Monday, 21 December 2015

ClinicSpeak: influence of fingolimod on peripheral blood lymphocyte subsets

Are you a fingolimoder? Are you aware about opportunistic infections? #ClinicSpeak #MSBlog #MSResearch

"The study below looks at relative changes in peripheral blood lymphocyte changes after starting fingolimod. Not surprising there are profound changes in the peripheral blood subsets. What does it mean? Not a lot. Please note that circulating lymphocytes in the blood only represent ~2% of the total body lymphocyte count and are not an accurate indicator of the body’s total lymphocyte count and function. This is particularly relevant to fingolimod, which is a non-depleting agent and traps lymphocytes in the peripheral lymph nodes. Following fingolimod discontinuation lymphocyte counts return to be within the normal range within 6-8 weeks and are above 80% of baseline values by 3 months. However, in a few MSers who have been on fingolimod for prolonged periods of time it may take much longer to repopulate their peripheral blood. At present we don't know much about these slow repopulators, but we need to be vigilant and identify them, particularly if we want to treat them with induction therapies."

"Please note that lymphopaenia in a fingolimod-treated MSer differs to most other forms of lymphopaenia; therapeutic dosing with fingolimod reduces the so called naïve and memory T cells, but not the effector memory T cells (the cells that fight infections). This occurs because naïve T cells and central memory T cells express a homing receptor that allows them to recirculate back to lymph nodes on a regular basis and allows them to get trapped in the lymph nodes by fingolimod. Therefore low lymphocyte counts in fingolimod-treated MSers does not have the same biological implications as low lymphocyte counts in other situations. Importantly, the effectiveness of fingolimod and adverse events is not related to the peripheral lymphocyte counts. As a result of this the FDA licensed fingolimod in the US without a mandatory requirement for lymphocyte monitoring. In contrast the European Medicine Agency (EMA) has recommended the need to check peripheral lymphocyte counts before initiating treatment and have recommended periodic testing at months 3 and then at least yearly after that. The EMA states that if an absolute lymphocyte count of less than 200 (<0.2x10**9/L) is confirmed, it should lead to treatment interruption until the lymphocyte count recovers. In the clinical studies ~20% of study subjects had a least one lymphocyte count below this level. Translating this to clinical practice it would mean that approximately 1 in 5 MSers on fingolimod would need to have their treatment stopped, interrupted or dose of fingolimod changed in response to this level of lymphopaenia. This is affecting how we use the drug in clinical practice and is resulting, in my opinion, a large number of unnecessary treatment interruptions. Therefore, several colleagues and I, have started using a lower threshold of <100 (0.1x10**9/L) as the cut-off for treatment interruptions; this means far fewer disruptions in the dosing schedule for our patients on fingolimod, makes it easier to use the drug in clinical practice, and brings us much closer to the clinical practice in the United States. We anticipate that additional evidence will emerge from the open-label extension and post-marketing surveillance studies, and real-life registers, to assess the clinical consequences of these recommendations. Until we get more clarity on this we have recommended more frequent blood count monitoring in MSers with lymphocyte counts less than 200, i.e. 3 monthly."

"We know that fingolimod is an immunosuppressive drug and is associated with opportunistic infections, for example PML and cryptococcal meningitis. Although these infections are uncommon we can't really derisk fingolimod in the same way we can with other drugs by stopping the drug when the total lymphocyte count drops below a critical cut-off value. All we can do is warn fingolimoders about the risk and ask them to be vigilant. So if you are a fingolimoder please don't ignore new symptoms; if in doubt report them."

BACKGROUND: Fingolimod is a drug administered orally to adult patients treated for relapsing remitting course of multiple sclerosis (MS). Mode of action of fingolimod is based on intense S1P1 receptor stimulation and "arresting" lymphocytes in lymphatic organs. Objective of the research was to assess changes in the frequencies of basic lymphocyte subsets in patients treated for multiple sclerosis with the use of fingolimod.

MATERIAL AND METHODS: Study group comprised of 25 previously untreated adult patients with MS. Venous blood samples were collected from each patient before and one month, three months and six months after treatment initiation. Peripheral blood lymphocyte immunophenotype was assessed with a set of monoclonal antibodies bounded to appropriate fluorochromes and flow cytometer FACSCalibur. Statistical analysis of the results was conducted using Statistica 9.0 software.

RESULTS: Before fingolimod administration median of lymphocyte subsets percentage in each patient was in reference range. After 1 month of treatment we noticed significant changes in frequencies of following lymphocyte subsets: NK cells - 51.22% (p = 0.016), T CD4+ cells - 11.58% (p = 0.01), T CD4+:T CD8+ cells ratio - 0.61 (p = 0.005). After 3 and 6 months of treatment there was further increase of deviation from normal state.

CONCLUSIONS: The use of fingolimod is associated with profound changes in lymphocyte subsets distribution, which might bear a risk of the development of cellular immune deficiency symptoms.

CoI: multiple


  1. Is it true: risk of PML: Gilenya = Tecfidera
    In this case, Gilenya is the better option (NEDA4).

  2. Could you please confirm if you are still advocating a lower threshold of <100 (0.1x10**9/L) as the cut-off for treatment interruptions? I am at 0.2 for several months and need to make the decision whether to continue taking Gilenya.

    1. Where are you living? In the USA they would ignore a 0.2 results In Europe the advice for someone at 0.2 is to continue as is. If the counts drop below 0.2 alternate day dosing is recommended. Regarding side effects and adverse events they are as likely to occur in someone with a lymphocyte count above 0.2 as below 0.2.


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