Journal of Neuroimmunology 285 (2015) 13–15
`
`Contents lists available at ScienceDirect
`
`Journal of Neuroimmunology
`
`j ou r n a l h o m e p a g e : w ww . e l s e v i e r . c om / l o c a t e / j n e u r o i m
`
`Short communication
`Safety and efficacy of reduced fingolimod dosage treatment
`Bassem I. Yamout, Maya M. Zeineddine, Raja A. Sawaya, Samia J. Khoury ⁎
`
`Multiple Sclerosis Center, Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Background: Oral fingolimod is a sphingosine-1-phosphate-receptor modulator that prevents the egress of
`lymphocytes from lymph nodes. Fingolimod reduces relapse rate and delays disability progression in patients
`with relapsing forms of multiple sclerosis (MS). Elevation of liver function tests (LFTs) and reduction in
`peripheral-blood lymphocyte counts were among the most common adverse events reported in phase II,
`phase III, and extension studies.
`Objective: To describe eight patients in whom fingolimod dose was reduced to every other day (n = 6) or every
`third day (n = 2) due to increased LFTs more than 3 times the upper limit of normal (ULN) (n = 2) or decreased
`lymphocyte count by ≤0.2 × 109/L (n = 6).
`Results: Fingolimod dose reduction resulted in reversal of laboratory abnormalities. Clinically, none of the 8
`patients developed clinical relapses, but five patients had new lesions on magnetic resonance imaging (MRI),
`one of whom with disability progression, and one patient converted to secondary progressive MS (SPMS).
`Conclusion: Reducing the frequency of fingolimod administration can reverse laboratory abnormalities but may
`have a negative impact on drug efficacy.
`
`© 2015 Elsevier B.V. All rights reserved.
`
`Article history:
`Received 23 March 2015
`Received in revised form 11 May 2015
`Accepted 13 May 2015
`
`Keywords:
`Fingolimod
`Dose
`Reduced
`Lymphopenia
`Liver enzymes
`Multiple sclerosis
`
`1. Introduction
`
`Fingolimod is an oral agent with proven efficacy and safety in
`relapsing–remitting multiple sclerosis (RRMS) (Cohen et al., 2010;
`David et al., 2012). Elevation of LFTs and reduction in peripheral-blood
`lymphocyte counts were among the most common adverse events
`reported in the initial studies. The drug label requires discontinuing the
`drug in case of lymphopenia (lymphocyte count of ≤200 × 106/L) or in-
`crease in liver enzymes by ≥5× ULN (Pelletier and Hafler, 2012). Given
`that fingolimod has a half-life of 6–9 days, and steady-state pharmacoki-
`netics are reached after 1–2 months of daily dosing (Kappos et al., 2010),
`we elected to decrease the frequency of fingolimod administration in
`patients with lymphopenia or elevated LFTs and observe whether this
`may improve the laboratory abnormalities without affecting the efficacy
`of the treatment. We report on eight patients in whom fingolimod dose
`was reduced to every other day (n = 6) or every third day (n = 2) due
`to increased LFTs of N3× ULN (n = 2) or decreased lymphocyte count
`by ≤200 × 106/L (n = 6) (Table 1).
`
`⁎ Corresponding author at: Multiple Sclerosis Center, American University of Beirut
`Medical Center, P.O. Box 11-0236, Riad El-Solh 1107 2020, Beirut, Lebanon.
`E-mail address: sk88@aub.edu.lb (S.J. Khoury).
`
`http://dx.doi.org/10.1016/j.jneuroim.2015.05.012
`0165-5728/© 2015 Elsevier B.V. All rights reserved.
`
`2. Material and results
`
`2.1. Case 1
`
`A 26 year-old man with RRMS since 2012 was treated with interferon-
`beta (IFNB)-1a 44 mcg three times weekly between September 2012 and
`June 2013. He was shifted to fingolimod 0.5 mg/day in July 2013 due to
`new enhancing lesions on brain MRI. Three months later, his serum
`glutamic pyruvic transaminase (SGPT) and glutamic oxaloacetic transam-
`inase (SGOT) rose to 199 and 82 respectively. Fingolimod was reduced to
`0.5 mg every other day in October 2013. In January 2014, he was clinically
`stable and had an unchanged MRI, but his serum SGPT and SGOT were
`still elevated (213 and 75 respectively). The dose was further decreased
`to 0.5 mg every third day. Follow up three months later showed that
`LFTs normalized (SGPT = 83 and SGOT = 25). The patient has since
`been stable clinically except for an episode of herpes zoster ophthalmicus.
`His most recent brain MRI in September 2014 was stable.
`
`2.2. Case 2
`
`A 38-year-old woman with RRMS of 1 year duration was started on
`fingolimod 0.5 mg daily in November 2011 after developing severe de-
`pression on IFNB-1a 44 mcg. Her lymphocyte count dropped gradually
`from 1100 × 106/L at baseline to 144 × 106/L within 5 months.
`Fingolimod was withheld for two weeks until her lymphocyte count
`normalized then restarted at the same dose, but one month later, her
`
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`14
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`B.I. Yamout et al. / Journal of Neuroimmunology 285 (2015) 13–15
`
`Table 1
`Clinical characteristics of patients treated with fingolimod before and after dose reduction.
`
`Follow up on reduced fingolimod dosage treatment
`
`Patient Age Sex Previous
`therapy
`
`Fingolimod
`dosing schedule
`
`Reason for decreasing
`dose
`
`Duration
`(months)
`
`Relapses Disability
`progression
`
`MRI
`activity
`
`Normalization
`of laboratory
`abnormalities
`
`Increased LFTs by ≥3× ULN
`0.5 mg every third day
`Lymphopenia
`0.5 mg every third day
`(lymphocyte = 189 × 106/L)
`then every other day
`0.5 mg every other day Lymphopenia
`(lymphocyte = 208 × 106/L)
`0.5 mg every other day Increased LFTs by ≥3× ULN
`
`0.5 mg every other day Lymphopenia
`(lymphocyte = 100 × 106/L)
`0.5 mg every other day Lymphopenia
`(lymphocyte = 198 × 106/L)
`0.5 mg every other day Lymphopenia
`(lymphocyte = 180 × 106/L)
`0.5 mg every other day Lymphopenia
`(lymphocyte = 160 × 106/L)
`
`12
`38
`
`15
`
`10
`
`21
`
`7
`
`20
`
`6
`
`No
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`Yes
`
`No
`
`Yes
`
`No
`
`No
`
`No
`
`No
`
`No
`Yes
`
`Yes
`
`No
`
`Yes
`
`Yes
`
`No
`
`Yes
`
`Yes
`Yes
`
`Yes
`
`Noa
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Reason to
`switch to
`fingolimod
`Inefficacy
`AEs: Depression
`
`AEs: Injection
`site reactions
`AEs: Flu-like
`symptoms
`Inefficacy
`
`26 M IFNB 1a 44 mcg
`38
`F
`IFNB 1a 44 mcg
`
`26
`
`F
`
`IFNB 1a 44 mcg
`
`32 M IFNB 1a 30 mcg
`
`41
`
`F
`
`IFNB1b 250 mcg
`
`24 M IFNB 1b 250 mcg Inefficacy
`
`34
`
`22
`
`F
`
`F
`
`IFNB 1a 44 mcg
`
`Inefficacy
`
`IFNB 1b 250 mcg AEs: Depression &
`flu-like
`symptoms
`
`1
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`M: male; F: female; IFNB: interferon-beta; AEs: adverse events; LFTs: liver function tests; ULN: upper normal limit; MRI: magnetic resonance imaging.
`a Patient on high doses of ibuprofen and acetaminophen.
`
`lymphocyte count decreased again to 189 × 106/L leading to discontin-
`uation of therapy. When the lymphocyte count recovered, fingolimod
`was reintroduced at a dose of 0.5 mg every other day in July 2012 but
`lymphopenia persisted (270 × 106/L). The dosage was decreased to
`0.5 mg every third day starting September 2012. Her lymphocyte
`count increased up to 320 × 106/L in February 2014. The patient did
`well with no further relapses, stable expanded disability progression
`(EDSS), and stable MRIs. In April 2014, her EDSS score increased from
`0 to 1.0 and brain MRI showed one new non-enhancing lesion in the
`brainstem. We assumed that the new disease activity was related to
`the reduced dose, and fingolimod was increased to every other day.
`Although her lymphocyte count recovered (600 × 106/L), her MRI in
`September 2014 revealed one new enhancing lesion. The patient was
`therefore switched back to once daily dosing. During her follow-up
`visit in January 2015, she was clinically stable without evidence of
`new relapses or disability progression, and her last lymphocyte count
`was 324 × 106/L. However, her brain MRI showed one new subcortical
`enhancing lesion leading to discontinuation of fingolimod therapy.
`
`2.3. Case 3
`
`A 26-year-old woman with RRMS since 2007 was maintained on
`subcutaneous IFNB-1a 44 mcg since November 2010 with no relapses
`or disability progression. A total of 5 MRIs performed between 2010
`and 2013 at 6 months intervals did not reveal any new or enhancing
`lesions. She was shifted to fingolimod 0.5 mg/day in December 2013
`after developing significant focal lipodystrophy and local skin infections
`at the injection sites. One month later, her lymphocyte count decreased
`from 1375 × 106/L to 208 × 106/L, associated with recurrent infections
`including upper respiratory tract infections, cellulitis and conjunctivitis.
`The dose of fingolimod was reduced to 0.5 mg every other day in January
`2014 leading to increased lymphocyte count to 854 × 106/L by April 2014.
`The patient has since been stable with no new relapses or disability pro-
`gression. Her last lymphocyte count in April 2015 was 455 × 106/L. Brain
`MRI in November 2014 did not show any new or enhancing lesions, but
`her most recent MRI in April 2015 revealed one new non-enhancing
`lesion.
`
`2.4. Case 4
`
`A 32-year-old man with RRMS since 2011 was started on fingolimod
`0.5 mg/day in June 2013. Eight months later, his liver function tests
`showed elevated SGPT of 203 (baseline of 34) and SGOT of 91 (baseline
`
`of 18). On reducing fingolimod dose to every other day in February
`2014, his serum SGPT and SGOT decreased to 114 and 77 respectively
`in June 2014. The patient was clinically stable with no evidence of
`new lesions on brain MRI. But in August 2014, LFTs increased again
`(SGPT = 271 and SGOT = 138). It was found that the patient has
`been taking excessive amounts of ibuprofen and acetaminophen
`which may be have contributed to his elevated LFTs. He was advised
`to keep the same fingolimod dosage and stop all analgesics. During his
`last follow up visit in December 2014, his serum SGPT and SGOT further
`decreased to 129 and 64 respectively but his EDSS worsened from 2.5 to
`6.5 indicating that the patient has entered the progressive phase of MS.
`
`2.5. Case 5
`
`A 41-year-old woman with RRMS since 2005 was started on
`fingolimod 0.5 mg/day in February 2013 after developing new enhancing
`lesions on brain MRI while on subcutaneous IFNB-1b. Her baseline
`lymphocyte count dropped from 2100 × 106/L to 100 × 106/L within
`three months of treatment initiation. Fingolimod was withheld until
`her lymphopenia resolved then reintroduced in May 2013 at a dose of
`0.5 mg every other day. Her lymphocyte count gradually increased to
`910 × 106/L by September 2013. The patient has since been clinically
`stable with resolution of her cerebellar and urinary symptoms. Her
`brain MRI was stable in February 2014, but showed one new non-
`enhancing lesion in February 2015. Her most recent lymphocyte count
`was 350 × 106/L in February 2015.
`
`2.6. Case 6
`
`A 24-year-old man with RRMS since 2009 was started on fingolimod
`0.5 mg/day in April 2014 following a relapse on IFNB-1b. One month
`later, his lymphocyte count dropped from 1444 × 106/L to 198 × 106/L
`leading to drug discontinuation with recovery of his lymphocyte count
`to 814 × 106/L. Fingolimod was resumed at a dose of 0.5 mg every
`other day in May 2014 and the patient has since been clinically stable
`without relapses or disability progression. His most recent lymphocyte
`count in November 2014 was 299 × 106/L but his brain MRI showed a
`new enhancing lesion.
`
`2.7. Case 7
`
`A 34-year-old female with RRMS since 2007 was started on
`fingolimod 0.5 mg/day in December 2012 following two clinical
`
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`B.I. Yamout et al. / Journal of Neuroimmunology 285 (2015) 13–15
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`15
`
`exacerbations on IFNB-1a 44 mcg. The patient moved to the USA and did
`not come back for a follow up visit until June 2014. She reported that she
`had been clinically and radiologically stable since starting fingolimod
`therapy, but was switched to every other day dose in April 2013 due to
`lymphopenia (180 × 106/L). Two brain MRIs in June and December
`2014 did not show any new or enhancing lesions. Her lymphocyte
`count increased to 760 × 106/L by December 2014 and her EDSS was
`stable.
`
`2.8. Case 8
`
`A 22-year-old female with RRMS since August 2011 was started on
`fingolimod in November 2011. She received IFNB-1b subcutaneously
`for 1 month and was shifted to fingolimod due to severe adverse events
`including depression and flu-like symptoms. She has been clinically and
`radiologically stable on daily fingolimod treatment but her brain MRI in
`October 2014 revealed one new enhancing lesion and her lymphocyte
`count decreased to 160 × 106/L leading to discontinuation of therapy for
`10 days and reintroduction of fingolimod at a dosage of 0.5 mg every
`other day. Although her lymphocyte count recovered to 390 × 106/L,
`her most recent brain MRI in April 2015 revealed 3 new lesions one of
`which was enhancing.
`
`3. Discussion
`
`In this case series, we report on the use of reduced dose fingolimod
`in the management of lymphopenia and increased liver enzymes. In
`the placebo controlled phase III (Cohen et al., 2010) trial of fingolimod,
`lymphopenia and increased LFTs were reported in 0.5% of subjects
`receiving 1.25 mg daily dose and in none of the subjects receiving the
`0.5 mg daily dose. In the phase III trial (David et al., 2012) of fingolimod
`versus IM IFNB, the reported rate of lymphopenia was 1.0% for the
`1.25 mg fingolimod group and 0.2% for the 0.5 mg group while LFT ele-
`vations were reported in 5.7% of the subjects taking 1.25 mg fingolimod
`and 6.5% of the subjects on 0.5 mg. In our clinical practice the rate of
`lymphopenia (lymphocyte count of b200 × 106/L) and LFT elevation
`of ≥3× ULN are around 4% and 1.6% respectively.
`To date, the European and American guidelines recommend periodic
`monitoring of liver enzymes and peripheral blood CBC and discontinu-
`ation of treatment if the lymphocyte count drops below 200 × 106/L
`and LFTs increased by ≥5× ULN. There are no clear guidelines regarding
`treatment resumption and what to do in cases of recurrent lymphope-
`nia or LFT abnormalities after re-exposure to the drug.
`Fingolimod is efficiently absorbed regardless of food intake, with
`an oral bioavailability of N90% (Kappos et al., 2010). Fingolimod has a
`half-life of 6–9 days, and steady-state plasma concentrations are
`attained after 1–2 months of treatment initiation (Kappos et al.,
`2010). The long half-life of fingolimod, together with its slow absorp-
`tion, means that fingolimod has a flat concentration profile over time
`(Kappos et al., 2010). Thus, we elected to reduce the frequency of
`fingolimod administration to manage lymphopenia and liver enzyme
`elevation. A recent Japanese case series (Tanak et al., 2013) of 3 patients
`who received fingolimod at reduced dosage due to lymphopenia or
`neutropenia suggested that alternative treatment schedules can satis-
`factorily correct the laboratory abnormalities.
`In our series the fingolimod dose was reduced to 0.5 mg every other
`day (n = 6) or every third day (n = 2) leading to restoration of labora-
`
`tory parameters to an acceptable range. The mean duration of follow-up
`on reduced dosage was 16.1 months. Only 2/8 patients remained both
`clinically and radiologically stable. One patient converted to SPMS
`with significant increase in disability, and another showed mild disabil-
`ity progression. In most cases (5/8) there were new and/or enhancing
`lesions on brain MRI. Patient 3 was maintained on IFNB for 3 years be-
`fore shifting to fingolimod and had no new/enhancing lesions on 5 con-
`secutive brain MRIs performed at 6 month intervals during that period.
`A new T2 lesion appeared on brain MRI 15 months after initiating the low
`dose regimen. Patient 8 was maintained on full dose fingolimod for
`3 years and showed only 1 enhancing lesion on repeated brain MRIs
`every 6 months. Her first MRI performed 6 months after lowering
`fingolimod dose revealed 3 new lesions one of which was enhancing. In
`one patient (Case 4) LFTs increased again after being stable for several
`months, possibly due to combining fingolimod with high doses of ibupro-
`fen and acetaminophen.
`Our case series highlights the fact that in clinical practice, reducing
`the frequency of fingolimod administration to every other or every
`third day can reverse laboratory abnormalities such as lymphopenia
`and elevated LFTs, but may have a negative impact on drug efficacy.
`Such conclusion however needs to be confirmed in a large randomized
`controlled trial, which is currently being carried by Novartis. This multi-
`center, randomized study (Novartis Pharmaceuticals, 2012) will com-
`pare the doses of 0.25 mg and 0.5 mg of fingolimod with glatiramer
`acetate 20 mg, and should provide us with a definite answer regarding
`the efficacy of the lower fingolimod dose.
`
`Funding
`
`This research received no specific grant from any funding agency in
`the public, commercial, or not-for-profit sectors.
`
`Conflict of interest
`
`Dr. Khoury received grant support from Novartis pharmaceuticals
`(IM.SK1.07).
`Dr Yamout received speaker honoraria from Merck-Serono, Bayer,
`Biogen, Novartis and Genzyme, and research funds from Merck-Serono
`by participating in international multicenter trials sponsored by the
`company.
`
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