CVfactor wrote:Thanks George,
As usual you have investigated all options with much detail. I think the best hope in my view is HSCT prior to becoming progressive, but it will be a while before it is accepted treatment availabe to all.
After thinking about what you wrote about these agents, it seems it might be of a concern for people who undergo the non-myeoblative method and have to be re-treated after a relapse. Any thoughts?
CV, you bring up an excellent point, as usual. I am going to apologize in advance for my long response that I wite in case anyone else doesn't know the background.
Over the past few years of seeing and learning more about the non-myeloablative specific HSCT protocol (heavily dependent upon cyclophosphamide + two additional non-alkylating chemical agents) and clinical results, I am really starting to have some concern about that specific non-myeloablative form of HSCT as opposed to the myeloablative HSCT (which is the one I received). My main concern is not about safety, but efficacy. But of course the two are intertwined. I'll explain my thinking. . . . . .
Myeloablative HSCT (the most widely used protocol being a four-drug regimin of BEAM) is extremely effective at eliminating virtually all of the in-vivo lymphocytes of the body. The four chemicals pretty much ablate the entire compliment of autoreactive lymphocytes of all epitope sub-types that are responsible for underlying MS disease activity and progression. In fact, following myeloablative HSCT the human body is rendered antigen naive, causing the body to loose immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens and vaccines.Because of this it also becomes necessary for myeloablative HSCT recipients to be re-vaccinated for diseases starting from the beginning again, just like a newborn child. An excellent surrogate indicator of the superior effectiveness of this treatment for hematologically-rooted autoimmune conditions such as MS. If there is any chance of stopping MS in a given individual, myeloablative protocols will do it with little remaining doubt.
The non-myeloablative HSCT protocol for the treatent of autoimmune diseases was pioneered by Prof. Shimon Slavin (formerly with Stanford and Fred Hutchinson) here in the US in the 1980's as a way to perform a "gentler" and "safer" (but only partial) immune ablation with a reduced risk of mortality. At that time, the fully myeloablative HSCT treatments were showing a high level of risk with a death rate in the 5-10% range. In the 1990's Dr. Richard Burt teamed up with Prof. Slavin and adopted this "reduced intensity conditioning" (RIC) approach and continued on with his own non-myeloablative clinical trials at NWU in Chicago (currently in phase III today). So the non-myeloablative HSCT protocol (as performed by Dr. Burt at NWU in Chicago) does not ablate the entire compliment of in-vivo lymphocytes, but instead "diminishes" them. So some autorective lymphocytes still survive, but with the objective that these autoreactive lymphocytes will be driven to a low enough population level to render the underlying MS pathology inactive.
Here is a graph I created that shows this difference between the two protocols:http://2.bp.blogspot.com/-3w43aw2GsWA/T ... rofile.jpg
So the original objective of the non-myeloablative HSCT was appropriate and admirable. . . . . a safer treatment of hematologically autoimmune disorders (and MS specifically) that was still efficacious.
However, two things have happened since the inception of the non-myeloablative clinical trials:
1) The fully-myeloablative (BEAM) HSCT treatment at experienced facilities has significantly improved the safety and mortality rates of the treatment (mainly by making the treatment "proactive" instead of "reactive"). BEAM performed at experienced hospital facilities now has a mortality rate somewhere in the sub-1% range (probably somewhere around 0.8%). The non-myeloablative HSCT protocol as administered at NWU in Chicago has a mortality rate in the range of approximately 0.4%. So clearly today these two treatment protocols are not "that" different in safety profiles. Neither one of which can be characterized as wildly risky.
2) Dr. Burt's non-myeloablative HSCT treatment has shown that a substantial portion of initially-treated patients have failed to have their MS pathology arrested. From the most recent phase II clinical trial data, fully 23% of non-myeloablative treated patients suffered a relapse following initial treatment. Dr. Burt's program identifies such failed treatment cases by identification of relapse activity, and then performs a "retreatment" of six months of monthly cyclophosphamide infusions. This is a very inefficient way to reduce the autoreactive lymphocyte population (the ones that still have antigen memory) because both autoreactive and niave cells are mixed together in the body and the population as a whole gets diminished; with lesser effectivity of autoreactive lymphocyte ablation each monthly re-treatment generation.
So going back to your original comment, it seems that falling into the 23% of failed treatment patients is not a good thing because cyclophosphamide re-treatments up the lifetime expose level and risk of a possible latent malignancy.
Two lessons that I can see from all this. . . . . it seems that in order to not fall into the 23% grouping of failed non-myeloablative HSCT treated patient population, then the myeloablative (BEAM) treatment would be a better option. The advantages being better probability of initial treatment success, together with no required re-treatments that up the chance of latent malignancies. Utilizing a stem cell graft is also a good strategy that allows for use of the "minimum necessary" alkylating chemical expose while still acheiving the objective of inactivating MS disease pathology. Once the myeloablative HSCT treatment is done, its done. No amount of additional re-treatment is going to improve the probability of a successfull outcome. Once is all it takes and there is nothing (yet) shown to work better and to me that means a 'realatively' safe treatment (since not a single MS patient has died from this chemical-only HSCT treatment protocol).
Additionally, what if a SPMS or PPMS treated patient fails to have their underlying MS disease activity arrested via non-myeloablative HSCT? How would you know or identify such a patient? Such patients don't have isolated relapses, just further progression. So for my opinion under all circumstances progressive MS patients should favor the myeloablative HSCT to avoid possibly being stuck in such a difficult-to-diagnose situation.
But I also have to acknowledge there are some downsides (I call them trade-offs) to having the myeloablative HSCT:
- Need to be re-vaccinated (not required with non myeloablative)
- Near-certain infertility and probable hormone dysfunction requiring HRT (This is only a partial chance with non-myeloablative protocol)
- Average longer recovery timeframe
- Slightly greater risk of complications (another reason to have any HSCT procdure performed at a good facility)