Wednesday, 16 April 2014

Clinic Speak: what happens when you stop taking natalizumab

NHS England green-lights switch from natalizumab to fingolimod in MSers at high-risk of PML #MSBlog #MSResearch #ClinicSpeak

Interferon-beta, GA or steroids not good enough to prevent rebound activity #MSBlog #MSResearch #ClinicSpeak

"The study below confirms what we already know; stopping natalizumab leads to rebound in MS disease activity. Switching to a DMT on a lower-tier of efficacy, i.e. interferon-beta or glatiramer acetate, or taking steroids does not prevent this rebound. In comparison, a higher-efficacy drug such as fingolimod appears to prevent this rebound provided it is started within 4 weeks after the last natalizumab infusion."

"Most MSers stopping natalizumab are doing it because they are at high-risk of developing PML. The major safety concern we have is so called carry-over PML; i.e. PML that presents in the first few months after starting fingolimod. I am aware of two cases of carry-over PML on fingolimod. Carry-over PML is a problem in that we rely on the immune response to clear you of PML; it takes about 6-8 weeks for fingolimod to wash-out of your system and during this time PML can cause devastating damage. Our practice, to prevent carry-over PML and rebound disease activity, is to do a MRI and lumbar puncture shortly after the last natalizumab infusion. If the spinal fluid analysis shows no JC virus DNA and the MRI shows no evidence of asymptomatic PML we start fingolimod within 4 weeks of the last natalizumab infusion. So far this practice seems to be  working; touch wood we have had no cases of carry-over PML."

"In clinic last week someone asked me about switching from natalizumab to alemtuzumab? Alemtuzumab is an induction agent and hence you can't reverse its action. If you developed carry-over PML after switching from natalizumab to alemtuzumab the chances are you will die from the PML as your immune system will not be able to respond quickly enough to clear the virus. Post alemtuzumab it takes over 3 months for your immune system to recover. For this reason I am telling my patients that it will be much safer for them to switch to a maintenance agent, for example fingolimod, for several months or years, before switching to alemtuzumab post-natalizumab. The latter advice is not evidence-based and is unlikely to become evidence-based in the future; this advice is based in scientific principles on how the different DMTs affect your immune system."

"For UK MSers who read this blog we have finally been given the green-light by NHS England to switch MSers at high-risk of PML on natalizumab to fingolimod, who have never been treated with interferon-beta or GA in the past. We applied for this policy change in June last year; therefore, it has taken 10 months to get this change in policy. I sincerely hope none of the MSers who have been caught in this bureaucratic quagmire  have developed, or will develop, PML as a result of this delay. We really need a more responsive system than the current one; 10 months is a long time in the life of an MSer not to mention my own anxieties, and the anxieties of my colleagues, over this issue."

Rebound MRI activity post-natalizumab. Arch Neurol. 2011;68(2):186-191. doi:10.1001/archneurol.2010.257.

Epub: Fox et al. MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study. Neurology. 2014 Mar.

OBJECTIVE: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab.

METHODS: Eligible MSers were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. MSers were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, MSers underwent clinical and MRI assessments every 4 weeks.

RESULTS: MSers (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 MSers evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab-treated MSers and in 15%-29% of MSers in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4-8 weeks (n = 2 in weeks 4-8) after the last natalizumab dose. Overall, 50/167 MSers (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity.

CONCLUSIONS: MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for MSers with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab. 

CoI: multiple

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