Recent Research on HSCT, the Stem Cell Therapy That May Soon Change the MS Treatment Landscape.

(Please note: the following article is quite long. Though it covers a very important topic and I’ve tried to make it as accessible as possible, I’d suggest getting comfy and grabbing a nice beverage before diving in…)

Over the last six months or so, there has been a wave of new and encouraging research published regarding HSCT (Hematopoietic Stem Cell Therapy) for the treatment of multiple sclerosis. HSCT is the type of stem cell therapy in which a patient’s existing immune system is completely eradicated through the use of powerful chemotherapy drugs and is then rebooted via an infusion of their own stem cells. Some of the results reported have been nothing short of astounding, and even previously skeptical neurologists are now being forced to consider HSCT as a potential game changer that may significantly impact the MS treatment landscape sometime in the not-too-distant future.

So that this article doesn’t take on the length of a Russian novel, rather than getting into the detailed specifics of what HSCT is and isn't I’d like to concentrate on the recent HSCT published research and its implications. For a comprehensive overview of HSCT, please read my previous post on the subject by (clicking here). For a rundown on the different types of stem cell therapies currently being trialed in MS, please (click here).

Just a few things before delving into the research. It’s vitally important that patients not confuse HSCT with regenerative stem cell therapy, which attempts to directly repair the central nervous system damage done by MS. HSCT is a completely different approach with a completely different goal. Regenerative stem cell therapy, such as that being trialed at the Tisch Center in New York (click here) generally does not involve any direct manipulation of patients’ immune systems. HSCT, on the other hand, is entirely directed at providing patients with a new immune system after completely wiping out their presumably defective existing set of immune cells. The two treatment approaches couldn’t be any more different; their only similarity is that they both use stem cells in an attempt to combat multiple sclerosis, albeit in very different ways.

There are currently two forms of HSCT being trialed on MS patients, termed the myeloblative and non-myeloblative treatment protocols. The myeloblative protocol uses a combination of very strong chemotherapy drugs to completely ablate (a fancy word for “destroy”) patients’ immune systems as well as their bone marrow (immune system cells are manufactured in the bone marrow). Non-myeloblative HSCT uses a gentler chemotherapy regimen that takes down the immune system but leaves bone marrow intact. There is some debate among researchers as to which treatment protocol is best suited for combating MS, an issue that is still being sorted out.

There’s also the question of which patients are most likely to respond to HSCT. Because HSCT is directed entirely at replacing a patient’s presumably defective immune system with a new one that doesn’t attack the body’s own nervous system cells, the prevailing thinking is that only patients displaying the hallmarks of immune system driven multiple sclerosis would likely respond well to the treatment. With this in mind, most HSCT research and treatment centers restrict the treatment to patients with active inflammatory MS, meaning that eligible patients must have recently experienced multiple MS relapses and/or displayed enhancing lesions on their MRI images (enhancing lesions are indicators of immune activity within the central nervous system). Since this excludes many secondary progressive (SPMS) and most primary progressive (PPMS) patients, who experience increasing disability in the complete absence of relapses or enhancing lesions, these requirements are understandably the source of much consternation among this patient population (myself included), who are currently presented with no effective treatment options. More on this later.

With these issues in mind, let’s take a look at some of the recently published HSCT research and explore the issues they raise…

A study out of Chicago that used the gentler, non-myeloblative form of HSCT on 151 MS patients (123 RRMS, 28 SPMS) resulted in some startling results on the RRMS patients taking part in the trial (click here). Not only did the vast majority of these patients see their disease stop in its tracks, but a large proportion also saw their levels of disability improve. Four years after treatment, 80% of trial subjects remained relapse free, and 87% showed no signs of disease progression. Furthermore, and perhaps even more astounding, there was a decrease in the disability scores in 50% of patients two years after treatment, and in 64% of patients four years after undergoing the treatment protocol without any further follow-up treatment (click here). Given that a reduction in disability scores is almost unheard of when treating MS patients, these are eye-popping results, to say the least, tempered only by the fact that the SPMS patients included in the trial were reported to have shown no benefit.

This trial was headed up by Dr. Richard Burt of Northwestern University, a leading HSCT researcher. I tried to reach out to Dr. Burt via email with several questions before writing this piece, but unfortunately received no reply. A very informative interview with Dr. Burt is available by (clicking here). If anybody out there knows Dr. Burt, please tell him I’m still patiently waiting for his email reply, fully understanding that he’s a very busy man. In the meantime, if Dr. Burt should find himself in New York City and happens to get run over by a speeding wheelchair, I’ll swear on a stack of research papers that I had nothing to do with it.

A smaller, 25 patient study, called HALT-MS, which used a harsher myeloblative chemotherapy regimen on patients with highly active relapsing disease who had failed to see benefit from at least two previous MS drugs reported impressive interim results (click here). Though study subjects are scheduled to be tracked for five years, the results reported were a snapshot of these patients at the three year mark after treatment. After three years, 78.4% of trial subjects were reported to be free of any disability progression, relapses, or new lesions. Digging deeper into the results revealed that 90.9% of subjects were progression free and 86.3% were relapse free after 36 months. Very impressive.

I managed to get hold of the full published paper of this study, which indicated that although the numbers had not yet been fully crunched, it did appear that the effect of the treatment lessened with time, as fewer patients were reported to be free of signs of the disease at the four and five year marks (68.6% and 58.8% respectively). Again, though, these four and five year numbers were very preliminary, as not all patients had reached this duration after treatment.

A friend of mine, Dave Bexfield, who runs the terrific MS website/forum Active MSers (click here) was one of the participants in the HALT-MS trial. Five years ago Dave was getting absolutely slammed by his disease despite having been on a series of MS drugs. He qualified for the HALT-MS trial and received myeloblative HSCT. His tremendously aggressive RRMS was put entirely into remission for several years, but unfortunately, after five years, Dave recently reported that his disease has shown signs of reawakening (click here) and he is now planning on going on one of the newer, more powerful MS drugs. Dave told me that even though his disease has returned, he has no regrets about undergoing HSCT back in 2010. Without the treatment he is sure the disease would have by now left him completely disabled, and HSCT bought him time at a point when it looked like multiple sclerosis would get the better of him. There are highly effective treatment options available today that weren’t available five years ago, and despite the reemergence of some of his MS symptoms, Dave is very grateful to have taken part in the study.

An Italian team did a head-to-head test of the effectiveness of HSCT versus mitoxantrone (also known as Novantrone) on SPMS patients who had enhancing lesions on their MRIs (click here), the presence of which indicated that they still had an active inflammatory component to their disease.

Currently, mitoxantrone is the only approved drug for use on patients suffering from SPMS. It’s a fairly wicked drug, so toxic to the heart that patients can only stay on it for a limited amount of time. Additionally, mitoxantrone has been linked to a dangerous increase in specific forms of leukemia and lymphoma. As a result of this daunting side effect profile, the use of mitoxantrone has largely fallen out of favor with most MS neurologists.

This phase 2 study used an intensive myeloblative form of HSCT on a small group of study subjects (21, 17 of whom completed the study), and the primary endpoint of the study was a reduction in the number of enhancing lesions detected by MRI. Four years after treatment, HSCT resulted in a 79% reduction in new lesions as compared to those treated with mitoxantrone Unfortunately, no difference in disease progression was reported, but the study was not ideally set up to detect changes in disease progression, a metric which has proven to be very difficult to track even in studies specifically designed to detect disability progression. An editorial accompanying the study, which adds commentary to the statistics provided in the study abstract, should be of interest to all readers (click here).

A very small study out of Hamburg, Germany attempted to directly address the difference in effectiveness of HSCT between RRMS patients with enhancing lesions and progressive MS patients not displaying lesion enhancement (click here). This very small 10 patient trial (four progressive MSers, six with RRMS) compared the results between the two groups two and half years after treatment. The researchers found that although five of the six RRMS patients did show benefit from treatment, none of the progressive patients followed suit. It should be noted that the RRMS patients were considerably less disabled at the start of the study than the progressive test subjects (EDSS 4.25 versus EDSS 6.25).

Previous studies have found that approximately 40% of patients with early PPMS display enhancing lesions on their MRIs (click here) and the presence of such lesions early in the disease may be an indicator of a more aggressive disease course. Patients undergoing the transition from RRMS to SPMS frequently continue to have enhancing lesions for some time after their disease has gone mostly progressive. Remember, enhancing lesions are a sign of active inflammation in the central nervous system, an indicator that the immune system is playing a primary role in driving the disease forward. Since HSCT directly attacks the peripheral immune system, it stands to reason that the treatment would be most effective on patients with active immune system involvement. In the later stages of SPMS, and in the majority of cases of PPMS, it appears that some other as yet undiscovered neurodegenerative process is at work, a process which seems impervious to treatments targeting the peripheral immune system. Studies testing some of the latest potent immunosuppressive drugs – which are highly effective in treating RRMS – on progressive patients have repeatedly failed, the latest such study involving the drug Gilenya (click here). For those of us with progressive MS such failures are very discouraging, and it is with great hope that I’ve looked for hard data supporting the notion that HSCT may benefit even hard-core progressive MSers, which leads us to the final study to be discussed…

Lastly, a study out of Moscow, Russia (click here) provided data suggesting that HSCT might be beneficial to progressive patients who don’t have enhancing lesions (as stated earlier, this includes many SPMS patients and the majority of PPMS patients). Unlike most HSCT treatment centers, the center in Moscow accepts patients with all types of MS (RRMS, SPMS, PRMS, and PPMS), regardless of whether or not they have enhancing lesions on their MRIs or have recently experienced relapses.. A total of 99 patients were included in the study, 43 with RRMS and 56 with various forms of progressive MS.

The summary of this study revealed that 49 months after undergoing treatment, 83.3% of RRMS patients and 75.5% of progressive patients exhibited no signs of relapses or disease progression. After eight years, 45% of treated patients exhibited an improvement in mobility scores, while 45% remained stable. These are compelling numbers, to say the least, particularly for someone like me who has never had enhancing lesions but has nevertheless experienced a constant progression of disability. So compelling, in fact, that I asked a physician friend of mine to provide me the full paper (I could have bought it myself for $40 but most doctors can get research papers for free, and, hey, that’s what friends are for) so that I could dig deeper into this apparently promising research.

Upon reading the full paper (sorry, I can’t link to it because of copyright laws) my enthusiasm was tempered a bit. Although the paper states that only 40% of study subjects had exhibited enhancing lesions before undergoing HSCT, it turns out that this statistic was based on a single MRI done soon before the patients underwent therapy. A single MRI can easily miss enhancing lesions, especially if patients had been on disease modifying drugs, which is why most HSCT centers require patients to have exhibited enhancing lesions and/or relapses (which are almost universally accompanied by enhancing lesions) at some point during the full year prior to treatment.

Additionally, the scope of the disease histories of the patients treated in Moscow varied widely and in many cases was severely deficient. The full paper clearly states this, saying that “patients enrolled in the study previously have been treated in different centers, and the information about disease activity prior in the disease course and its treatment was inhomogeneous and in some cases quite scarce.” I found this sentence to be disquieting, as without comprehensive disease and treatment histories it’s almost impossible to accurately assess the disease state of any individual patient suffering from an illness as complicated as multiple sclerosis. In fact, the abstract of the study, which is available to the general public, even warns that because of this dearth of patient info “comparison with the results in the literature should be done with caution.” This line throws up a big red flag, as the ability to compare and replicate results from study to study is among the foundational basics of the scientific method.

Furthermore, despite publishing statistics that appear to indicate the treatment as practiced in Moscow was effective across a wide spectrum of MS patients, the authors state that “the best candidates for transplantation seem to be relatively young patients with active inflammatory lesions of relatively short duration and rapidly progressive disease, but still low disability scores, unresponsive to conventional therapy.” This was among a number of apparently contradictory elements contained in this research that left me with more questions than answers. While these results certainly can’t be discounted entirely, without a comprehensive, detailed data set it’s impossible to properly discern their value and validity when compared to other studies, a point the authors themselves reiterate on several occasions.

Based on this accumulated HSCT research, certain trends seem clear. HSCT treatment definitely seems remarkably effective on patients with active inflammatory relapsing remitting multiple sclerosis, in the majority of cases resulting in complete remission of the disease for five or more years, sometimes accompanied by a reduction in disability as well. This is far more effective than any of the currently approved disease modifying drugs with the possible exception of Lemtrada, whose mechanism of action in many ways mirrors that of HSCT (for more information on Lemtrada, which was recently approved by the FDA and is covered by most insurance companies, please click here and here).

The safety profile of HSCT as now practiced seems quite robust. None of the above studies reported any HSCT related mortalities, although some serious adverse events above and beyond those that would be considered normal for patients undergoing chemotherapy were described (most in the form of opportunistic infections). Clearly, the decision to undergo HSCT should not be taken lightly, as at its heart the treatment involves using strong chemotherapy drugs to completely eradicate a patient’s existing immune system. Multiple sclerosis is serious business, though, and many patients would gladly accept this risk/reward scenario for a chance at complete remission lasting years or even decades.

Despite the fact that there are credible anecdotal reports on various HSCT websites from progressive MS patients who state that they’ve been helped by the treatment, and even though I’ve desperately wanted – for my own selfish reasons – to find research to back up such statements, I’ve yet to come across any hard data to back up these claims. Research has shown that the treatment can be effective on progressive patients showing signs of active inflammatory disease (enhancing lesions), but there is little hard objective evidence to support the notion that HSCT benefits patients experiencing progression in the absence of active inflammation.

Because the rate of disability progression varies widely from patient to patient suffering from progressive MS, and can sometimes temporarily “plateau” or even cease entirely, predicting disease progression can be quite difficult, even for patients themselves. Using myself as an example, my wife likes to chide me that I’ve been telling her that I’ll probably be bedridden in six months for the last five years. In order to properly assess the effectiveness of any treatment for progressive MS using disability scores as markers, studies would need to last much longer than the 2-3 years typical MS trials generally run, which is among the reasons why so few trials on progressive MS have been conducted. Even in the recent, much talked about successful study involving the use of biotin to treat progressive MS patients (click here), it was shown that after one year only 13% of patients taking placebo showed evidence of disease progression (compared to 4% taking biotin). I certainly hope that the patients with nonenhancing progressive MS reporting benefit do turn out to be success stories and that some form of HSCT does demonstrably prove effective on noninflammatory multiple sclerosis, but so far, at least, the data is lacking.

Also lacking is long-term data on the durability of HSCT derived benefits on patients of all stripes. One older study (click here) looked at patients with aggressive multiple sclerosis 15 years after treatment and found that 44% of patients who had exhibited enhancing lesions before treatment and 10% who didn’t remained progression free. It should be noted that the patients included in this study were treated with earlier, much harsher forms of chemotherapy, and one would hope that the refinements made in the technique more recently would increase durability.

Although all of the studies reported on in this article are considered early to mid-stage trials, they do suggest that HSCT is an extremely promising and potentially game changing treatment for multiple sclerosis. Further trials will be necessary before HSCT receives any kind of official approval for the treatment of multiple sclerosis. Although the treatment is being offered to patients in quite a few clinics around the world, the cost is quite high and most insurance companies will not cover the expense. Given the exorbitant cost of multiple sclerosis drugs, though, as more reliable data is released this situation should change. Paying $100,000 for a one-time treatment that keeps the disease at bay for even 5-7 years is far more cost-effective than paying the roughly $50,000-$60,000 per year currently charged for the FDA approved disease modifying drugs, a point that I’m sure will not be lost on the insurance company bean counters. It should be interesting to see how the pharmaceutical companies react to the HSCT threat to their bottom lines.

Those patients currently considering HSCT therapy should limit their choice of treatment centers to those which have extensive experience administering HSCT, as study after study has shown that safety and efficacy increases exponentially with the number of procedures done. This treatment is not to be taken lightly, and cutting corners for cost or convenience could prove quite the egregious mistake.

Given the current quickening pace of HSCT research, I would guess that the treatment could approach widespread acceptance sometime within the next five years, as long as the financial considerations of the pharmaceutical companies don’t get in the way (and that may prove to be a mighty big if). Based on the latest data, once approved HSCT should prove to be the most effective treatment available for patients with very aggressive active inflammatory multiple sclerosis, but will likely be reserved for those patients who have first failed current frontline therapies. As for patients with nonenhancing progressive disease, though objective hard data supporting the use of HSCT is lacking, given the anecdotal evidence I hope and expect expect future research will be done on such patients in an attempt to clarify the matter. The stakes are quite high for these patients, and even if the odds of success seem slight, the potential gains warrant further investigation. With neuroregenerative and neuroprotective compounds now in the research pipeline, and with HSCT offering so much promise, there is much reason for MSers to harbor hope for a brighter future.

Stay strong, my friends…

Geez, what was that I said about this article not becoming as long as a Russian novel? Maybe I should change my name to Tolstoy (many apologies to Tolstoy)…