Immunological consequences of cladribine treatment in multiple sclerosis: A real-world study

Rolfes, Leoni; Pfeuffer, Steffen; Huntemann, Niklas; Schmidt, Mariella; Su, Chuanxin; Škuljec, Jelena; Aslan, Derya; Hackert, Jana; Kleinschnitz, Konstanze; Hagenacker, Tim; Pawlitzki, Marc; Ruck, Tobias; Kleinschnitz, Christoph; Meuth, Sven G.; Pul, Refik

doi:10.1016/j.msard.2022.103931

Cited by 16 publications

(16 citation statements)

References 21 publications

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“…Noticeably, two of three cases of oral herpes occurred in nonelderly adult patients coming from a previous DMF treatment, whereas one was not previously treated. This aligns with recent literature [20], which reported that herpes infections predominantly occurred in patients who had received DMF as prior therapy.…”

Section: Discussionsupporting

confidence: 92%

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop)

Schiavetti,

Signori,

Albanese

et al. 2024

Euro J of Neurology

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Background and purposeCladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited.MethodsThis retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2‐year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2‐year treatment course.ResultsA total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12‐month follow‐up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event.ConclusionsThis study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real‐world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long‐term impact are necessary.

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Section: Discussionsupporting

confidence: 92%

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop)

Schiavetti,

Signori,

Albanese

et al. 2024

Euro J of Neurology

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“…Whereas the anti-inflammatory activity of cladribine has been attributed to the depletion of memory B cells [26], seroconversion and protection after vaccination upon vaccination in cladribine-treated MS patients are likely the result of immature/naïve B-cell repopulation, occurring after the development of a 1 to 3% B-cell repopulation [27]. In our previous study, we showed that cladribine-treated patients maintained 1% B cell levels and CD19+ B cells recovered to at least 10-20 CD19+ B cells/µL rapidly after cladribine dosing [5]. Therefore, the selective kinetics of lymphocyte repopulation induced by cladribine, including incomplete reduction and subsequent prompt recovery of immature/naïve B cells [26], may explain why vaccine responses in cladribine-treated MS patients resembled those treated with platform DMTs.…”

Section: Discussionmentioning

confidence: 90%

“…Cladribine is a synthetic purine analogon that induces lymphocyte depletion due to an accumulation of intracellular chloro-deoxyadenosine triphosphate. Immunophenotyping studies showed that cladribine only modestly affects T cells, whereas it vastly reduces B-cell counts [5], particularly class-switched and unswitched memory B cells [6,7].…”

Section: Introductionmentioning

confidence: 99%

Immune Response to Seasonal Influenza Vaccination in Multiple Sclerosis Patients Receiving Cladribine

Rolfes

Pfeuffer

Škuljec³

et al. 2023

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Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration.

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“…Cladribine is a purine nucleoside analog that has shown to be an effective treatment for multiple sclerosis patients ( 14 – 18 ). Since cladribine tablets have also been shown to affect total CD19+ B cells during the treatment of MS patients ( 19 – 21 ), we were now interested in the effects of cladribine treatment on peripheral blood B cell repertoires.…”

Section: Introductionmentioning

confidence: 99%

Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients

et al. 2023

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IntroductionB cells are acknowledged as crucial players in the pathogenesis of multiple sclerosis (MS). Several disease modifying drugs including cladribine have been shown to exert differential effects on peripheral blood B cell subsets. However, little is known regarding functional changes within the peripheral B cell populations. In this study, we obtained a detailed picture of B cell repertoire changes under cladribine treatment on a combined immunoglobulin (Ig) transcriptome and proteome level.MethodsWe performed next-generation sequencing of Ig heavy chain (IGH) transcripts and Ig mass spectrometry in cladribine-treated patients with relapsing-remitting multiple sclerosis (n = 8) at baseline and after 6 and 12 months of treatment in order to generate Ig transcriptome and Ig peptide libraries. Ig peptides were overlapped with the corresponding IGH transcriptome in order to analyze B cell clones on a combined transcriptome and proteome level.ResultsThe analysis of peripheral blood B cell percentages pointed towards a significant decrease of memory B cells and an increase of naive B cells following cladribine therapy. While basic IGH repertoire parameters (e.g. variable heavy chain family usage and Ig subclasses) were only slightly affected by cladribine treatment, a significantly decreased number of clones and significantly lower diversity in the memory subset was noticeable at 6 months following treatment which was sustained at 12 months. When looking at B-cell clones comprising sequences from the different time-points, clones spanning between all three time-points were significantly more frequent than clones including sequences from two time-points. Furthermore, Ig proteome analyses showed that Ig transcriptome specific peptides could mostly be equally aligned to all three time-points pointing towards a proportion of B-cell clones that are maintained during treatment.DiscussionOur findings suggest that peripheral B cell related treatment effects of cladribine tablets might be exerted through a reduction of possibly disease relevant clones in the memory B cell subset without disrupting the overall clonal composition of B cells. Our results -at least partially- might explain the relatively mild side effects regarding infections and the sustained immune response after vaccinations during treatment. However, exact disease driving B cell subsets and their effects remain unknown and should be addressed in future studies.

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Immunological consequences of cladribine treatment in multiple sclerosis: A real-world study

Cited by 16 publications

References 21 publications

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop)

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop)

Immune Response to Seasonal Influenza Vaccination in Multiple Sclerosis Patients Receiving Cladribine

Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients

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