Wednesday, 23 September 2015

ClinicSpeak: DMF & PML - more vigilance is needed

What cut-off of lymphopaenia for Tecfidera PML risk? 500 or 800? #ClinicSpeak #MSBlog #MSResearch

"In response to several questions yesterday regarding PML risk and dimethyl fumarate (DMF). In addition to previous (1) immunosuppressive treatment, (2) duration of immunosuppression, (3) level of lymphopaenia, (4) JCV serostatus, (5) level of JCV antibody index, (6) genetic (HLA), (7) immunological factors (L-selectin, lymphocyte subset function), (8) viral factors and (9) mode of action of drug, (10) age plays a role as well."

"The two cases studies below are of two people with psoriasis who developed PML on DMF with moderate lymphopaenia (counts > 500/mm3). However, both of these cases were relatively old (69-year old male and a 64-year old woman). Of all the patients with de novo PML without an identifiable risk factor I have seen they have all be old (>60 years). Therefore, age-related immune dysfunction or immunosenescence is a risk factor for PML. Should these cases affect our management? Yes, they do ours. Most centres set their cutoff for stopping or interrupting DMF treatment at a lymphopaenic level of 500/mm3 (WHO grade 2/3 boundary). At Barts-MS we have a cut-off at 800/mm3 (WHO grade 1/2 boudary). We have adopted this more conservative approach from our years of experience using other immunosuppressive drugs, such as azathioprine, and until we get further guidance from the EMA who unlike the FDA have yet to rule on this issue."

"It is better to err on the side of caution and wait for data to emerge. A third case of PML on Tecfidera with relatively few patients on Tecfidera treatment beyond 2 years suggests more cases will emerge and it is only a matter of time that one of these will have a lymphocyte count above 500mm3. I suspect the latter case to have other risk factors and/or to be over the age of 60."

"Finally, yes the mode of action of DMF may have a role to play in causing PML. We have yet to fully delineate how DMF works and its exact role in the development of PML. At present lymphopaenia appears to be the most modifiable risk factor associated with DMF, but other risk factors specific to DMF may emerge with time. The papers on DMF being an anti-trafficking agent are weak and we simply need more data on this; if and when this data is published we will comment on it. And no I have not been nobbled by Biogen; if I had we won't be posting posts like this."

Are the three PML cases on Tecfidera the tail of the curve with more cases to come?

Hoepner et al. Progressive multifocal leukoencephalopathy during fumarate monotherapy of psoriasis. Neurol Neuroimmunol Neuroinflamm 2015; 2(3):e85.

Excerpt: In September 2013, a 69-year-old Caucasian man who was anti–JC virus (JCV) antibody positive was admitted to our hospital with slowly progressing right hemiparesis and aphasia lasting for approximately 6 months. Medical history revealed arterial hypertension, biological aortic valve replacement, and psoriasis vulgaris, treated with 3–6 tablets daily of dimethylfumarate (DMF; 120 mg)/ethylhydrogenfumarate (EHF; 95 mg) (Fumaderm) since December 2008 (table e-1 at Neurology.org/nn). No other immunosuppressive pretreatment had been given. In April/May 2013, the patient recognized a steadily progressing weakness of the right leg. In June 2013, an external diagnosis of ischemic stroke was made. An MRI scan  which was performed after deterioration of clinical symptoms, revealed a subcortical left hemispheric lesion; biopsy demonstrated macrophage-dominated inflammation, dysmorphic astrocytes, simian virus 40 positivity, and several p53- and MiB1-positive cells, suggestive of a JCV encephalitis. JCV DNA was detected in CSF at 2 different time points using a highly sensitive PCR protocol (September 24, 2013, 16 copies/mL; October 7, 2013, 42 copies/mL),1 leading to the diagnosis of progressive multifocal leukoencephalopathy (PML) in September 2013. Further diagnostic workup unmasked toxic bone marrow damage and an increased excretion of kappa light chains in urine without any evidence for a plasmocytoma. Taking into account the patient's initial presentation with a slowly progressive paresis since April/May 2013 as well as the initial MRI scan, which is compatible with the PML diagnosis, we believe that the onset of PML was in April/May without preexisting leukopenia and only moderate lymphopenia (grade 2 lymphopenia: 724–738 cells/µL). Several weeks later, white blood cell count dropped to a minimum of 4,800 cells/µL with 288 cells/µL lymphocytes under continuous Fumaderm treatment. Fumaderm was discontinued, and treatment with mirtazapine (45 mg/day), mefloquine (250 mg/week), and levetiracetam (1,000 mg/day) was initiated.


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

Excerpt: On July 18, 2014, a 64-year-old woman presented with a 2-week history of progressive apraxia. She had been receiving topical glucocorticoids and compounded delayed-release DMF (Psorinovo) for the treatment of psoriasis since June 2012. Magnetic resonance imaging (MRI) of the brain showed multiple subcortical white-matter lesions. Leukocyte and lymphocyte counts were normal before DMF treatment but reached a nadir of 4000 cells and 792 cells per cubic millimeter, respectively, in June 2014. Analysis of the cerebrospinal fluid showed normal levels of leukocytes, protein, and glucose. The patient was seronegative for the human immunodeficiency virus. At that time, a diagnosis of PML was considered. However, testing of the cerebrospinal fluid for JC virus DNA on polymerase-chain-reaction (PCR) assay was negative. Treatment with DMF was discontinued, and the patient received the diagnosis of atypical ischemic stroke.

Owing to progressive hemiparesis and somnolence, she was transferred to our hospital on August 14, 2014. Follow-up MRI showed a rapid and widespread dissemination of lesions suggestive of PML–immune reconstitution inflammatory syndrome (IRIS). Treatment with mefloquine, mirtazapine, and glucocorticoids was initiated. The patient's condition continued to deteriorate, and she died on August 26, 2014. PML was confirmed on histologic analysis of brain tissue and positive results on PCR assay for JC virus DNA in brain tissue and cerebrospinal fluid.


CoI: multiple


8 comments:

  1. Based on time on treatment do you think Tecfidera has a higher risk of PML than Gilenya? I am about to start treatment and was offered both these options. Any advice would be helpful. Thank you for taking the time to post on this blog, it is the best source of MS information out there.

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    1. Wondering why you weren't offered Aubagio?

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    2. Aubagio has low efficacy.

      In terms of PML they are both low risk but check out side effects, efficacy, convenience and keep an eye on your white cell count. I'm not a neuro and cant advise and not sure neuro can either
      .

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  2. I think it should add PML data Fumaderm,Psorinovo...
    http://www.medscape.com/viewarticle/803100

    PML in a woman 42 years old treated with dimethyl fumarate: http://www.nejm.org/doi/full/10.1056/NEJMc1215357?af=R&rss=currentIssue

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  3. Thanks Prof G for adding the Barts MS Tecfidera clinical guidance.

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  4. Would it be an idea to monitor lymphocyte levels every three months for all on Tecfidera?
    A lot can happen in six months with regards to levels changing.

    I know this would mean a bit more expense for the NHS but it would be more vigilant. Also for patient peace of mind. I would feel much more comfortable with my levels tested every three months on Tecfidera.

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  5. Yes, more vigilance is needed - but the next question is, what to do after stopping DMF? Treat with less effective medications (thus exposing the patient to the risk of rebound or MS reactivation)? Treat with other orals? But there is some risk of PML on fingolimod as well. Treat with alemtuzumab, rituxan, etc.? I assume natalizumab is not an option for JCV-positive patients with lymphopenia.

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  6. with Gilenya/Fingolimod, the German Society of Neurologists has defined the cut-off at 200/mm3 - what could the reasoning be for setting a lower limit for this than for the medications cited above? As a user of Gilenya hovering around 300/mm3 this is a very important question to me and I am greatful for any feedback!

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