Friday, 31 October 2014

ClinicSpeak: update on Tecfidera PML case

#Tecfidera update: very low lymphocyte counts are the preventable PML risk factor. #ClinicSpeak #MSBlog #MSResearch

"Biogen-Idec have give us the green light to go public on the fact that the patient who developed PML, and died, whilst taking dimethyl fumarate (Tecfidera) had had a lymphocyte count of less than 500/mm3, or 0.5 X 10**9/L for over three and a half years."


"This information has led us to formulate the following interim guidelines to manage DMF-related lymphopaenia in our centre. These are not evidence-based, but are based on well founded immunological principles and anecdotal clinical observations to date."

"I would like to thank Biogen-Idec for being so responsive in providing the information in such a timely manner; we have also used the information their medical information department has provided us in the past to draft our interim guidelines (below)."

"I have also asked Biogen-Idec to look at their data in more detail to see if DMF-related lymphopaenia is reversible, and if it is reversible do the lymphocyte counts return to the pre-treatment baseline levels; this information will clearly impact on future updates of our guidelines."

Guidelines

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.


CoI: multiple

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