iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: http://pubmed.ncbi.nlm.nih.gov/37808497/
A five-year observational prospective mono-center study of the efficacy of alemtuzumab in a real-world cohort of patients with multiple sclerosis - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 21:14:1265354.
doi: 10.3389/fneur.2023.1265354. eCollection 2023.

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  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

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 et al. Front Neurol. .

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.

PubMed Disclaimer

Conflict of interest statement

SS has received compensation for lectures and/or advisory board membership from Merck. LN has received lecture honoraria from Biogen, Novartis, Teva, Sanofi and has served on advisory boards for Merck, Janssen and Sanofi. MA has received compensation for lectures and/or advisory boards from Biogen, Genzyme, and Novartis. CM has received honoraria for lectures and advisory board memberships from Biogen, Merck, Novartis, and SanofiAventis. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB BBS, which is a part of the GU Ventures Incubator Program outside submitted work. JL has received travel support and/or lecture honoraria and has served on scientific advisory boards for Alexion, Almirall, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator-initiated study. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Study design. Schematic illustration of the study design. Month 0 (baseline). ALZ, alemtuzumab; MRI, magnetic resonance imaging; LP, lumbar puncture.
Figure 2
Figure 2
ARR over five years. ARR at baseline (yellow dot), i.e., the year before ALZ initiation (year 0), and at year 1–5 (blue dots) of follow-up. The dots represent mean values, and error bars represent the SD. ARR, annualized relapse rate; ALZ, alemtuzumab; SD, standard deviation. *p ≤ 0.05.
Figure 3
Figure 3
MRI outcomes. Kaplan–Meier plot shows probability of MRI event free survival. Yellow solid line represents the probability of contrast-enhancing T1 lesion free MRI, and blue dashed line represents the probability of new or enlarged T2 lesion free MRI, during follow-up. MRI, magnetic resonance imaging.
Figure 4
Figure 4
SDMT scores over five years. SDMT scores at baseline (i.e., year 0) and at year 1–5 of follow-up for RRMS patients (green dots), as well as for the NEDA-3 (blue dots) and EDA-3 (yellow dots) subgroups. For SCs (red dots) SDMT scores at baseline and year five are shown. The dots represent mean values. SDMT, symbol digit modality test; RRMS, relapsing–remitting multiple sclerosis; SCs, symptomatic controls; NEDA-3, no evidence of disease activity-3; EDA-3, evidence of disease activity.
Figure 5
Figure 5
CSF and serum NfL levels in RRMS patients and SCs. (A) CSF NfL levels in SCs (red dots), RRMS patients (green squares), as well as in NEDA-3 (blue triangles) and EDA-3 (yellow hexagons) subgroups, at baseline (month 0), and at re-sampling at 24 months after treatment initiation. The scatter plot represent individual values, with a line at median. (B) Serum NfL levels in SCs (red dots), RRMS patients (green squares), as well as in NEDA-3 (blue triangles) and EDA-3 subgroups (yellow hexagons), at baseline (month 0), and at re-sampling at 24, and 60 months after treatment initiation. The scatter plot represent individual values, with a line at median. CSF, cerebrospinal fluid; RRMS, relapsing–remitting multiple sclerosis; SCs, symptomatic controls; GFAP, glial fibrillary acidic protein; NfL, neurofilament light; NEDA-3, no evidence of disease activity-3; EDA-3, evidence of disease activity; ns, not statistically significant. *p ≤ 0.05, **p ≤ 0.01, ****p ≤ 0.0001.
Figure 6
Figure 6
CSF and serum NfL levels in patients, grouped by reason for initiating ALZ. (A) CSF NfL levels in active (blue dots) patients (treatment naïve and breakthrough disease activity despite DMT), and inactive (yellow squares) patients (natalizumab treated patients with increased JC virus antibody index or patients with an adverse event on other DMT), at baseline (month 0), and at re-sampling at 24 months after treatment initiation. The scatter plot represent individual values, with a line at median. (B) Serum NfL levels in active (blue dots) and inactive (yellow squares) patients, at baseline (month 0), and at re-sampling at 24 months after treatment initiation. The scatter plot represent individual values, with a line at median. CSF, cerebrospinal fluid; NfL, neurofilament light; ALZ, alemtuzumab; DMT, disease-modifying treatment; ns, not statistically significant. **p ≤ 0.01, ***p ≤ 0.001.
Figure 7
Figure 7
Probability of EDA-3, relative to age and CSF NFL. Kaplan–Meier plot shows the probability of RRMS patients to reach EDA-3 at the indicated time (years), according to baseline variables (A) age ≤ 30 years (n = 11) represented by yellow solid line, or age > 30 years (n = 38) represented by blue dashed line, and (B) CSF NfL ≤ 2,136 pg/mL (n = 22) represented by yellow solid line, or CSF NfL > 2136 pg/mL (n = 12) represented by blue dashed line. RRMS, relapsing–remitting multiple sclerosis; EDA-3, no evidence of disease activity-3; CSF, cerebrospinal fluid; NfL, neurofilament light.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Jeffery DR. Early intervention with immunomodulatory agents in the treatment of multiple sclerosis. J Neurol Sci. (2002) 197:1–8. doi: 10.1016/S0022-510X(02)00039-4, PMID: - DOI - PubMed
    1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol. (2018) 31:233–43. doi: 10.1097/WCO.0000000000000561 - DOI - PubMed
    1. Ruck T, Bittner S, Wiendl H, Meuth SG. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int J Mol Sci. (2015) 16:16414–39. doi: 10.3390/ijms160716414, PMID: - DOI - PMC - PubMed
    1. Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, et al. . Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. (2005) 35:3332–42. doi: 10.1002/eji.200535075, PMID: - DOI - PubMed
    1. Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, et al. . IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. (2009) 119:2052–61. doi: 10.1172/JCI37878, PMID: - DOI - PMC - PubMed

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.