Switching From S1P Modulators to Anti-CD20 Therapy in Multiple Sclerosis
By Clinical Content Hub
Background
In certain patients with multiple sclerosis (MS), there may be a need or desire to switch from an sphingosine-1-receptor (S1P) modulator to an anti-CD20 monoclonal antibody, but the optimal timing of the treatment transition remains uncertain.1,2 Concerns regarding rebound MS inflammatory activity following discontinuation of an S1P modulator, in addition to the variations in clinical approaches to mitigate this rebound effect, have resulted in unanswered questions about how best to approach transitions from S1P modulators to anti-CD20 agents.3,4
This Journal Club discussion will focus on an analysis of real-world data, conducted by Rowles and colleagues, that evaluated the association between MS inflammatory activity and the transition period from the S1P modulator fingolimod to an anti-CD20 therapy in patients with MS.2 A panel of neurology experts from the University of Texas Southwestern Medical Center in Dallas, led by Kyle Blackburn, MD, reviewed the results of the analysis and evaluated the implications on clinical practice.
Methods
The retrospective analysis focused on data extracted from the medical records of 108 patients (women, 68.5%; mean age, 44.6 years) from a single center who transitioned from fingolimod to either rituximab or ocrelizumab between 2010 and 2020. Rowles and colleagues reviewed the time periods prior to fingolimod discontinuation, the interval between fingolimod and initiation of an anti-CD20 therapy, and the interval following the first anti-CD20 infusion. The primary outcome was clinical relapses, defined as new or worsening neurologic symptoms for at least 24 hours in the absence of fever or infection, and secondary outcomes included magnetic resonance imaging (MRI) activity, time to absolute lymphocyte count (ALC) recovery, and infections.
Results
Approximately 68.5% of patients in the study were diagnosed with relapsing-remitting MS. Overall, the median period between discontinuation of fingolimod and initiation of an anti-CD20 therapy was 28 (IQR, 1-115.2) days. Within 6 months of fingolimod discontinuation, 11.8% (n=6/51) of patients with intervals greater than 1 month and 0% (n=0/57) of patients with intervals shorter than 1 month experienced an MRI-confirmed relapse. A total of 4 (3.7%) patients in the original cohort experienced a relapse in the year following anti-CD20 initiation. Relapse occurred at a median of 214.5 (range, 163-239) days following infusion. Approximately 7% of patients undergoing contrast-enhanced MRIs developed gadolinium-enhancing (Gd+) lesions. At 12 months, 57 of 92 patients reported normalization of ALC counts following S1P discontinuation. Uncensored data from all time points showed that only 3 of 92 patients had sustained low ALC (<0.8 × 10E9/L) following anti-CD20 therapy initiation.
Discussion
Kyle Blackburn, MD
Linda Nguyễn, MD
Natalia Gonzalez Caldito, MD
Kyle Blackburn, MD, assistant professor; Linda Nguyễn, MD, fourth-year resident, Department of Neurology, University of Texas Southwestern Medical Center, Dallas; and Natalia Gonzales Caldito, MD, a fellow at Northwestern University, Chicago, participated in this Journal Club discussion.
Kyle Blackburn, MD (KB): Thank you both for joining me today. We are here to discuss this paper, which addresses an important clinical question. Just to give a little bit of background before we dive into it: S1P modulator drugs are moderately efficacious for patients with MS, so they are commonly prescribed. But, while serious adverse events (AEs) are rare,5 there are a number of people who have to come off of them for a variety of reasons.
Unfortunately, coming off fingolimod or one of the other S1P drugs generally has some risk to it. In the months after stopping an S1P therapy, patients are at risk of having a rebound of their previous disease activity. Sometimes, patients will experience a severe relapse that is much worse than anything they had previously experienced, and this can cause accumulating disability going forward.3,4 There is really a need to address this issue, and that is what is at the heart of this study.
Natalia, do you want to touch on the overall approach and methods of this study?
Natalia Gonzales Caldito, MD (NGC): Yes, thank you. Through chart review, the researchers identified 108 patients who transitioned from fingolimod to ocrelizumab or rituximab. Researchers categorized patients into 2 groups based on the duration of the interval between treatments. The duration of intervals was interpreted first as a continuous variable and second as a categorical variable. Based on that, the researchers studied how many patients experienced a relapse and how many patients had clinical or imaging evidence of new activity. They also studied the risk for infections and time to ALC recovery, which I think was very important. Patients are concerned about immunosuppression when switching therapies. This was basically the idea of the study, and the researchers aimed to show if there were differences between the groups in terms of all these variables.
KB: You are right — the researchers did do this as a continuous analysis, but they also made the decision to separate patients into short vs long interval groups. Based upon the median time, they defined long intervals as greater than 30 days and short intervals as under 30 days. I really like the point you just made about immunosuppression. We often do not think about this, because we are also worried about rebound disease activity, but there is at least a theoretical concern for immunosuppression because fingolimod causes artificial lymphopenia, meaning fingolimod traps immune cells in the lymph nodes and so the patient is functionally lymphopenic for a while. There is a concern that adding another therapy, a more aggressive therapy on top of that, could lead to immunosuppression and an increased risk of infection, so there is definitely a good argument to be made that there may be a reason to wait longer before initiating therapy. Linda, do you have anything you want to add to that?
Linda Nguyễn, MD (LN): Yes, I wanted to note that the researchers were really focused on that interval between the transition, with the goal of addressing clinical relapse as a primary endpoint. Then, they looked at the secondary outcome measures of infection and ALC recovery. What is really interesting is that they point out that this is real-world data. This transition period from fingolimod to ocrelizumab is not available in clinical studies because they excluded patients who had a prior history of one of these agents in clinical trials. I think it is definitely important to us because it provides us with new information.
KB: I agree and it is a good point. Previously, a lot of studies excluded patients on S1P therapy, so it is important to see how this transition will occur in the real world. Linda, do you want to delve into the results a bit? Maybe we will start with the patients before they made the switch to to anti-CD20 therapy?
LN: Yes. I think in terms of those data, the researchers were comparing the clinical and demographic characteristics of the patients who were separated into the short vs long interval groups. They found some information that was interesting, but overall it was similar in terms of the clinical and demographic characteristics. They did note that reasons for fingolimod discontinuation differed between the longer and shorter intervals, with the long interval group having less disease breakthrough activity on fingolimod and more perceived inefficacy of fingolimod against disease progression. Other than that, many of the characteristics were similar before fingolimod was discontinued.
KB: I agree, and that the point you made about breakthrough disease being more common in the short interval group is going to come up a little bit later as well. Then, the researchers looked at relapses and MRI activity in the patients who were in the interval between stopping fingolimod and starting anti-CD20 therapy. Natalia, what was your understanding of what they found there?
NGC: It sounds like, in terms of clinical relapses, the researchers found that the patients who had clinical relapses were all over the 1-month period between treatments. Relapses were primarily identified in the patients who had delayed treatment for over a month. In the 12 months after anti-CD20 initiation, patients in the short interval group also experienced some relapses. The rationale was that perhaps this group had more active disease: If the patient experienced a relapse, even though this relapse was happening in the short interval group, it was because they had more active disease rather and not as a result of fingolimod discontinuation. One of the main points I took from this is that, among the patients who were in the short interval group, they did not experience relapse in that interval. Of course, the interval was very short, but the patients who relapsed were all from the long interval period.
KB: You are right. Every patient who experienced a relapse while they were awaiting anti-CD20 therapy were in the long interval group. There were 6 MRI-confirmed relapses, which was 11.8% of patients in the long interval group — that is certainly a significant number. You started to get into another point, which is that in the 12 months following initiation of anti-CD20 therapy, 4 patients in the short interval group, who had a more favorable response and no relapse in the interval between switching therapies, experienced a relapse.
In the paper’s eTables, the data show that many of the 4 patients who experienced a relapse actually had fairly high Expanded Disability Status Scale (EDSS) scores. Three of those 4 patients had switched because of disease activity or breakthrough disease. This would certainly lend to the idea that perhaps this wasn’t true rebound disease, but these were patients who were bound to be more active.
LN: Yes, I saw the discrepancy between how they defined the short interval group, long interval group, and the period before starting anti-CD20 therapy. Then, after anti-CD20 therapy, relapses were all seen in patients in the short interval group. Definitely, as you were bringing up, this is more likely due to their underlying high relapse rate.
KB: Now, the authors go on to talk about the other point that Natalia was making, which is that we worry about double immunosuppression. We certainly do not want patients to take on more risk than they need to whenever they are switching therapies. The researchers measured this using ALC. Linda, do you have any comments on the ALC data they presented?
LN: This is all real-world data, so there are no specific time points. All the patients had the collection done, so it is all very variable in how they had their ALC retrieved. There was no difference in ALC between the short interval and long interval groups, indicating that in the long run, a patient’s ALC is going to recover whether ocrelizumab is started sooner or later, which is what I gathered from the data.
KB: I think that is definitely fair. For the patients who had available data, it looks like the vast majority of them had normalized ALC and lymphocyte counts up to 12 months. The majority of patients had a normal ALC 12 months after they switched therapies, which is a fairly good number. Of the 92 patients who had ALC data available, 89 had normal ALC levels 12 months after they switched therapies, which is a fairly good number. We may not be taking on a risk of very prolonged lymphopenia whenever we switch therapies, and that is certainly good data to have. Now, the researchers do talk a little bit about the ALC with respect to relapse risk and infections. Natalia, did you see evidence to determine a correlation between ALC and relapse risk and the risk of infection?
NGC: From what I understood, there was no correlation even when the ALC is not normalized, which is actually reassuring. We can argue that this tells us these patients already were on ocrelizumab, so then perhaps that is why they were not experiencing a relapse.
KB: I believe approximately 30% of the group had an infection, but it did not matter which group you were in. The researchers really didn’t see an association between having received an anti-CD20 therapy the day after or many, many months after stopping fingolimod.
I think we have dissected the results enough. Let’s just take a big step back and look at this paper. Linda, what do you view to be the strengths and some of the limitations of the paper?
LN: I alluded to this in the beginning, but the researchers provided us with data that was not available in the clinical trials, and so this data on the transition period between fingolimod and ocrelizumab are really relevant to us in clinical practice. That is a major strength of this paper. Also, having around 100 patients is a good number to see AEs or the benefits related to the transition period or transition to treatment period. I think one of the negatives or downsides of the paper is that it was a single-center study. Certainly, they say the data is generalizable because the patient demographic is similar to the MS population, but I think having multicenter studies would be better.
Also, nothing is systematic in this real-world collection. A patient who is experiencing a lot of breakthrough disease may have insurance problems that prevents their access to care, or there may be some other reason that causes a patient to have a prolonged period of time between treatments, but this understanding is kind of out of our hands. That is a different point, but nevertheless, I think we need to account for these things when we look at the clinical data and factor it in when we determine if it was disease activity or something else that was the reason for the long duration between treatments.
KB: For sure. I think an important point here is that for some patients who had a long duration between treatments, it was due to an AE to fingolimod. They may have stayed on the therapy if they had not had that AE, so that certainly is important to say. Natalia, anything else to add to that?
NGC: The only other limitation is that the timing of the MRIs was not consistent. I think that this article is actually very relevant for practice; it gives us reassurance that we do not have to wait to initiate therapy, and this will potentially change our practice and prevent MS flares in those patients. Based on these data, this it is a very important article that will change the way I practice. Perhaps this could be done with a larger sample size and with more scheduled imaging, ALC counts, and infection recording.
KB: My last question is regarding how you feel about the clinical relevance of this paper. You have already addressed that, Natalia. Linda, anything to add in terms of clinical practice and its relevance?
LN: I think Natalia’s right. This study gives us reassurance that we do not have to monitor the ALC as a reason to hold off further therapy and/or worry about the infection risk to start the next therapy. It shows us that the shorter interval between starting treatments is better at preventing relapse in that period of time.
KB: I ultimately agree with you guys here. I think this is very reassuring data in that we are not harming our patients by initiating therapy or by initiating therapy in a short interval. It validates that this is safe to do, and I think it argues that, to prevent a relapse in that timeframe, it may be a very reasonable thing to do. My last point would probably be that this is retrospectively-collected data, and both of you have said that there are missing data points along the way that make it hard to interpret a few things. The researchers even acknowledge there are some limitations, especially on their ALC data, and that they cannot do some of the analyses that they would want to have done. I think there is a great opportunity here to collect these data and AEs in a more systematic way. There is a huge opportunity here for a trial on transitioning from an S1P therapy to an anti-CD20 therapy. This paper would be a very nice prelim to a trial like that, so I certainly hope going forward they pursue that.
This article was edited for clarity and length.
References
1. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788. doi:10.1212/WNL.0000000000005347
2. Rowles WM, Hsu WY, McPolin K, et al. Transitioning from S1P receptor modulators to B cell-depleting therapies in multiple sclerosis: clinical, radiographic, and laboratory data. Neurol Neuroimmunol Neuroinflamm. 2022;9(4):e1183. doi:10.1212/NXI.0000000000001183
3. Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves JS. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol. 2016;73(7):790-794. doi:10.1001/jamaneurol.2016.0826
4. Pantazou V, Pot C, Pasquier RD, Goff GL, Théaudin M. Recurrence of disease activity after fingolimod discontinuation in older patients previously stable on treatment. Mult Scler Relat Disord. 2021;51:102918. doi:10.1016/j.msard.2021.102918
5. Comi G, Hartung HP, Bakshi R, Williams IM, Wiendl H. Benefit-risk profile of sphingosine-1-phosphate receptor modulators in relapsing and secondary progressive multiple sclerosis. Drugs. 2017;77(16):1755-1768. doi:10.1007/s40265-017-0814-1
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Reviewed September 2022
