Monday, 25 September 2017

Delayed Repopulation white cell population after stopping DMF

Bhupendra O. Khatri, Sergey S. Tarima, Benjamin Essig, Jean Sesing, Tayo Olapo. Delayed lymphocyte re-population following discontinuation of dimethyl fumarate and after switching to other disease modifying drug therapies MSARDS DOI: http://dx.doi.org/10.1016/j.msard.2017.09.014

Background:Dimethyl fumarate (DMF) reduces absolute lymphocyte counts, CD4, and CD8 counts, without significantly affecting total white blood cell counts. However, the recovery rate of these cells after discontinuation of DMF is unknown. The effect of subsequent disease modifying therapies (DMTs) on re-population rate is also unknown.
Objectives:To study the re-population rate of absolute lymphocytes, CD4, and CD8 counts back to baseline after discontinuation of DMF. 2. To measure the effect of subsequent DMTs on the re-population rate of these cells after DMF therapy. 3. To study the effect of the duration of exposure to DMF on repopulation of these cells.
Methods:A retrospective chart review of subjects who had discontinued DMF and in whom, CBC with differential, CD4 and CD8 counts were available at baseline, discontinuation and at follow-up (n=113).
Results: DMF causes a significant drop in absolute lymphocyte, CD4, and CD8 counts. Re-population of these cells after discontinuation of DMF is significantly delayed, irrespective of whether or not a subsequent DMT is used, although there is a difference in re-population rate among DMTs. The re-population rate is also dependent on the duration of time patients have been exposed to DMF; longer exposure was associated with more delayed recovery.
Conclusion:During this 30 month study period, re-population rates were significantly delayed post-DMF, irrespective of what subsequent DMT the patients received. Furthermore, no recovery of lymphocyte counts occurred in patients who were started on fingolimod or alemtuzumab after DMF was discontinued; in fact there was a continued decline in all of the cell populations studied.



As I have been saying for some time, when you start a DMT you have to think of what next after the DMT, as many will fail particularly the lower efficacy agents. DMT is higher efficacy agent. It is an immune depleting agent, which is pretty good at getting rid of CD8 T cells. It is moderate at removing memory B cells so that affects its ranking in my mind. But what else does it do. It is evident that some people who take DMF, deplete their cells and they do not functionally recover for some time, suggesting that DMF must hit the baby T cells so that there is little to repopulate with.
This offers a conundrum of when is best to start, because you don't want to wait too long before starting the next treatment so rebound does not occur, but if you are adding a lymphopenia inducing drug when you are lymphopenic are you going to be more susceptible to infections?
Worth knowing and discussing with your neuro before the switch.  ProfG maybe can expand on the DMF switch when he wakes up in Trumpland.

7 comments:

  1. Dmf would seem to me to be a poor choice of dmt if only moderate depletion of memory B cells at the expense of significant depletion of Ts occurs. Especially if memory Bs recover quickly but Ts stay low for ages (forever?) after. If you're going to be put at risk of infections due to T cell depletion, you might as well make it worthwhile with a highly effective therapy like alemtuzumab or cladribine. Oh not everyone qualifies for those. Sounds like a case for off-label cladribine :) why use anything else?

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  2. Is there a study that looks at rebound after discontinuing DMF? Does rebound correlate with the T-cells repopulating?

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  3. This overkill is bad because it creates lymphopenia and makes you vulnerable to infections. Why it isn't good for MS at the same time though?

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    1. Because most of our lymphocytes are T cells and MS is not a T cell disease? Just a suggestion :( from a pwMS and pw not many lymphocytes two years post very short course dmf :(

      Good question, in peripheral blood, how many of our lymphocytes are T? 80%?

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    2. Doesn't this study just dispove the CD8 theory? Shouldn't we be good or at least better after DMF -even in an sterile world? The great mysteries of DMTs, chapter 4.

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  4. Why not only do short courses of DMF, then? Or on-off courses?

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    1. I think it's cos dmf only depletes B cells whilst you're taking it so as soon as stop they start coming back? Meanwhile even a short course might be enough to deplete T cells for a long time. So in my case no CD8 2 years post dmf and MS getting worse. Sorry for the n=1 case, appreciate not much help. Tad annoying though :(

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