Tuesday, 1 November 2016

#ClinicSpeak & #NeuroSpeak: not all immunosuppressives are made equal

Lymphopaenia and opportunistic infections; the new marketing battleground in MS. #ClinicSpeak #Neurospeak #MSBlog

There is has been a rather large response to my post yesterday on opportunistic infections in alemtuzumabers. A large number of you have been asking me about opportunistic infections on other DMTs, in particular fingolimod and DMF. Fingolimod mainly suppresses lymphocyte responses and can't be derisked; i.e. a fingolimod works by causing a lymphopaenia. In addition, most of the opportunistic infections on fingolimod have occurred with lymphocytes above 200/mm3, the EMA's recommended cut-off for dose interruption. 

The table below summarises the types of infections to expect with the nature of the immunosuppression. DMF (dimethyl fumarate) does cause lymphopaenia, in 5-15% of treated MSers. However, we derisk DMF-induced lymphopaenia by switching patients onto another DMT. At Barts-MS our cut-off is 800/mm3, but other centres use 500/mm3

Cladribine is similar to alemtuzumab in its mode of action, but you don't get a profound depletion of lymphocytes. Cladribine also leave the innate cells relatively intact, therefore Listeria is unlikely to be a problem with cladribine. In addition, we adjust the dose of cladribine to prevent grade 4 lymphopaenia (<200/mm3). 

Daclizumab (anti-CD25) is an outlier in that it does not cause a global lymphopaenia and as a monotherapy has not been associated with opportunistic infections. Lymphocyte counts drop by about 10-15% on daclizumab, which rarely takes the total counts below normal. The main issue with daclizumab is that common infections may be more serious. However, these can be treated earlier and more actively. 

Ocrelizumab (anti-CD20) only depletes B-cells; in the short-term this strategy looks clean. However, with time B-cell depletion may affect antibody responses (long-lived plasma cells don't live forever) and then we would expect to see infections occurring with encapsulated bacteria (streptococci, meningococci, etc.).

It is clear that lymphopaenia and opportunistic infections are becoming the new battle ground between the DMTs. Safety, in particular long-term safety is going to be a major differentiator between the DMTs.


CoI: multiple

7 comments:

  1. Thanks for this informative post. You're right about the battle ground, IMHO cladribine sounds good!
    My GP reckons that everyone has low lymphocytes! Makes me think that the normal distribution isn't that normal! Do we worry unnecessarily?

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  2. I'm not sure I agree with your GP Judy. I don't have low lymphocytes, my range is between 2 to 2.5 and I'm on DMF.

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    1. My typical range is 0.8 to 1 and I managed 4 months on DMF before lymphocytes dropped to 0.3. There doesn't seem to be anything anyone will prescribe for me and MS is progressing fast.

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  3. What about Natalizumab?

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  4. I was taken off Tecfidera as after 1 year my lymphocytes dropped to below 0.5 (0.3 or 0.4 for 4 months). My lymphocytes took 6 weeks to get back to 0.9. Two months later (Sept 2016) I started Aubagio. Due to my lymphocyte counts my gp added FBC bloods to my fortnightly LFT monitoring. After 2 weeks my lymphocytes were at 0.5 after 4 weeks they are at 0.3 - you don't comment on Aubagio and Lymphopaenia. I have to admit to being concerned and wondering how safe it is to continue with Aubagio

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    1. Same here - first of Tecfidera with below the level lymphos then switch to Aubagio due to fear of PML then after months checked lymphos again and they were again lower than expected - so I dropped the drugs altogether.

      It seems to me that patients need to be checked BEFORE they start a therapy for lymphos - some may have had low lymphos to begin with like me and are not suited well for immunosuppression.

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  5. What about teriflunomide and interferon-beta?

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