Sunday, 20 January 2013

PML and fumarates

Clarification: I have just found out that the case report below and the third case in the BfArM's ADR Database (10130944) are the same case. Therefore there has only been 4 reported cases of PML on Fumaderm, one of which was on Efalizumab a known cause of PML, and one new case on a compounded formulation of fumarate. I hope this clarifies things for our readers.

#MSBlog: Are fumarates associated with PML? I am not convinced. 

In response to the queries regarding BG12, fumarates and PML. Yes, there have been 4 cases of PML in people on Fumaderm for psoriasis. One of these cases has been presented at an academic meeting in Germany and the abstract is presented below all the cases that have been reported via the German Adverse Drug Reaction Database (below).

Ermis et al. Fumaric acid-associated progressive multifocal leukencephalopathy (PML), treatment and survival in a patient with psoriasis. Kongress der Deutschen Gesellschaft für Neurologie mit Fortbildungsakademie28.09.2011 - 01.10.2011.


Background: Fumaric acid and/or its derivates were found to be effective and safe in the treatment of psoriasis vulgaris. In addition, treatment with fumaric acid is currently evaluated in phase II/III trials for the therapy of multiple sclerosis. PML is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals, including 4 to 5% of HIV-positive patients with AIDS, also occurring in association with leukemia and lymphoma. 

Clinical case: They describe a 74-year-old male with psoriasis who developed subacute neurologic symptoms after 3 years of monotherapy with fumaric acid. The patient had a history of psoriasis for more than 5 years and he was treated with different immunosuppressive and immunomodulatory therapies including corticosteroids, a second generation retinoid, and methotrexate.

Results: MRI scan demonstrated a subcortical area of T2-hyperintensity within the white matter of the left temporal lobe, without gadolinium enhancement. PML was confirmed by brain biopsy and positive JC virus-PCR in the brain biopsy and cerebrospinal fluid (CSF). Discontinuation of fumaric acid resulted in an induction of an immune reconstitution inflammatory syndrome (IRIS) with gadolinium enhancement after five weeks. The patient was treated with mefloquine and mirtazapine. At 5 months there was improvement of neurological symptoms, regression of MRI lesions and JC virus load in the CSF was below detection limit.

Conclusions: This is the first report of PML associated with the small molecule fumaric acid, a therapy that in contrast to other modern immune therapies that may cause PML like rituximab, natalizumab, efalizumab, and infliximab does not belong to the group of monoclonal antibodies. JC virus associated PML occurs in patients with an immunosuppressive syndrome, e.g. lymphoma or HIV infection and in most cases inevitably leads to death of the patients. Four patients treated with Efalizumab for psoriasis reportedly developed PML, all of them died within short duration of the disease. Lately several multiple sclerosis patients who had been treated with natalizumab developed a PML and survived the disease after cessation of the immunosuppressive treatment. With this present case, we describe for the first time fumaric acid-associated PML and IRIS in a patient with psoriasis and the successful clinical management.


The following are the brief summaries of all of the 4 cases of PML in patients with psoriasis treated with Fumaderm since its launch in Germany in 1993. The extract is from the German BfArM's ADR Database. The case report does not match with any of the four cases reported in BfArM's ADR. 





"In addition to this another case developed PML, whilst on another formulation of fumaric acid. This case had lymphopenia, a PML risk factor. If, and when, we get more information on this case we will let you know." 

"One of the cases in the BfArM's ADR developed PML on Efalizumab; a known cause of PML. Therefore the number of cases of PML in patients receiving fumarates is 5 in total. This number needs to be viewed in relation to the denominator, i.e. the total number of cases treated with fumarates, and whether or not these cases have other predisposing factors. Until we have all this information it is difficult to comment on whether of not fumarates are the likely cause of PML or not."


"Importantly, there have been no cases of PML in MSers treated with BG12. This is reassuring and only long-term follow-up of MSers treated with BG12 in the clinical trials and an active post-marketing surveillance programme will answer this question."

"BG12 does cause a drop in lymphocyte counts. As lymphopenia is a risk factor for PML blood counts will need to be monitored and if too low the drug will have to be stopped. In my opinion, the lymphopenia is a manageable side effect of BG12. Based on the number of patient years of follow-up of psoriasis patients on Fumaderm PML and other opportunistic infections are unlikely to be a problem"


CoI: multiple; as I was the principal investigator on the Define phase 3 BG-12 trial at Barts Health, and sit on the Define BG12 steering committee, and I am co-author on several papers and conference abstracts in relation to BG12, you may want to ignore everything I have say on this topic. 

3 comments:

  1. Based on these fumaderm cases will you warn people going onto BG-12 about PML?

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    Replies
    1. Yes, why wouldn't I? A quick search via Google will alert most people to this issue. Transparency is the name of the game.

      I would however frame my answer is a specific way: "PML as a complication of BG-12 therapy is a potential risk that is currently undefined. The risk is likely to be very low and limited to patients with lymphopaenia. We will monitor your blood counts for lymphopaenia and if your counts drop too low we would obviously stop the drug."

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  2. Would previous therapy with Cladribine be an increased risk factor for PML in light of this? I had a drop in lymphocytes as part of that therapy (expected outcome) but was told that Cladribine also permanently affected the DNA of the lymphocytes.

    BG-12 was touted as the preferred treatment for the Cladribine cohort and we have been waiting in some frustration for its release as we have been unable to be treated with anything else since our treatment with Cladribine was pulled out from under us 18 months ago.

    Now feeling slightly apprehensive in light of this, the delays in approval and Teva's recommendation to the FDA.

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