- •People with advanced (“progressive”) MS (pwPMS) currently have only one licensed disease modifying treatment (DMT) option (ocrelizumab), and this option is highly restricted to a specific MS subpopulation living in high cost economies.
- •The cerebro-spinal fluid (CSF) neurofilament light chain (NfL) level is a sensitive index of ongoing neuro-axonal damage.
- •pwPMS who had significantly elevated NfL levels alongside MRI detectable disease activity, were treated using off-label injectable cladribine.
- •Cladribine was well tolerated without any side effects and led to reduction of disease activity as indicated by a substantial drop in CSF NfL concentration alongside reduction in active MRI lesions, whilst total lymphocyte counts remained within the normal reference range.
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.
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.
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.
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.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Multiple Sclerosis and Related Disorders
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis.Mult. Scler. J. 2017; (1352458517726380)
- Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis.Ann. Clin. Trans. Neurol. 2017;
- Treating multiple sclerosis with cladribine.J. Neurol. Neurosurg. Psychiatry. 2016; 87 (e1–e1)
- Both cladribine and alemtuzumab may effect MS via B-cell depletion.Neurol. Neuroimmunol. Neuroinflammation. 2017; 4
- Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis.EBioMedicine. 2017; 16: 41-50
- Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS.Neurol Neuroimmunol Neuroinflamm. 2016; 3: e271
- The cladribine trial in secondary progressive multiple sclerosis: a reanalysis.Neuroepidemiology. 2000; 19: 109-112
- The treatment of chronic progressive multiple sclerosis with cladribine.Proc. Natl. Acad. Sci. USA. 1996; 93: 1716-1720
- Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients.Ann. Neurol. 2000; 48: 893-901
- Assessing tissue damage in multiple sclerosis: a biomarker approach.Acta Neurol. Scand. 2014; 130: 81-89
- Malignancies after mitoxantrone for multiple sclerosis: a retrospective cohort study.Neurology. 2016; 86: 2203-2207
- Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.J. Neurol. 2018; 265: 1199-1209
- Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.Lancet. 2012; 380: 1819-1828
- Multiple sclerosis.Lancet. 2008; 372: 1502-1517
- Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.Mult. Scler. 2011; 17: 578-593
- Change practice now! Using atraumatic needles to prevent post lumbar puncture headache.Eur. J. Neurol. 2014; 21: 305-311
- Disease modification in advanced MS: Focus on upper limb function.Mult. Scler. 2017; (1352458517717811)
- Science is 1% inspiration and 99% biomarkers.Mult. Scler. 2017; 23: 1442-1452
- Axonal damage in acute multiple sclerosis lesions.Brain. 1997; 120 (Pt 3): 393-399
- Review of the novelties from the 31st ECTRIMS congress, 2015, presented at the 8th post-ECTRIMS meeting.Rev. Neurol. 2016; 62: 559-569
- Effect of ocrelizumab on upper limb function in patients with primary progressive multiple sclerosis in the ORATORIO study.Mult. Scler. J. 2017; 23: 658
- A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.N. Engl. J. Med. 2010; 362: 416-426
- Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.Lancet Neurol. 2011; 10: 329-337
- Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.Mult. Scler. Relat. Disord. 2017; 12: 70-78
- Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study.Mult. Scler. 2017; (1352458517727603)
- Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial.Lancet. 2002; 360: 2018-2025
- Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH.N. Engl. J. Med. 1983; 308: 173-180
- Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial.Ann. Neurol. 2009; 66: 460-471
- Guidelines on cerebrospinal fluid analysis.in: Deisenhammer F. Sellebjerg F. Teunissen C.E. Tumani H. Cerebrospinal Fluid in Clinical Neurology. Springer International Publishing, Cham2015: 407-428
- Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis.Brain. 2011; 134: 2755-2771
- Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension.Lancet Neurol. 2018;
- Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis.Neurology. 2015; 84: 1639-1643
- Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis.Acta Neurol. Scand. 2013; 128: e33-e36
- Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).Neurology. 1983; 33: 1444-1452
- Oral Cladribine for early MS (ORACLE MS) study group. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial.Lancet Neurol. 2014; 13: 257-267
- Cladribine: mode of action and implications for treatment of multiple sclerosis.Clin. Neuropharmacol. 2011; 34: 28-35
- Evidence for a two-stage disability progression in multiple sclerosis.Brain. 2010; 133: 1900-1913
- On the pharmacokinetics of 2-chloro-2-deoxyadenosine (CdA) in cerebrospinal fluid (CSF).Blood. 1992; 80: 471a
- Defining the clinical course of multiple sclerosis: the 2013 revisions.Neurology. 2014; 83: 278-286
- Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis.Acta Neuropathol. 2018;
- Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the general practice research database.J. Neurol. Neurosurg. Psychiatry. 2014; 85: 76-84
- Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology.Brain. 2007; 130: 1089-1104
- Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS.Neurology. 2003; 61: 1720-1725
- PO134 personalised dosing of cladribine to treat multiple sclerosis.J. Neurol. Neurosurg. Psychiatry. 2017; 88: A47-A48
- Ocrelizumab versus placebo in primary progressive multiple sclerosis.N. Engl. J. Med. 2017; 376: 209-220
- Immunosuppressive agents in multiple sclerosis.Neurotherapeutics. 2007; 4: 654-660
- Elevated neurofilament levels in neurological diseases.Brain Res. 2003; 987: 25-31
- Neurofilament and glial fibrillary acidic protein in multiple sclerosis.Neurology. 2004; 63: 1586-1590
- No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine.Neurol. Neuroimmunol. Neuroinflammation. 2015; 2: e158
- A Textbook of Neuroanatomy.John Wiley & Sons, 2016
- Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss.J. Neurol. Sci. 2005; 233: 183-198
- Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial.Neurology. 2000; 54 (Cladribine MRI Study Group): 1145-1155
- Neurofilament protein levels in CSF are increased in dementia.Neurology. 1999; 52: 1090-1093
- Cladribine in treatment of chronic progressive multiple sclerosis.Lancet. 1994; 344: 9-13
- Axonal transection in the lesions of multiple sclerosis.N. Engl. J. Med. 1998; 338: 278-285
- N-acetylaspartate and neurofilaments as biomarkers of axonal damage in patients with progressive forms of multiple sclerosis.J. Neurol. 2014; 261: 2338-2343
- Interferon beta-1b for the treatment of primary progressive multiple sclerosis: five-year clinical trial follow-up.Arch. Neurol. 2011; 68: 1421-1427
Published online: May 15, 2018
Accepted: May 11, 2018
Received in revised form: April 18, 2018
Received: January 30, 2018
© 2018 Published by Elsevier B.V.