Author Topic: Rebound syndrome in MS patients after stopping Gilenya  (Read 9790 times)

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Offline agate

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Rebound syndrome in MS patients after stopping Gilenya
« on: February 17, 2016, 10:44:11 am »
Being presented at the annual ACTRIMS (Americas Committee for Treatment and Research in Multiple Sclerosis) conference in New Orleans, February 18-20, 2016.

Quote
Rebound syndrome in multiple sclerosis patients after cessation of fingolimod

Ms. Stacy E Hatcher, BS1, Dr. Emmanuelle Waubant, MD, PhD2, Dr. Bardia Nourbakhsh, MD1, Dr. Elizabeth Crabtree-Hartmann, MD1 and Dr. Jennifer S Graves, MD, PhD, MAS2

1UCSF, San Francisco, CA, 2University of California, San Francisco, San Francisco, CA

Background:

Rebound syndrome after natalizumab cessation has been well-documented. However, rebound activity after discontinuation offingolimod, a sphingosine-1-phosphate receptor modulator used to treat relapsing remitting multiple sclerosis is less well understood.

Objectives:

To describe multiple sclerosis (MS) rebound syndrome after fingolimod cessation.

Methods:

We identified patients at the UCSF MS Center who experienced severe relapse with multiple new enhancing lesions upon cessation of fingolimod. Clinical and demographic data were extracted from electronic medical records and magnetic resonance images (MRI) were reviewed by UCSF MS neurologists. We conducted a literature search and identified additional cases of severe relapse upon fingolimod cessation.

Results:


Five women (ages 29-45) with a history of relapsing-remitting MS experienced severe relapse at 4-16 weeks post fingolimod cessation. Reasons for stopping therapy included pregnancy attempts (n=2), clinical progression on fingolimod (n=2), and medication side effects (n=1).

Despite varying prior disease course, all experienced unexpectedly severe clinical relapses accompanied by drastic increases in MRI lesion burdens. In three patients new lesion development persisted for 3-6 months despite treatment with corticosteroids and in two patients, initiation of B cell depleting therapy. Eleven patients identified through literature review were reported as having severe relapses consistent with a rebound syndrome.

Conclusion:

These cases provide evidence for a rebound syndrome following cessation of fingolimod. They highlight the need to determine the best methods for sequencing or discontinuing MS therapies.

Further study is also needed to prevent rebound in women [stopping] therapies for pregnancy. These issues will become increasingly important as newer agents with strong immunological effects are introduced on the market.

Inclusion in phase II clinical trials of at least a 2-3 month observation phase for patients who discontinue study drug may provide valuable information to clinicians prescribing [these drugs and monitoring their patients in  the transition to and from them].
« Last Edit: May 02, 2016, 04:09:19 pm by agate »
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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An article by the same authors on the same topic appears inJAMA Neurology, May 2, 2016, and is available in its entirety online. This is the abstract:

Quote
Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment

Stacy Ellen Hatcher, BS1; Emmanuelle Waubant, MD, PhD1; Bardia Nourbakhsh, MD1; Elizabeth Crabtree-Hartman, MD1; Jennifer S. Graves, MD, PhD, MAS1

 Author Affiliations

1Department of Neurology, University of California, San Francisco


Importance

The appropriate sequencing of agents with strong immune system effects has become increasingly important. Transitions require careful balance between safety and protection against relapse.

The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods (4 weeks) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies, such as rituximab.

Objective 

To describe rebound syndrome in patients with multiple sclerosis (MS) after cessation of fingolimod treatment.

Design, Setting, and Participants

Clinical and demographic data were extracted from electronic medical records from the University of California, San Francisco, Multiple Sclerosis Center from January 2014 to December 2015. Magnetic resonance images were reviewed by MS neurologists (J.S.G., E.W., B.N., and E.C.H.).

Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, with the development of multiple new or enhancing lesions exceeding baseline activity.

We reviewed the PubMed database from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation.

Participants were included if they stopped receiving fingolimod between January 2014 and December 2015. Five patients were identified who experienced rebound after ceasing fingolimod treatment.

Exposures

 Each patient received treatment with oral fingolimod for various durations.

Main Outcomes and Measures 

Occurrence of rebound after ceasing fingolimod treatment.

Results 

The mean (SD) age of the 5 female patients presented in this case series was 35.2 (6.4) years. Of the 46 patients who stopped fingolimod treatment within the 2-year period, 5 (10.9%) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment.

Despite varying prior severity of relapsing-remitting course, all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidenced by a median (range) increase of 9 (0->30) new gadolinium-enhancing lesions and a median (range) of 9 (0->30) new T2 lesions. New lesion development persisted for 3 to 6 months despite treatment with corticosteroids (n = 3) and initiation of B-cell depleting therapy (n = 2).

In addition, 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases.

Conclusions and Relevance 


These cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.

The entire article can be seen here.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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The same issue (May 2) of JAMA Neurology contains an editorial about the article above. It points out that both Tysabri and Gilenya have involved rebound effects when patients stopped taking the drug, while the older disease-modifying drugs have not involved a rebound effect.

The editorial goes on to summarize a couple of instances of combinations of drugs--indicating that estriol combined with Copaxone showed good results in a Phase 2 trial in terms of the relapse rate.

http://app.jamanetwork.com/#page=issuesContainer

NOTE: Using the above link, you  need to click on "Continue without promo code" to see the text of the editorial.
« Last Edit: May 07, 2016, 05:01:06 pm by agate »
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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A couple of letters and an authors' reply about this article, in  JAMA Neurology, September 26. The first is from some Novartis employees, and the second is from an MD in psychopharmacology, and they are followed by the authors' reply. 







MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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Presented at the AAN annual meeting in Boston (April 2017):

Quote
Rebound of Multiple Sclerosis Disease Activity Following Fingolimod Cessation

Afagh Garjani1, Esmaeil Nikfekr1, Jithin George1

1
Neurology Department, University Hospitals Leicester NHS Trust

Objective:

To describe the rebound of multiple sclerosis (MS) disease activity after cessation of fingolimod treatment.

Background:

Fingolimod is a sphingosine 1-phosphate receptor modulator which prevents lymphocyte release from lymphoid tissue. While rebound of disease activity in MS after discontinuation of natalizumab is well-known, evidence of rebound after stopping fingolimod has emerged recently. Further studies on the impact of fingolimod cessation on relapses would have implications in planning the transition between disease modifying treatments.

Design/Methods:


We retrospectively reviewed medical records of patients with MS from the University Hospitals of Leicester, United Kingdom who had fingolimod discontinued since 2013.

 In this case series, we present the clinical, laboratory, and imaging findings of five patients [who] experienced severe recurrence of MS relapses after fingolimod withdrawal which exceeded their baseline disease activity.

We reviewed the literature from PubMed database using the search term ‘fingolimod rebound’.

Results:

Five (31.2%) of the 16 patients with relapsing-remitting MS [who] stopped receiving fingolimod suffered from an unexceptionally severe clinical relapse 2 weeks to 6 months after fingolimod cessation.

The mean (SD) duration of fingolimod treatment in these female patients was 21.8 (13.9) months. In all five cases, fingolimod was discontinued for escalation to natalizumab as a result of highly active MS. All patients demonstrated substantial
new and enhancing lesions on magnetic resonance imaging (MRI). Three patients had tumefactive demyelinating lesions.

All patients received corticosteroids. One patient with encephalopathy and positive John Cunningham virus antibody required further treatment with cyclophosphamide.

Conclusions:

These cases along with similar reports in the literature highlight the need to establish a scheme for switching from fingolimod to other therapies. Further investigations that incorporate patients who have discontinued fingolimod
for reasons other than highly active MS, such as adverse effects of fingolimod or progression to secondary progressive MS, can help to identify predictors of MS rebound after fingolimod discontinuation.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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From Multiple Sclerosis News Today (November 27, 2018), "FDA Warns about Rare Risk of Severe Worsening of MS Disability after Stopping Gilenya":


https://multiplesclerosisnewstoday.com/2018/11/26/fda-warns-about-risk-of-severe-worsening-of-ms-disability-after-stopping-gilenya/
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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From PubMed (April 25, 2022)--"Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis":


https://pubmed.ncbi.nlm.nih.gov/35462167/
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

 

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