Clinic Speak: switching from natalizumab to fingolimod

Rebound post-natalizumab can be prevented or reduced by early switch to fingolimod. #MSBlog #MSResearch #ClinicSpeak

"The study below confirms the results of the TOFINGO study, MSBase and several smaller studies, which show that if you have a wash-out period when switching from natalizumab you are  more likely to have a relapse  than if you don't have a washout. Why? Natalizumab has a circulating half-life close to 2 weeks; the half-life describes the period of time it takes for the levels to drop by 50%. It therefore takes about 10-12 weeks (5-6 half lives) for natalizumab levels to drop to low enough levels to allow lymphocytes to start trafficking back into the brain and spinal cord. If these cells are autoimmune cells they will set-up an local inflammatory response and trigger a relapse. This process takes several weeks. This is why we see rebound disease activity (relapses or MRI activity) about 3-4 months after stopping natalizumab. Therefore it is not a good idea to stop natalizumab without starting another DMT to prevent this rebound. Unfortunately, interferon beta and GA have not proven to be very effective post-natalizumab. What about oral drugs? We don't have data yet on teriflunomide (Aubagio) or BG12 (Tecfidera). However, fingolimod has been studied and provided it is started with 8 weeks of stopping natalizumab it can prevent most of the rebound. The sooner you start it the better. At the Royal London Hospital we have adopted this practice for sometime now. If the switch is in a JCV positive MSers we do an MRI for new white matter lesions and lumbar puncture to analyse the spinal fluid for JCV DNA. If these test are clear the likelihood of asymptomatic PML is low and we start fingolimod. This typically occurs at around week 3 or 4 after the last infusion of natalizumab. As it takes about 6 weeks for fingolimod to take an effect by the time natalizumab is out of your system fingolimod is working."

"If you are being switched from natalizumab to fingolimod and your neurologist wants to do a prolonged washout ask him/her why?"

"What is most intriguing about stopping natalizumab is the rebound activity that is often very severe and greater than that what was seen prior to starting natalizumab. Why? I suggest you read my post from last year on this topic; it generated a lot of discussion about MS and its potential cause."

Rebound activity post-natalizumab; image from Arch Neurol. 2011;68(2):186-191.

Cohen et al. Switching From Natalizumab to Fingolimod in Multiple Sclerosis: A French Prospective Study. JAMA Neurol. 2014 Feb 24. doi: 10.1001/jamaneurol.2013.6240.

IMPORTANCE: The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of MSers to our knowledge.

OBJECTIVE: To collect data from MSers switching from natalizumab to fingolimod.

DESIGN, SETTING, AND PARTICIPANTS: A survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod.

MAIN OUTCOMES AND MEASURES: Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod.

RESULTS: Thirty-six French MS tertiary referral centers participated. In total, 333 MSers switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for MSers receiving natalizumab. Twenty-seven percent of MSers relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). MSers who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of MSers relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). 

CONCLUSIONS AND RELEVANCE: In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

CoI: multiple

Labels: , , , , ,