“The following is the provisional update from the EMA regarding dimethyl fumarate or DMF (Tecfidera).”
Having reviewed the available information on the risk of PML, EMA has recommended the following to minimise this risk with Tecfidera:
- Prior to initiating treatment with Tecfidera, a complete blood count including a lymphocyte count should be performed and a baseline MRI scan should be available (usually within 3 months) as a reference. After starting therapy, complete blood counts including lymphocytes should be performed every 3 months.
“For how long? Biogen’s data states that if you don’t develop lymphopaenia in the first year you are unlikely to do so; why then do we need to continue 3-monthly monitoring indefinitely?”
- If during treatment with Tecfidera the lymphocyte count drops below 0.5×109/L for more than 6 months, the benefit-risk of continued treatment with Tecfidera should be re-considered in the context of other therapeutic options available. Clinical factors and evaluation of any laboratory and imaging investigations could be included as part of this re-consideration. If Tecfidera is discontinued, the lymphocyte count should be closely monitored until recovery.
“I don’t agree with this cut-off. Why? There have been two cases of PML in patients with psoriasis on fumarates who developed PML with a lymphocyte count above 0.5, but below 0.8. This is why I will stick to 0.8 as my cut-off. However, I suspect JCV-serostatus may play a role here. If you are JCV-ve the risk of PML will be low.”
- PML can only occur in the presence of JC virus infection. If an anti-JC virus antibody test is done, it should be considered that the influence of lymphopenia on the accuracy of such tests has not been studied in patients treated with Tecfidera. Doctors should also note that a negative antibody test (in the presence of normal lymphocyte counts) does not preclude the possibility of subsequent JC virus infection.
“This is stating the obvious.”
- During treatment with Tecfidera, the need for further MRI scans should be considered in accordance with national and local recommendations. MRI imaging may be considered as part of increased vigilance in patients considered at increased risk of PML. In case of clinical suspicion of PML, MRI should be performed immediately for diagnostic purposes.
- If therapy is continued in patients with severe prolonged lymphopenia, these patients should be considered at increased risk for PML and should be monitored closely for signs and symptoms of new neurological dysfunction (e.g. motor dysfunction, cognitive or psychiatric symptoms).
- In case PML is suspected, treatment with Tecfidera should be withheld immediately and further evaluations performed.
“No advice on treating PML? This may be an indication for a donor lymphocyte transplant from a MHC identical donor who is JCV+ve. What these patients need is a robust and quick cytotoxic CD8+ lymphocyte response against JCV infected cells so that they can recover from their PML. The latter is an experiment waiting to happen.”
- No studies have been performed evaluating the efficacy and safety of Tecfidera when switching patients from other disease-modifying therapies to Tecfidera. The contribution of prior immunosuppressive therapy to the development of PML in patients treated with Tecfidera is unknown. When switching patients from other disease-modifying therapy to Tecfidera, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time reducing the risk of disease reactivation.
“Good point. As I have said before if you switch from other immunosuppressive drugs you are likely to take some risk with you. PML is a complex process with the virus needing to mutate and acquire several mutations. The latter are unlikely to unwind on switching therapies.”