The Special One: Cladribine acting in the CNS

Blood 1994;84:1237-42

Cancer Res 1994;54:1235-9

Leukaemia in children - what do these studies have to do with the use of Cladribine (2-chlorodeoxyadenosine) in pwMS?  

Well, they revealed over 20 years ago that Cladribine penetrates into the spinal fluid, and in relevant concentrations (about 1/5 - 1/4 of plasma)

Whilst this property is not unique (among drugs used for pwMS) to Cladribine, it is the only drug where its mechanism of action strongly suggests a direct effect within the central nervous system. 

Penetration into the brain may be important for the mechanism by which Cladribine could potentially work not only in those recently diagnosed with MS, but also in people with advanced MS (EDSS>6): Even though at this stage there is generally less significant blood brain barrier leakage and therefore less overt entry of inflammatory cells from the blood stream into the brain, we know that inflammation plays a role throughout the disease, including its advanced stage.  A drug that can attack T and B lymphocytes, and perhaps plasma cells, in the brain of pwMS directly, even without overt blood brain barrier breakdown, may be effective in preserving important functions such as upper limb strength & coordination, cognition and speech.

MD has added
"There are some people who believe that progressive MS is due to the action of B cells within the brain. 

As cladribine can cross the blood brain barrier and can kill dividing and non-dividing T and B cells and can apparently kill plasma cells. It could target plasma cells in the brain, unlike any other MS drug. 

In some studies there has been an affect on oligoclonal bands supporting this view, unlike with Alemtuzumab for example. Ocrelizumab  being an antibody may have limited access into the brain and anti-CD20 is not expressed by plasma cells.

Some people still believe progressive disease is caused by T cells. Cladribine can deal with them both in the periphery and could also target them in the brain.

Whilst you will say Cladribine does not stop progressive MS(Rice et al. 2000), DrK will say that the trials were too short to ever show an effect on progressive MS and so the jury is still out. 

It would certainly target the active inflammation (present in all people with MS, including progressive MS) and being an induction therapy where the drug will be gone within about 24h of its last dose, it allows one to layer other neuroprotective/repair agents on top with no drug-drug interactions to worry about. This would not be the case with any daily treatment of immune modulator. 

The question is which neuroprotective should we layer on top?".