Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres

Pfeuffer, Steffen; Rolfes, Leoni; Hackert, Jana; Kleinschnitz, Konstanze; Ruck, Tobias; Wiendl, Heinz; Klotz, Luisa; Kleinschnitz, Christoph; Meuth, Sven G.; Pul, Refik

doi:10.1177/13524585211012227

Cited by 52 publications

(62 citation statements)

References 22 publications

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“…Despite analyzing a cohort substantially comparable in terms of sample size and demographic- and disease-related features to the one recruited from Germany tertiary centers [ 12 ], we did not identify any prior exposure to specific DMTs as risk factor for suboptimal response to cladribine.…”

Section: Discussionmentioning

confidence: 96%

“…More recently, additional analyses suggested a better response in patients with high disease activity in the year prior to cladribine start [ 9 ], regardless of their pre-enrollment treatment status (naïve or previously treated) [ 10 ]. Data from real-world studies, including less disabled patients with RRMS with shorter disease duration and a larger variety of previous treatments compared with the RCTs, have suggested suboptimal disease control in cladribine-treated patients switching from natalizumab [ 11 ], and a higher risk of severe lymphopenia and subsequent herpes virus infections in patients previously treated with dimethyl fumarate [ 12 ]. As the MS therapeutic portfolio continues to expand, the identification and confirmation of potential risk factors of suboptimal response to specific disease-modifying therapies (DMTs) is of fundamental value.…”

Section: Introductionmentioning

confidence: 99%

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Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study

et al. 2022

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Introduction Cladribine administration has been approved for the treatment of relapsing–remitting multiple sclerosis (MS) in 2017; thus, data on cladribine in a real-world setting are still emerging. Methods We report on cladribine effectiveness, safety profile, and treatment response predictors in 243 patients with MS followed at eight tertiary MS centers. Study outcomes were: (1) No Evidence of Disease Activity-3 (NEDA-3) status and its components (absence of clinical relapses, MRI activity, and sustained disability worsening); (2) development of grade III/IV lymphopenia. The relationship between baseline features and the selected outcomes was tested via multivariate logistic models. Results Of the 243 subjects included in the study (66.5% female, age 34.2 ± 10 years, disease duration 6.6 ± 9.6 years), 64% showed NEDA-3 at median follow-up (22 months). Patients with higher number of previous treatments had lower probability to retain NEDA-3 [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.41–0.98, p = 0.04] and were more prone to experience clinical relapses (OR 1.6, 95% CI 1–2.6, p = 0.04). The presence of active lesions at baseline was associated with follow-up magnetic resonance imaging (MRI) activity (OR 1.92, 95% CI 1.04–3.55, p = 0.04). Patients with higher rate of relapses in the year prior to cladribine start were at higher risk of developing sustained disability worsening (OR 2.95% CI 1–4.2, p = 0.04). Lymphopenia grade III/IV over the follow-up was associated with baseline lymphocyte count (OR 0.998, 95% CI 0.997–0.999, p = 0.01). Conclusion In this large cohort, we confirm previous data about cladribine effectiveness on disease activity and disability worsening and provide information on response predictors that might inform therapeutic choices.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study

et al. 2022

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“…However, regarding confirmed disease progression for 6 months, NEDA, and overall adverse event risk, oral cladribine did not differ significantly from most alternative DMDs ( 54 ). A recent study on 270 MS patients from Germany, reported that patients switching from natalizumab to cladribine tablets were prone to re-emerging disease activity ( 55 ). Similarly, recent evidence from patients switching from natalizumab to other DMDs shows that cladribine has a higher risk for relapses and MRI activity than ocrelizumab, but similar to rituximab ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

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BackgroundMultiple sclerosis (MS) is an incurable autoimmune disease mediated by a heterogeneous T cell population (CD3+CD161+CXCR3−CCR6+IFNγ−IL17+, CD3+CXCR3+CCR6+IFNγ+IL17+, and CD3+CXCR3+IFNγ+IL17− phenotypes) that infiltrates the central nervous system, eliciting local inflammation, demyelination and neurodegeneration. Cladribine is a lymphocyte-depleting deoxyadenosine analogue recently introduced for MS therapy as a Disease Modifying Drug (DMD). Our aim was to establish a method for the early identification and prediction of cladribine responsiveness among MS patients.MethodsAn experimental model was designed to study the cytotoxic and immunomodulatory effect of cladribine. T cell subsets of naïve relapsing-remitting MS (RRMS) patients were analyzed ex vivo and in vitro comparatively to healthy controls (HC). Surviving cells were stimulated with rh-interleukin-2 for up to 14days. Cell proliferation and immunophenotype changes were analyzed after maximal (phorbol myristate acetate/ionomycin/monensin) and physiological T-cell receptor (CD3/CD28) activation, using multiparametric flow cytometry and xMAP technology.ResultsEx vivo CD161+Th17 cells were increased in RRMS patients. Ex vivo to in vitro phenotype shifts included: decreased CD3+CCR6+ and CD3+CD161+ in all subjects and increased CD3+CXCR3+ in RRMS patients only; Th17.1 showed increased proliferation vs Th17 in all subjects; CD3+IL17+ and CD3+IFNγ+IL17+ continued to proliferate till day 14, CD3+IFNγ+ only till day 7. Regarding cladribine exposure: RRMS CD3+ cells were more resistant compared to HC; treated CD3+ cells proliferated continuously for up to 14 days, while untreated cells only up to 7 days; both HC/RRMS CD3+CXCR3+ populations increased from baseline till day 14; in RRMS patients vs HC, IL17 secretion from cladribine-treated cells increased significantly, in line with the observed proliferation of CD3+IL17+ and CD3+IFNγ+IL17+ cells; in both HC/RRMS, cladribine led to a significant increase in CD3+IFNγ+ cells at day 7 only, having no further effect at day14. IFNγ and IL17 secreted in culture media decreased significantly from ex vivo to in vitro.ConclusionsCD3+ subtypes showed different responsiveness due to selectivity of cladribine action, in most patients leading to in vitro survival/proliferation of lymphocyte subsets known as pathogenic in MS. This in vitro experimental model is a promising tool for the prediction of individual responsiveness of MS patients to cladribine and other DMDs.

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“…As older patients with MS in the real world are likely to have received prior DMTs, it is unclear how immunosenescence and prior DMT use might impact the effect of cladribine tablets in these patients; this is a subject that requires further research. Recently published realworld studies of cladribine tablets patients (mostly non-elderly) who switched from another DMT showed that cladribine's effect on lymphocyte changes and clinical and magnetic resonance imaging outcomes were broadly similar in those who were previously untreated compared with those previously treated with DMF, fingolimod, beta-interferons, glatiramer acetate, or teriflunomide (29,30). Adverse events were also shown to be similar in a small group of patients treated with cladribine, ocrelizumab or rituximab after immediate prior natalizumab use.…”

Section: Discussionmentioning

confidence: 99%

Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets

et al. 2021

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Cladribine tablets (CladT) preferentially reduce B and T lymphocyte levels. As aging is associated with a decline in immune function, the effect of CladT on lymphocyte levels may differ by age. This post hoc analysis combined data from the Phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies to examine the effect of age (≤50 or >50 years) on lymphopenia following CladT 3.5 mg/kg (CladT3.5; cumulative dose over 2 years) treatment over 96 weeks. Both CladT3.5 and placebo were given over Weeks 1 and 5 (Year 1 treatment) and Weeks 48 and 52 (Year 2 treatment) from the start of the studies. Absolute lymphocyte count (ALC) and levels of lymphocyte subsets were examined in 1564 patients (Age ≤50 [placebo: N=566; CladT3.5: N=813]; Age >50 [placebo: N=75; CladT3.5: N=110]). In both age groups, following CladT3.5 treatment, nadir for ALC occurred at Week 9 (8 weeks following start of Year 1 treatment) and Week 55 (7 weeks following start of Year 2 treatment) of the 96-week period; for CD19+ B lymphocytes, nadir occurred at Week 9 (Year 1) and Week 52 (Year 2). For CD4+ T lymphocytes, nadir occurred at Week 16 (Year 1) in both age groups, and at Weeks 60 and 72 (Year 2) in the Age ≤50 and >50 groups, respectively. Nadir for CD8+ T lymphocytes occurred at Week 16 (Year 1) and Week 72 (Year 2) in the Age ≤50 group and levels remained in the normal range; nadir occurred at Week 9 (Year 1) and Week 96 (Year 2) in the Age >50 group. Lymphocyte recovery began soon after nadir following CladT3.5 treatment and median levels reached normal range by end of the treatment year in both age groups. By Week 96, ~25% of patients treated with CladT3.5 reported ≥1 episode of Grade ≥3 lymphopenia (Gr≥3L). The rate of certain infections was numerically higher in older versus younger patients who experienced Gr≥3L. In conclusion, CladT3.5 had a similar effect on ALC and lymphocyte subsets in both younger and older patient groups.

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Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres

Cited by 52 publications

References 22 publications

Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study

Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets

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