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Disease activity in progressive multiple sclerosis can be effectively reduced by cladribine
Multiple Sclerosis and Related Disorders 24 (2018) 20–27
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Disease activity in progressive multiple sclerosis can be effectively reduced by cladribine
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O. Yildiza,b, Z. Maoa,c,d, A. Adamse, N. Dubuissona, K. Allen-Philbeyb, G. Giovannonia,b, ⁎ A. Malaspinaa,b, D. Bakera, S. Gnanapavana,b, K. Schmierera,b, a
The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom Clinical Board: Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom c Department of Neurology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China d Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, China e Department of Neuroradiology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom b
A R T I C LE I N FO
A B S T R A C T
Keywords: Progressive multiple sclerosis Neurofilaments Cerebro-spinal fluid Cladribine Disease activity
Background: Evidence suggests people with non-relapsing deteriorating (“progressive”) multiple sclerosis (pwPMS) may benefit from disease-modifying immune therapy (DMT). However, only one such treatment (ocrelizumab) has been licensed and is highly restricted to pwPMS suffering from the primary progressive phenotype. The difficulties assessing treatment outcome in pwPMS is one important reason for the lack of respective DMT. The concentration of neurofilaments in the cerebrospinal fluid (CSF) provides a biomarker of neuro-axonal damage, and both neurofilament light (NfL) and heavy chain (NfH) levels have been used as outcome indices and to guide treatment choices. Methods: We report on two pwPMS, who were treated with subcutaneous cladribine undergoing CSF NfL testing, alongside MRI and clinical follow-up, before and after treatment. Results: Cladribine treatment was well tolerated without any side effects. CSF NfL after treatment revealed significant reduction (by 73% and 80%, respectively) corroborating the MRI detectable drop in disease activity. Disability mildly progressed in one, and remained stable in the other pwPMS. Conclusions: pwPMS with detectable disease activity (MRI, elevated NfL) should be considered for DMT. NfL appears to be a sensitive index of treatment effect in pwPMS, and may be a useful outcome in clinical trials targeting this patient group. Over and above its licensed indication (relapsing MS), cladribine may be an effective treatment option for pwPMS.
1. Introduction Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disease of the central nervous system (Compston and Coles 2008), and the most common cause of non-traumatic disability among young adults in the Northern Hemisphere (Mackenzie et al., 2014). Most people with multiple sclerosis (pwMS) will experience a progressive course of their condition at some point. This may be from onset (primary progressive MS) or more commonly following a period dominated by relapses and remissions, which after an average disease duration of 10 years, transitions into “secondary progressive” MS in natural history studies (Leray et al., 2010). Whilst eleven different classes of disease-modifying treatments (DMTs) have been licensed for people with early/relapsing MS in Europe and the USA, there is currently only one such treatment, ocrelizumab, which is partially effective
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in people with progressive MS (Montalban et al., 2017). There is, thus, an evident need for more effective DMTs for people with progressive MS (pwPMS). Development of DMTs for this patient population, however, has been slow due to a number of factors including (i) the regulatory environment and its adherence in clinical trials to the expanded disability status scale (EDSS) (Kurtzke 1983) as key primary outcome, in spite of the EDSS’ well known shortcomings in terms of precision, and its ambulation bias driving an “eligibility cutoff” based on the ability to walk (Dubuisson et al., 2017a), (ii) the concept of MS, as a “two stage disease” with an early inflammatory followed by a largely non-inflammatory progressive phase (Leray et al., 2010), and (iii) a disregard for the differences in size and connectivity of the cortical representation for upper and lower limb function, and abundance of corticospinal tracts supplying upper compared to lower limbs (Patestas and Gartner 2016) resulting in a physiological
Corresponding author at: Queen Mary University of London, Blizard Institute (Neuroscience), London, UK. E-mail address: [email protected] (K. Schmierer).
https://doi.org/10.1016/j.msard.2018.05.010 Received 30 January 2018; Received in revised form 18 April 2018; Accepted 11 May 2018 2211-0348/ © 2018 Published by Elsevier B.V.
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Glossary CNS CSF DMT DNA EDSS Gd JC virus MRI
MS NF NF-L OCB PP pwMS pwRMS pwPMS s.c. SP
central nervous system cerebrospinal fluid disease modifying treatment Deoxyribonucleic acid expanded disability scale score gadolinium John Cunningham virus magnet resonance imaging
multiple sclerosis neurofilaments neurofilament light chain oligoclonal bands primary progressive people with multiple sclerosis people with relapsing multiple sclerosis people with progressive multiple sclerosis subcutaneous secondary progressive
Fig. 1. Axial T2 and post contrast T1 weighted MRI 18 months before treatment (A), at baseline (B), 12 months after the first (C), and five months after the second cladribine treatment cycle (D). Arrows indicate areas of gadolinium enhancement. 21
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with 2–3 relapses/year. Despite this high frequency of relapses, he did not start another DMT for the following nine years until he was first seen in our service at The Royal London Hospital (Barts Health NHS Trust), London, UK. His EDSS at that point was 4.0, based on pyramidal weakness of left-sided limbs, gait ataxia and reduced walking range (>500 m). MRI of the head revealed significant burden of demyelinating lesions in the periventricular and subcortical white matter, brainstem and cerebellum including three gadolinium-enhancing (Gd+) lesions in the left centrum semiovale, the right peritrigonal region and corona radiata (Fig. 1A). Following discussion of risks and potential benefits, the patient decided to start take dimethyl-fumarate (Tecfidera®) 240 mg BD. Within three weeks, however, he stopped taking the medication due to side effects including fatigue, flushing, and abdominal discomfort. He refused treatment with teriflunomide (Aubagio®). Natalizumab (Tysabri®) was also considered, however due to the positive titre for John Cunningham virus (JCV) this was abandoned as an option. Whilst considering his treatment options, and after reviewing his recent disease course, it became evident that rather than relapses as his principal mode of disability accrual, he had developed chronic deterioration for at least the past six months indicating that he had entered the secondary progressive phase. Over the time course of 18 months since we had first seen him, his EDSS had increased from 4.0 to 6.0.
disadvantage of the lower limbs in pwMS (Giovannoni et al., 2017a). Based on trial results in pwPMS reported during the 1990s (Sipe et al., 1994; Beutler et al., 1996; Rice et al., 2000), and more recent evidence from large studies in relapsing MS (Giovannoni et al., 2017b, 2010), as well as a safety analyses (Pakpoor et al., 2015), we offered cladribine as a compassionate off-label treatment to patients in our care since late 2014 (Alvarez-Gonzalez et al., 2017, 2016). The development of indices providing robust prediction of longterm outcome following an intervention in pwPMS is ongoing. The level of neurofilaments in the cerebrospinal fluid (CSF) and the peripheral blood has shown promise to become such a marker (Dubuisson et al., 2017b). Here, we report the cases of two pwPMS in whom we were able to collect CSF before and after commencing cladribine administration, to detect the level of neurofilament light chain (NfL) as a potential readout of treatment effect. 1.1. Case 1 This case is of a man of Asian extraction who was diagnosed with relapsing MS at the age of 21 following unilateral optic neuritis as first manifestation of inflammatory demyelination. After diagnosis, he commenced treatment with interferon beta-1a (Rebif®). However, after two years he decided to stop taking it due to ongoing disease activity
Fig. 2. Axial T2 weighted MRI one year after onset (∼one year prior to starting cladribine treatment), at baseline (B), and seven months later (∼six months after the first treatment cycle) (C), with corresponding T1 post contrast images at two time points. Arrows indicate a single gadolinium enhancing lesion six months after treatment, down from 38 such lesions at baseline. 22
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initiated one month after MRI and NfL results had been collected. Written informed consent to receive the treatment on a compassionate basis was obtained prior to starting the intervention. Safety evaluation prior to treatment included ruling out active hepatitis B and C, tuberculosis (TB Elispot), syphilis and Human Immunodeficiency virus. Immunoreactivity against Varicella zoster (VZV) was confirmed. At total dose of 60 mg cladribine s.c. was given. All procedures were undertaken through the neuroscience day case & outpatients service. Treatment was as follows: week 1 administration of cladribine 10 mg on three consecutive days; week 4 confirmation of normal blood counts (including total lymphocyte count); week 5 administration of cladribine 10 mg on three consecutive days (Mao et al., 2017). The treatment was very well tolerated with no adverse effects observed. Depletion of the total lymphocyte count, CD3+, CD4+, CD8+ and CD19+ cells was observed whilst CD56+ cells remained virtually unchanged (Fig. 3A). One year after the treatment, the patient's EDSS had increased from 6.0 to 6.5 owing to more pronounced gait ataxia requiring bilateral
Follow-up MRI brain acquired revealed that of his numerous T2 hyperintense lesions in the brainstem, cerebellar hemispheres and supratentorial white matter 10 enhanced on T1 weighted scans after injection of gadolinium-DTPA (Gd+). There was also loss of brain volume disproportionate for his age, and numerous T1 hypo-intensities (“black holes” ) predominantly in the periventricular white matter were evident (Fig. 1B). Unrelated to any recent clinical relapse, his CSF, obtained using an atraumatic procedure (Davis et al., 2014), revealed elevated protein (700 mg/l; norm <400 mg/l). White blood cell (WBC) count was <1/ µl (norm: 0–5 cells/µl), and glucose normal (3.1 mmol/l; norm >60% of serum glucose: 3.4 mmol/l). CSF oligoclonal bands (OCBs) were positive, serum negative (type 2) (Hegen et al., 2015). Using a commercial ELISA (UmanDiagnostics NF-Light ELISA assay) a NfL level of 1700 pg/ml was detected (age matched reference: <380 pg/ml). Given the significant disease activity supported by his MRI and NfL findings, and in the absence of clinical relapses, treatment with subcutaneous (s.c.) cladribine (Litak®) was discussed and subsequently
Fig. 3. Cladribine-induced reduction of NfL in the absence of significant peripheral lymphopenia. 23
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l. CSF remained acellular with normal glucose. A second cycle of cladribine s.c. was given one year after her first set of injections. Given her total lymphocyte count was still depleted to 0.9 × 109/l 11 months after her first treatment cycle, a total of only 30 mg cladribine s.c. divided over three consecutive days was administered.
support to walk 20 m. MRI brain revealed two new lesions on T2 weighted scans, one juxtacortical lesion in the left middle frontal gyrus, and a small Gd+ lesion adjacent to the right lateral ventricle. CSF obtained at this point showed mildly raised CSF protein (500 mg/l), WBC count was 5 cells/µl, and glucose 3,3 mmol/l). NfL was reduced to 453 pg/ml (Fig. 3A).CSF OCBs remained type 2. A second cycle of cladribine (total does = 60 mg) according to the same schedule as the first. No adverse effects were observed. On examination five months after this second cycle, the patient described some improvement in his mobility, however this did not reflect in his EDSS, which remained at 6.5. MRI brain showed stable appearance compared to scans acquired six months earlier, prior to second course of treatment (Fig. 1D).
2. Discussion To halt disease deterioration in pwPMS remains a significant challenge, particularly against the backdrop of only one recently licensed DMT, ocrelizumab, for primary progressive MS (Montalban et al., 2017). Thanks to its license, ocrelizumab is not accessible to the largest group of pwPMS, i.e. those developing steady deterioration following a period of relapses and remissions - secondary progressive MS. Although the recent revisions of MS disease courses by Lublin and co-workers, go some way to dissolve the somewhat arbitrary distinction between patients with primary versus secondary progressive disease (Lublin et al., 2014), this is unlikely to significantly impact on the license and use of ocrelizumab in clinical practice. However, the new criteria by Lublin, et al. provide a framework to explore alternative treatments in pwPMS for whom no licensed DMT are currently available. Since it is well established that inflammatory lesions are associated with acute axonal loss (Ferguson et al., 1997; Trapp et al., 1998), an important substrate of disability evolution (Bjartmar et al., 2000), MRI-detectable inflammatory disease activity (new T2 lesions compared to earlier reference scans, Gd+ lesions) in pwPMS strongly suggests that at least part of the pathophysiology driving disability accrual in these patients is caused by ongoing inflammatory demyelination. The importance of inflammatory demyelination throughout the disease course has most recently been underpinned by a study from the Netherlands Brain Bank based on 182 post mortem cases of MS. Of the 7562 histologically analysed lesions 57% showed chronic activity after a mean disease duration of 29 years. Cases of primary and secondary MS showed comparable lesion activity, and shorter time to EDSS 6 correlated with higher lesion load and a higher proportion of chronic active lesions (Luchetti et al., 2018). Against this backdrop there is evident potential for DMT, through depletion of lymphocyte populations that drive MS activity (Baker et al., 2017a), to modify the disease such that slowing, stopping or even partial reversal of MS-derived disability in pwPMS is conceivable (AlvarezGonzalez et al., 2017). Though preliminary evidence suggests potential for cladribine to be an effective DMT for pwPMS (Beutler and Koziol 2000) a definitive clinical trial in this patient cohort has yet to be undertaken. For several reasons, cladribine is an ideal candidate drug to treat pwPMS: (i) oral cladribine (Mavenclad®) has been shown to be highly effective in people with a clinical isolated syndrome of demyelination (Leist et al., 2014) and relapsing MS (Giovannoni et al., 2011), (ii) evidence from phase II studies suggests cladribine is effective in pwPMS too (Sipe et al., 1994; Beutler et al., 1996; Rice et al., 2000), (iii) cladribine enters the CNS (Leist and Weissert 2011), where it may reduce meningeal inflammation and lymphoid-like B and T cell clusters, which have been described to be biologically meaningful in pwPMS (Magliozzi et al., 2007; Howell et al., 2011), (iv) cladribine is a short-term intervention with longlasting effects on both B and T cell populations (Baker et al. 2017b), most prominently on memory B cells (Ceronie et al., 2018), a likely key mechanism underlying the control of the inflammatory response in MS (Baker et al. 2017a), (v) cladribine is well-tolerated (Giovannoni et al., 2010; Afolabi et al., 2017) and comes with few monitoring requirements, (vi) Cladribine has been licensed for more than 25 years to treat patients with hairy cell and chronic lymphoid leukaemia. Hence, over and above the oral preparation, recently licensed by the European Medicines Agency (EMA) for highly-active relapsing MS, several generic yet bioequivalent injectable preparations are available. We used an s.c. preparation for ease of administration in a day case setting. This would also have potential value in pwPMS with difficulties swallowing.
1.2. Case 2 This case is of a Caucasian woman who developed gradually deteriorating pyramidal left leg weakness from the age of 43 years. Review of her history two years after onset, when she was first seen in our service, did not reveal any hint pointing towards a past relapse and remission of neurological dysfunction. A diagnosis of primary progressive MS was made following exclusion of potential mimics and supported by MRI brain (acquired outside our organisation), which revealed significant burden of partially confluent demyelinating lesions, mainly in the left cerebral hemisphere. Central parenchymal volume loss was also seen (Fig. 2A). Multiple foci of high signal were also noted in the thoracic spinal cord, whereas no lesions were seen in the cervical proportion. No gadolinium was given on this occasion. Of note, CSF at this time point was normal with no OCBs detected. Neurological examination two years after onset, when we first saw the patient, revealed nothing of note with respect to head and cranial nerve function. Upper limb examination revealed bilateral dysdiadochokinesia and symmetric intention tremor with past pointing, but no weakness. Pyramidal weakness was detected of the left leg, prompting her to use a unilateral crutch for ambulation. Reflexes were brisk and pronounced on the left throughout. Plantar sign was extensor bilaterally. Walking range without support was just under 100 m. A sensory level was detected at T6. She reported urinary urgency without incontinence. Her EDSS was summarised as 5.5. Follow-up MRI brain showed significantly more lesions in the periventricular and subcortical white matter compared to her above described diagnostic MRI study obtained 10 months earlier. A total of 38 Gd+ lesions was detected on T1 weighted scans (Fig. 2B). Numerous spinal cord lesions were seen in the cervical and thoracic cord, several of which were Gd+on T1. CSF at this time point was abnormal. Whilst her WBC count was <1 cells/µl, total protein was elevated to 770 mg/l with normal glucose (3,4 mmol/l; serum: 5.3 mmol/l). OCBs were type 3, i.e. bands detected in the serum with additional bands in the CSF. CSF NfL was “off the scale” elevated to >10,000 pg/ml using the same system and kit as in case 1 above. The patient's progressive clinical course associated with significant inflammatory disease activity underpinned by MRI and CSF findings, prompted us to offer her off-label treatment with cladribine s.c. After providing written informed consent and undergoing the same safety assessments as described above, drug was administered using the schedule outlined for case 1. The treatment was very well-tolerated with no adverse effects observed. Blood counts obtained over several time points after treatment showed the expected decrease in total lymphocyte count, with all subtypes CD3+, CD4+, CD8+ and CD19+ (Fig. 3B). After one year of follow-up, EDSS has remained stable at 5.5. MRI brain obtained seven months after her previous scans (six months after treatment initiation) revealed no change in T2 lesion load. A single punctate focus of Gd enhancement was seen in the right periventricular white matter (Fig. 2C). CSF obtained six months after baseline revealed a reduction of NfL to 2025 pg/ml. OCBs remained positive (type 2), and protein level elevated, though mildly less so than prior to treatment at 526 mg/ 24
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completely suppressed after the second cladribine treatment cycle. The second case with a history of two years of progressive MS from onset had an excessive NfL > 10.000 pg/ml that dropped to 2025 pg/ml within six months of the first treatment cycle, and 38 Gd+ lesions were reduced to a single spec of enhancement within the same time frame. We were thus able to correlate the effective depletion of NfL levels with a significant reduction - to virtually zero - of new lesion activity on MRI (Burman et al., 2014). Our observations indicate a significant effect of cladribine in the two pwPMS reported here. The significant reduction of NfL alongside MRI activity strongly suggest that cladribine treatment resulted in both, a virtual halt of detectable inflammatory activity and a reduction in associated neuronal damage. That these changes did not result in a reduction of disability as measured by the EDSS is in line with the concept of “therapeutic lag” between (i) shutting down inflammatory activity and its associated acute axonal damage, and (ii) tangible clinical change (Tur et al., 2011; Giovannoni et al., 2017a). Moreover, the EDSS is dominated by lower limb function, and may thus fail to capture upper limb function with more reserve capacity (Fox and Markowitz 2017; Patestas and Gartner 2016). Additional tools, such as the 9-holepeg test, may be more sensitive to detect short term change. In conclusion, the two cases presented here support the case to study cladribine as a DMT in pwPMS leading to (i) selective long-term immune reconstitution, (ii) associated long-term depletion of inflammatory activity and consequential reduction in acute axonal damage, and (iii) avoidance of drug-drug interactions with symptomatic treatments, which become increasingly common as people age and MS advances. All this comes with a decent safety record, high convenience, and at potentially rather low cost. Where the clinical course does not facilitate treatment decisions, CSF–NfL may serve as a biomarker, over and above MRI, of disease activity.
Alternative treatment options we considered included rituximab (Hawker et al., 2009), ocrelizumab (Montalban et al., 2017), natalizumab (Kapoor et al., 2018), mitoxantrone (Hartung et al., 2002) and cyclophosphamide (Hauser et al., 1983). However, due to adverse risk, particularly regarding mitoxantrone (Buttmann et al., 2016) and cyclophosphamide (Neuhaus et al., 2007) and cost (all mentioned monoclonals), none of these options were considered superior, or economically viable, compared to cladribine. Following a comprehensive meta-analysis rebutting the previously suspected cancer risk from cladribine in people with MS (Pakpoor et al., 2015), we addressed a further concern - the risk associated with severe lymphopenia – raised by the European Medicines Agency in their first assessment of oral cladribine (Movectro®) for MS in 2010/11 (http:// www.ema.europa.eu/docs/en_GB/document_library/Application_ withdrawal_assessment_report/2011/03/WC500104393.pdf). First, we calculated the parenteral drug dose required, based on 100% bioavailability of parenteral cladribine compared to 42% or the oral prodrug (Lillemark and Juliusson 1992). Our calculations indicated 60 mg cladribine/year in an individual weighing <90 kg resembles bioequivalence with the oral 3.5 mg/kg dose used in the pivotal CLARITY MS study (Giovannoni et al., 2010). Second, by adjusting the drug dose to individual total lymphocyte count we successfully avoided lymphopenia beyond toxicity level 1 (0.8 × 109/l) (Mao et al., 2017) in these two cases. Cladribine was very-well tolerated, especially when compared to other potentially high efficacy agents (Hawker et al., 2009; Cohen et al., 2012; Fernandez et al., 2016), including the absence of secondary autoimmunity (Cohen et al., 2012). Our two cases corroborate the knowledge about the side-effect profile of cladribine (Cook et al., 2011), which is very well manageable. We believe these factors will play an important role in determining the future place of cladribine in MS therapy. As neuro-axonal structural proteins, neurofilaments released into the CSF are an a priori plausible biomarker of neuro-axonal injury (Petzold, 2005). Neurofilament light and heavy chain levels have meanwhile successfully been used to monitor disease burden and activity in a number of conditions characterised by neuro-axonal damage (Norgren et al., 2003). Various neurofilament subunits can be measured using immunoassays (Norgren et al., 2003; Petzold, 2005). We used a validated, commercial NfL kit that has been applied in large cohorts of pwMS (Kuhle et al., 2013; Malmeström et al., 2003). Evidence suggests elevated CSF–NfL levels are associated with worsening disability (Trentini et al., 2014; Norgren et al., 2004) and disease activity on MRI (Burman et al., 2014). The use of CSF–NfL as a surrogate outcome in a placebo-controlled trial of fingolimod in pwMS underpinned its clinical utility (Kuhle et al., 2015). Alongside the detection of Gd+ lesions, indicating acute blood brain barrier disruption, the presence of significantly elevated NfL levels in our two patients strongly suggested inflammatory demyelination as the key driver of neuro-axonal injury in spite of a clinically “progressive” disease course, often considered a degenerative phase of MS where the adaptive-inflammatory response is felt to play a negligible role (Leray et al., 2010). However, the cases presented here challenge this claim and represent good examples of the category “active, with progression” in the updated set of definitions of progressive MS (Lublin et al., 2014). CSF–NfL can be detected in healthy people, particularly with increasing age (Rosengren et al. 1999). NfL can also be measured in serum creating the possibility for less invasive NfL monitoring (Bergman et al. 2016). In our two cases CSF–NfL levels were well above the age-adjusted upper reference limit. Both cases demonstrated a significant drop in NfL levels following only one cycle of cladribine treatment, and this result was associated with significantly reduced activity on MRI brain. In the first case with a 13 year-history of relapsing MS, and one year of secondary progression, NfL was 1700 pg/ ml before, and 453 pg/ml 12 month after treatment. Likewise, the number of actively-enhancing lesions was reduced from 11 to 2, and
Disclosures SG has received travel support and consultancy fees from Biogen, Novartis, Teva, Pfizer, and support from Sanofi-Genzyme and Takeda. GG has received fees for participation in advisory board for AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis and Teva. Research support from Biogen, Genzyme, Ironwood, Merck, Merck Serono, Novartis and Takeda. KS has been a PI of trials sponsored by Medday, Novartis, Roche and Teva and involved in trials sponsored by Biogen, Sanofi-Genzyme, BIAL, Cytokinetics, and Canbex; has received research support from Biogen and Novartis, and honoraria and meeting support from Biogen, Lipomed, Merck Serono, Novartis, Roche and Teva. Acknowledgements This study has been supported by Multiple Sclerosis of Great Britain & Northern Ireland award reference 69/2017. OY is funded by the MND association. ZM has been supported by an ECTRIMS Clinical Training fellowship 2016/17. The authors are grateful for the support of this research by the team of our Neuroscience Research & Daycare unit (Ward 11D, Lead: Maria Espasandin) at The Royal London Hospital. References Afolabi, D., Albor, C., Zalewski, L., Altmann, D.R., Baker, D., Schmierer, K., 2017. Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis. Mult. Scler. J 1352458517726380. Alvarez-Gonzalez, C., Adams, A., Mathews, J., Turner, B.P., Giovannoni, G., Baker, D., Schmierer, K., 2017. Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis. Ann. Clin. Trans. Neurol. Alvarez-Gonzalez, C., Allen-Philbey, K., Mathews, J., Turner, B.P., Baker, D., Gnanapavan, S., Marta, M., Giovannoni, G., Schmierer, K., 2016. Treating multiple
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Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Disease activity in progressive multiple sclerosis can be effectively reduced by cladribine
T
O. Yildiza,b, Z. Maoa,c,d, A. Adamse, N. Dubuissona, K. Allen-Philbeyb, G. Giovannonia,b, ⁎ A. Malaspinaa,b, D. Bakera, S. Gnanapavana,b, K. Schmierera,b, a
The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom Clinical Board: Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom c Department of Neurology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China d Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, China e Department of Neuroradiology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom b
A R T I C LE I N FO
A B S T R A C T
Keywords: Progressive multiple sclerosis Neurofilaments Cerebro-spinal fluid Cladribine Disease activity
Background: Evidence suggests people with non-relapsing deteriorating (“progressive”) multiple sclerosis (pwPMS) may benefit from disease-modifying immune therapy (DMT). However, only one such treatment (ocrelizumab) has been licensed and is highly restricted to pwPMS suffering from the primary progressive phenotype. The difficulties assessing treatment outcome in pwPMS is one important reason for the lack of respective DMT. The concentration of neurofilaments in the cerebrospinal fluid (CSF) provides a biomarker of neuro-axonal damage, and both neurofilament light (NfL) and heavy chain (NfH) levels have been used as outcome indices and to guide treatment choices. Methods: We report on two pwPMS, who were treated with subcutaneous cladribine undergoing CSF NfL testing, alongside MRI and clinical follow-up, before and after treatment. Results: Cladribine treatment was well tolerated without any side effects. CSF NfL after treatment revealed significant reduction (by 73% and 80%, respectively) corroborating the MRI detectable drop in disease activity. Disability mildly progressed in one, and remained stable in the other pwPMS. Conclusions: pwPMS with detectable disease activity (MRI, elevated NfL) should be considered for DMT. NfL appears to be a sensitive index of treatment effect in pwPMS, and may be a useful outcome in clinical trials targeting this patient group. Over and above its licensed indication (relapsing MS), cladribine may be an effective treatment option for pwPMS.
1. Introduction Multiple sclerosis (MS) is an inflammatory demyelinating and degenerative disease of the central nervous system (Compston and Coles 2008), and the most common cause of non-traumatic disability among young adults in the Northern Hemisphere (Mackenzie et al., 2014). Most people with multiple sclerosis (pwMS) will experience a progressive course of their condition at some point. This may be from onset (primary progressive MS) or more commonly following a period dominated by relapses and remissions, which after an average disease duration of 10 years, transitions into “secondary progressive” MS in natural history studies (Leray et al., 2010). Whilst eleven different classes of disease-modifying treatments (DMTs) have been licensed for people with early/relapsing MS in Europe and the USA, there is currently only one such treatment, ocrelizumab, which is partially effective
⁎
in people with progressive MS (Montalban et al., 2017). There is, thus, an evident need for more effective DMTs for people with progressive MS (pwPMS). Development of DMTs for this patient population, however, has been slow due to a number of factors including (i) the regulatory environment and its adherence in clinical trials to the expanded disability status scale (EDSS) (Kurtzke 1983) as key primary outcome, in spite of the EDSS’ well known shortcomings in terms of precision, and its ambulation bias driving an “eligibility cutoff” based on the ability to walk (Dubuisson et al., 2017a), (ii) the concept of MS, as a “two stage disease” with an early inflammatory followed by a largely non-inflammatory progressive phase (Leray et al., 2010), and (iii) a disregard for the differences in size and connectivity of the cortical representation for upper and lower limb function, and abundance of corticospinal tracts supplying upper compared to lower limbs (Patestas and Gartner 2016) resulting in a physiological
Corresponding author at: Queen Mary University of London, Blizard Institute (Neuroscience), London, UK. E-mail address: [email protected] (K. Schmierer).
https://doi.org/10.1016/j.msard.2018.05.010 Received 30 January 2018; Received in revised form 18 April 2018; Accepted 11 May 2018 2211-0348/ © 2018 Published by Elsevier B.V.
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Glossary CNS CSF DMT DNA EDSS Gd JC virus MRI
MS NF NF-L OCB PP pwMS pwRMS pwPMS s.c. SP
central nervous system cerebrospinal fluid disease modifying treatment Deoxyribonucleic acid expanded disability scale score gadolinium John Cunningham virus magnet resonance imaging
multiple sclerosis neurofilaments neurofilament light chain oligoclonal bands primary progressive people with multiple sclerosis people with relapsing multiple sclerosis people with progressive multiple sclerosis subcutaneous secondary progressive
Fig. 1. Axial T2 and post contrast T1 weighted MRI 18 months before treatment (A), at baseline (B), 12 months after the first (C), and five months after the second cladribine treatment cycle (D). Arrows indicate areas of gadolinium enhancement. 21
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with 2–3 relapses/year. Despite this high frequency of relapses, he did not start another DMT for the following nine years until he was first seen in our service at The Royal London Hospital (Barts Health NHS Trust), London, UK. His EDSS at that point was 4.0, based on pyramidal weakness of left-sided limbs, gait ataxia and reduced walking range (>500 m). MRI of the head revealed significant burden of demyelinating lesions in the periventricular and subcortical white matter, brainstem and cerebellum including three gadolinium-enhancing (Gd+) lesions in the left centrum semiovale, the right peritrigonal region and corona radiata (Fig. 1A). Following discussion of risks and potential benefits, the patient decided to start take dimethyl-fumarate (Tecfidera®) 240 mg BD. Within three weeks, however, he stopped taking the medication due to side effects including fatigue, flushing, and abdominal discomfort. He refused treatment with teriflunomide (Aubagio®). Natalizumab (Tysabri®) was also considered, however due to the positive titre for John Cunningham virus (JCV) this was abandoned as an option. Whilst considering his treatment options, and after reviewing his recent disease course, it became evident that rather than relapses as his principal mode of disability accrual, he had developed chronic deterioration for at least the past six months indicating that he had entered the secondary progressive phase. Over the time course of 18 months since we had first seen him, his EDSS had increased from 4.0 to 6.0.
disadvantage of the lower limbs in pwMS (Giovannoni et al., 2017a). Based on trial results in pwPMS reported during the 1990s (Sipe et al., 1994; Beutler et al., 1996; Rice et al., 2000), and more recent evidence from large studies in relapsing MS (Giovannoni et al., 2017b, 2010), as well as a safety analyses (Pakpoor et al., 2015), we offered cladribine as a compassionate off-label treatment to patients in our care since late 2014 (Alvarez-Gonzalez et al., 2017, 2016). The development of indices providing robust prediction of longterm outcome following an intervention in pwPMS is ongoing. The level of neurofilaments in the cerebrospinal fluid (CSF) and the peripheral blood has shown promise to become such a marker (Dubuisson et al., 2017b). Here, we report the cases of two pwPMS in whom we were able to collect CSF before and after commencing cladribine administration, to detect the level of neurofilament light chain (NfL) as a potential readout of treatment effect. 1.1. Case 1 This case is of a man of Asian extraction who was diagnosed with relapsing MS at the age of 21 following unilateral optic neuritis as first manifestation of inflammatory demyelination. After diagnosis, he commenced treatment with interferon beta-1a (Rebif®). However, after two years he decided to stop taking it due to ongoing disease activity
Fig. 2. Axial T2 weighted MRI one year after onset (∼one year prior to starting cladribine treatment), at baseline (B), and seven months later (∼six months after the first treatment cycle) (C), with corresponding T1 post contrast images at two time points. Arrows indicate a single gadolinium enhancing lesion six months after treatment, down from 38 such lesions at baseline. 22
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initiated one month after MRI and NfL results had been collected. Written informed consent to receive the treatment on a compassionate basis was obtained prior to starting the intervention. Safety evaluation prior to treatment included ruling out active hepatitis B and C, tuberculosis (TB Elispot), syphilis and Human Immunodeficiency virus. Immunoreactivity against Varicella zoster (VZV) was confirmed. At total dose of 60 mg cladribine s.c. was given. All procedures were undertaken through the neuroscience day case & outpatients service. Treatment was as follows: week 1 administration of cladribine 10 mg on three consecutive days; week 4 confirmation of normal blood counts (including total lymphocyte count); week 5 administration of cladribine 10 mg on three consecutive days (Mao et al., 2017). The treatment was very well tolerated with no adverse effects observed. Depletion of the total lymphocyte count, CD3+, CD4+, CD8+ and CD19+ cells was observed whilst CD56+ cells remained virtually unchanged (Fig. 3A). One year after the treatment, the patient's EDSS had increased from 6.0 to 6.5 owing to more pronounced gait ataxia requiring bilateral
Follow-up MRI brain acquired revealed that of his numerous T2 hyperintense lesions in the brainstem, cerebellar hemispheres and supratentorial white matter 10 enhanced on T1 weighted scans after injection of gadolinium-DTPA (Gd+). There was also loss of brain volume disproportionate for his age, and numerous T1 hypo-intensities (“black holes” ) predominantly in the periventricular white matter were evident (Fig. 1B). Unrelated to any recent clinical relapse, his CSF, obtained using an atraumatic procedure (Davis et al., 2014), revealed elevated protein (700 mg/l; norm <400 mg/l). White blood cell (WBC) count was <1/ µl (norm: 0–5 cells/µl), and glucose normal (3.1 mmol/l; norm >60% of serum glucose: 3.4 mmol/l). CSF oligoclonal bands (OCBs) were positive, serum negative (type 2) (Hegen et al., 2015). Using a commercial ELISA (UmanDiagnostics NF-Light ELISA assay) a NfL level of 1700 pg/ml was detected (age matched reference: <380 pg/ml). Given the significant disease activity supported by his MRI and NfL findings, and in the absence of clinical relapses, treatment with subcutaneous (s.c.) cladribine (Litak®) was discussed and subsequently
Fig. 3. Cladribine-induced reduction of NfL in the absence of significant peripheral lymphopenia. 23
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l. CSF remained acellular with normal glucose. A second cycle of cladribine s.c. was given one year after her first set of injections. Given her total lymphocyte count was still depleted to 0.9 × 109/l 11 months after her first treatment cycle, a total of only 30 mg cladribine s.c. divided over three consecutive days was administered.
support to walk 20 m. MRI brain revealed two new lesions on T2 weighted scans, one juxtacortical lesion in the left middle frontal gyrus, and a small Gd+ lesion adjacent to the right lateral ventricle. CSF obtained at this point showed mildly raised CSF protein (500 mg/l), WBC count was 5 cells/µl, and glucose 3,3 mmol/l). NfL was reduced to 453 pg/ml (Fig. 3A).CSF OCBs remained type 2. A second cycle of cladribine (total does = 60 mg) according to the same schedule as the first. No adverse effects were observed. On examination five months after this second cycle, the patient described some improvement in his mobility, however this did not reflect in his EDSS, which remained at 6.5. MRI brain showed stable appearance compared to scans acquired six months earlier, prior to second course of treatment (Fig. 1D).
2. Discussion To halt disease deterioration in pwPMS remains a significant challenge, particularly against the backdrop of only one recently licensed DMT, ocrelizumab, for primary progressive MS (Montalban et al., 2017). Thanks to its license, ocrelizumab is not accessible to the largest group of pwPMS, i.e. those developing steady deterioration following a period of relapses and remissions - secondary progressive MS. Although the recent revisions of MS disease courses by Lublin and co-workers, go some way to dissolve the somewhat arbitrary distinction between patients with primary versus secondary progressive disease (Lublin et al., 2014), this is unlikely to significantly impact on the license and use of ocrelizumab in clinical practice. However, the new criteria by Lublin, et al. provide a framework to explore alternative treatments in pwPMS for whom no licensed DMT are currently available. Since it is well established that inflammatory lesions are associated with acute axonal loss (Ferguson et al., 1997; Trapp et al., 1998), an important substrate of disability evolution (Bjartmar et al., 2000), MRI-detectable inflammatory disease activity (new T2 lesions compared to earlier reference scans, Gd+ lesions) in pwPMS strongly suggests that at least part of the pathophysiology driving disability accrual in these patients is caused by ongoing inflammatory demyelination. The importance of inflammatory demyelination throughout the disease course has most recently been underpinned by a study from the Netherlands Brain Bank based on 182 post mortem cases of MS. Of the 7562 histologically analysed lesions 57% showed chronic activity after a mean disease duration of 29 years. Cases of primary and secondary MS showed comparable lesion activity, and shorter time to EDSS 6 correlated with higher lesion load and a higher proportion of chronic active lesions (Luchetti et al., 2018). Against this backdrop there is evident potential for DMT, through depletion of lymphocyte populations that drive MS activity (Baker et al., 2017a), to modify the disease such that slowing, stopping or even partial reversal of MS-derived disability in pwPMS is conceivable (AlvarezGonzalez et al., 2017). Though preliminary evidence suggests potential for cladribine to be an effective DMT for pwPMS (Beutler and Koziol 2000) a definitive clinical trial in this patient cohort has yet to be undertaken. For several reasons, cladribine is an ideal candidate drug to treat pwPMS: (i) oral cladribine (Mavenclad®) has been shown to be highly effective in people with a clinical isolated syndrome of demyelination (Leist et al., 2014) and relapsing MS (Giovannoni et al., 2011), (ii) evidence from phase II studies suggests cladribine is effective in pwPMS too (Sipe et al., 1994; Beutler et al., 1996; Rice et al., 2000), (iii) cladribine enters the CNS (Leist and Weissert 2011), where it may reduce meningeal inflammation and lymphoid-like B and T cell clusters, which have been described to be biologically meaningful in pwPMS (Magliozzi et al., 2007; Howell et al., 2011), (iv) cladribine is a short-term intervention with longlasting effects on both B and T cell populations (Baker et al. 2017b), most prominently on memory B cells (Ceronie et al., 2018), a likely key mechanism underlying the control of the inflammatory response in MS (Baker et al. 2017a), (v) cladribine is well-tolerated (Giovannoni et al., 2010; Afolabi et al., 2017) and comes with few monitoring requirements, (vi) Cladribine has been licensed for more than 25 years to treat patients with hairy cell and chronic lymphoid leukaemia. Hence, over and above the oral preparation, recently licensed by the European Medicines Agency (EMA) for highly-active relapsing MS, several generic yet bioequivalent injectable preparations are available. We used an s.c. preparation for ease of administration in a day case setting. This would also have potential value in pwPMS with difficulties swallowing.
1.2. Case 2 This case is of a Caucasian woman who developed gradually deteriorating pyramidal left leg weakness from the age of 43 years. Review of her history two years after onset, when she was first seen in our service, did not reveal any hint pointing towards a past relapse and remission of neurological dysfunction. A diagnosis of primary progressive MS was made following exclusion of potential mimics and supported by MRI brain (acquired outside our organisation), which revealed significant burden of partially confluent demyelinating lesions, mainly in the left cerebral hemisphere. Central parenchymal volume loss was also seen (Fig. 2A). Multiple foci of high signal were also noted in the thoracic spinal cord, whereas no lesions were seen in the cervical proportion. No gadolinium was given on this occasion. Of note, CSF at this time point was normal with no OCBs detected. Neurological examination two years after onset, when we first saw the patient, revealed nothing of note with respect to head and cranial nerve function. Upper limb examination revealed bilateral dysdiadochokinesia and symmetric intention tremor with past pointing, but no weakness. Pyramidal weakness was detected of the left leg, prompting her to use a unilateral crutch for ambulation. Reflexes were brisk and pronounced on the left throughout. Plantar sign was extensor bilaterally. Walking range without support was just under 100 m. A sensory level was detected at T6. She reported urinary urgency without incontinence. Her EDSS was summarised as 5.5. Follow-up MRI brain showed significantly more lesions in the periventricular and subcortical white matter compared to her above described diagnostic MRI study obtained 10 months earlier. A total of 38 Gd+ lesions was detected on T1 weighted scans (Fig. 2B). Numerous spinal cord lesions were seen in the cervical and thoracic cord, several of which were Gd+on T1. CSF at this time point was abnormal. Whilst her WBC count was <1 cells/µl, total protein was elevated to 770 mg/l with normal glucose (3,4 mmol/l; serum: 5.3 mmol/l). OCBs were type 3, i.e. bands detected in the serum with additional bands in the CSF. CSF NfL was “off the scale” elevated to >10,000 pg/ml using the same system and kit as in case 1 above. The patient's progressive clinical course associated with significant inflammatory disease activity underpinned by MRI and CSF findings, prompted us to offer her off-label treatment with cladribine s.c. After providing written informed consent and undergoing the same safety assessments as described above, drug was administered using the schedule outlined for case 1. The treatment was very well-tolerated with no adverse effects observed. Blood counts obtained over several time points after treatment showed the expected decrease in total lymphocyte count, with all subtypes CD3+, CD4+, CD8+ and CD19+ (Fig. 3B). After one year of follow-up, EDSS has remained stable at 5.5. MRI brain obtained seven months after her previous scans (six months after treatment initiation) revealed no change in T2 lesion load. A single punctate focus of Gd enhancement was seen in the right periventricular white matter (Fig. 2C). CSF obtained six months after baseline revealed a reduction of NfL to 2025 pg/ml. OCBs remained positive (type 2), and protein level elevated, though mildly less so than prior to treatment at 526 mg/ 24
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completely suppressed after the second cladribine treatment cycle. The second case with a history of two years of progressive MS from onset had an excessive NfL > 10.000 pg/ml that dropped to 2025 pg/ml within six months of the first treatment cycle, and 38 Gd+ lesions were reduced to a single spec of enhancement within the same time frame. We were thus able to correlate the effective depletion of NfL levels with a significant reduction - to virtually zero - of new lesion activity on MRI (Burman et al., 2014). Our observations indicate a significant effect of cladribine in the two pwPMS reported here. The significant reduction of NfL alongside MRI activity strongly suggest that cladribine treatment resulted in both, a virtual halt of detectable inflammatory activity and a reduction in associated neuronal damage. That these changes did not result in a reduction of disability as measured by the EDSS is in line with the concept of “therapeutic lag” between (i) shutting down inflammatory activity and its associated acute axonal damage, and (ii) tangible clinical change (Tur et al., 2011; Giovannoni et al., 2017a). Moreover, the EDSS is dominated by lower limb function, and may thus fail to capture upper limb function with more reserve capacity (Fox and Markowitz 2017; Patestas and Gartner 2016). Additional tools, such as the 9-holepeg test, may be more sensitive to detect short term change. In conclusion, the two cases presented here support the case to study cladribine as a DMT in pwPMS leading to (i) selective long-term immune reconstitution, (ii) associated long-term depletion of inflammatory activity and consequential reduction in acute axonal damage, and (iii) avoidance of drug-drug interactions with symptomatic treatments, which become increasingly common as people age and MS advances. All this comes with a decent safety record, high convenience, and at potentially rather low cost. Where the clinical course does not facilitate treatment decisions, CSF–NfL may serve as a biomarker, over and above MRI, of disease activity.
Alternative treatment options we considered included rituximab (Hawker et al., 2009), ocrelizumab (Montalban et al., 2017), natalizumab (Kapoor et al., 2018), mitoxantrone (Hartung et al., 2002) and cyclophosphamide (Hauser et al., 1983). However, due to adverse risk, particularly regarding mitoxantrone (Buttmann et al., 2016) and cyclophosphamide (Neuhaus et al., 2007) and cost (all mentioned monoclonals), none of these options were considered superior, or economically viable, compared to cladribine. Following a comprehensive meta-analysis rebutting the previously suspected cancer risk from cladribine in people with MS (Pakpoor et al., 2015), we addressed a further concern - the risk associated with severe lymphopenia – raised by the European Medicines Agency in their first assessment of oral cladribine (Movectro®) for MS in 2010/11 (http:// www.ema.europa.eu/docs/en_GB/document_library/Application_ withdrawal_assessment_report/2011/03/WC500104393.pdf). First, we calculated the parenteral drug dose required, based on 100% bioavailability of parenteral cladribine compared to 42% or the oral prodrug (Lillemark and Juliusson 1992). Our calculations indicated 60 mg cladribine/year in an individual weighing <90 kg resembles bioequivalence with the oral 3.5 mg/kg dose used in the pivotal CLARITY MS study (Giovannoni et al., 2010). Second, by adjusting the drug dose to individual total lymphocyte count we successfully avoided lymphopenia beyond toxicity level 1 (0.8 × 109/l) (Mao et al., 2017) in these two cases. Cladribine was very-well tolerated, especially when compared to other potentially high efficacy agents (Hawker et al., 2009; Cohen et al., 2012; Fernandez et al., 2016), including the absence of secondary autoimmunity (Cohen et al., 2012). Our two cases corroborate the knowledge about the side-effect profile of cladribine (Cook et al., 2011), which is very well manageable. We believe these factors will play an important role in determining the future place of cladribine in MS therapy. As neuro-axonal structural proteins, neurofilaments released into the CSF are an a priori plausible biomarker of neuro-axonal injury (Petzold, 2005). Neurofilament light and heavy chain levels have meanwhile successfully been used to monitor disease burden and activity in a number of conditions characterised by neuro-axonal damage (Norgren et al., 2003). Various neurofilament subunits can be measured using immunoassays (Norgren et al., 2003; Petzold, 2005). We used a validated, commercial NfL kit that has been applied in large cohorts of pwMS (Kuhle et al., 2013; Malmeström et al., 2003). Evidence suggests elevated CSF–NfL levels are associated with worsening disability (Trentini et al., 2014; Norgren et al., 2004) and disease activity on MRI (Burman et al., 2014). The use of CSF–NfL as a surrogate outcome in a placebo-controlled trial of fingolimod in pwMS underpinned its clinical utility (Kuhle et al., 2015). Alongside the detection of Gd+ lesions, indicating acute blood brain barrier disruption, the presence of significantly elevated NfL levels in our two patients strongly suggested inflammatory demyelination as the key driver of neuro-axonal injury in spite of a clinically “progressive” disease course, often considered a degenerative phase of MS where the adaptive-inflammatory response is felt to play a negligible role (Leray et al., 2010). However, the cases presented here challenge this claim and represent good examples of the category “active, with progression” in the updated set of definitions of progressive MS (Lublin et al., 2014). CSF–NfL can be detected in healthy people, particularly with increasing age (Rosengren et al. 1999). NfL can also be measured in serum creating the possibility for less invasive NfL monitoring (Bergman et al. 2016). In our two cases CSF–NfL levels were well above the age-adjusted upper reference limit. Both cases demonstrated a significant drop in NfL levels following only one cycle of cladribine treatment, and this result was associated with significantly reduced activity on MRI brain. In the first case with a 13 year-history of relapsing MS, and one year of secondary progression, NfL was 1700 pg/ ml before, and 453 pg/ml 12 month after treatment. Likewise, the number of actively-enhancing lesions was reduced from 11 to 2, and
Disclosures SG has received travel support and consultancy fees from Biogen, Novartis, Teva, Pfizer, and support from Sanofi-Genzyme and Takeda. GG has received fees for participation in advisory board for AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis and Teva. Research support from Biogen, Genzyme, Ironwood, Merck, Merck Serono, Novartis and Takeda. KS has been a PI of trials sponsored by Medday, Novartis, Roche and Teva and involved in trials sponsored by Biogen, Sanofi-Genzyme, BIAL, Cytokinetics, and Canbex; has received research support from Biogen and Novartis, and honoraria and meeting support from Biogen, Lipomed, Merck Serono, Novartis, Roche and Teva. Acknowledgements This study has been supported by Multiple Sclerosis of Great Britain & Northern Ireland award reference 69/2017. OY is funded by the MND association. ZM has been supported by an ECTRIMS Clinical Training fellowship 2016/17. The authors are grateful for the support of this research by the team of our Neuroscience Research & Daycare unit (Ward 11D, Lead: Maria Espasandin) at The Royal London Hospital. References Afolabi, D., Albor, C., Zalewski, L., Altmann, D.R., Baker, D., Schmierer, K., 2017. Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis. Mult. Scler. J 1352458517726380. Alvarez-Gonzalez, C., Adams, A., Mathews, J., Turner, B.P., Giovannoni, G., Baker, D., Schmierer, K., 2017. Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis. Ann. Clin. Trans. Neurol. Alvarez-Gonzalez, C., Allen-Philbey, K., Mathews, J., Turner, B.P., Baker, D., Gnanapavan, S., Marta, M., Giovannoni, G., Schmierer, K., 2016. Treating multiple
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