PML Risk with Natalizumab in Multiple Sclerosis

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The MD Magazine Peer Exchange “Strategies in the Management of Relapsing-Remitting Multiple Sclerosis” features a panel of physician experts discussing the importance of early therapy in multiple sclerosis treatment, factors that affect choice of management strategy, the need for ongoing monitoring, and other aspects of treating patients with multiple sclerosis.

This Peer Exchange is moderated by Fred D. Lublin, MD, FAAN, FANA, Saunders Family Professor of Neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Icahn School of Medicine at Mount Sinai, New York.

The panelists are:

• Patricia K. Coyle, MD, professor and vice chair (Clinical Affairs) and director of the Multiple Sclerosis Comprehensive Care Center at Stony Brook University Medical Center, New York
• Clyde E. Markowitz, MD, associate professor of neurology and director of the Multiple Sclerosis Comprehensive Care Center at Perelman School of Medicine, University of Pennsylvania, Philadelphia,
• Claire S. Riley, MD, assistant professor of neurology and director of the Columbia University Multiple Sclerosis Clinical Care and Research Center, Department of Neurology, Columbia University, New York

Patricia K. Coyle, MD: Coming off natalizumab raises 2 central issues. Number 1 is the washout, and number 2 is incipient PML (progressive multifocal leukoencephalopathy).

Natalizumab is one of the two DMTs (disease-modifying therapies) that has caused concern in a minority for rebound increase activity. Natalizumab is out of your system 3 months, approximately, after you’ve stopped it. And typically, it’s being used in high-disease activity groups, it will be gone. It doesn’t change the degree of disease activity and there’s risk of increased disease activity.

So, you want as short a washout as possible. You probably want a washout that’s not more than about a month. At the same time, we know that PML has occurred as late as 6 months after coming off natalizumab, and we’re dating it to the natalizumab because PML can remain silent. As you come off it, I think you have to have an exit brain MRI. If there’s any question that there’s any lesion that could represent PML, then you need to go ahead and do a lumbar puncture for that patient for JC virus with a PCR (polymerase chain reaction) analysis. You may need to do 2 exit brain MRIs to be certain because, I think, you’re obligated to get them on their next drug about a month after you’ve discontinued the natalizumab. It’s a little bit dicey.

Fred D. Lublin, MD, FAAN, FANA: What worries you more? A bad rebound flare-up or the risk of PML with the next agent?

Patricia K. Coyle, MD: They’re both unusual circumstances, but, probably, rebound is a little bit higher risk than PML. I’m discussing this with the patient, but this is going through my mind. These are the 2 features you’re really concerned about.

Fred D. Lublin, MD, FAAN, FANA: You would agree with 4 weeks?

Claire S. Riley, MD: Yes.

Clyde E. Markowitz, MD: Absolutely.

Fred D. Lublin, MD, FAAN, FANA: Yes, and this is where the community has moved. They went from 3 months, and over the last couple of years…

Clyde E. Markowitz, MD: Initially, 6 months was the recommendation to be washing out natalizumab.

Clyde E. Markowitz, MD: Then you see all the activity come up and put it to 3 months, now 2, then 1, and then no washout.

Claire S. Riley, MD: Yes, 1 month is not washout.

Fred D. Lublin, MD, FAAN, FANA: That’s right. It’s just when the next dose is due.

Claire S. Riley, MD: In fact, 1 month is probably some overlap depending on what the person’s body mass is.

Clyde E. Markowitz, MD: The next question is, do we start it while they’re still taking it?

Claire S. Riley, MD: Well, they sort of are. At 28 days from your last natalizumab dose, your receptor occupancy is still pretty high.

Clyde E. Markowitz, MD: Right. But if you were going to take a patient and transition him/her to another agent, could you start at a couple of months before you stop their natalizumab?

Patricia K. Coyle, MD: You want to make sure it doesn’t have any immunosuppressive capability, of course.

Claire S. Riley, MD: Who’s going to pay for that?

Fred D. Lublin, MD, FAAN, FANA: When you’re dealing with folks in the community who we’re getting more and more questions from as this becomes more complicated, what are you advising them of in terms of MRI monitoring within the constraints of insurance carriers?

Clyde E. Markowitz, MD: In my practice, I usually am recommending that they get scanned at baseline—and 6 months on therapy—then get another 6-month scan at 1 year, and then usually every year after.

If they’re on natalizumab, I might actually push that to every 6 months—at least a brain scan. You could just get a flare if that’s a concern. Then, for anybody who has a clinical event while on a therapy that I’m concerned about—like let’s say somebody is having new symptoms on fingolimod, or dimethyl fumarate, or natalizumab—I’m getting a scan on them because I can’t say for sure that this is not a manifestation of a complication of the medication (possibly a PML or some other infectious concern).

I’m using MRI a lot more frequently than I used to. For anybody who’s got any new neurologic symptoms, I’m usually going to get them a scan. Even if it’s somebody that I have known for many years and they are on glatiramer or on interferon, if they’re having a mild relapse, I may not push that issue. But, it’s usually for the ones that I’m more concerned about, such as PML risk, etc.

Claire S. Riley, MD: In individuals who are JC-virus, antibody-positive, and in whom we choose to keep on natalizumab, I do quarterly scans every 3 months.

Clyde E. Markowitz, MD: Yes, we do that as well.

Claire S. Riley, MD: I will also do a limited protocol that includes FLAIR and diffusion—as a PML screen.

Patricia K. Coyle, MD: The Consortium actually came out with a formal recommendation in JC virus-positive individuals—for patients at 18 months or more on natalizumab—to do it every 3 to 6 months, and do the diffusion FLAIR. You don’t necessarily have to do contrast or the full protocol brain MRI in that situation.

Clyde E. Markowitz, MD: What I’ve started to do recently—and I’m not sure if this is a fully data-driven conversation—but in people who have been on natalizumab greater than 2 years who are JC virus antibody-positive, and want to continue to be on it, I actually space out the frequency of their infusions.

Patricia K. Coyle, MD: I totally agree.

Clyde E. Markowitz, MD: There’s a small amount of data that is suggesting that there might be a reduced risk for PML. I’ve started to do that.

Fred D. Lublin, MD, FAAN, FANA: At 6 weeks?

Patricia K. Coyle, MD: At 8 weeks.

Clyde E. Markowitz, MD: I’m doing 8 weeks, currently.

Claire S. Riley, MD: Are you looking at body mass to make that decision?

Patricia K. Coyle, MD: No. At 8 weeks, all of the patients that I have done the prolonged dosing to have continued to have very good response. There’s interesting data that suggests you may not need to give as much natalizumab over time to really saturate and get the maximum effect. So, I’m doing the exact same thing, Clyde.