Friday, 10 April 2015

ClinicSpeak: another case of PML on dimethyl fumarate

PML dimethyl fumarate (Tecfidera) Update. #ClinicSpeak #MSBlog #MSResearch

"In this week's NEJM there there are two case reports of PML in people on fumarates. We have discussed the one case of PML in an MSer on dimethyl fumarate (Tecfidera) in detail on this blog in the past. This MSer had a grade 3 lymphopaenia (<500/mm3, or 0.5 X 10**9/L) for over three and a half years."

Rosenkranz et al. PML in a Patient with Lymphocytopenia Treated with Dimethyl Fumarate. N Engl J Med. 2015 Apr 9;372(15):1476-1478.

"The following graph plots this MSers peripheral blood white blood cell and lymphocyte counts over time. Unfortunately, this MSer was left on DMF despite her low lymphocyte count simply because the trial protocol mandated stopping DMF on a total white cell, or leukocyte, count rather than the lymphocyte count."

Source: N Engl J Med. 2015 Apr 9;372(15):1476-1478.

"Based on this case we at Barts-MS have instituted lymphocyte count monitoring and formulated the following interim guidelines to manage DMF-related lymphopaenia in patients treated at our centre."


1. Before starting DMF an up-to-date (within the last 4 weeks) full blood count (FBC) is required in addition to lymphocyte subsets*.

2. The monitoring of FBC with lymphocyte counts and subsets should be done at 3 months and 6 months, and then at 6 monthly intervals in patients with lymphocyte counts above 1.2 x 10**9/L. In patients with total lymphocyte counts less than 1.2 x 10**9/L monitoring should be done at 3 monthly intervals.

3. If the lymphocyte counts return to above 1.2 x 10**9/L, then 6 monthly monitoring should be reinstated.

4. If the total lymphocyte count falls below 0.8 x 10**9/L, and is confirmed on a second FBC and the patient wants to stay on DMF it may be worth checking the JCV virus status. As DMF-related lymphopaenia is a form of immunosuppression** the JCV index, as measured using the STRATIFY JCV assay, cannot be used to assess PML risk. Please note a lymphocyte count cut-off of 0.8 x 10**9/L (WHO grade 2) may considered by some as being too conservative; but until data emerges to show that DMF-related lymphopaenia is reversible we feel this conservative approach is justified.

5. If lymphocytes remain persistently below 0.8 x 10**9/L, consider the risks and benefits of continuing DMF.

6. If lymphocytes go below 0.5 x 10**9/L we recommend stopping DMF.

7. At present we are not aware of any data to indicate that reducing the dose of DMF will result in the lymphocyte counts recovering. In addition, a lower dose than 240mg BD of DMF is unlikely to be effective.

8. All patients treated with DMF should have annual Gd-enhanced MRI studies according to our Barts MS MRI protocol, and additional MRI studies if clinically indicated.

*At present we are not aware of the effect of DMF on the distribution of peripheral blood lymphocyte subsets; performing this test and collecting this data may affect clinical decision making and will provide much need information on the immunological effects of DMF in patients with MS.

**We define significant immunosuppression on DMF as persistent lymphopaenia for greater than 6 months with a total lymphocyte count of less than 1.2 x 109/L (WHO Grade 1). In patients with a past history of significant immunosuppression the JCV serology index, as measured using the STRATIFY JCV assay, cannot be used to complement PML risk profiling.

"Subsequent to us producing guidelines the FDA has acknowledged the PML risk associated with DMF (dimethyl fumarate) therapy in their highlights of prescribing information and have chosen 0.5 x 10^9/L, or 500/mm^3, as their threshold for interrupting DMF therapy. This cutoff is now being questioned based on the second case reported in this week's NEJM. This is a 64-year-old woman who had been receiving topical glucocorticoids and compounded delayed-release DMF (Psorinovo) for the treatment of psoriasis. Her white blood cell (leukocyte) and lymphocyte counts were normal before DMF treatment, but reached a low of of 4000 cells and 792 cells/mm^3 on treatment. Importantly, her lymphocyte counts did not appear to drop below the 500/mm^3 cut-off proposed by the FDA. In contrast our guidelines with a more conservative cut-off or 800 cell/mm^3 would have triggered us to consider interrupting her DMF therapy or at least checking her JCV status and making a decision to stop her DMF therapy if  JCV-positive."

Nieuwkamp et al. PML in a Patient without Severe Lymphocytopenia Receiving Dimethyl Fumarate. N Engl J Med. 2015 Apr 9;372(15):1474-1476.

"Should this case change our practice? I would say no. I think the fact that this lady was using topical glucocorticoids may have been an additional risk factor for PML as well as her age. I have seen 3 patients in my career with spontaneous, or sporadic, PML in whom no risk factors for PML could be identified. All these patients were elderly, i.e. over the age of 60 years. I therefore think age is a risk factor for PML independent of immunosuppression. Why? I suspect the risk with increasing age relates to immunosenescence of the elderly. Unfortunately, as we get older our immune systems are less responsive, with poorer memory responses, that predispose one to infections, including opportunistic infections. We therefore simply need to be more vigilant in MSers over the age of 60, in particular if they have other risk factors for PML."

"Is this the last we have heard about DMF, lymphopaenia and PML? Definitely not. Biogen put out a 'Dear Doctor' letter in December last year (see below), which has been followed up by a drug safety update from the MHRA last month, neither of which advise on using a lymphocyte cut-off to make decisions about interrupting DMF therapy. They simply state: 'The licence-holder is working with the European Medicines Agency to evaluate the evidence for the risk of PML and to consider changes to the prescribing information. We will communicate any new advice for healthcare professionals as soon as it is finalised'. Until we get advice from the EMA we will continue to implement our local guidelines."

"The important message to MSers on DMF (Tecfidera) is that the PML risk is low (<1 in 10,000) and is unlike that seen in MSers who are JCV-positive on natalizumab. This PML risk estimate is based on the number of treated MSers who have been DMF for over 2 years. I have been told that Biogen will be releasing data on this later this month and we will obviously report on it as soon as the information is in the public domain."

CoI: multiple


  1. Team G , I am at 0.59*10^9 on Fingolimod .. I am wondering if these guidelines shall apply to Fingolomod too ?

    1. Re: "I am at 0.59*10^9 on Fingolimod .. I am wondering if these guidelines shall apply to Fingolimod too?"

      No fingolimod's mode of action is very different to DMF's. We cover the issue of lymphopaenia on fingolimod in the following post:

    2. Thanks proff , gave me peace of mind as I'm 3x the 0.2 cutoff :)

    3. 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 lyphocite and leukocity at people on fingolimod?


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