#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.
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