Sequencing of DMTs is the next big issue in MS. How do you derisk and manage the sequencing of DMTs in an increasingly complex treatment landscape.
I saw a patient earlier this week who has a persistent lymphopaenia on dimethyl fumarate (total lymphocyte count of <500/mm3). She is is JCV-seronegative and her current neurologist seems happy to watch her. I am not sure I agree with this approach. PML is not the only risk associated with a low lymphocyte count. Other opportunistic infections may emerge and then there is the issue of long-term safety, in particular the risk of secondary malignancy.
This particular patient is concerned about simply stopping DMF because of the risk of rebound disease activity. I personally don’t don’t think rebound is a big problem with so called immunomodulators such as DMF, GA and IFNbeta. These agents have system, or downstream, effects that take months to reverse. Unlike anti-trafficking agents such as natalizumab and fingolimod were rebound is well described and closely linked to wash-out of the drugs’ effects. Despite these insights this particular patient is not prepared to take the risk of a prolonged washout period. I am not surprised because DMF-associated lymphopaenia can take months, and possibly years, to correct itself and I am aware of some patients whose counts have never returned to normal. These issues raises the question of what DMT to use in this patient after DMF? Clearly you can’t stop DMF and use a T-cell depleter or IRT, for example alemtuzumab or cladribine, or fingolimod (please note we are now classifying fingolimod as a depleter as well, this is based on recent insights about the drug). The risk with these DMTs is that the patient may be left with irreversible long-term lymphopaenia. What about a B-cell depleter such as ocrelizumab? This would be much safer, provide high efficacy, and at least allow the T-cell compartment time to repopulate. The agent of choice would be glatiramer acetate as it does not affect T-cell numbers and is safe. If I recall correctly this patient is not keen to step down in efficacy and is not keen on a frequent injectable. What about interferon beta? Yes, this would be possible, but it also suppresses lymphocyte numbers and I would be uncomfortable starting an interferon until the lymphocyte counts had returned to being above 800/mm3. Natalizumab? This would be a great option as this patient is JCV-seronegative, but we are not allowed under NHS England guideline to use the drug. Other options are daclizumab and teriflunomide, these drugs are not overtly immunosuppressive but are associated themselves with a slight drop in lymphocyte counts. Again before starting either of these agents I would want to see total lymphocyte counts rise above 800/mm3, this would mean a washout.
So in summary, this patient is forcing a difficult decision on herself. Without a DMF washout, to wait for her lymphocyte counts to rise above 800/mm3, I would favour glatiramer acetate, or natalizumab as she is JCV-ve, or ocrelizumab. The latter option is hypothetical as we don’t have it available under the NHS at the moment. Less appealing options would be interferon-beta, teriflunomide or daclizumab. Alemtuzumab, cladribine and fingolimod would be the agents to avoid in this situation. In reality natalizumab is also not an option as it can only be used in the NHS if you have rapidly evolving severe MS (two disabling attacks in a 12 month period with MRI evidence of disease activity).
I suspect the person who I saw earlier this week may read this post and appreciate the complexity of the decision making behind sequencing of her treatment. What I haven’t touched on in this post are the other issues relating to personal factors that may need to be considered for example pregnancy, concomitant medication, comorbidities, travel, adherence with monitoring, stage of MS (early), vaccination needs, etc.
I am hoping, time permitting, to write a DMT sequencing web app for our ClinicSpeak site to highlight all the issues that need to be considered when sequencing DMTs. To make this happen I need time, a software engineer, a designer and a medical writer who can dejargonise my prose. In other words I need resource.