Changes in lymphocytes, neutrophils and immunoglobulins in year-1 cladribine treatment in multiple sclerosis

Spiezia, Antonio Luca; Cerbone, Vincenza; Molinari, E; Capasso, Nicola; Lanzillo, Roberta; Carotenuto, Antonio; Petracca, Maria; Novarella, Federica; Covelli, Bianca; Scalia, Giulia; Morra, Vincenzo Brescia; Moccia, Marcello

doi:10.1016/j.msard.2021.103431

Cited by 8 publications

(15 citation statements)

References 10 publications

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“…By contrast, memory B cells remained close to their lower nadir level to month 12. This confirms the findings from a small observational study of Italian patients treated with cladribine tablets 21 and those from a cross-sectional study of people with MS treated with a different preparation of cladribine. 22 The strong association between the time course of B-cell subtype depletion and the apparent inhibition of new lesion evolution on MRI demonstrated in MAGNIFY-MS, as well as the sustained and significant reduction in memory B cells over at least 12 months, suggest an important role of this specific B-cell subset for sustained disease control in people with MS. 5 , 23 Monoclonal B-cell depleting antibodies such as alemtuzumab, 24 ocrelizumab, 25 or rituximab 26 (although the latter is not licensed, it is commonly used off-label in people with MS) 27 lead to similar patterns of rapid and general B-cell depletion followed by reconstitution of B-cell subsets, except for memory B cells.…”

Section: Discussionsupporting

confidence: 88%

Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets

Wiendl

Schmierer

Hodgkinson

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesCladribine tablets cause a reduction in lymphocytes with a predominant effect on B-cell and T-cell counts. The MAGNIFY-MS substudy reports the dynamic changes on multiple peripheral blood mononuclear cell (PBMC) subtypes and immunoglobulin (Ig) levels over 12 months after the first course of cladribine tablets in patients with highly active relapsing multiple sclerosis (MS).MethodsImmunophenotyping was performed at baseline (predose) and at the end of months 1, 2, 3, 6, and 12 after initiating treatment with cladribine tablets. Assessments included lymphocyte subtype counts of CD19+B cells, CD4+and CD8+T cells, CD16+natural killer cells, plasmablasts, and Igs. Immune cell subtypes were analyzed by flow cytometry, and serum IgG and IgM were analyzed by nephelometric assay. Absolute cell counts and percentage change from baseline were assessed.ResultsThe full analysis set included 57 patients. Rapid reductions in median CD19+, CD20+, memory, activated, and naive B-cell counts were detected, reaching nadir by month 2. Thereafter, total CD19+, CD20+, and naive B-cell counts subsequently reconstituted, but memory B cells remained reduced by 93%–87% for the remainder of the study. The decrease in plasmablasts was slower, reaching nadir at month 3. Decrease in T-cell subtypes was also slower and more moderate compared with B-cell subtypes, reaching nadir between months 3 and 6. IgG and IgM levels remained within the normal range over the 12-month study period.DiscussionCladribine tablets induce a specific pattern of early and sustained PBMC subtype dynamics in the absence of relevant Ig changes: While total B cells were reduced dramatically, T cells were affected significantly less. Naive B cells recovered toward baseline, naive CD4 and CD8 T cells did not, and memory B cells remained reduced. The results help to explain the unique immune depletion and repopulation architecture regarding onset of action and durability of effects of cladribine tablets while largely maintaining immune competence.Trial Registration InformationClinicalTrials.govIdentifier:NCT03364036. Date registered: December 06, 2017.

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Section: Discussionsupporting

confidence: 88%

Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets

Wiendl

Schmierer

Hodgkinson

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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“… 21 This is somewhat unexpected on the basis that cladribine has been shown to significantly reduce levels of antibody-producing CD19 + B cells as well as T lymphocytes. 4 , 11 , 19 One possible explanation for this is that the CD19 + B cell suppression seen with cladribine is transient, with levels returning towards threshold within 30 weeks. 11 This supports the concept that cladribine acts via immune reconstitution rather than long-term immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…17,18 To date, there is limited evidence of the effect of cladribine on immunoglobulin levels when used as the lower oral doses in RRMS, with a single small retrospective study suggesting no change in the first year after dosing. 19 This is important as low immunoglobulin levels, particularly low IgM and IgG, have been correlated with infection risk in patients on B cell targeting therapies and in patients with acquired or genetic immunodeficiency syndromes. [12][13][14][15]20 The use of cladribine in RRMS has been associated with an increased risk of some infections, particularly herpes zoster.…”

Section: Introductionmentioning

confidence: 99%

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The effect of cladribine on immunoglobulin levels compared to B cell targeting therapies in multiple sclerosis

Lycett

Lea

Maltby

et al. 2023

Multiple Sclerosis Journal - Experimental, Translational and Cl

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Background Cladribine is a useful therapeutic option in RRMS with moderate to high disease activity. Its oral formulation and tolerability make it a useful alternative to infusion therapies. Cladribine is known to deplete CD19+ B lymphocytes, but its effect on immunoglobulin subsets is unclear. Objective To identify whether cladribine therapy in pwMS reduces immunoglobulin subset levels as a surrogate marker of infection risk. Methods A ‘real-world’ retrospective analysis of 341 pwMS presenting to a single tertiary centre between March 2017 and July 2021. Differences in immunoglobulin levels between cladribine, other disease-modifying therapies and no active treatment were assessed using a univariate ANOVA. Results Three hundred and forty-one patients had immunoglobulin levels assessed, with 29 patients treated with cladribine. The mean IgG, IgM and IgA levels on cladribine therapy were 10.44 ± 0.40, 0.99 ± 0.09 and 2.04 ± 0.18 g/L respectively. These were not significantly different from patients not on active treatment. There was a statistically significant reduction in IgG and IgM levels for patients treated with ocrelizumab (9.37 ± 0.19 and 0.68 ± 0.04 g/L) and natalizumab (8.72 ± 0.53 and 0.69 ± 0.12 g/L) compared to patients not on treatment. Conclusion Cladribine therapy for RRMS was not associated with immunoglobulin subset deficiencies. This is contrasted to ocrelizumab and natalizumab which demonstrate significant reductions in both IgG and IgM levels.

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“…In clinical studies of cladribine, 87% of cladribine-treated patients experienced lymphopenia, and reductions in lymphocyte count were dose dependent. The lowest absolute lymphocyte counts occurred ~ 2-3 months after the start of each treatment course and were lower with each subsequent course [41]; hypogammaglobulinemia has not been described for patients with MS taking cladribine [94]. Cases of severe (including fatal) neutropenia (low neutrophil counts) within 2 months of alemtuzumab infusion, and mild to moderate decreases in platelet counts (starting at the time of alemtuzumab infusion and often resolving without treatment), have also been reported [42].…”

Section: Hematologic Abnormalitiesmentioning

confidence: 99%

High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing–Remitting Multiple Sclerosis

et al. 2022

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There are > 18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). Given the multitude of available treatment options, and recent international consensus guidelines offering differing recommendations, there is broad heterogeneity in how the DMTs are used in clinical practice. Choosing a DMT for newly diagnosed patients with MS is currently a topic of significant debate in MS care. Historically, an escalation approach to DMT was used for newly diagnosed patients with RRMS. However, the evidence for clinical benefits of early treatment with high-efficacy therapies (HETs) in this population is emerging. In this review, we provide an overview of the DMT options and MS treatment strategies, and discuss the clinical benefits of HETs (including ofatumumab, ocrelizumab, natalizumab, alemtuzumab, and cladribine) in the early stages of MS, along with safety concerns associated with these DMTs. By minimizing the accumulation of neurological damage early in the disease course, early treatment with HETs may enhance long-term clinical outcomes over the lifetime of the patient.

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Changes in lymphocytes, neutrophils and immunoglobulins in year-1 cladribine treatment in multiple sclerosis

Cited by 8 publications

References 10 publications

Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets

Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets

The effect of cladribine on immunoglobulin levels compared to B cell targeting therapies in multiple sclerosis

High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing–Remitting Multiple Sclerosis

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