Saturday, 11 April 2015

ClinicSpeak: Lymphopaenia on DMTs

Should MSers take control of monitoring their own lymphocyte counts? #ClinicSpeak #MSBlog #MSResearch

"In view of the interest in yesterday's post on lymphopaenia, PML and DMF, I have reposted this post. Please read it, it may be relevant to you if you on a DMT."

In response to Helen Scott’s comment on "Bad News as first PML case appears to be linked to...":

‘The 'heart attack' was Biogen's response to the share drop. What sort of medical practitioner sanctions a patient having a low WBC for three and a half years? And why wasn't the patient savvy enough to question it?’

“I would appreciate it if you could complete the survey at the end of this post to address this issue."

"At a meeting I attended yesterday there was a heated discussion amongst several MSologists about how to monitor and manage patients with lymphopaenia. It was clear that there was no consensus on what constitutes a lymphopaenia and how to manage patients. May be Helen is right in suggesting MSers need to be savvy enough to make decisions concerning their management themselves or to at least ask the right questions. Helen is correct in stating that if this patient had known about the type of lymphopaenia he/she had and its risks he/she may have made the unilateral decision to come off dimethyl fumarate (DMF or Tecfidera) and be alive today? What do you think?"

"Lymphopaenia refers to a low circulating blood lymphocyte count. The normal levels vary depending on which labs report the result. In general the normal lymphocyte count is between 1,200 and 4,000 lymphocytes/mm3, or 1.2 and 4.0 X 10**9/L. I am aware that some labs set the lower limits of normal at 1,000 and other at 1,500. The WHO classifies lymphopaenia into four grades of increasing severity based on the absolute lymphocyte counts:

Normal > 1200/mm3 or 1.2x10**9/L

Grade 1 = 800-1200/mm3 or 0.8–1.2x10**9/L

Grade 2 = 500-800/mm3 or 0.5–0.8x10**9/L

Grade 3 = 200-500/mm3 or 0.3–0.5x10**9/L

Grade 4 < 200/mm3 or 0.2x10**9/L

MSologists deal with DMT-related lymphopaenia all the time. Lymphopaenia is a frequent occurrence on interferon-beta, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, azathioprine, methotrexate, cyclophosphamide, cladribine, steroids and alemtuzumab. What we do depends on the mode of action of the drug, whether or not the lymphopaenia is associated with immunosuppression and whether or not it is reversible."

"For some drugs such as azathioprine I titrate, or adjust, the dose to cause a mild lymphopaenia (grade 1) to make sure the drug is in its therapeutic range. We do this because people metabolise, or breakdown the drug, at different rates and each person has a slightly different optimal azathioprine dose; for fast metabolisers it is typically somewhere between 4-5mg/kg/day and for intermediate metabolizers between 2-3mg/kg/day. I avoid using the drug in slow metabolisers because it not only causes a severe lymphopaenia, but tends to suppress the other white cell counts, for example neutrophils, as well. In the case of azathioprine we can test people’s ability to metabolise the drug before we start to get an idea of what dose they require, this is a good example of pharmacogenomics in practice. The good thing about azathioprine is that if you stop the drug the lymphocyte counts return to normal within 2-4 weeks."

What do we know about dimethyl fumarate (DMF)?

"Well I didn’t know myself so before starting to prescribe DMF I asked Bioge-Idec for some guidance earlier this year on this exact issue (see letter below); the following is a summary of their response."

"On average, lymphocyte counts decreased by approximately 30% of baseline values, on DMF. Average lymphocyte counts remained within normal limits in the clinical studies. Lymphocyte counts <0.5x10**9/L were observed in 6% of patients treated with DMF. A lymphocyte count <0.2x10**9/L was observed in only 1 patient treated with DMF. In the phase 2 & 3 studies, an increased incidence of infections and serious infections was not observed in patients with lymphocyte counts <0.8x10**9/L or <0.5x10**9/L. At present there is no advice within the SmPC (Summary of Product Characteristics; see below) regarding cessation of therapy following lymphocyte count reductions below a certain level (I suspect with this recent case of PML this will need to change). To Helen’s point above in the phase IIb and III studies, and now the phase 4 study, there were/are no stopping rules based on low lymphocyte counts. However, there were/are criteria for stopping based on the total white blood cell (WBC) counts. Across the phase 2&3 studies, one patient in the DMF TID group discontinued study drug due to an adverse event associated with leukopaenia. No DMF treated patients discontinued study drug due to lymphopaenia. Prior to initiating treatment with DMF, a recent complete blood count (i.e. within 6 months) should be available. Assessments of complete blood counts are also recommended after 6 months of treatment and every 6 to 12 months thereafter and as clinically indicated. At present there are no specific recommendations for the management of reduced lymphocyte counts in patients receiving DMF and management is at the clinical discretion of the prescribing physician."

"I would suggest, therefore, that in the short-term what we need to do is be more vigilant about lymphopaenia and if someone on DMF develops a persistently low lymphocyte count the drug will need to be stopped. Until we get more data, on the reversibility of the lymphopaenia, I would suggest anyone with a lymphocyte count less than 800/mm3, or 0.8x10**9/L, takes a drug holiday for several weeks until their lymphocyte counts recover above 1200/mm3, or 1.2x10**9/L; if the lymphocyte counts don’t recover, or drop below this proposed threshold on restarting DMF the drug will need to be stopped. Please note that a threshold or cut-off of 800 (WHO grade 1 lymphopaenia) is very conservative and we may be able to set the cut-off at 500 (WHO grade 2 lymphopaenia) if it is reversible. I think setting cut-offs like this need to be evidence-based. I would suggest that we institute 6 monthly monitoring of lymphocyte counts as we do for patients on interferon-beta and if they are lymphopaenic (<1200) every 3 months. What we need to avoid is long-term lymphopaenia."

What about JCV testing and PML?

"The fact that there have been several cases of PML on DMF in both psoriasis and now MS it suggests that DMF is immunosuppressive. The risk factor for PML appears to be related to the lymphopaenia itself. Therefore if you are JCV positive on DMF and have a normal lymphocyte count there is probably nothing to worry about; but as long-term data emerges this may change. There is some data from the psoriasis literature suggesting that DMF may have a mode of action in addition to lymphopaenia, that may add to the PML risk; it seems to interfere with adhesion of leukocytes to blood vessels and reduce trafficking of cells. This situation is not too dissimilar to natalizumab in which we know that the PML risk is linked to the mode of action of natalizumab, i.e. its stops trafficking of lymphocytes into the brain and reduces immune surveillance for infections. Yyou are probably aware that in JCV positive individuals prior immunosuppression is a risk factor for developing natalizumab-associated PML, based on this case of PML we would have to classify DMF as prior immunosuppression. This also means that the JCV antibody index or level cannot be used in patients on DMF, or with prior exposure to DMF. The JCV-antibody index as a risk factor of natalizumab-associated PML can only be used in patients without prior immunosuppression."

Should we start routine JCV testing in patients about to start DMF or who are on DMF?

"No I don’t think this is necessary. The only situation I envisage this happening is if someone is doing well on DMF and has a lymphopaenia and wants to stay on the drug. Being JCV seronegative may give this person, and their clinician, more confidence in leaving them on DMF."

Should we not start someone on DMF if they already have a lymphopaenia?

"This will depend on the cause of the lymphopaenia. If for example they are switching from fingolimod, that causes a reversible lymphopaenia, it would seem reasonable to check lymphocyte counts after 4-8 weeks to make sure they are recovering. If the cause of lymphopaenia is due to previous immunosuppression, for example secondary to corticosteroids, cladribine, alemtuzumab, mitoxantrone, or teriflunomide, I would be more careful. In this situation a decision will need to be made once considering the level of lymphopaenia and how active the patients MS is. This may be one situation were a JCV serology may help. Please note that prior immunosuppressive therapies is in itself a major risk factor for PML; therefore if the patient is JCV seropositive you will need to be more careful."

Is there something specific about DMF that causes PML?

"As I have alluded to above there is nothing in the known mode of action of DMF that would implicate DMF, outside of the lymphopaenia, as a high risk drug for PML. This may change with future knowledge. Future knowledge is important. We really need to know much more about what DMF does to lymphocyte function and trafficking into the CNS; does it affect the ratio of the so called CD4 and CD8 subsets? What is the effect of DMF on lymphocyte activation? Does DMF affect the function of the thymus, where new T cells are born, or the bone marrow and spleen? Does DMF affect antigen presentation, for example does it affect ones responses to live and inactivated vaccines? The most pressing question is DMF-related lymphopaenia reversible; if it is not reversible then then the 800 limit I propose above is sensible, in comparison if it is reversible then the 500 limit may be appropriate based on the data from the phase 3 studies."

"I have always been very impressed how Biogen-Idec dealt with the natalizumab-PML crisis and how they essentially saved a very effective drug for MSers. I have little doubt that they will rise to the challenge and answer these questions. However, based on what we know at present I don’t think there is anything at present that substantially changes the risk:benefit ratio of DMF as a treatment for MS. What changes is the way we use and monitor the effects of drug and the sequencing of other drugs, before and after DMF; in particular natalizumab if you are JCV seropositive."

What about the other MS DMTs?

"For drugs that cause lymphopaenia and are induction therapies, i.e. mitoxantrone, cladribine and alemtuzumab, there is little one can do but to note the lymphopaenia and to avoid retreatment if the lymphocyte counts are too low. The reason for the latter is that with each round of therapy the lymphocyte counts tend to recover slower and to a lower baseline level; this is why we have strict redosing rules, abased on the total white cell and lymphocyte counts when using mitoxantrone and cladribine."

"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. Imortantly, 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."

"For those reading this post for the first time we mustn’t get distracted from the fact that the trigger for the focus on lymphocyte counts is the tragic death of someone with MS. This person died as consequence of side effect of a treatment for MS that up until now was considered relatively safe. We need to learn from this case and make sure no one else suffers the same consequence or at least reduce the risk of this happening again. My condolences go out to the family and friends of this patient. From my perspective this complication was avoidable; however, it is always easy to be critical in hindsight. We must also not forget that this patient participated in the DMF clinical trial that led to the licensing of DMF; without his/her participation other MSers would not be benefiting from this drug or benefitting from the knowledge of this tragic complication. We must make sure we learn from this tragic case.”

EMA's Tecfidera SPC

CoI: multiple


  1. This post is so long that I couldn't be bothered getting to the end and completing the survey.

    1. Perhaps others will be more persistent. It's a subject of great significance to many.

    2. Anonymous (Monday, October 27, 2014 10:32:00 am) I note you managed to skip to the end to leave a sarcastic comment so why not complete the survey?

      Sarcasm is the lowest form of wit.

    3. I guess there is a place for emojis after all:). I read it and I get from it that 1)Prof G was querying DMF and lymphocyte counts before he started prescribing it, 2)lymhopaenia seems to occur with most DMTs. 3)No one is clear why as it depends in the mode of action of a particular drug and 4)doesn't explain to me why this wasn't picked up sooner with the person that died, unless their death was not related to this?

      Err that's about it ...emoji emoji

    4. Anonymous has a point; check-out the infographic below: "every piece of content should be as long as it takes to convey the message, and no longer". I will do a short post for those with Twitter-like attention spans.

    5. Re: "...doesn't explain to me why this wasn't picked up sooner with the person that died, unless their death was not related to this?"

      It was picked-up sooner. There was a death of a patient from PML who had psoriasis and had prolonged lymphopaenia on monotherapy with a formulation of DMF. The case has now been published (van Oosten et al., 2013). The message was there, we even posted about the issue on this blog.

      Biogen-Idec were so adamant that Tecfidera and Fumaderm, and other related DMF compounds, were different compounds that they missed the opportunity to take appropriate actions to potentially prevent this from happening. I sort of anticipated this happening, which is why I asked Biogen-Idec for guidance on how to manage DMF-related lymphopaenia.

      It is a real pity that the opportunity was missed. However, vision is always 20/20 in hindsight. This death occurred on a clinical trial. After the death of the psoriasis patient the trial protocol should have been changed to prevent this from happening. I would be interested to know if the data and safety monitoring committee of the DMF studies were made aware of this case?

      What we need to do as a community is to learn from this and make sure the death of this MSer was not in vain.

      van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013 Apr 25;368(17):1658-9.

  2. "What changes is the way we use and monitor the effects of drug and the sequencing of other drugs, before and after DMF; in particular natalizumab if you are JCV seropositive."

    Does this mean that someone could not access Tsybari after taking Tecfidera?

    1. Re: "Does this mean that someone could not access Tsybari after taking Tecfidera?"

      I would define significant immunosuppression on DMF as persistent lymphopaenia for greater than 6 months with a total lymphocyte count of less than 1.2 x 10**9/L (WHO Grade 1). In patients with a past history of significant immunosuppression the JCV serology index cannot be used to complement PML risk profiling (Plavina et al. 2014). It simply means that you have another risk factor for PML and would not want to be on natalizumab if you are JCV positive. If you are JCV negative this does not apply.

      Pavina et al. Anti-JCV antibody levels in serum or plasma further define risk of natalizumab-associated PML. Ann Neurol. 2014 Oct 1. doi: 10.1002/ana.24286. [Epub ahead of print] PubMed PMID: 25273271.

  3. Is it possible to get rid of the lymphopenia by giving a lymphocyte transfusion?

  4. What about IgG levels: is it important to monitor them?

  5. Prof G, I am very grateful for your two posts on this subject, and have shared the information with three social media groups, including one devoted to Tecfidera. I actually started Tecfidera three weeks ago so this information was timely.

    From reading the posts above, one of my queries was answered, i.e. that at the time the drug would have been known as BG-12 and would have been available only by clinical trial or a Special Access Scheme ( for Australian). I note that you have stated that the patient was in a clinical trial, which disturbs me further. So it would appear that patient remained in an immune compromised state for over four years and was vulnerable to infection. My forensically inclined epidemiological heart would like to ask more questions, but there probably would not be able to be answered e.g. did the patient have flu shots etc. You are right, an opportunity may have been missed here. Like Tysabri, PML was detected at the clinical trial stage but was released to market, and we all know what happened next. Tecfidera has not been on the market for the time frame as the patient on the clinical trial. The US were the early adopters, so it is to be hoped that they are being monitored.

    Perhaps a supplementary post on what a patient can do protect themselves as best they can when they are on immune suppressing drugs would be helpful, i.e. the vexed question of vaccinations, places and people to avoid.

  6. Are there any guidlines regarding the number/level of leukocite while on fingolimod? Is there any critical value at what it is recomended to monitor or stop the therapy? What is the average value of lymphocite and leukocyte at people on fingolimod?

  7. Such a looooooooooooooong post. Dre is right in saying these drugs are being given willy-nilly, and when one of us dies then the neurologist says, "MSers need to be savvy enough to make decisions concerning their management themselves or to at least ask the right questions"

    How many more of must die before neurologists learn their lesson? How many more of us must be duped into taking these deadly medicines? This blog is favouring Big Pharma's interests, not ours.

    1. Disagree with you. Have you read any of the off label posts? Definitely not favouring Big Pharma.

    2. I suggest you dig into the blog archive and you'll see that this blog is certainly not favouring Big Pharma.

  8. I'm 6 months post-HSCT and my lymphocytes are up and down like a fiddler's elbow...!

    I was at 0.6 at 2 months, 1.1 at 3 months, then I got a flu-like lurgy and they dropped to 0.2, then climbed to 0.5 a couple of days later.

    Nobody seems particularly bothered. My neutrophils are ok. They say they should level back out in time, but there's nothing to be done apart from try to avoid sick people...

  9. PML will kill. We know this. But so will pneumonia if you've got a shitty enough WBC. So I don't know why doctors are so keen to keep prescribing this crap. Hurry up on induction therapies.

  10. Is this risk not negated slightly with lemtrada as opposed to the other options?


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