Friday, 5 June 2015

ClinicSpeak: Did we need a trial lasting 4 months to show the interval of switching of natalizumab to fingolimod?

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

"Finally the TOFINGO results are out and confirm the results of 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, steroids, interferon beta, GA and DMF (dimethyl fumarate) have not been shown to be effective post-natalizumab to prevent rebound. What about teriflunomide? We don't have data on teriflunomide (Aubagio) yet, but there is currently an ongoing study looking at this issue."

"Fingolimod is now  the most widely 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."

"What about alemtuzumab and other induction therapies, for example anti-CD20 treatments (Rituximab)? I have posted on the issue of switching from alemtuzumab to fingolimod before and have outlined  three strategies. At the moment we bridge with fingolimod for 6-12 months. As predicted there has been one carry-over PML case from natalizumab to alemtuzumab and the unfortunate MSer paid the ultimate price and died from PML. I suspect there will be many more such cases; on a recent trip to the US I heard that it is now common practice to switch MSers from natalizumab to alemtuzumab with a minimal washout. What about rituximab? I personally have no experience, but am aware of this being the most common strategy employed in Sweden. I have been told that there has been no carry-over PML with this strategy and a registry analysis has shown that rituximab is more effective than fingolimod in preventing rebound. The latter data has been submitted to ECTRIMS so hopefully I will be able to update you later this year with hard facts. Rituxumab is really not an option in the UK as it is not licensed to treat MS and NHS England have been rejecting our IFR (individual funding requests) to use it in MS. This will be academic once we have access to ocrelizumab, which will presumably get through the EMA and NICE."

"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.

Epub: Kappos et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. Neurology. 2015 May 29. pii: 10.1212/WNL.0000000000001706.

OBJECTIVE: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod. 

METHODS: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24.

RESULTS: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7-2.6]) and 12-week WO groups (1.7 [1.3-2.2]) and higher in the 16-week WO group (8.2 [7.3-9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2-0.6]; 12 weeks, 2.1 [1.6-2.6]; 16 weeks, 3.6 [3.0-4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67-22.53]) than in the 12-week (21.3 [1.41-41.19]) or 16-week (18.5 [8.40-28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred.

CONCLUSIONS: Initiating fingolimod therapy 8-12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO.

CoI: multiple, Prof G is a co-author on this paper


  1. I've been confused about claims in the literature to have identified a rebound effect. Most papers that report a rebound effect have found it in no more than 20% of patients. Isn't rebound activity, as currently defined, expected in many patients just by chance? The pre-natalizumab baseline is a noisy estimate of how much disease activity these patients are naturally prone to. Some of these patients will be prone to disease activity which is higher than this estimate, and some will be prone to disease activity which is lower. So the observed rebound effect may just be these patients returning to their natural disease course. Not only that, but the patients being put on natalizumab are those with a poor prognosis and severe disease. Won't some proportion of these people be expected to have catastrophic relapses (as have been observed post-natalizumab) by chance? What was the base rate of such relapses in the population before any DMTs became available?

  2. If these drugs are not good at stopping rebound is it tellings us about these drugs in MS.

  3. Daclizumab may be a good option for bridging agent between Natalizumab and Alemtuzumab since Daclizumab is not immunosuppresive, right?

  4. I have MS. I have been dealing with swelling lymph nodes (cervical and deep cervical) for the past 4 months off and on lasting up to 4 days. No symptoms of infection, no fever, no congestion, no sinus issues. Just pain and swelling in my lymph nodes. Could this be my MS? Should I have a biopsy?


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