Relapses Rebound in Patients With MS Stopping Fingolimod

Pauline Anderson

May 12, 2016

New research shows that patients with multiple sclerosis (MS) experience severe clinical relapses after stopping fingolimod treatment.

On the basis of the data collected for the study, "fingolimod, like natalizumab, causes rebound, and the rebound frequency is high enough to warrant attention and clinical consideration," said study author Jennifer S. Graves, MD, PhD, assistant professor, Department of Neurology, University of California at San Francisco (UCSF).

Clinicians should think carefully about how to take a patient off fingolimod, said Dr Graves. "Just as the community has adapted to thinking about this for natalizumab, we also have to think about this for fingolimod."

The case series was published online May 2 in JAMA Neurology.

Researchers reviewed medical records of all patients at the UCSF MS center who discontinued fingolimod treatment between January 2014 and December 2015 as part of another ongoing study. They found 46 patients had stopped receiving the drug, most because they wanted to become pregnant but others because of adverse effects or breakthrough disease activity.

Of these 46 patients, 5 (10.9%) experienced a rebound syndrome, defined as new severe neurologic symptoms, with the development of multiple new or enhancing lesions exceeding baseline activity. In these patients, the severe disease reactivation occurred 4 to 16 weeks after discontinuation of fingolimod.

A literature search uncovered 11 other cases of this MS rebound phenomenon after fingolimod discontinuation.

In their paper, the authors described the five cases at their center. All five had severe clinical relapses, with a very large number of new or enhancing lesions on MRI.

Surprising Severity

"Whereas a typical relapse may have one or just a few lesions, these had very excessive, very large numbers of new lesions," said Dr Graves. "These cases were surprising in their severity."

For example, in one case, brain MRI showed 25 new lesions (2 enhancing) compared with MRI findings from 11 months earlier.

All patients were women, ranging in age from their mid-20s to mid-40s, and all were diagnosed with relapsing-remitting MS of 4 to 18 years' duration. However, according to Dr Graves, this doesn't necessarily mean that this syndrome occurs only in women; there were some men among patients found in literature review, she said.

Two of the five women stopped fingolimod because they wanted to become pregnant. Both resumed the drug after the rebound.

Like natalizumab, fingolimod is considered "mid-category risk" during pregnancy, but for a different reason, said Dr Graves. Fingolimod is linked to teratogenicity. With natalizumab there is concern about miscarriage with early exposure and hematologic changes in infants exposed late in the pregnancy; the drug crosses the placenta after the second trimester.

Both fingolimod and natalizumab affect immune "trafficking," Dr Graves noted. Fingolimod is a sphingosine-1-phosphate receptor modulator that sequesters lymphocytes in lymph nodes, preventing entry into the central nervous system. Natalizumab acts on α-4 integrin receptors on lymphocytes to block passage across the blood–brain barrier and reduce their infiltration into the brain.

Thus, it's perhaps not unexpected that, as with natalizumab, rebound MS could also occur after discontinuation of fingolimod, she said.

"Essentially, the immune cells are being sequestered in the lymph nodes and then released when the medication is stopped," explained Dr. Graves. "When that happens, one could postulate that reconstitution of the immune system back into the blood stream is related to this phenomenon."

Judging from the cases outlined in the paper, the rebound MS is challenging to treat, just as it is with rebound after stopping natalizumab.

The new information underlines the importance of developing different strategies for medication discontinuation, said Dr Graves. "We have to look very carefully at the balance of safety and the potential of this rebound event when we are stopping the medication."

The idea that a significant washout period is needed between medications to ensure the immune system reconstitutes may have to be reconsidered, she said.

She also suggested the importance of further studying this process. "We are not formally studying that end period of exposure or formally studying how long we should be going between medications."

In the paper, she and her colleagues proposed that clinical trials should include an additional follow-up period, after the end of drug exposure, to gather additional safety and immunologic data about exposures.

Salient Discussion

Given this new finding of a potential rebound relapse after stopping fingolimod, a discussion on the altered risk-benefit ratio for this drug "is salient" and should be considered in the context of larger treatment-related issues in MS, said Rhonda Voskuhl, MD, Department of Neurology, University of California, Los Angeles, in an accompanying editorial.

There are two schools of thought regarding how aggressive treatments should be in patients with early relapsing-remitting MS, said Dr Voskuhl. In the past, most physicians started patients with the safest MS treatment, escalating to a more aggressive second-line treatment if warranted.

"The disadvantage was that precious years may have been spent receiving a treatment that was not potent enough for some patients, potentially leaving to irreversible disability."

According to the more recent school of thought, physicians should aim to achieve "no evidence of disease activity" by starting aggressive therapies as soon as possible after diagnosis. The disadvantage of this approach, said Dr Voskuhl, is that some patients may be needlessly exposed to relatively high risks for toxicities.

Dr Voskuhl noted that two of the five women with MS in the study had rebound relapses when they stopped fingolimod to try to get pregnant. She suggested that an alternative to more aggressive treatments with unexpected toxicities for such women is a combination of safer treatments.

"Safe combination treatments could entail combining two long-standing first-line disease-modifying MS treatments or using one first-line treatment with a repurposed treatment, considering repurposed treatments generally have vast postmarking experience and therefore fewer unexpected toxicities."

She pointed out that in a recent multicenter phase 2 trial she and her colleagues carried out, when estriol, a repurposed candidate oral treatment, was used in combination with glatiramer acetate injections, relapse rates were reduced by 32% to 48% over and above glatiramer acetate plus placebo.

For Lily Jung Henson, MD, chief of neurology, Piedmont Healthcare, Atlanta, Georgia, the issue isn't as much about the safety of this drug as it is about its effectiveness in reducing the inflammation associated with MS.

As for the rebound seen with natalizumab, "the struggle is what to do with patients if they need to come off the drug, whether it is because of side effects or because of lack of efficacy," said Dr Jung Henson.

"How do we help them transition to the next most appropriate therapy to get their disease under control? And how do we sequence our treatments so that we get control of disease activity quickly?"

Funding for this study came from grants to individual investigators from the National Institutes of Health, the National Multiple Sclerosis Society, and the Race to Erase Multiple Sclerosis. Dr Graves has disclosed no relevant financial relationships. Dr Voskuhl has received funding from the California Community Foundation and is an inventor on University of California, Los Angeles, patents related to estriol treatment.

JAMA Neurol. Published online May 2, 2016. Abstract Editorial

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