When we discuss NEDA (no evident disease activity) I always make the point of rebaselining. The reason is if you don’t rebaseline then you will be taking into account disease activity that occurs before the drug works and blaming the drug for being ineffective when it may not be. With maintenance therapies the rebaselining needs to be done quite early, typically 3-6 months after starting the treatment, with the exception of glatiramer acetate that takes longer to have a full impact on MRI activity. In reality, an for pragmatic, reasons rebaseling at 6 or 12 months is fine.
When it comes to PIRTs, rebaselining needs to be done much later. Why? The mode of action of pulsed immune reconstitution therapies (PIRTs) is due to both depletion and reconstitution. The depletion may happen quickly, for example in the case of alemtuzumab and HSCT, or be more delayed in the case of cladribine. However, most consider the mode of action to be what happens post-reconstitution, i.e. when the immune system resets itself with new regulatory mechanisms. The reconstitution takes many months, if not years, to occur. Therefore it only makes sense to rebaseline at a point in time when you can do something about ongoing disease activity, i.e. in the case of alemtuzumab and cladribine offer another course of treatment. This is why we recommend 24 months in our Barts-MS algorithm.
Not all people agree with using the 24 months for rebaseling with alemtuzumab. Some have suggested using 12 months, i.e. before the second course has had time to work. The advantage of using the second year is that it at least allows you to compare alemtuzumab with other maintenance therapies. In the NEDA study below we simply looked at what happened to the 50% (175/349) of subjects who were rendered NEDA in year 2 (prior to alemtuzumab having had a chance to have its full effect). The other 50% of subjects had activity and hence should be looked at in year-3 and beyond; this analysis is being done. What this study tells you that if you are in the 50% of subjects that responds quickly to alemtuzumab by being NEDA in year 2 (prior to full activity) then you have 60% chance of being NEDA over the whole time period to year 5. That is all this poster says; it is not trying to make any other claim but that. Clearly, what happens to the other 50% is important and this information will be presented in a future publication. But more importantly is what happens to all these subjects over the next 10-15 years. This information will tell us if the promise of a ‘potential cure’ is real or not.
People need to realise that PIRTs are not necessarily miracle drugs; all they offer is a different apporach to treating MS. What is clear is that the way we use them and monitor their activity is very different.