Approach to Fingolimod‐Induced Lymphopenia in Multiple Sclerosis Patients: Do We Have a Roadmap?

Avasarala, Jagannadha; Jain, Sandip; Urrea-Mendoza, Enrique

doi:10.1002/jcph.945

Cited by 9 publications

(6 citation statements)

References 15 publications

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“…These data are in line with several studies presenting primarily mild to moderate infections during fingolimod ( 8 , 18 , 28 ) The most relevant infectious complication in fingolimod treated patients is defined by varicella-zoster virus (VZV) and herpes simplex virus (HSV) infection or reactivation ( 8 , 18 , 33 ). However, individual variation of VZV specific T cell responses are assumed to be more relevant for upcoming VZV activation rather than absolute lymphocyte counts ( 34 , 35 ). Up to date, we are not able to confirm that monitoring of absolute lymphocyte count or its subtypes can assist to predict higher infectious risk at lymphocyte counts of 0.2 GPT/l.…”

Section: Discussionmentioning

confidence: 99%

“…Up to date, we are not able to confirm that monitoring of absolute lymphocyte count or its subtypes can assist to predict higher infectious risk at lymphocyte counts of 0.2 GPT/l. Instead, cases of severe upcoming disease activity after fingolimod cessation because of lymphopenia (< 0.2 GPT/l) are known ( 35 , 36 ). Though, fingolimod interruption on the basis of lymphopenia of < 0.2 GPT/l has to be critically discussed in the individual context.…”

Section: Discussionmentioning

confidence: 99%

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Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients

et al. 2018

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Objective:Fingolimod is approved for the treatment of highly active relapsing remitting multiple sclerosis (MS) patients and acts by its unique mechanism of action via sphingosine-1-phosphate receptor-modulation. Although fingolimod-associated lymphopenia is a well-known phenomenon, the exact cause for the intra- and inter-individual differences of the fluctuation of lymphocyte count and its subtypes is still subject of debate. In this analysis, we aim to estimate the significance of the individual variation of distinct lymphocyte subsets for differences in absolute lymphocyte decrease in fingolimod treated patients and discuss how different lymphocyte subset patterns are related to clinical presentation in a long-term real life setting.Methods/Design:One hundred and thirteen patients with MS were characterized by complete blood cell count and immune cell phentopying of peripheral lymphocyte subsets before, at month 1 and every 3 months up to 36 months of fingolimod treatment. In addition, patients were monitored regarding clinical parameters (relapses, disability, MRI).Results:There was no significant association of baseline lymphocyte count and lymphocyte subtypes with lymphocyte decrease after fingolimod start. The initial drop of the absolute lymphocyte count could not predict the level of lymphocyte count during steady state on fingolimod. Variable CD8+ T cell and NK cell counts account for the remarkable intra- and inter-individual differences regarding initial drop and steady state level of lymphocyte count during fingolimod treatment, whereas CD4+ T cells and B cells mostly present a quite uniform decrease in all treated patients. Selected patients with lymphocyte count >1.0 GPT/l differed by higher CD8+ T cells and NK cell counts compared to lymphopenic patients but presented comparable clinical effectiveness during treatment.Conclusion:Monitoring of the absolute lymphocyte count at steady state seems to be a rough estimate of fingolimod induced lymphocyte redistribution. Our results suggest, that evaluation of distinct lymphocyte subsets as CD4+ T cells allow a more detailed evaluation to weigh and interpret degree of lymphopenia and treatment response in fingolimod treated patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients

et al. 2018

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“…As such, unexpected adverse effects on lymphocyte counts differ for the individual DMTs. Some of these laboratory changes have been associated with an increased risk of infections or other adverse clinical events [9][10][11][12][13]. The total number of lymphocytes (extent of lymphopenia), distinct changes in the overall leukocyte subpopulations, as well as the timing and sequence of immune reconstitution following cell depletion, have been related to possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations.…”

Section: Introductionmentioning

confidence: 99%

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

et al. 2020

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Modern disease-modifying therapies (DMTs) in multiple sclerosis (MS) have variable modes of action and selectively suppress or modulate the immune system. In this review, we summarize the predicted and intended as well as unwanted adverse effects on leukocytes in peripheral blood as a result of treatment with DMTs for MS. We link changes in laboratory tests to the possible therapeutic risks that include secondary autoimmunity, infections, and impaired response to vaccinations. Profound knowledge of the intended effects on leukocyte counts, in particular lymphocytes, explained by the mode of action, and adverse effects which may require additional laboratory and clinical vigilance or even drug discontinuation, is needed when prescribing DMTs to treat patients with MS.

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“…However, no recommendations exist for grade 3 (i.e., < 300/mm 3 ) sustained (more than 6 months) lymphopenia, despite the theoretical risk for severe infections, whilst the need for treatment interruptions to manage lymphopenic events are not exempt of risk of relapses for the subjects. 3,4,5 On the other hand, although the association of lymphopenia with medicinal products that block the S1P receptor, like ngolimod or siponimod, among others, is well known, uncertainties regarding the factors accounting for the high inter and intraindividual variability observed in the frequency and magnitude of lymphopenia still remain. [6][7][8][9] Although grade 4 lymphopenia was reported in 3.3% of patients treated with siponimod 2 mg in the previous double-blind trials, 1 we hypothesized that higher rates of severe lymphopenia would occur in clinical practice given the restrictive selection criteria applied in the clinical trials, 1 which might have underestimated the actual magnitude of the risk.…”

Section: Introductionmentioning

confidence: 99%

Title: The need for a closer monitoring of novel drugs in MS: a Siponimod retrospective cohort study (Realhes Study)

Sancho-Lopez

Ruíz-Antorán

Hernán-Gómez

et al. 2023

Preprint

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Background Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile.Objective To evaluate the incidence of lymphopenia during the first 3–6 months of siponimod treatment in clinical practice. Secondary objectives include analyses of factors predisposing to and the clinical relevance of lymphopenia events.Methods In this multicenter retrospective cohort study, collected information from the medical records of 129 patients with MS, from 15 tertiary hospitals in Spain, who initiated treatment with siponimod, were followed-up for at least 3 months and had at least one lymphocyte count evaluation.Results Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade ≤ 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for Grade ≤ 3 and Grade 4 lymphopenia, respectively).Conclusion In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow up studies to properly characterize this risk.Trial registration EU PAS Register (http://encepp.eu), identifier #EUPAS45187 (January 17, 2022)

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Approach to Fingolimod‐Induced Lymphopenia in Multiple Sclerosis Patients: Do We Have a Roadmap?

Cited by 9 publications

References 15 publications

Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients

Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

Title: The need for a closer monitoring of novel drugs in MS: a Siponimod retrospective cohort study (Realhes Study)

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