Time course of lymphocyte repopulation after dimethyl fumarate-induced grade 3 lymphopenia: contribution of patient age

Briner, Myriam; Bagnoud, Maud; Miclea, Andrei; Friedli, Christoph; Diem, Lara; Chan, Andrew T.; Hoepner, Robert; Salmen, Anke

doi:10.1177/1756286419843450

Cited by 25 publications

(19 citation statements)

References 8 publications

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“…Therefore, these data demonstrate that the use of DMF per label recommendations generally allows for lymphocyte recovery within 2-4 months, similar to data observed in a smaller study. 16 Of the patients with severe, prolonged lymphopenia in this analysis, there were no differences in rates of serious or opportunistic infections, and the majority did not have a relapse in the 6 months after DMF discontinuation. There is no washout recommended between stopping DMF (per country-specific guidelines) and starting an alternate DMT.…”

Section: Discussionmentioning

confidence: 70%

“…Therefore, time to ALC recovery will be longer for patients with severe rather than mild lymphopenia at discontinuation, confirming previous smaller studies. 16,17 On average, ALC reconstitution is linear for the first 8 weeks after DMF discontinuation, and then the recovery rate slows (figures 2 and 4A). Lymphocyte reconstitution is influenced by duration of severe lymphopenia on DMF, as suggested by the 38 patients with severe, prolonged lymphopenia who recovered to ≥LLN in ;12-18 months.…”

Section: Discussionmentioning

confidence: 97%

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Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS

et al. 2020

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BackgroundDelayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF.MethodsData sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation.ResultsThe majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC ≥0.8 × 109/L was 2–4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC ≥0.91 × 109/L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation; rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for ≥3 years, lymphocyte reconstitution to ≥0.91 × 109/L was 12–18 months vs 2–3 months in patients with lymphopenia persisting <6 months.ConclusionsThe majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2–4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 97%

Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS

et al. 2020

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“…Recently, a single case of a 78-yearold PPMS patient treated with ocrelizumab without prior immunotherapy was reported to develop and succumb to PML (Roche, data on file). Immunosenescence may contribute to a heightened risk of PML also for patients treated with DMF and fingolimod [81]. Additional cases of PML occurred during ocrelizumab therapy in patients switched from natalizumab or fingolimod (so-called carryover cases) (Roche and Novartis, data on file).…”

Section: Progressive Multifocal Leukoencephalopathy (Pml)mentioning

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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“…Lymphopenia is also a fairly common and potentially dangerous side effect of DMF seen in approximately 16.5% of patients,28 contributing to the development of infections such as upper respiratory infections. More serious opportunistic infections, such as progressive multifocal leukoencephalopathy (PML) may also occur in patients on DMF.…”

Section: Dimethyl Fumaratementioning

confidence: 99%

<p>Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives</p>

Ozel

Vaughn

Eckert

et al. 2019

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Dimethyl fumarate (DMF) is a commonly prescribed oral medication for the treatment of relapsing forms of multiple sclerosis (MS) with a wide range of hypothesized downstream mechanisms of action. Randomized clinical trials have established its clinical efficacy by using standard objective clinical measures. However, MS is a chronic disease that, apart from physical ailments, can affect an individual’s mood, psychosocial status, and quality of life which cannot be captured by using only objective assessment tools. Given the challenge of determining the efficacy of the treatment in a real-world clinical setting, the use of patient-reported outcomes (PROs) may help us to better address these aspects of patient care and establish a more patient-centered approach to MS care. To date, a review of PubMed identified six studies which reported on PROs in patients who are taking DMF. In total, twelve different kinds of PRO measures were utilized and 6359 patients provided at least one form of PRO in these studies. Upon review of these studies, we were able to conclude that people with MS had decreased quality of life compared to the healthy population in the US. MS patients on DMF, however, had better health-related quality of life assessment scores compared to those using a placebo. Previous studies also suggested that DMF decreased work productivity impairment scores after one year of use compared to baseline. DMF was associated with less impairment in fatigue and depression scales along with improved treatment quality assessment and adherence scores. This review will present a brief synopsis of the published literature and will provide indications for future directions with respect to PROs and DMF in people with MS.

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Time course of lymphocyte repopulation after dimethyl fumarate-induced grade 3 lymphopenia: contribution of patient age

Cited by 25 publications

References 8 publications

Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS

Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS

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

<p>Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives</p>

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