2 Years Post HSCT And MS Still Stopped

[CVfactor]

Also, it seems like your immune system health at the time of challenge would be a key factor. For example it has been shown that low vitamin D levels during childhood is likely a risk factor for MS. So I would definetely want to have a healthy Vitamin D level after HSCT. So as you said before George you would have to have the same combination to the MS lock to re-acquire the disease. I think the odds would be very low, but time will tell.

[georgegoss]

Also, it seems like your immune system health at the time of challenge would be a key factor. For example it has been shown that low vitamin D levels during childhood is likely a risk factor for MS. So I would definetely want to have a healthy Vitamin D level after HSCT. So as you said before George you would have to have the same combination to the MS lock to re-acquire the disease. I think the odds would be very low, but time will tell.

What you state makes good sense to me.

[HUD45]

]

Hi KMG, I was wondering if you could explain a little further what "further immunosupression" means. More MS drugs or another chemo procedure or what? Just curious..HUD

Hi Hud,

I found out the answer as this is all becoming clearer to me over time. . . . because the non-myeloablative HSCT protocol walks a fine line between too little immunoablation (won't stop the MS) and too much immunoablation (causing dangerous lymphoproliferative disorder), the infused chemical cocktail dosage to the body must be extremely carefully controlled (by body weight), and therefore they sometimes come down on the side of slightly less chemical density (for patient treatment safety). So it makes sense that there would be a possibility that a few patients would relapse. So to get the patient back into remission post-transplantation they infuse additional doses of cyclophosphamide which has the effect of clearing out more lymphocytes that they didn't get with the main procedure.

This is an interesting contrast to the myeloablative protocol which is not so sensitive to drug dosing (although the dose is still important). The BEAM therapy is basically a binary treatment in which nearly the entire lymphocyte population of the body is eliminated (which is also why it is considered more aggressive) and post-transplantation relapses are fewer (if at all). As opposed to the myeloablative protocol, the non-myeloablative HSCT treatment doesn't eliminate all the lymphocytes of the body. It just reduces the total population, as described by Dr. Burt. . . .

[For the non-myeloablative HSCT protocol for MS] "Autoreactive memory cells survive and autoantibodies, while significantly diminished, generally remain positive."

This is also why the myeloablative (BEAM) protocol requires re-vaccination and the non-myeloablative does not. Basically, the non-myeloablative HSCT protocol is actually more complex and harder for the doctors to administer compared with the myeloablative protocol. Also why there are few facilities around the world that will perform the procedure.

Regards,

George

Hey thanks George... This is pretty much what I assumed the answer to "further immunosupression" would entail. However it would be very interesting for me at least to know the exact way evaluation for and determination of course of action then for further treatment as well how long in between the immunosupressive treatments. In other words is there a formula or is the providor just winging it on a case by case basis? I'll bet they wing it but we will find out in the future.

Thanks again and keep diggin...HUD

[CVfactor]

If they are doing this in a trial setting it seems like it would negate the trial. It would be akin to changing the dosage in the middle of a drug trial to effect the outcome.

[georgegoss]

Hi Hud,

Although I don't actually know if Burt has some specific criteria, I bet you are likely correct that he just evaluates on a case-by-case basis. But also, because he generally restricts his treatment population to patients that have episodic manifestation of MS, it probably would be easy to see / know / detect when a patient is relapsing with further underlying disease activity. Seems like your case (PPMS) would be special from this perspective as progressive cases wouldn't have such obvious isolated discrete indication of further active disease progression as compared to RRMS. Seems logical that the only way to guage ongoing activity in such cases would be a further deterioration from baseline over some interval of time.

Although in a 'general' sense, I suppose that is one more 'possible' argument to made for the myeloablative (BEAM) HSCT protocol. . . so long as it is administered properly, there would be virtually no chance of an unintended relapse because nearly the entire in-vivo immune cell population has been eliminated.

Of course I'm not at all suggesting that your disease is not stopped. Still seems rather early post-transplantation to engage in that kind of speculation (especially considering that most post-HSCT treated patients very often have strong pre-treatment symptomatic fluctuations for the first year that eventually resolve, just like in my and Asher's SPMS cases). Slavin is a pretty smart doctor. I have to imagine that he must have considered these factors for your treatment. But also, if it ever came to it, I would bet cyclophosphamide re-treatment might also have a similar benefit for PPMS cases to effect remission similar to that of RRMS. But of course that's purely a guess on my part.

Sorry for my wandering disconnected thoughts. I hope you're not excessively stressing out about this right now. If it were me I'd wait until closer to a year post-transplantation to start thinking about how to guage such an effect. Important to first get completely past the chemo after-effects that can often be confused with symptomatic (re)progression during the timeframe you are currently in.

- George

[georgegoss]

If they are doing this in a trial setting it seems like it would negate the trial. It would be akin to changing the dosage in the middle of a drug trial to effect the outcome.

Excellent point, CV. Perhaps this is a possible weakness of the non-myeloablative protocol? Dr. Nash in the HALT-MS myeloablative trial never engaged in such re-treatments (it was never necessary).

[packo]

I am not an expert, but if I would have to apply both myeloablative and non-myeloablative protocols on a various group of individuals, I would go with the myeloablative on those patients with a) RRMS, especially those with very active (inflammatory) disease and low EDSS score and b) those individuals with aggressive disease who accumulated lots of disability in a very short period, and non-myeloablative for everybody else, mostly patients with SPMS and PPMS, but this is just my opinion, call it a hunch based on my understanding of the disease. Opinions?

[CVfactor]

Personally, I am going to try Copaxone first to see if I am a lucky one who it works on. If this fails and I continue to progress I will work on getting funds for a BEAM procedure.

If I had PPMS I would try to get BEAM as soon as possible because there really are no other alternatives. I guess in my view I don't really understand the theory of the non-myoablative procedure. If I was going to undergo HSCT I would only want to do it once.

[georgegoss]

I am not an expert, but if I would have to apply both myeloablative and non-myeloablative protocols on a various group of individuals, I would go with the myeloablative on those patients with a) RRMS, especially those with very active (inflammatory) disease and low EDSS score and b) those individuals with aggressive disease who accumulated lots of disability in a very short period, and non-myeloablative for everybody else, mostly patients with SPMS and PPMS, but this is just my opinion, call it a hunch based on my understanding of the disease. Opinions?

Hey Packo. . . I can see your thinking here. Also makes sense and I wouldn't argue against it. Just one thought regarding progressive cases. . . how can one determine an "agressive" PPMS case? I suppose that could only be detrermined by the rate of diasability and EDSS deterioration? Would you also support a myeloablative protocol for a rapid agressive PPMS disease as well an RRMS one? Or only reserve it for aggressive RRMS? I could easily see the logic cutting both ways. But like you, I also have no hard data to back up my thinking here.

The only thing I know for certain is that, as opposed to the non-myeloablative protocol, for the myeloablative protocol there are few remaining reactive lymphocytes and autoantibodies following treatment. But of course, I don't know what that would directly impact. Other than only guessing as to what's going on at the cellular level, the only way to measure protocol efficacy vs. disease morphology is (like you've already said) to randomize these groups to either of the two protocols and then measure EDSS over time. A good idea but I'm thinking this won't happen for a long time to come. Perhaps the next step of the clinical trial work after HSCT becomes FDA-approved? Maybe there's still time for us to earn our medical degrees and then you and I can run the trial!

[shucks]

I had a chance to discuss the issue with dr Burt a month or so ago. He told me that the goal was to come up with a specific treatment that would stop the disease course without undue toxicity. He believes they lympho ablative to be just that. He was very matter of fact about it.

[georgegoss]

I had a chance to discuss the issue with dr Burt a month or so ago. He told me that the goal was to come up with a specific treatment that would stop the disease course without undue toxicity. He believes they lympho ablative to be just that. He was very matter of fact about it.

Agreed. That's the real objective of the non-myeloablative protocol. First developed by Prof Slavin and then worked-on collaboratively between he and Dr. Burt, the objective was to maintain efficacy while reducing toxicity and mortality risk.

But at the time they developed the non-myeloablative protocol the mortality rate of the myeloalative (BEAM) protocol was around 5%. Rather risky. (I personally am not favorably thrilled with a 1-in-20 death rate.) But things are different today. A good experienced hospital facility that administers BEAM currently has a documented mortality of less than 1% for an otherwise healthy person. The risk for the non-myeloablative protocol is definitely safer at a theoretical 0.4%. But frankly as of today its not "that" much different in safety. The BEAM protocol could hardly be considered wildly risky. Both protocols are reasonably safe.

I'm not knocking the non-myeloablative protocol, but clearly the rationale and motivation is diminished now that the myeloablative protocol administration has become so safe. Either way for treatment of MS, so far there have been zero deaths with the updated protocols for both approaches. Since treatment safety has now been put on a more closely equal footing, in my own mind there are only two significant advantages of the non-myeloablative protocol. . . . 1) More prompt "average" patient recovery time, and 2) No need to re-vaccinate. Since these issues were not important factors for me personally, I preferred the myeloabative (BEAM) protocol since the safety profile for both approaches is quite similar. I'm just glad that as of today both protocols have demonstrated substantially similar curative efficacy for MS. We'll see how this unfold over a longer period of time with a larger treatment population.

[HUD45]

Personally, I am going to try Copaxone first to see if I am a lucky one who it works on. If this fails and I continue to progress I will work on getting funds for a BEAM procedure.

If I had PPMS I would try to get BEAM as soon as possible because there really are no other alternatives. I guess in my view I don't really understand the theory of the non-myoablative procedure. If I was going to undergo HSCT I would only want to do it once.

Hope you get relief CV.

I think it is important to remind those considering HSCT,especially if specifically interested in the BEAM protocol that showing a history of using an immunomodulator type drug can be critical if not absolutely essential in being deemed a candidate. The drug therapy should show at least some effect on the MS course or symptoms for full consideration of candidacy. Even those with PPMS and no FDA approved drug should at least try and be able to document at least minimal positive outcome for acceptance into myeloblative HSCT......HUD

[packo]

I am not an expert, but if I would have to apply both myeloablative and non-myeloablative protocols on a various group of individuals, I would go with the myeloablative on those patients with a) RRMS, especially those with very active (inflammatory) disease and low EDSS score and b) those individuals with aggressive disease who accumulated lots of disability in a very short period, and non-myeloablative for everybody else, mostly patients with SPMS and PPMS, but this is just my opinion, call it a hunch based on my understanding of the disease. Opinions?

Hey Packo. . . I can see your thinking here. Also makes sense and I wouldn't argue against it. Just one thought regarding progressive cases. . . how can one determine an "agressive" PPMS case? I suppose that could only be detrermined by the rate of diasability and EDSS deterioration? Would you also support a myeloablative protocol for a rapid agressive PPMS disease as well an RRMS one? Or only reserve it for aggressive RRMS? I could easily see the logic cutting both ways. But like you, I also have no hard data to back up my thinking here.

The only thing I know for certain is that, as opposed to the non-myeloablative protocol, for the myeloablative protocol there are few remaining reactive lymphocytes and autoantibodies following treatment. But of course, I don't know what that would directly impact. Other than only guessing as to what's going on at the cellular level, the only way to measure protocol efficacy vs. disease morphology is (like you've already said) to randomize these groups to either of the two protocols and then measure EDSS over time. A good idea but I'm thinking this won't happen for a long time to come. Perhaps the next step of the clinical trial work after HSCT becomes FDA-approved? Maybe there's still time for us to earn our medical degrees and then you and I can run the trial!

Regarding those trials, it's a deal , I must say medicine, and especially neurology, is very intriguing.

What I meant to say was that in my opinion maybe the myeloablative protocol is more suitable for inflammatory phase, and non-myeloablative for degenerative. Now of course every case is different, I personally would go with the non-myeloablative for some mild RR cases, but I think that the success of both of those protocols and their similar results proves the (aforementioned) hypothesis that MS is a complex disease in which many elements have to come together - genetic susceptibility, viruses, stress, low D levels and who knows what more.

Of course the myeloablative protocol offers the higher margin of safety with regards to this autoimmune aspect of the disease (so does total body irradiation+myeloablative, compared to myeloablative alone, yet it was abandoned), but for example, can the agents used in such a protocols compromise the existing neurological damage in patients with MS, both directly and indirectly? I met some people that went through the myeloablative protocol and never regained the EDSS they had before the protocol, but of course this has very much to do with the standard of medical care.

Just one more note regarding the non-myeloablative protocol, Prof. Slavin likes to apply it not just on MS but on various conditions, such are cancer(!!) and some life-threatening nonmalignant disorders. So that fact clearly illustrates how much Prof. Slavin believes in this method.

@shucks
Do not have any doubt about the non-myeloablative protocol and Dr. Burt...

[CVfactor]

For the non-myeoblative procedure, what is the recovery like? I know that with the myeoblative it is very critical to maintain sanitary conditions since you basically have no immune system after the procedure.

If the non-myeoablative method is less risky as far as post infection, this would probably seem like a more marketable option for people in the early stages of the disease.

[packo]

For the non-myeoblative procedure, what is the recovery like? I know that with the myeoblative it is very critical to maintain sanitary conditions since you basically have no immune system after the procedure.

It did not take long before I regained my strength, as for immune system, well it took some time, I had urinary infection 1,5 years post HSCT (but the real question is can that infection be attributed to the HSCT, my MS regardless of HSCT, or combination of those two) and herpes zoster 2 years post transplant (this probably has something to do with HSCT), I wore a mask while being in some public places (elevators, airports) for some 6 months post HSCT. But bare in mind that my immune system was already a bit weaker prior to HSCT due to mitoxantrone, steroids and maybe even Rebif. This latter is (as probably vast majority of you know) immunomodulator, not immunosuppressant, but since my body produced neutralizing antibodies, basically that was allergic reaction, so all that exhausted my body and probably also weakened my immune system (lack of movement, lack of exercise, all very important for immune system). But every case is different, my EDSS was high, let's say 6.25.

Today my immune system functions perfectly, reminds me of times when I was a professional athlete...