Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study
Background and objectivesCladribine tablets (CladT) represent an effective immune reconstitution therapy, administered in short treatment courses over two consecutive years. To better understand the amplitude of immune changes, we performed a comprehensive analysis during the 2-year study period for...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| author | Heinz Wiendl Frederik Barkhof Frederik Barkhof Xavier Montalban Anat Achiron Anat Achiron Tobias Derfuss Andrew Chan Suzanne Hodgkinson Alexandre Prat Letizia Leocani Letizia Leocani Letizia Leocani Klaus Schmierer Klaus Schmierer Finn Sellebjerg Finn Sellebjerg Patrick Vermersch Hulin Jin Anita Chudecka Andreas Kloetgen Dongdong Lin Lidia Gardner Nicola De Stefano |
| author_facet | Heinz Wiendl Frederik Barkhof Frederik Barkhof Xavier Montalban Anat Achiron Anat Achiron Tobias Derfuss Andrew Chan Suzanne Hodgkinson Alexandre Prat Letizia Leocani Letizia Leocani Letizia Leocani Klaus Schmierer Klaus Schmierer Finn Sellebjerg Finn Sellebjerg Patrick Vermersch Hulin Jin Anita Chudecka Andreas Kloetgen Dongdong Lin Lidia Gardner Nicola De Stefano |
| author_sort | Heinz Wiendl |
| collection | DOAJ |
| description | Background and objectivesCladribine tablets (CladT) represent an effective immune reconstitution therapy, administered in short treatment courses over two consecutive years. To better understand the amplitude of immune changes, we performed a comprehensive analysis during the 2-year study period for the entire MAGNIFY-MS population (N=270). In addition to lymphocyte kinetics, we studied intracellular cytokines serum proteins, and their associations with clinical outcomes. To put these changes into perspective, we analyzed transcriptional changes in T and B cells and associated biological pathways before and after each treatment course with CladT.MethodsImmunophenotyping and transcriptomics were performed at regular visits with major differences reported between baseline (BL) and after each yearly treatment course. Assessments included: lymphocyte dynamics, RNA sequencing (B and T cells), intracellular cytokines, serum proteins (immunoglobulins [IgG and IgM], and serum neurofilament light chain [sNfL]). Clinical measures included: MRI activity, annualized relapse rate (ARR), 6-month confirmed disability progression (6mCDP), timed 25-foot walk (T25FW), and 9-hole peg test (9HPT).ResultsAll B, T and NK cells were reduced at month (M)3 after CladT administration, except regulatory B cells which increased above BL from M3 to M24. Naïve and transitional B cells recovered at M6; all other B and T cell subsets remained below BL levels. Reductions in all NK cell subtypes were observed at M3, CD16lowCD56bright and NKp46 cells reconstituted at M6 and M12 respectively. Changes in genes and pathways associated with innate and adaptive immune response were observed after CladT treatment, along with reductions in pro-inflammatory cytokine-producing B and T cells and increases in anti-inflammatory cytokine-producing T cells. IgG and IgM levels remained above the lower limits of normal in most participants. sNfL levels decreased, remaining reduced by M24. Significant reductions in the annualized combined unique active lesion count occurred from M2 onwards. ARR was 0.11 (95% confidence interval: 0.09,0.15), with 83% participants free of qualifying relapses. Over 90% of participants were free of 6mCDP, around 87% had no confirmed progression on T25FW and 9HPT. No significant correlations were seen between clinical parameters and lymphocyte dynamics to M6. The safety profile was consistent with previous reports.DiscussionDeep longitudinal immunophenotyping, analysis of transcriptional changes, reduction in cells expressing pro-inflammatory cytokines, along with the marker of neuroaxonal damage provide novel and innovative evidence of CladT rebalancing the immune system towards a more homeostatic and less pathogenic state.Clinical Trial Registrationhttps://clinicaltrials.gov/study/, identifier NCT03364036. |
| format | Article |
| id | doaj-art-49252b9d439a4d23a12dc2404c36d7eb |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-49252b9d439a4d23a12dc2404c36d7eb2025-02-03T05:12:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15121891512189Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS studyHeinz Wiendl0Frederik Barkhof1Frederik Barkhof2Xavier Montalban3Anat Achiron4Anat Achiron5Tobias Derfuss6Andrew Chan7Suzanne Hodgkinson8Alexandre Prat9Letizia Leocani10Letizia Leocani11Letizia Leocani12Klaus Schmierer13Klaus Schmierer14Finn Sellebjerg15Finn Sellebjerg16Patrick Vermersch17Hulin Jin18Anita Chudecka19Andreas Kloetgen20Dongdong Lin21Lidia Gardner22Nicola De Stefano23Department of Neurology, Institute of Translational Neurology, University of Münster, Münster, GermanyDepartment of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, NetherlandsQueen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, United KingdomDepartment of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d’Hebron, Barcelona, SpainMultiple Sclerosis Center, Sheba Academic Medical Center, Ramat Gan, IsraelFaculty of Medicine, Tel-Aviv University, Tel-Aviv, IsraelDepartment of Neurology, University Hospital Basel, Basel, SwitzerlandDepartment of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandIngham Institute for Applied Medical Research, University of New South Wales Medicine and Liverpool Hospital, Sydney, NSW, Australia0Department of Neurosciences, Université de Montréal, Montréal, QC, Canada1Department of Neurology, University Vita-Salute San Raffaele, Milan, Italy2Experimental Neurophysiology Unit, Scientific Institute IRCCS San Raffaele, Milan, Italy3Department of Neurorehabilitation Science, Casa di Cura Igea, Milan, Italy4The Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom5Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS, Trust, London, United Kingdom6Danish MS Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark7Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark8Univ. Lille, Inserm U1172 LilNCog, CHU Lille, FHU Precise, Lille, France9Clinical Measurement Sciences, Merck Healthcare KGaA, Darmstadt, Germany0Clinical Research Services, Cytel Inc., Geneva, Switzerland9Clinical Measurement Sciences, Merck Healthcare KGaA, Darmstadt, Germany1Clinical Measurement Sciences, EMD Serono Research & Development Institute, Inc., an affiliate of Merck KGaA, Billerica, MA, United States2Neurology & Immunology Medical Unit, EMD Serono Research & Development Institute, Inc., an affiliate of Merck KGaA, Billerica, MA, United States3Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, ItalyBackground and objectivesCladribine tablets (CladT) represent an effective immune reconstitution therapy, administered in short treatment courses over two consecutive years. To better understand the amplitude of immune changes, we performed a comprehensive analysis during the 2-year study period for the entire MAGNIFY-MS population (N=270). In addition to lymphocyte kinetics, we studied intracellular cytokines serum proteins, and their associations with clinical outcomes. To put these changes into perspective, we analyzed transcriptional changes in T and B cells and associated biological pathways before and after each treatment course with CladT.MethodsImmunophenotyping and transcriptomics were performed at regular visits with major differences reported between baseline (BL) and after each yearly treatment course. Assessments included: lymphocyte dynamics, RNA sequencing (B and T cells), intracellular cytokines, serum proteins (immunoglobulins [IgG and IgM], and serum neurofilament light chain [sNfL]). Clinical measures included: MRI activity, annualized relapse rate (ARR), 6-month confirmed disability progression (6mCDP), timed 25-foot walk (T25FW), and 9-hole peg test (9HPT).ResultsAll B, T and NK cells were reduced at month (M)3 after CladT administration, except regulatory B cells which increased above BL from M3 to M24. Naïve and transitional B cells recovered at M6; all other B and T cell subsets remained below BL levels. Reductions in all NK cell subtypes were observed at M3, CD16lowCD56bright and NKp46 cells reconstituted at M6 and M12 respectively. Changes in genes and pathways associated with innate and adaptive immune response were observed after CladT treatment, along with reductions in pro-inflammatory cytokine-producing B and T cells and increases in anti-inflammatory cytokine-producing T cells. IgG and IgM levels remained above the lower limits of normal in most participants. sNfL levels decreased, remaining reduced by M24. Significant reductions in the annualized combined unique active lesion count occurred from M2 onwards. ARR was 0.11 (95% confidence interval: 0.09,0.15), with 83% participants free of qualifying relapses. Over 90% of participants were free of 6mCDP, around 87% had no confirmed progression on T25FW and 9HPT. No significant correlations were seen between clinical parameters and lymphocyte dynamics to M6. The safety profile was consistent with previous reports.DiscussionDeep longitudinal immunophenotyping, analysis of transcriptional changes, reduction in cells expressing pro-inflammatory cytokines, along with the marker of neuroaxonal damage provide novel and innovative evidence of CladT rebalancing the immune system towards a more homeostatic and less pathogenic state.Clinical Trial Registrationhttps://clinicaltrials.gov/study/, identifier NCT03364036.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1512189/fullmultiple sclerosiscladribine tabletsbiomarkerstranscriptomics, immunophenotypingimmune reconstitution therapy |
| spellingShingle | Heinz Wiendl Frederik Barkhof Frederik Barkhof Xavier Montalban Anat Achiron Anat Achiron Tobias Derfuss Andrew Chan Suzanne Hodgkinson Alexandre Prat Letizia Leocani Letizia Leocani Letizia Leocani Klaus Schmierer Klaus Schmierer Finn Sellebjerg Finn Sellebjerg Patrick Vermersch Hulin Jin Anita Chudecka Andreas Kloetgen Dongdong Lin Lidia Gardner Nicola De Stefano Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study Frontiers in Immunology multiple sclerosis cladribine tablets biomarkers transcriptomics, immunophenotyping immune reconstitution therapy |
| title | Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study |
| title_full | Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study |
| title_fullStr | Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study |
| title_full_unstemmed | Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study |
| title_short | Blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets: results of the 2-year MAGNIFY-MS study |
| title_sort | blood biomarker dynamics in people with relapsing multiple sclerosis treated with cladribine tablets results of the 2 year magnify ms study |
| topic | multiple sclerosis cladribine tablets biomarkers transcriptomics, immunophenotyping immune reconstitution therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1512189/full |
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