Disease activation after alemtuzumab. Was it the B cells? or the fingolimod?

Rebound disease activity in people taking alemtuzumab.

Whats it the B cell surge or

Because they had taken fingolimid

Activation of disease during therapy with alemtuzumab in 3 patients with multiple sclerosis.

Wehrum T, Beume LA, Stich O, Mader I, Mäurer M, Czaplinski A, Weiller C, Rauer S.

Neurology. 2018 Jan 19. pii: 10.1212/WNL.0000000000004950. doi: 10.1212/WNL.0000000000004950. [Epub ahead of print]

OBJECTIVE:To report 3 patients with multiple sclerosis showing severe activation of disease during immunotherapy with alemtuzumab.

METHODS:

Retrospective case series.

RESULTS:

Patient 1, a 21-year-old woman, developed severe cognitive impairment, sight deterioration, severe gait ataxia, urinary retention, and extensive progression of cerebral lesion load, including new lesions that exhibited gadolinium ring enhancement and dominance of CD19/20-positive B lymphocytes, 6 months after induction of alemtuzumab.

Patient 2, a 28-year-old man, developed left-sided hemihypesthesia and ∼60 new cerebral and spinal lesions including lesions with gadolinium ring enhancement 6 months after induction of alemtuzumab.

Patient 3, a 37-year-old woman, developed ataxia and numbness of the left thigh, 16 new gadolinium-positive supratentorial lesions, and partly ring-enhancing and dominance of CD19/20-positive B lymphocytes 6 months after induction of alemtuzumab.

CONCLUSION:

This is a case series reporting severe activation of disease during immunotherapy with alemtuzumab. All patients showed onset of symptoms 6 months after induction of alemtuzumab, strikingly similar MRI lesion morphology, and unexpected high total B cell count, which may suggest a B-cell-mediated activation of disease.

This study reports on the development of highly active disease after alemtuzumab treatment and they suggest that it may be due to B cells, hence I have decided to report it as it keeps up the B cell momentum.

But importantly was the reactivation really due to B cells. previously it has been reported that repopulation of CD19 B cells was not associated with relapse activity in alemtuzumab studies. We also reported that this was the case with cladribine too. But are we looking at the right B cells. In these studies the B cells had repopulated to over 250% of their starting value after 6 months and so this is high compared to what you might expect. We have said previously that alemtuzumab may not clear the bone marrow well and so immature and then mature B cells rapidly repopulate the blood. However, what happened to the memory B cell subset. Did they repopulate. studies to properly interrogate the repopulating B cell subsets

However importantly all three of these individuals were switched from fingolimod. So is the real interest from these three individuals. In a study from a group in Wales 25% of those switching to alemtuzumab after fingolimod. So it is important to think how you switch from one treatment to another. In this case people were switched from alemtuzumab to rituximab. It will be interesting to know if these people will develop secondary autoimmunity due to alemtuzumab. It would help us know if it is the B cell hyperproliferation in the absence of T cell regulation that is the key...Time will tell.