694089 MSJ0010.1177/1352458517694089Multiple Sclerosis JournalC Zecca, A Merlini
`
`research-article2017
`
`MULTIPLE
`SCLEROSIS MSJ
`JOURNAL
`
`Original Research Paper
`
`Half-dose fingolimod for treating
`relapsing-remitting multiple sclerosis:
`Observational study
`
`Chiara Zecca, Arianna Merlini, Giulio Disanto, Mariaemma Rodegher, Letizia Panicari,
`Marzia Anita Lucia Romeo, Ursula Candrian, Maria Josè Messina, Emanuele Pravatà,
`Lucia Moiola, Catia Stefanin, Angelo Ghezzi, Patrizia Perrone, Francesco Patti, Giancarlo Comi,
`Claudio Gobbi and Vittorio Martinelli
`
`Abstract
`Objectives: To investigate the efficacy and safety of fingolimod (FTY) 0.5 mg administered every other
`day (FTY-EOD) compared to every day (FTY-ED) in multiple sclerosis patients.
`Methods: Multicentre retrospective observational study. Clinical, laboratory and neuroimaging data were
`consecutively collected from 60 FTY-EOD and 63 FTY-ED patients. Baseline characteristics were com-
`pared using logistic regression. Efficacy in preventing occurrence of relapses and demyelinating lesions
`was tested using propensity score–adjusted Cox and linear regressions.
`Results: Weight was inversely associated with risk of switch to FTY-EOD because of any reason (odds
`ratio (OR) = 0.94, 95% confidence interval (95% CI) = 0.89–0.99, p = 0.026), and female sex and lower
`baseline lymphocyte count were positively associated with switch because of lymphopenia. Compared to
`FTY-ED patients, FTY-EOD patients were at higher risk of developing relapses (hazard ratio (HR) = 2.98,
`95% CI = 1.07–8.27, p = 0.036) and either relapses or new magnetic resonance imaging (MRI) demyelinat-
`ing lesions (combined outcome, HR = 2.07, 95% CI = 1.06–4.08, p = 0.034). Within FTY-EOD, treatment
`with natalizumab before FTY and lower age were positively associated with risk of developing relapses
`and combined outcome, respectively (HR = 25.71, 95% CI = 3.03–217.57, p = 0.002 and HR = 0.85, 95%
`CI = 0.77–0.96, p = 0.005). FTY-EOD was overall well tolerated.
`Conclusion: Disease reactivation was observed in a significant proportion of patients treated with FTY-
`EOD. Neurologists should be cautious when reducing FTY administration to every other day, especially
`in younger patients and those previously treated with natalizumab.
`
`Keywords: Demyelination, fingolimod, lymphopenia, multiple sclerosis, relapsing-remitting, treatment
`response
`
`Date received: 31 October 2016; revised: 9 January 2017; accepted: 15 January 2017
`
`Introduction
`Fingolimod (FTY) 0.5 mg is the first oral treatment
`approved for relapsing-remitting multiple sclerosis
`(RRMS). It is a sphingosine analogue that acts as a
`functional antagonist of sphingosine-1-phosphate
`receptors (S1P1) and prevents the S1P1-mediated
`egress of lymphocytes from secondary lymphoid tis-
`sues. This reduces their recirculation to the central
`nervous system and subsequent inflammatory dam-
`age.1 FTY does not interact with food and its oral
`bioavailability is >90%. The prolonged half-life
`(6–9 days) and slow absorption of FTY contribute to
`
`its stable concentration over time.2–4 Three different
`doses of FTY (0.5, 1.25 and 5 mg once daily) have
`been tested and showed superiority in reducing
`clinical and radiological activity of disease against
`placebo or intramuscular interferon beta-1a in phase
`III clinical trials.1,5,6 No dose–response effect was
`observed and the FTY 0.5 mg every-day dose
`(FTY-ED) was therefore approved because of the
`favourable safety profile. Despite this, side effects
`such as persistent severe lympho-leucopenia or ele-
`vated liver enzymes can lead to FTY-ED discontinua-
`tion in a significant proportion of patients.7,8 Given its
`
`Multiple Sclerosis Journal
`
` 1 –8
`
`DOI: 10.1177/
`https://doi.org/10.1177/1352458517694089
`1352458517694089
`https://doi.org/10.1177/1352458517694089
`
`© The Author(s), 2017.
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`Correspondence to:
`C Gobbi
`Neurocenter of Southern
`Switzerland, Ospedale
`Regionale di Lugano, Via
`Tesserete 46, 6903 Lugano,
`Switzerland.
`Claudio.Gobbi@eoc.ch
`
`Chiara Zecca
`Giulio Disanto
`Letizia Panicari
`Ursula Candrian
`Emanuele Pravatà
`Claudio Gobbi
`Neurocenter of Southern
`Switzerland, Ospedale
`Regionale di Lugano,
`Lugano, Switzerland
`
`Arianna Merlini
`Marzia Anita Lucia Romeo
`Lucia Moiola
`Giancarlo Comi
`Vittorio Martinelli
`Department of Neurology,
`San Raffaele Scientific
`Institute, Milan, Italy
`
`Mariaemma Rodegher
`Maria Josè Messina
`San Donato Hospital, Milan,
`Italy
`
`Catia Stefanin
`Angelo Ghezzi
`Multiple Sclerosis Study
`Center, Gallarate Hospital,
`Gallarate, Italy
`
`Patrizia Perrone
`Legnano Hospital, Legnano,
`Italy
`
`Francesco Patti
`Department of Neuroscience,
`University of Catania,
`Catania, Italy
`
`http://msj.sagepub.com
`
`1
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2069
`
`

`

`Multiple Sclerosis Journal
`
`long half-life and stable plasma concentration, reduc-
`ing the frequency of FTY administration has been
`proposed as an alternative to drug discontinuation.
`Previous studies suggested that reduced FTY doses
`may not control disease activity effectively,9,10 but
`these studies are hampered by their small sample size
`and heterogeneity of FTY reduction strategies. We
`therefore aimed at investigating the efficacy of FTY
`0.5 mg administered every other day (FTY-EOD) in a
`multicentre study of larger simple size.
`
`every 3 months thereafter. Relapses were defined as
`newly developing neurological symptoms or reactiva-
`tion of pre-existing neurological deficits for a mini-
`mum of 24 hours in the absence of an increase in body
`temperature or infections occurring at least 30 days
`after the preceding episode and accompanied by new,
`objective neurological findings. In the case of a
`suspected relapse, patients received neurological
`assessment
`including EDSS assessment within
`2 weeks of symptom onset as per clinical practice at
`all participating centres.
`
`Methods
`
`Study design
`This was a multicentre retrospective observational
`study performed in one Swiss (Lugano) and four
`Italian (Milan, Gallarate, Legnano, Catania) multiple
`sclerosis (MS) centres.
`
`Study aims
`The aims of the study were to: (1) characterize MS
`patients who switched from FTY-ED to FTY-EOD for
`safety reasons, during real-world clinical practice;
`(2) compare the efficacy and safety of FTY-EOD
`versus FTY-ED; and (3) define potential factors
`predicting good therapeutic response to FTY-EOD.
`
`Patient population
`All RRMS patients treated with FTY-EOD were
`identified during routine follow-up visits at partici-
`pating centres between June and November 2015.
`Their clinical, laboratory and magnetic resonance
`imaging (MRI) data were collected retrospectively
`from medical records and compared with those of
`a similar number of unselected FTY-ED patients
`(N = 63) who were consecutively seen at follow-up
`visits at the same centres and during the same period.
`All patients receiving FTY-EOD were originally
`treated with FTY-ED and switched to FTY-EOD
`after different time intervals according to local med-
`ical decision with a mean of 10.3 (9.2) months. No
`uniform criteria were applied for the FTY-EOD
`switch among centres. The reasons motivating the
`switch to FTY-EOD were based on local medical
`decisions and are summarized in the populations’
`baseline characterization.
`
`Laboratory assessment
`Pretreatment screening was performed in all patients
`and included complete blood cell count with white
`blood cell differential, liver enzymes, creatinine,
`screening for varicella zoster virus, human immunode-
`ficiency virus, B and C hepatitis, tuberculosis as well
`as a basal electrocardiogram. Complete blood cell
`count, white blood cell differential and liver function
`tests were repeated before switching to FTY-EOD, at
`month 1 and 3 of FTY-ED/EOD treatment, and every
`3 months thereafter (according to medical practice).
`
`Neuroimaging assessment
`Brain MRIs were performed within 6 weeks prior
`to FTY-ED start and at least annually thereafter.
`Additional brain MRIs were performed based on indi-
`vidual neurologists’ decision, clinical course and at
`the time of switch to FTY-EOD. Images were acquired
`using either a 3T MRI scanner (Lugano) or 1.5T scan-
`ners (Milan, Gallarate, Legnano, Catania), complying
`with the neuroimaging protocol guidelines suggested
`by Simon et al.11 and Filippi et al.12 All repeat follow-
`up examinations were performed on the same MRI
`scanner. Brain MRI examinations were reviewed at
`each corresponding Centre by a referring neuroradi-
`ologist, who was blind to patients’ clinical data and
`treatment, on a Digital Imaging and Communications
`(DICOM)-compliant PC workstation. Images were
`inspected for relevant artefacts before lesion counting.
`The number of T2-hyperintense lesions was counted
`at the baseline scan. Then, new and/or enlarging
`T2-hyperintense lesions (NT2) were counted by
`comparing each follow-up scan with the previous
`one. Gadolinium-enhancing lesions (Gd+) were also
`recorded for each scan.
`
`Clinical assessment
`Clinical follow-up of patients was homogeneous
`across centres. All patients received a complete neu-
`rological examination with Expanded Disability
`Status Scale (EDSS) assessment at FTY start and
`
`Statistics
`Categorical and continuous variables were described
`by counts and percentages or mean and standard devi-
`ation (SD), respectively. Univariable and multivaria-
`ble logistic regression models were used to identify
`
`2
`
`http://msj.sagepub.com
`
`

`

`C Zecca, A Merlini et al.
`
`Table 1. Characteristics of FTY-EOD and FTY-ED patients at FTY start.
`
`Age, mean (SD)
`Gender (F), n (%)
`Weight, mean (SD)
`Disease duration, mean (SD)
`EDSS, median (IQR)
`Relapses in last year, mean (SD)
`Number of T2 lesions
` 1–9, n (%)
` >9, n (%)
`Lymphocyte count, mean (SD)
`
`All (N = 123)
`
`42.3 (10.6)
`86 (69.9)
`64.0 (11.8)
`12.5 (7.9)
`2.5 (1.5–3.5)
`0.63 (0.80)
`
`26 (21.1)
`97 (78.9)
`1.84 (0.75)
`
`FTY-EOD (N = 60)
`
`FTY-ED (N = 63)
`
`41.0 (10.0)
`51 (85.0)
`59.5 (9.0)
`11.8 (7.9)
`2.0 (1.5–3.5)
`0.75 (0.89)
`
`17 (28.3)
`43 (71.7)
`1.61 (0.75)
`
`43.6 (11.2)
`35 (55.5)
`68.2 (12.6)
`13.1 (7.9)
`2.0 (1.5–3.5)
`0.51 (0.69)
`
`9 (14.3)
`54 (85.7)
`2.01 (0.71)
`
`FTY: fingolimod; ED: each day; EOD: each other day; F: female; SD: standard deviation; IQR: interquartile range; EDSS: Expanded
`Disability Status Scale.
`
`those variables associated with a higher risk of being
`switched to FTY-EOD (i.e. considering FTY-EOD vs
`FTY-ED status as the predicted dependent variable).
`A similar analysis was performed comparing those
`patients who were switched to FTY-EOD because of
`severe leucopenia and/or lymphopenia versus all
`remaining patients. Cox regression models were used
`to compare the time to the occurrence of first relapse,
`NT2, Gd+ lesions or combined outcome (either
`relapse, NT2 or Gd+ lesion) in FTY-EOD versus
`FTY-ED patients. We considered time of FTY start
`and time of FTY dose reduction as baseline in FTY-ED
`and FTY-EOD patients, respectively. Time to last fol-
`low-up and time to last MRI were calculated in
`months as the time between baseline ascertainment
`and the last one occurred before study inclusion
`(between June and November 2015). The assumption
`of proportional hazards was tested by including time-
`dependent covariates (interactions) in the model. The
`annualized relapse rate (ARR), NT2 and Gd+ lesion
`rates were calculated by dividing the number of these
`events by the length of follow-up expressed in years.
`These rates were compared between FTY-EOD and
`FTY-ED using linear regressions. To limit the poten-
`tial bias due to imbalances in baseline covariate distri-
`butions between FTY-EOD and FTY-ED groups, both
`Cox and linear regression analyses were carried out
`with and without adjustment by propensity scores
`(PS) (i.e. the conditional probability of belonging to a
`treatment group given certain covariates).13,14 The PS
`for this study were built based on age, sex, disease
`duration, EDSS scores, T2 lesion load (1–9 vs >9 T2
`lesions), number of Gd+ lesions, number of relapses
`in the year before starting FTY and last treatment
`before FTY (natalizumab vs other treatments). All
`following variables were tested for association with
`time to first relapse, NT2 lesion, Gd+ lesion and com-
`bined outcome within the group of FTY-EOD patients
`
`using univariable and multivariable Cox regression
`models: sex, age, weight, EDSS, occurrence of relapses
`in the year prior to FTY, baseline T2 lesion load, last
`treatment before FTY (natalizumab vs other treat-
`ments), duration of FTY-ED treatment, last lympho-
`cyte count before FTY-ED initiation, last lymphocyte
`count before FTY-ED discontinuation and mean lym-
`phocyte count during FTY-EOD treatment. All analy-
`ses were performed using R (https://www.r-project.
`org/) and the R packages ‘rms’ and ‘non-random’.
`
`Standard protocol approvals, registrations, and
`patient consents
`This research project was approved by the competent
`Ethics Committees. Patients’ consent to re-use of clin-
`ical data was obtained.
`
`Results
`
`Baseline characteristics
`The characteristics of FTY-EOD and FTY-ED patients
`at the time of starting FTY are presented in Table 1.
`This was a retrospective study and the reasons moti-
`vating the switch to FTY-EOD were based on local
`medical decisions. In all, 45 among 60 (75.0%)
`patients were switched to FTY-EOD because of lym-
`phopenia, 13 (21.7%) because of persistent increased
`liver enzymes and 2 (3.3%) because of recurrent
`infections. No uniform criteria were used to define
`lymphopenia requiring FTY dose reduction. However,
`all patients who were switched to FTY-EOD because
`of lymphopenia had a reduction in lymphocyte count
`as compared to baseline of at least 75%. The mean
`lymphocyte count at FTY-ED interruption before
`dose reduction was 270/µL. Only four patients were
`treatment naïve before starting FTY (2 ED and
`
`http://msj.sagepub.com
`
`3
`
`

`

`Multiple Sclerosis Journal
`
`Table 2. Univariable and multivariable logistic regression for FTY-EOD versus FTY-ED status.
`
`Variable
`
`Category
`
`Univariable
`
`Multivariable
`
`Gender
`Age
`Weight
`Disease duration
`Previous treatment
`Relapses in last year
`EDSS
`T2 lesions
`
`F versus M
`
`NTZ versus other
`
`>9 versus <9
`
`OR
`
`4.53
`0.98
`0.93
`0.99
`0.85
`1.48
`0.82
`0.42
`
`95% CI
`
`1.91–10.78
`0.94–1.01
`0.89–0.96
`0.99–1.00
`0.34–2.14
`0.93–2.37
`0.63–1.07
`0.17–1.03
`
`p Value
`
`0.0006
`0.182
`0.0001
`0.355
`0.731
`0.101
`0.138
`0.06
`
`OR
`
`2.30
`0.99
`0.94
`1.00
`0.70
`1.28
`0.83
`0.35
`
`95% CI
`
`0.70–7.52
`0.95–1.04
`0.89–0.99
`0.99–1.01
`0.24–2.00
`0.77–2.12
`0.60–1.15
`0.12–0.99
`
`p Value
`
`0.165
`0.846
`0.026
`0.781
`0.508
`0.344
`0.263
`0.049
`
`FTY: fingolimod; ED: each day; EOD: each other day; F: female; M: male; CI: confidence interval; OR: odds ratio; NTZ: natalizumab; EDSS: Expanded
`Disability Status Scale.
`ORs for age and weight are estimated per 1 year and 1 kg increase, respectively.
`
`2 EOD), and natalizumab was the last treatment
`before FTY in 10 (16.7%) FTY-EOD and 12 (19.0%)
`FTY-ED patients. The mean duration of FTY-ED
`treatment before switching to FTY–EOD was 10.3
`(9.2) months. Female sex and low weight were both
`associated with FTY-EOD status in univariable logis-
`tic regression (Table 2). In multivariable analyses,
`only low weight remained clearly associated with
`the risk of being switched to FTY-EOD (odds
`ratio (OR) = 0.94, 95% confidence interval (95%
`CI) = 0.89–0.99, p = 0.026), while a marginal signifi-
`cance was detected for T2 lesion load (OR = 35, 95%
`CI = 0.12–0.99, p = 0.049) (Table 2).
`
`We then restricted the analyses to those patients
`switching to FTY-EOD because of lymphopenia. In
`this group of patients, female sex was significantly
`associated with a higher risk of being switched to
`FTY-EOD in both univariable and multivariable anal-
`yses (OR = 20.44, 95% CI = 2.06–202.78, p = 0.009).
`Baseline lymphocyte count was also marginally and
`inversely associated with risk of being switched in the
`multivariable model (OR = 0.51, 95% CI = 0.24–1.03,
`p = 0.059).
`
`Efficacy of FTY-EOD versus FTY-ED
`Both FTY and FTY-EOD patients performed neuro-
`logical assessment and blood examinations (including
`complete blood cell count and liver enzymes) every
`3 months. Brain MRIs were performed within 6 weeks
`prior to FTY-ED start and at least annually thereafter.
`Additional brain MRIs were performed based on indi-
`vidual neurologists’ decision, clinical course and at
`the time of switch to FTY-EOD. The mean follow-up
`was 12.4 (7.6) and 22.9 (12.2) months in FTY-EOD
`and FTY-ED patients, respectively. Patients experi-
`encing relapses were 14 (23.3%) in FTY-EOD versus
`
`7 (11.1%) in FTY-ED. The mean time to first relapse
`was 6.8 (5.2) and 12.0 (10.6) months in FTY-EOD
`and FTY-ED, respectively (Table 3).
`
`FTY-EOD patients were at higher risk of develop-
`ing relapses and fared worse at the combined out-
`come in survival analyses (hazard ratio (HR) = 3.27,
`95% CI = 1.27–8.44, p = 0.014 and HR = 2.19, 95%
`CI = 1.17–4.09, p = 0.014, respectively). This asso-
`ciation remained significant after adjusting by PS
`(HR = 2.98, 95% CI = 1.07–8.27, p = 0.036 and
`HR = 2.07, 95% CI = 1.06–4.08, p = 0.034, respec-
`tively) (Figure 1, Supplementary material Table 1).
`As an additional sensitivity analysis, we included
`both PS and time spent under treatment with FTY-ED
`before switching to FTY-EOD in the model and FTY-
`EOD patients were still at increased risk of relapses
`and combined outcome (HR = 3.58, 95% CI = 1. 14–
`11.20, p = 0.028 and HR = 2.39, 95% CI = 1.054–5.42,
`p = 0.037, respectively). Findings were independent
`from lymphopenia motivating the switch to FTY-
`EOD (data not shown). Similarly, when using linear
`regression, the ARR and NT2 rate were significantly
`higher in FTY-EOD than FTY-ED patients (regres-
`sion coefficient = 0.45, p = 0.003 and regression coef-
`ficient = 1.36, p = 0.001, respectively). This difference
`remained significant after adjusting by PS (Figure 2).
`
`Variables associated with response to FTY-EOD
`In the univariable Cox regression analyses, weight
`(HR = 0.92, 95% CI = 0.87–0.98, p = 0.017) and treat-
`ment with natalizumab before FTY (HR = 3.02, 95%
`CI = 1.01–9.05, p = 0.048) were negatively and posi-
`tively associated with a shorter time to first relapse in
`FTY-EOD patients, respectively. However, only treat-
`ment with natalizumab before FTY remained signifi-
`cant in the multivariable analysis (HR = 25.71, 95%
`
`4
`
`http://msj.sagepub.com
`
`

`

`Table 3. Description of follow-up, occurrence of relapses, NT2 and Gd+ lesions.
`
`C Zecca, A Merlini et al.
`
`Patients with MRI during FU, n (%)
`Time to last MRI, mean (SD)
`Time to last FU, mean (SD)
`Patients with relapses, n (%)
`Time to first relapse, mean (SD)
`Total no. of relapses, mean (SD)
`ARR, mean (SD)
`Patients with NT2, n (%)
`Time to first NT2, mean (SD)
`Total no. of NT2, mean (SD)
`NT2 rate, mean (SD)
`Patients with Gd, n (%)
`Time to first Gd, mean (SD)
`Total no. of Gd, mean (SD)
`Gd rate, mean (SD)
`
`FTY-EOD
`
`45 (75.0)
`11.9 (7.0)
`12.4 (7.6)
`14 (23.3)
`6.8 (5.2)
`0.35 (0.7)
`0.49 (1.19)
`17 (37.8)
`8.1 (4.5)
`1.0 (1.6)
`1.64 (2.86)
`10 (22.2)
`10.8 (6.0)
`0.4 (1.1)
`0.51 (1.23)
`
`FTY-ED
`
`52 (82.5)
`21.6 (11.0)
`22.9 (12.2)
`7 (11.1)
`12.0 (10.6)
`0.09 (0.3)
`0.04 (0.14)
`16 (30.8)
`15.0 (8.9)
`0.4 (0.8)
`0.28 (0.69)
`7 (13.5)
`11.6 (8.2)
`0.2 (0.7)
`0.20 (0.78)
`
`NT2: T2-hyperintense lesions; Gd+: gadolinium-enhancing lesions; FTY: fingolimod; ED: every day; EOD: every other day;
`MRI: magnetic resonance imaging; FU: follow-up; SD: standard deviation; ARR: annualized relapse rate.
`
`Figure 1. Survival curves with numbers at risk for time to first relapse, first NT2 lesion, first GD+ lesion and combined
`outcome in FTY-EOD (red) versus FTY-ED (green) patients.
`
`CI = 3.03–217.57, p = 0.002). Sex, age, baseline
`EDSS, relapses in the year prior to FTY start, T2
`lesion load, duration of FTY-ED treatment before
`FTY-EOD, lymphocyte count at FTY-ED start,
`FTY-ED stop as well as mean lymphocyte count dur-
`ing FTY-EOD treatment were not associated with the
`risk of relapses (Supplementary material Table 2).
`
`When considering the combined outcome, only
`younger age was associated with a shorter time to
`first event in both univariable and multivariable anal-
`yses (HR = 0.93, 95% CI = 0.89–0.97, p = 0.001 and
`HR = 0.85, 95% CI = 0.77–0.96, p = 0.005, respec-
`tively), while the association of natalizumab treat-
`ment before FTY became attenuated (HR = 3.84, 95%
`
`http://msj.sagepub.com
`
`5
`
`

`

`Multiple Sclerosis Journal
`
`Figure 2. Mean and 95% CI of ARR, NT2 rate and Gd+ rate in FTY-EOD versus FTY-ED patients with corresponding
`results from linear regression analyses.
`
`CI = 0.78–18.94, p = 0.098) (Supplementary material
`Table 3). Similarly, age was the only significantly dif-
`ferent variable between patients with (n = 22) versus
`without (n = 16) relapses or demyelinating lesions on
`MRI within 12 months of FTY-EOD treatment (36.9
`(7.3) vs 44.8 (10.8) years, respectively, OR = 1.13,
`95% CI = 1.02–1.24, p = 0.013). No other associations
`were detected.
`
`Safety
`FTY-EOD was overall well tolerated and was asso-
`ciated with an increase in lymphocyte count above
`300/µL in the majority of patients switched because
`of lymphopenia (n = 42, 93.3%; 66.7% within 1 month
`and 24.4% within 3 months). A total of 20 patients
`interrupted FTY-EOD during the follow-up because
`of insufficient efficacy (n = 10), persistent leuco–lym-
`phopenia (n = 4), infections (n = 1), restoration of
`white blood cell counts (n = 2) or other reasons (n = 3).
`Other laboratory parameters were unremarkable.
`No serious adverse events occurred during the obser-
`vational period.
`
`Discussion
`In this observational study, the main reason to
`switch patients from FTY-ED to FTY-EOD was the
`occurrence of lymphopenia (75% of patients).
`
`A lymphocyte count decrease below 200/µL is indeed
`a common event during FTY-ED treatment, occur-
`ring in 15%–20% of the patients15,16 and representing
`a formal criterion for treatment discontinuation in the
`pivotal trials. This is also indicated in the EU label.
`
`We observed that both lower weight and female sex
`were associated with the risk of being switched to
`FTY-EOD because of any reason or lymphopenia in
`univariable analyses. Interestingly, in the multivari-
`able models, only weight remained significantly
`associated with risk of switching because of any rea-
`son, while only female sex remained significantly
`associated with risk of switching because of lym-
`phopenia. While it is still possible that female gen-
`der may particularly predispose to lymphopenia, and
`weight to all potential reasons to be switched to
`FTY-EOD, we believe that both gender and weight
`likely influence both outcomes. A trend for an asso-
`ciation between lower lymphocyte count at baseline
`and risk of being switched because of lymphopenia
`was also observed. These results are largely in line
`with those reported in two large German and Swedish
`MS cohorts, in which exactly the same variables
`(female gender, lower weight and lower lymphocyte
`count at baseline) were associated with a higher
`risk of developing lymphopenia during FTY-ED
`treatment.16 We believe these results carry important
`implications in the selection of candidates to FTY
`treatment.
`
`6
`
`http://msj.sagepub.com
`
`

`

`C Zecca, A Merlini et al.
`
`Notably, the risk of experiencing a relapse and either
`a relapse or a new demyelinating lesion on MRI was
`approximately three times and two times higher in
`FTY-EOD patients as compared to FTY-ED patients.
`This association remained significant even after cor-
`recting for PS. FTY-EOD was overall safe and well
`tolerated. These results appear in line with the single,
`small case series published on this topic by Yamout
`et al.10 showing radiological reactivation of disease
`after a mean follow-up of 16.1 months in five out
`of eight patients treated with FTY every second or
`third day.10 In our cohort, the efficacy of FTY-EOD
`appeared especially low among those patients at
`higher risk of inflammatory disease activity, that is,
`younger individuals and those who discontinued
`treatment with natalizumab before FTY. It is indeed
`known that the occurrence of relapses decreases with
`age and is likely higher after natalizumab discontinu-
`ation because of a post-natalizumab rebound effect
`and a higher baseline disease activity, that is, the fac-
`tor leading to natalizumab treatment.17 Instead, we
`did not find any association of gender, baseline EDSS,
`relapses in the year prior to FTY start, duration of
`FTY-ED treatment before FTY-EOD, T2 lesion load,
`lymphocyte count at FTY-ED start, FTY-ED stop as
`well as mean lymphocyte count during FTY-EOD
`treatment with the risk of experiencing disease activ-
`ity under FTY-EOD.
`
`During the follow-up, we noticed a rapid increase in
`lymphocyte count above 300/µL in the majority
`(93%) of patients switched to FTY-EOD because of
`lymphopenia, in line with the report by Tanaka et al.9
`However, the efficacy of FTY-EOD was not associ-
`ated with lymphocyte count at baseline, at the time of
`switch to FTY-EOD or during FTY-EOD treatment.
`The clinical significance of the degree of lymphope-
`nia occurring during FTY treatment remains therefore
`elusive. The absolute lymphocyte count did not cor-
`relate with the rate of infections in the phase III FTY
`studies15 and, to our knowledge, no data concerning
`the efficacy of FTY and lymphocyte count have been
`published so far. Other reasons motivating treatment
`switch to FTY-EOD were liver enzyme elevation
`(21.7%) and recurrent infections (3.3%). We observed
`that also in these groups the reduced dose contributed
`to the attenuation of the side effects. However, the
`small number of patients did not allow us to perform
`further analyses of efficacy in these subgroups.
`
`This study presents the following limitations. First,
`the sample size was relatively small as compared to
`that of most clinical trials sponsored by pharmaceu-
`tical companies and testing therapeutic agents in
`MS. This precluded the possibility to analyse with
`
`sufficient statistical power the efficacy of the two dis-
`tinct doses of FTY in different subgroups of patients.
`Therefore, we cannot exclude that certain groups of
`patients could equally respond to FTY-ED and FTY-
`EOD and this should be investigated in the future.
`A second limitation is represented by the retrospective
`design of the study and the absence of a randomiza-
`tion procedure. On the other hand, our study was per-
`formed in tertiary academic MS centres and our
`population is the largest ever published on this topic,
`with baseline characteristic (e.g. age, disease duration
`and EDSS) that are very close to those of patients
`included in the FREEDOMSII trial.5 We have also
`attempted to correct for baseline differences between
`groups by calculating PS and all main findings
`remained significant even after correcting for these.
`The MS population investigated in this study consists
`of patients who are routinely seen in our clinics and
`they, therefore, represent daily practice more appro-
`priately than common clinical trials settings. Third,
`we cannot exclude that some drop-outs may be related
`to the different efficacy of the two doses and to the
`risk of informative censoring, but our careful and sys-
`tematic follow-up makes this less likely. Since base-
`line for FTY-EOD patients was by definition preceded
`by treatment with FTY-ED, the risk of immortal time
`bias also needs to be considered. We therefore per-
`formed sensitivity analyses by including time spent
`under FTY-ED before switching to FTY-EOD in the
`survival models and this did not affect the results.
`In addition, time under FTY-ED was not associated
`with risk of relapses and combined outcome within
`FTY-EOD patients. Although we acknowledge that
`only a randomized design would eliminate this poten-
`tial bias, these analyses suggest that the increased dis-
`ease activity seen in FTY-EOD patients is not driven
`by the length of previous treatment with FTY-ED and
`make the risk of immortal time bias less likely. Finally,
`there was a difference in the MRI field strength
`between patients examined in Lugano (3T) compared
`to the remaining centres (1.5T). These differences
`could have potentially led to an increased number of
`lesions detected in the former group.18 However, a
`similar proportion of patients examined in Lugano
`were included in the FTY-ED and FTY-EOD groups,
`thus mitigating this potential confounding factor.
`
`In conclusion, this study shows disease reactivation in
`a significant proportion of patients treated with FTY-
`EOD, particularly in younger individuals and those
`with a recent natalizumab treatment. While we cannot
`exclude that some patients may still benefit from
`FTY-EOD treatment, we suggest neurologists should
`be cautious when reducing FTY administration to
`every other day and should evaluate with each patient
`
`http://msj.sagepub.com
`
`7
`
`

`

`Multiple Sclerosis Journal
`
`the benefit/risk profile of starting a low FTY dosage as
`compared to switching to another disease-modifying
`treatment.
`
` 4. Scott LJ. Fingolimod: A review of its use in the
`management of relapsing-remitting multiple sclerosis.
`CNS Drugs 2011; 25: 673–698.
`
`Acknowledgements
`The authors thank Liliane Petrini (PhD), Neurocenter
`of Southern Switzerland, for help with manuscript
`submission. C.Z., A.M., C.G. and V.M. contributed
`equally to the manuscript.
`
`Declaration of Conflicting Interests
`The author(s) declared the following potential
`conflicts of interest with respect to the research,
`authorship and/or publication of this article: the
`employer of C.Z., G.D., L.P., U.C., E.P. and C.G.
`receives financial support from Teva, Merck Serono,
`Roche, Biogen Idec, Genzyme and Novartis. The
`submitted work is not related to these agreements.
`A.M., M.R., M.A.L.R., M.J.M. and C.S. have nothing
`to disclose. L.M. has received honoraria from
`Sanofi-Genzyme, Biogen, TEVA, Merck Serono and
`Novartis. A.G. serves on scientific advisory boards or
`as a consultant for Merck Serono, Novartis, Genzyme,
`Biogen Idec and Teva; received honoraria for
`speaking from Merck Serono, Serono Symposia
`International Foundation, Biogen Idec, Almirall,
`Genzyme, Teva and Novartis. P.P. received honoraria
`from Novartis, TEVA, Biogen, Serono and Genzyme.
`F.P. received honoraria for scientific lectures and
`travel payment from Biogen, Novartis, Teva,
`Genzyme, Bayer Schering, Merck Serono and
`Almirall. G.C. received compensation for consulting
`services from Novartis, Teva, Sanofi, Genzyme,
`Merck, Biogen, Excemed, Roche, Almirall, Chugai,
`Receptos and Forward Pharma and compensation for
`speaking activities from Novartis, Teva, Sanofi,
`Genzyme, Merck, Biogen, Excemed and Roche. V.M.
`received honoraria from Genzyme, Biogen Idec,
`TEVA, Bayer, Merck Serono and Novartis.
`
`Funding
`The author(s) received no financial support for the
`research, authorship and/or publication of this article.
`
`References
` 1. Kappos L, Radue EW, O’Connor P, et al. A placebo-
`controlled trial of oral fingolimod in relapsing
`multiple sclerosis. N Engl J Med 2010; 362: 387–401.
`
` 2. Budde K, Schmouder RL, Brunkhorst R, et al. First
`human trial of FTY720, a novel immunomodulator,
`in stable renal transplant patients. J Am Soc Nephrol
`2002; 13: 1073–1083.
`
` 5. Calabresi PA, Radue EW, Goodin D, et al. Safety
`and efficacy of fingolimod in patients with relapsing-
`remitting multiple sclerosis (FREEDOMS II): A
`double-blind, randomised, placebo-controlled, phase
`3 trial. Lancet Neurol 2014; 13: 545–556.
`
` 6. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod
`or intramuscular interferon for relapsing multiple
`sclerosis. N Engl J Med 2010; 362: 402–415.
`
` 7. Kappos L, Cohen J, Collins W, et al. Fingolimod in
`relapsing multiple sclerosis: An integrated analysis
`of safety findings. Mult Scler Relat Disord 2014; 3:
`494–504.
`
` 8. Kappos L, O’Connor P, Radue EW, et al. Long-
`term effects of fingolimod in multiple sclerosis: The
`randomized FREEDOMS extension trial. Neurology
`2015; 84: 1582–1591.
`
` 9. Tanaka M, Park K and Tanaka K. Reduced
`fingolimod dosage treatment for patients with
`multiple sclerosis and lymphopenia or neutropenia.
`Mult Scler 2013; 19: 1244–1245.
`
` 10. Yamout BI, Zeineddine MM, Sawaya RA, et al.
`Safety and efficacy of reduced fingolimod dosage
`treatment. J Neuroimmunol 2015; 285: 13–15.
`
` 11. Simon JH, Li D, Traboulsee A, et al. Standardized
`MR imaging protocol for multiple sclerosis:
`Consortium of MS Centers consensus guidelines.
`AJNR Am J Neuroradiol 2006; 27: 455–461.
`
` 12. Filippi M, Rocca MA, Bastianello S, et al. Guidelines
`from The Italian Neurolog