MS: What We Know About Sequencing

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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

Fred D. Lublin, MD, FAAN, FANA: We’ve discussed the complexity of employing new therapies, both in dosing and monitoring. Things like that have become challenges for us, and for all neurologists or clinicians who are taking care of MS.

One of the challenges is if you have someone on natalizumab and you need to switch them to another therapy. The most common reason would be development of JC-positivity while on therapy. There’s also the small number of individuals who just don’t respond, or who develop antibodies. How are you doing your sequencing now?

Claire S. Riley, MD: If someone has gone to natalizumab as a first-line therapy and has treatment inexperience to other options, I would almost start fresh. Of course, you would consider the reasons that a person went on natalizumab in the first place.

Was it because they had a high burden of disease activity and poor prognostic indicators? In that case, I’d probably discuss oral therapies—particularly fingolimod or dimethyl fumarate—knowing that there is some risk in transition from natalizumab to other agents that suppress lymphocyte activity in terms of development of PML (progressive multifocal leukoencephalopathy).

But also, I’d potentially talk about off-label use with cell-directed therapy, which currently is rituximab. It’s a longer conversation, and potentially, can be a very effective approach. I have not had the experience of going from natalizumab to alemtuzumab.

Clyde E. Markowitz, MD: I think sequencing is a challenge. One of the things that I worry about in our current way of thinking is that natalizumab gets looked at as first-line—as a separate group—and that’s a small segment of my patient population. Commonly, they are on an injectable therapy. They were escalating up to something.

The bigger question is what to do in terms of these oral agents, like fingolimod, teriflunomide, and dimethyl fumarate, as being immune suppressant—like molecules? Does it matter whether or not you have had them on those before you go to natalizumab, or whether those three carry an immunosuppressant risk prior to going to natalizumab, and whether or not that sequence puts them at high risk to go on to development of PML? That would be similar to the patients who’ve been looked at with azathioprine, Cytoxan, and one of the three risk factors for PML. We don’t know the answer to that.

Only time is going to tell us whether or not that’s going to be an issue, but I worry about that. I tend to go with injectable therapies, and then up to an oral or natalizumab arena in the next sequence. Then, depending upon how they’re doing, I can always switch within that conversation. I usually use alemtuzumab much later, mainly because of the safety issues related to that. I’m hoping that in the near future, with the possibility of ocrelizumab becoming available, that that will be in the mix as well. But it’s a challenge. We just don’t have the data to say, “This is the right sequence to take.”

Claire brought up induction therapy earlier. Maybe we should be hitting everybody up front with a high efficacious medication, and then follow that with something a little bit safer? We don’t know, and there’s no real data. Even though the Europeans do this all the time, there’s no data that says that that is the method that’s going to get this disease under control.

Claire S. Riley, MD: You bring up an important point, though, which asks what the durability of the effect is, and how we should perceive and categorize treatment with these oral immunotherapies or with any of our immunotherapies in terms of future risk.

In my view, alemtuzumab is probably the only true induction therapy—maybe mitoxantrone. But alemtuzumab really changes the immune system forever, whereas I view natalizumab, fingolimod, and dimethyl fumarate as significantly changing immune function while the patient is on the therapy, but not necessarily forever. I do not categorize those as immunosuppressants that would alter that PML risk. I’d be interested to hear what you guys think.

With teriflunomide, I’m not sure. I think that potentially—and I don’t think we have the data to tell us this—there might be effects that are more durable and might raise that concern of if we should elevate that risk when we’re doing a PML risk calculation.