A five-year observational prospective mono-center study of the efficacy of alemtuzumab in a real-world cohort of patients with multiple sclerosis

Sofia Sandgren; Lenka Novakova; Anna Nordin; Markus Axelsson; Clas Malmeström; Henrik Zetterberg; Jan Lycke

doi:10.3389/fneur.2023.1265354

A five-year observational prospective mono-center study of the efficacy of alemtuzumab in a real-world cohort of patients with multiple sclerosis

Front Neurol. 2023 Sep 21:14:1265354. doi: 10.3389/fneur.2023.1265354. eCollection 2023.

Authors

Sofia Sandgren^{1

2}, Lenka Novakova^{1

2}, Anna Nordin^{1

2}, Markus Axelsson^{1

2}, Clas Malmeström^{1

2

3}, Henrik Zetterberg^{4

5

6

7

8

9}, Jan Lycke^{1

2}

Affiliations

¹ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
² Region Västra Götaland, Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.
³ Laboratory for Clinical Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁴ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁶ Department of Neurodegenerative Disease, University College London (UCL) Queen Square Institute of Neurology, London, United Kingdom.
⁷ UK Dementia Research Institute at University College London (UCL), London, United Kingdom.
⁸ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, Hong Kong SAR, China.
⁹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.

Abstract

Background: Alemtuzumab (ALZ) is a pulsed immune reconstitution therapy for multiple sclerosis (MS).

Objective: To assess basic characteristics, therapeutic effects, and prognostic biomarkers on clinical and imaging parameters of disease activity for relapsing-remitting MS (RRMS) patients selected for ALZ, in a real-world long-term setting.

Methods: Fifty-one RRMS patients [female = 31; mean age 36 (standard deviation 7.1) years; median expanded disability status scale (EDSS) 2 (interquartile range (IQR) 1.5)] initiating ALZ treatment, were consecutively included. Patients were assessed at baseline and thereafter annually for 5 years with clinical measures, symbol digit modality test (SDMT), and magnetic resonance imaging (MRI). Concentrations of glial fibrillary acidic protein (GFAP), reflecting astrogliosis, and neurofilament light (NfL), reflecting axonal damage, were measured in cerebrospinal fluid (CSF) and serum samples collected at baseline and after 2 years in CSF, and annually in serum. Control subjects were symptomatic controls (SCs, n = 27), who were examined at baseline and after 5 years without evidence of neurological disease.

Results: While the mean annualized relapse rate was significantly reduced from baseline at each year of follow-up, disability was essentially maintained at a median EDSS of 1.5 and IQR between 1.13 and 2.25. New MRI activity was recorded in 26 patients (53%) over 5 years. The proportion of patients who achieved no evidence of disease activity (NEDA-3), 6-months confirmed disability worsening (CDW), and 6-months confirmed disability improvement (CDI) at 5 years were 33, 31, and 31%, respectively. The SDMT score was reduced for patients (p < 0.001), but unchanged for SCs. ALZ treatment did not change GFAP levels, whereas there was a significant decrease for RRMS patients in median CSF and serum NfL levels at follow-up [CSF month 24: 456 pg./mL (IQR 285.4) (p = 0.05); serum month 24: 6.7 pg/mL (IQR 4.7) (p < 0.01); serum month 60: 7.2 pg/mL (IQR 4.7) (p < 0.01)], compared to baseline [CSF: 1014 pg/mL (IQR 2832.5); serum 8.6 pg/mL (IQR 17.4)].

Conclusion: In this real-world mono-center population, we observed a progression-free survival of 69%, cumulative NEDA-3 of 33%, and reduced NfL levels, over a five-year follow-up. This confirms ALZ as an effective pulsed immune reconstitution therapy that significantly reduces neuro axonal loss, and therefore has the potential to reduce long-term neurological disability. ALZ did not appear to affect astrogliosis.

Keywords: alemtuzumab; glial fibrillary acidic protein; neurofilament light; prospective study; relapsing–remitting multiple sclerosis.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the Swedish Federal Government [LUA/ALF agreement, ALFGBG-722081]; the Swedish Society of the Neurologically Disabled; the Research Foundation of the Multiple Sclerosis Society of Gothenburg; the Edit Jacobson Foundation; the Berit Linnea and Ragnar Bakken Foundation; the AFA Foundation; the Swedish Medical Research Council; the Swedish Brain Foundation; NEURO Sweden; the Rune and Ulla Amlövs Foundation for Neurological Research; the Torsten Söderberg Foundation at the Swedish Royal Academy of Science; the Göran Jahnsons Foundation; and by unconditional grants from Novartis and Biogen. HZ was a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union’s Horizon Europe Research and Innovation Programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.