an increased relapse risk when switching from natalizumab to fingolimod (Havla et al. J Neurol 2013;260:1382-187). A new study in Spain found that a shorter washout period (60 days) was associated with a lower risk of clinical and MRI activity compared to a longer washout period (90 days) (Clares et al. AAN 2015; abstract P3.291). In the group of 10 patients with the shorter washout, there was one relapse in the year after switching to fingolimod, one patient had persistent enhancing lesions, and mean EDSS was essentially unchanged (3.5 to 3.6).

At the University of Colorado MS centre, 278 patients on natalizumab for at least a year were switched to another agent (Alvarez et al. AAN 2015; abstract P3.288). The risk of relapse was 0.8% in those switching to rituximab, 1.8% for those switching to fingolimod, and 4.0% for those switching to DMF. A rituximab switch was associated with significantly fewer enhancing lesions. The washout periods were one month for rituximab and fingolimod, and no washout period for DMF. The switch from natalizumab to DMF will also be examined in the observational STRATEGY study that is ongoing in the U.S. (Cohan et al. AAN 2015; abstract P3.293).

A different strategy to minimize disease activity after natalizumab discontinuation has also been explored. A one-year phase IV study enrolled 50 anti-JCV Ab-positive patients who had received 24 or more natalizumab infusions (Weinstock-Guttman et al. AAN 2015; abstract P3.287). Subjects either immediately discontinued natalizumab or dose-tapered prior to starting another DMT. Dose tapering consisted of two additional natalizumab infusions at 6- and 8-week intervals. IV methylprednisolone was allowed. The number of relapses was three-fold lower in the tapered group (8 vs. 28 relapses) at 12 months. Most relapses occurred in the first three months after discontinuation. The tapered group also had fewer new T2 and T1 lesions compared to the immediate-discontinuation group.

Guest Reviewer: Dr. Daniel Selchen, Head of Neurology, St. Michael’s Hospital, Toronto, Canada

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