Rebound Management Strategies for MS Therapies

Fred D. Lublin, MD: That gets into sequestration more than it does half-life, actually. Although we’ll have to wait and see because some of the S1P1s [sphingosine 1-phosphate receptor 1s] that we’re going to talk about have a shorter half-life.

Peter A. Calabresi, MD:That’s right.

Fred D. Lublin, MD: We don’t know the answer with those yet. But the sequestration and then having those cells readily available is an issue, and it’s led to changing the label. We have it for natalizumab and we have it for fingolimod that there is the potential for rebound, which does impact how you use it and dose it. So I don’t start either one of those agents on someone where I think I’m going to have to stop it at some point. For example, planning pregnancies would be one. When someone gets into a safety issue, you really have your hands tied. But I think one of the lessons, and I’d be interested in your opinions on this, that I think there is for natalizumab, where we first saw this idea of rebound, is to start your next agent sooner rather than later. That the risk of double immunomodulation is much less than the risk of a serious flare-up. I see heads nodding. Anyone disagree with that?

Peter A. Calabresi, MD:No. We’ve shortened the interval for all the reasons you mentioned. We were concerned about infections and not overlapping drugs, and many times would wait 6 or 8 weeks after coming off natalizumab. And we’ve gradually shortened that to almost keeping them right in cycle if it’s a monoclonal antibody or starting an oral agent almost immediately, presuming that you’re not switching them for fear of them having PML [progressive multifocal leukoencephalopathy]. And I think that’s the 1 caveat, and there have been some carryover cases. You have to be as sure as you can be that they’re not infected already.

Patricia K. Coyle, MD: We would start the next drug 4 weeks after the last natalizumab.

Fred D. Lublin, MD: We were saying, the next cycle. I think we would do it the same way.

Stephen C. Krieger, MD: The other complicating factor there with fingolimod specifically, just to finish on that particular agent, is how to transition from stopping fingolimod to starting an anti-CD20. Because here you’ve got a circumstance where you have to wait some period of time for those lymphocytes to get back into circulation for the anti-CD20 agent to exert its desired B-cell suppressing effect. But you don’t want to wait too long for them to potentially cause rebound activity. I think that’s a real challenge that I wish we had data to help guide what that timing and the pharmacodynamics of that ought to look like.

Fred D. Lublin, MD: The sequestered lymphocytes, are they going to get the effect? Will they show up after the half-life of the monoclonal antibody?

Amit Bar-Or, MD, FRCP:It’s a very fair concern. We do know that on the average within a few weeks, people will bring back lymphocyte counts to at least approaching lower limit normal but not necessarily their baseline levels. And there are a few patients, especially after it seems long treatment courses, who will reconstitute rather slowly. And we believe that the anti-CD20, which especially administered intravenously, will have very high levels in the blood. Circulating B-cells will be the ones targeted. They go to the reticuloendothelial system. They’re knocked off. The depth of penetration and the presence of the mechanisms, the molecular mechanisms, that would be associated with killing, be it complement-mediated or antibody-dependent, differs depending on the tissue you’re in and the depths within lymphoid organs. And so trapped cells will not have as much access of the antibody, and it’s a fair consideration.

Peter A. Calabresi, MD:To follow up on that point, there’s now evidence that some CD4s and CD8s can have CD20. And so if you come in with a lymphopenic patient and further deplete them, we’ve seen some patients start out around 800 mg where you felt comfortable, and then after you thought the drug had washed out, Ocrevus drops them down to 500 for a period. And so I think we have to be very cautious. And it’s not everyone who seems to have the T-cell targeting, so we’ve taken to looking at T-cell subsets before we go in with therapy to try to further characterize what the profile is of that patient.

Amit Bar-Or, MD, FRCP:It’s interesting as to whether those T-cells that express CD20, one of the thoughts is that they may be T-cells that have been repeatedly stimulated, chronically activated, and they may or may not be as susceptible in terms of recirculation through the lymphoid system to sequestration. So they may represent a higher proportion than usual. Did you see any results to suggest that?

Peter A. Calabresi, MD:Not yet.