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.
CoI: multiple
Very useful post showing the complexities of choosing DMTs and that each of them has its risks. But it's also very good that there are so many DMTs for pwRRMS."then there is the issue of long-term safety, in particular the risk of secondary malignancy"Could you please elaborate on this topic and write a post about it? Does the risk apply to all DMTs? How long is long? Should pwMS switch their DMT after a couple of years to another one or it doesn't help? Where are malignancies more likely to develop?
Malignancies might develop with chronically low immune system function, because your immune system isn't killing cancerous cells.The most effective therapies (Alemtuzumab, Cladribine) actually have less risk of this long term because they are induction therapies.
Alemtuzumab is a drug that many fear may be linked to secondary malignancies if I am not mistaken.Also, Cladribine was initially rejected based on the fact that some patients who developed cancer during the clinical drugs. It could be 'bad luck' and unrelated to cladribine, but that's why it was rejected.
dt – the control group in the cladribine trial had an unusually low incidence of cancer, which consequently made the cladribine group appear to have a high incidence (which it did not in isolation). Any therapy, induction or not, which alters the immune system poses a theoretical risk of secondary malignancy. Alemtuzumab no more than the next. Although I would be less inclined to alter my immune system with maintenance DMTs. At least after induction therapies the immune system has the opportunity to rebuild and mount attacks against what it needs to.
Really appreciate this post. I'm on Fingolimod (5yrs). My lymphopenia is severe (200) with accompanying leukopaenia/neutropaenia while JCV low +ve. And has been lymph about 200 for some time made more challenging to sort while I had chemo for breast cancer and allowed for a period of marrow recovery after. It has kept me relapse free until i reduced dose to try and improve WCC & got ophthalmoplegia; I was lucky as it was eloquent but functionally insignificant but as I may be less fortunate if there is a next time I chose to risk all the leukopaenia issues over relapse while I try to decide which DMT to switch to and how to transition. Any ideas welcome.
Re: "Any ideas welcome."Unfortunately, I am not allowed to give personal advice on this blog. But your situation is a difficult one. What is clear that the effectiveness of DMF is not simply linked to total lymphocyte counts.
Thanks for this post. I too had persistent lymphopaenia with dmf and had understood this was only permitted for six months max so chose to stop. I did not know about persistence. I'm now 18 months post and at 500. Sounds like I'm not alone.
To clarify above I meant 'did not know about persistence after stopping dmf'. You suggested ProfG this could be months or even years? It's not that I'm risk averse, the very opposite. But it's a risk benefit calculation and I'm really not convinced dmf is worth it….
I am aware from colleagues of mine that in some patients the lymphopaenia has been long-term, i.e. greater than 12 months. Whether this will be permanent I don't know.
This was really interesting. At what level would they need to recover to for alemtuzumab/cladribine/fingolimod to be a reasonably sensible option?My levels have never been great on DMF – 0.7-0.9 over the last 9-12 months and I was being encouraged to think of switching. it's tricky!!
Re: "At what level would they need to recover to for alemtuzumab/cladribine/fingolimod to be a reasonably sensible option?"I would be happy treating provided the count was above 800. I am aware that some of my colleagues would want a level above 1,000. Please note this advice is not evidence-based, but is based on scientific principles.
I am concerned. I am also less than 500 lymphocytes. A UTI suddenly went a bit severe and I'm on cipro now. I dntvknow my JC virus status, but I think I need to be tested. Thanks so much for this post. It has really helped. Incidentally, Joan Beal has kindly informed the public that beta interferons increase your risk of stroke. Gee, thanks. I haven't seen that research anywhere before. Its almost like she's an ms researcher or something!
I have an idea on how to get your application started. Hacking Health. That is something I recently started looking into (I work in IT and have MS which is how I started to think about it.) Conceptually this is a manageable size of project. The key is to find the right person to pitch such an initiative. There is also no guarantee it will go anywhere but its an idea. I'll put some thought into it.