Low lymphocyte counts on Tecfidera in MS


The degree of efficacy of MS drugs equates to the degree of immunosuppression. The latter is not the result of anything convoluted, but simply due to a depletion in lymphocyte counts (also called treatment related lymphopenia). Even drugs that proport not to be immunosuppressive (fingolimod and natalizumab) are immunosuppressive, but in a compartmentalized fashion. This explains the risk of zoster infections with fingolimod and PML with natalizumab.

Those that lack immunosuppressive effects fall into the category of immunomodulators. These include the injectables and to a large extent teriflunomide (aubagio), i.e. the platform or 1st line therapies and comprise the bulk of MS therapies prescribed.

So, why is it important to know whether the drug you’re on is immunosuppressive or immunomodulatory?

Outside of efficacy, immunosuppression is associated with an increase in side effects; namely infections. Often repeated peripheral blood counts are performed on a regular basis to monitor lymphocyte counts and regulatory agencies are very pedantic on their frequency based on a perceived likelihood of occurrence.

Figure: Lymphopenia and the risk of infection-related deaths (source:PLOS ONE)

If we take tecfidera, for instance, it is one of the most widely used 1st line drugs. This is because for a 1st line drug it has ~54% reduction in annualized relapse rate reduction (ARR) vs. others in the same tier that stand around ~30% ARR. This notable effect is due to the fact that tecfidera straddles a fine line between immunomodulation and immunosuppression. But, as patient or clinician what you don’t want to be faced with is steadily reducing lymphocyte counts when things are going well. Especially coming from a 1st line drug!

– Grade 1 Absolute lymphocytes count (ALC) 800-900/ul
– Grade 2 ALC 500-799/ul
– Grade 3 ALC 200-499/ul
– Grade 4 ALC <200/ul

To understand some of this, a consortium of Spanish neurologists have merged their patient databases to see if there are some trends to the occurrence of lymphopenia on tecfidera. What they have noted seems like common sense or obvious, but still worth pointing out:

  1. 40% develop lymphopenia; individuals tend to be older at initiation (44y vs 38y old), longer disease duration, more disabled and lower ALC before starting.
    If you’re older your immune system is less ‘stressable’ and having an autoimmune disorder for longer or prior immunomodulatory/immunosuppressive treatments also results in the same.
  2. It can occur at any time (3-18 months), with those depleting in the first three months at the greatest risk (see Figure below).
    This exposes the vulnerability of your immune system; the quicker your lymphocytes deplete the more likely you will deplete in totality.
Fig 3
Figure: Mean absolute lymphocyte count (ALC) changes along dimethyl fumarate treatment in patients who developed (red line) or not (green line) lymphopenia.


Mult Scler Relat Disord. 2022 Feb 4;59:103669. doi: 10.1016/j.msard.2022.103669. Online ahead of print.

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis

Susana Sainz de la MazaJulia Sabin MuñozBelén Pilo de la Fuente, Israel ThuissardCristina Andreu-VázquezVictoria Galán Sánchez-SecoPaula Salgado-Cámara Lucienne Costa-Frossard Enric Monreal Lucía Ayuso-Peralta Lorena García-Vasco José Manuel García-DomínguezMaría Luisa Martínez-Ginés Carmen Muñoz FernándezJudit Díaz-DíazCelia Oreja-Guevara Mayra Gómez-MorenoHugo Martín Laura Rubio-Flores María Rosario Blasco  Luisa María Villar-Guimerans Yolanda AladroDimethyl Fumarate Study Group

Background: Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter.

Objectives: To identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia.

Methods: In this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve.

Results: Among 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia.

Conclusions: A pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia.

About the author

Neuro Doc Gnanapavan


    • I’m ok with Grade 1 lymphopenia, and to some extent even ones fluctuating between 0.6/0.8. I stop the treatment on the rest where the count is continuing to drift down from 0.6 (using two blood tests 3 months apart).
      Then wait for the lymphocytes to recover and do a lateral swap to aubagio (teriflunomide) once the lymphocyte count is up to 0.7/0.8. I have found re-challenging with tecfidera in these instances is a waste of time as the same happens again. It’s clear that certain individuals require a much less dose of the drug!

      • This is very interesting. Thank you for sharing. I was diagnosed with RRMS. Tecfidera was my first DMT. After 6 months my lymphocytes dipped to 0.8 and by 12 months to 0.4 so I was advised to stop it. I’ve been medication free for 19 months as my lymphocytes have not stabilised at or above 1 for more than 2 successive months (I have been advised they need to stabilise at 1 or above for 3 months). I have been offered copaxone as an alternative or to resume tecfidera, dose to be determibed. I’ve not knowingly had a relapse, although my MS may be smouldering. I have read numerous articles on lymphopaenia, treatment options etc, but have not found the holy grail, if it indeed exists!

        • The recovery period does vary from individual to individual, but total lymphocyte count shouldn’t be used as a marker of potential resurgence of activity during recovery phase. It’s the initial drop that gives an indication of response, how your immune cells recover and which ones go back to being the autoimmune ones is very individual.

          • It seems to me to be an unnecessary gamble with someone’s (possibly permanent) immune health to continue with TMF down to the 0.6 level and beyond, once the trajectory seems established. Wouldn’t it be safer to switch earlier?

  • The danger of dmf in RRMS is longterm (or permanent) lymphopaenia could exclude future treatment options. Eg escalating to fingolimod, starting siponimod in SPMS or even joining a trial like ChariotMS.
    It’s not even a particularly great dmt!

  • Dear NDG,

    I used the starter dose for 2 weeks. No problems at all.

    After switching from starter dose to full dose, I had stomach and bowel trouble. Throwing up blood and blood from my behind.
    First 2 days I sat on the toilet almost whole day.
    The belly ache was unbelievable.

    Have you seen this with your patients? Do you know if there is anything written about this?

    I stopped immediately and when my belly was back to normal the ms nurse wanted me to try it again. Yeah right! I didn’t.

    Thanks & Regards



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