What's the Optimal Washout After Natalizumab in MS?

June 15, 2015

The question of how long to wait before starting a new treatment when stopping natalizumab (Tysabri, Biogen)in multiple sclerosis (MS) is the subject of discussion with the publication of a study suggesting that shorter rather than longer washout periods are better when patients are switched to fingolimod (Gilenya, Novartis).

The TOFINGO study, published online in Neurology on May 29, was conducted by a team led by Ludwig Kappos, MD, University of Basel, Switzerland, and shows that washout periods of 8 or 12 weeks were associated with less MS disease activity compared with a 16-week washout.

The study, funded by Novartis, was first presented at the ECTRIMS meeting in 2013 and reported by Medscape Medical News at that time.

In the current paper, they authors conclude: "This study provides Class II evidence that for patients with RRMS [relapsing-remitting MS] switching from natalizumab to fingolimod, shorter natalizumab WO [washout] periods are associated with less MRI disease activity than are longer WO periods."

In an accompanying editorial, Olaf Stüve, MD, University of Texas Southwestern Medical Center, Dallas, and Dennis Bourdette, MD, Technische Universität München, Germany, agree that these results confirm other studies that indicate a 16-week or longer period of natalizumab washout risks increased disease activity and support washout periods of no longer than 8 to 12 weeks to avoid disease reactivation.

But the editorialists ask whether a washout period is needed at all. They say that there is little research to guide decisions on this and the biological rationale for a washout is unclear.

Natalizumab-Fingolimod Switch

Dr Kappos and coauthors explain that natalizumab can be associated with progressive multifocal leukoencephalopathy (PML), an uncommon but severe and potentially fatal opportunistic brain infection caused by the JC virus, which most likely results from compromised brain immune function. Therefore, in patients found to be seropositive for JC virus, a switch from natalizumab to another treatment is often considered, with fingolimod one of the suitable options.

But there is concern about potential risk of additive effects on the immune system because natalizumab has a long elimination half-life and prolonged immunosuppressive effects.

For the current study, 142 patients with relapsing-remitting MS were randomly assigned to 8-, 12-, or 16-week washout periods after their last natalizumab infusion before starting fingolimod treatment. Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24.

Washout periods of 8 weeks or 12 weeks were associated with less MRI and clinical disease activity compared with the 16-week washout. Evidence from secondary endpoints on disease activity favored the 8-week washout over longer washout periods.

Table. Number of New Active Lesions After Various Washout Periods

Endpoint 8-Week Washout 12-Week Washout 16-Week Washout
No. of new/newly enlarged T2 lesions after 8 weeks of fingolimod 2.1 (1.7 - 2.6) 1.7 (1.3 - 2.2) 8.2 (7.3 - 9.1)
No. of new/newly enlarged T2 lesions during washout period 0.4 (0.2 - 0.6) 2.1 (1.6 - 2.6) 3.6 (3.0 - 4.2)
No. of gadolinium enhancing T1 lesion counts at week 24 14.1 (5.67 - 22.53) 21.3 (1.41 - 41.19) 18.5 (8.40 - 28.60)
Relapse free (%) 88 91 84

Values in parentheses are 95% confidence intervals.

 

Adverse events were experienced by 68% of patients and were mostly mild or moderate, with similar incidence across the three washout groups. No unusually severe relapses or opportunistic infections occurred.

The authors report that although there was a higher overall incidence of infections in the 8-week washout group in this study, these were mainly due to mild or moderate nasopharyngitis and urinary tract infections. "[A]n increased incidence during the first few weeks of fingolimod treatment, when natalizumab may not have fully washed out, was reassuringly not observed," they add.

In their editorial, Dr Stüve and Dr Bourdette note that the immunologic effects of natalizumab may last for many months, so "it is questionable that much is being accomplished by having a washout lasting 8–12 weeks."

Noting that other agents that may be started after natalizumab have a low risk of causing PML, and that MS disease activity occurs after natalizumab is stopped, they ask: "Are we doing more harm than good in having washout periods of any length?"

They conclude: "As we seek to personalize the treatment of RRMS using the array of medications now available, we need accurate information not only about the individual medication, but also about how to transition from one medication to another. It is not good enough to rely on guessing and expert opinion."

The study was sponsored by Novartis Pharma AG. Dr Kappos's institution (University Hospital Basel) has received the following in the last 3 years, used exclusively for research support: steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; royalties from Neurostatus Systems GmbH; and grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, and the European Union and Roche Research Foundations.

Neurology. Published online May 29, 2015. Full text Editorial

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