Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients

Kimberley Allen-Philbey¹, Stefania De Trane², Zhifeng Mao³, Cesar Álvarez-González⁴, Joela Mathews⁵, Amy MacDougall⁶, Andrea Stennett¹, Xia Zhou¹, Ozlem Yildiz¹, Ashok Adams⁷, Lucia Bianchi², Camilla Blain⁸, Christine Chapman², Karen Chung⁹, Cris S Constantinescu¹⁰, Catherine Dalton⁸, Rachel A Farrell⁹, Leonora Fisniku¹¹, Helen Ford¹², Bruno Gran¹⁰, Jeremy Hobart¹³, Zhaleh Khaleeli¹⁴, Miriam Mattoscio¹⁵, Sue Pavitt¹⁶, Owen Pearson¹⁷, Luca Peruzzotti-Jametti¹⁸, Antonio Scalfari¹⁹, Basil Sharrack²⁰, Eli Silber²¹, Emma C Tallantyre²², Stewart Webb²³, Benjamin P Turner¹, Monica Marta¹, Sharmilee Gnanapavan¹, Gunnar Juliusson²⁴, Gavin Giovannoni¹, David Baker², Klaus Schmierer²⁵

Affiliations

¹ Neuroscience, Clinical Board Medicine, The Royal London Hospital, Barts Health NHS Trust, London, UK.
² Neuroscience, Surgery and Trauma, The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
³ Kingmed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
⁴ Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
⁵ Pharmacy Department, The Royal London Hospital, Barts Health NHS Trust, London, UK.
⁶ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
⁷ Neuroradiology Department, The Royal London Hospital, Barts Health NHS Trust, London, UK.
⁸ St George's University Hospitals NHS Foundation Trust, London, UK.
⁹ The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁰ Department of Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹¹ Brighton and Sussex University Hospitals NHS Trust, Brighton, UK; Brighton and Sussex Medical School, Brighton, UK.
¹² Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹³ Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
¹⁴ Department of Neuroinflammation, National Hospital for Neurology and Neurosurgery, London, UK.
¹⁵ Queen's Hospital, Barking Havering and Redbridge Hospital NHS Trust, Romford, UK; Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
¹⁶ Dental Translational and Clinical Research Unit, School of Dentistry, University of Leeds, Leeds, UK.
¹⁷ Department of Neurology, Swansea Bay University Health Board, Port Talbot, UK.
¹⁸ Department of Clinical Neurosciences and National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁹ Centre of Neuroscience, Department of Medicine Charing Cross Hospital, Imperial College London, London, UK.
²⁰ Department of Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
²¹ Department of Neurology, King's College Hospital, London, UK.
²² Department of Neurology, University Hospital of Wales, Cardiff, UK.
²³ Institute of Neuroscience, Department of Neurology, Queen Elizabeth University Hospital, Glasgow, UK.
²⁴ Department of Hematology, Skåne University Hospital, Lund, Sweden.
²⁵ Neuroscience, Clinical Board Medicine, The Royal London Hospital, Barts Health NHS Trust, London, UK Neuroscience, Surgery and Trauma, The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.

PMID: 35173808
PMCID: PMC8842147
DOI: 10.1177/17562864211057661

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients

Kimberley Allen-Philbey et al. Ther Adv Neurol Disord. 2021.

. 2021 Nov 25:14:17562864211057661.

doi: 10.1177/17562864211057661. eCollection 2021.

Authors

Affiliations

¹ Neuroscience, Clinical Board Medicine, The Royal London Hospital, Barts Health NHS Trust, London, UK.
² Neuroscience, Surgery and Trauma, The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
³ Kingmed College of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
⁴ Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
⁵ Pharmacy Department, The Royal London Hospital, Barts Health NHS Trust, London, UK.
⁶ Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
⁷ Neuroradiology Department, The Royal London Hospital, Barts Health NHS Trust, London, UK.
⁸ St George's University Hospitals NHS Foundation Trust, London, UK.
⁹ The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
¹⁰ Department of Neurology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
¹¹ Brighton and Sussex University Hospitals NHS Trust, Brighton, UK; Brighton and Sussex Medical School, Brighton, UK.
¹² Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹³ Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
¹⁴ Department of Neuroinflammation, National Hospital for Neurology and Neurosurgery, London, UK.
¹⁵ Queen's Hospital, Barking Havering and Redbridge Hospital NHS Trust, Romford, UK; Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
¹⁶ Dental Translational and Clinical Research Unit, School of Dentistry, University of Leeds, Leeds, UK.
¹⁷ Department of Neurology, Swansea Bay University Health Board, Port Talbot, UK.
¹⁸ Department of Clinical Neurosciences and National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Cambridge, UK.
¹⁹ Centre of Neuroscience, Department of Medicine Charing Cross Hospital, Imperial College London, London, UK.
²⁰ Department of Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
²¹ Department of Neurology, King's College Hospital, London, UK.
²² Department of Neurology, University Hospital of Wales, Cardiff, UK.
²³ Institute of Neuroscience, Department of Neurology, Queen Elizabeth University Hospital, Glasgow, UK.
²⁴ Department of Hematology, Skåne University Hospital, Lund, Sweden.
²⁵ Neuroscience, Clinical Board Medicine, The Royal London Hospital, Barts Health NHS Trust, London, UK Neuroscience, Surgery and Trauma, The Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.

PMID: 35173808
PMCID: PMC8842147
DOI: 10.1177/17562864211057661

Abstract

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak^®) in multiple sclerosis (MS) patients.

Methods: Litak^® was offered to MS-patients irrespective of disease course. Litak^® 10 mg was administered for 3-4 days during week 1. Based on lymphocyte count at week 4, patients received another 0-3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts.

Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17-72) years and EDSS 0-8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data (n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data (n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months.

Conclusions: Litak^® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

Keywords: NEDA; NEPAD; cladribine; disease-modifying treatment; multiple sclerosis; treatment access.

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Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.A.P., S.D.T., Z.M., A.M., A.S., X.Z., O.Y., A.A., L.B., C.C., C.D., S.P., L.P.J., B.S. and S.W. have no conflicts of interest to declare. C.A.G. is a founder of NeuroCreare Ltd. J.M. has received honoraria and meeting support from Arvelle, Biogen, Novartis, Merck Serono, Roche and Sanofi Genzyme. C.B. has received travel costs and honoraria from Novartis, Genzyme, Teva and Biogen. K.C. has received honoraria and travel grants from Biogen, Sanofi-Genzyme and Roche. C.S.C. has received support for research, attendance of conferences, and consultancy from Biogen, GW Pharmaceuticals, Novartis, Teva, Merck, Morphosys, Roche, Sanofi Pasteur MSD and Sanofi Genzyme. R.A.F. has received honoraria and consultancy fees from Merck, TEVA, Novartis, Genzyme, GW Pharma, Allergan, Merz, Ipsen, and Biogen. R.A.F.’s current research activity is supported by the NIHR Biomedical Research Centre UCLH. L.F. has received consultancy fees from Biogen, Novartis, Roche and Genzyme. L.F. has received support for educational events from Biogen, Genzyme, Merck, Novartis, Teva, and the Neurology Academy. H.F. has received support from the Health Technology Assessment Programme (NIHR) and the UK MS Society. In the past 3 years, H.F. has been a local principal investigator for trials in MS funded by Novartis, Roche, and Biogen Idec and has taken part in advisory boards and consultancy for Biogen Idec, Merck, Novartis and Roche. B.G. has received personal compensation for consultancy from Merck, Roche, Biogen, Teva UK, and GW Pharma. B.G. has received unrestricted research grants from Biogen Idec, Merck, Bayer Healthcare, Teva UK, Novartis, and Genzyme. B.G. has received support for the attendance of clinical and research conferences from Biogen, Merck, Bayer Healthcare, Teva UK, Novartis, Genzyme, and CelGene. J.H. has received consultancy fees, meeting support, or grants to support clinical services or research from: Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche, Celegene, Oxford pharmagenesis. Z.K. has received honoraria and travel costs from Roche, Biogen and Novartis. M.M. has received travel support and speaker honoraria from Biogen Idec, Genzyme, Merck-Sereno, Novartis, Roche and Teva and consultation for Celgene, Merck-Serono, Novartis and Roche. O.P. has received speaking fees and travel expenses from, and/or served on advisory boards for, Biogen, Bayer, Celegene, Janssen, Merck Novartis, Roche, Sanofi and Teva. A.S. has received honoraria, travel grants and been a member of advisory boards for Biogen, Novartis, Teva, Celgene, Sanofi, and Merck. E.S. has received consulting fees and/ or support to attend academic meetings from Merck. E.T. has received honorarium for consulting work from Novartis, Merck, Biogen, and Roche. E.T. has received travel grants to attend or speak at educational meetings from Biogen, Merck, Roche, Takeda, and Novartis. B.P.T. has received honoraria, travel grants, and been a member of advisory boards for Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Roche. M.M. has received honoraria and travel costs from Genzyme, AbbVie, Roche, and Novartis. S.G. has received honoraria from Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche, and Teva and grant support from ECTRIMS, Genzyme, Merck, National MS Society, Takeda, and UK MS Society. G.J. has received speaker honoraria from and is a member of advisory boards of AbbVie, Astellas, Celgene, and Novartis. G.G. has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex. He also serves as chief editor for Multiple Sclerosis and Related Disorders. D.B. has received compensation from InMuneBio, Lundbeck, Merck, Novartis, Rock, and Teva. K.S. has received research support from Biogen, Merck KGaA, and Novartis, speaking honoraria from, and/or served in an advisory role for, Amgen, Biogen, EMD Serono, Merck KGaA, Novartis, Roche, Sanofi-Genzyme, and Teva; and remuneration for teaching activities from AcadeMe, Medscape and the Neurology Academy.

Figures

**Figure 1.**
Dosing schedule of Litak^® adjusted to body weight and lymphocyte count. *Treatment course 1*: Following injections of Litak^® 10 mg on 3–4 consecutive days in week 1, total lymphocyte count (TLC) was measured at week 4. If TLC was ⩾1.0 × 10⁹ L⁻¹, further injections of Litak^® 10 mg were given on three consecutive days in week 5. If TLC was 0.8–0.9 × 10⁹ L⁻¹, further injections of Litak^® 10 mg were given on two consecutive days in week 5. If TLC was 0.5–0.7 × 10⁹ L⁻¹, one further injection of Litak^® 10 mg was given in week 5. If TLC was <0.5 × 10⁹ L⁻¹, no further injection of Litak^® was given during this treatment course. *Treatment course 2 A*: If TLC at week 44 was ⩾1.0 × 10⁹ L⁻¹, injections of Litak^® 10 mg were given on three consecutive days in week 48. TLC was then measured at week 51. If TLC was ⩾1.0 × 10⁹ L⁻¹, further injections of Litak^® 10 mg were given on three consecutive days in week 52. If TLC was 0.8–0.9 × 10⁹ L⁻¹, further injections of Litak^® 10 mg were given on two consecutive days in week 52. If TLC was 0.5–0.7 × 10⁹ L⁻¹, one further injection of Litak^® 10 mg was given in week 52. If TLC was <0.5 × 10⁹ L⁻¹, no further injection of Litak^® was given. *Treatment course 2B*: If TLC at week 44 was 0.8–0.9, injections of Litak^® 10 mg were given on two consecutive days in week 48. If TLC was 0.5–0.7 × 10⁹ L⁻¹, one further injection of Litak^® 10 mg was given in week 48. If TLC was <0.5 × 10⁹ L⁻¹, no further injection of Litak^® was given.

**Figure 2.**
CONSORT flow diagram showing patient selection for No Evidence of Disease Activity (NEDA), No Evidence of Progression or Active Disease (NEPAD) and NEPAD less the Timed 25 foot Walking Test (NEPAD*) analysis based on criteria for data completeness.

**Figure 3.**
(a) Proportion of patients receiving the maximum and reduced dose of Litak^® at courses 1 and 2. (b) Total dose of Litak^® administered at courses 1 and 2.

**Figure 4.**
Total lymphocyte count (TLC) in patients treated with Litak^® dose-adapted to body weight and TLC.

**Figure 5.**
Composite measures indicating effectiveness of Litak® in patients with relapsing and progressive multiple sclerosis. (a) Venn diagrams representing the proportion of patients achieving No Evidence of Disease Activity (NEDA), (b) No Evidence of Progression or Active Disease (NEPAD), and (c) NEPAD excluding the Timed-25-foot-Walking-Test (NEPAD*). CI, confidence interval.

**Figure 6.**
Cerebro-spinal fluid neurofilament light chain (CSF-NfL) levels in 23 patients with MS before and after treatment with Litak^®.

See this image and copyright information in PMC

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Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients

Affiliations

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources