Are you up for HSCT in MS? Do you think the ZEUS trial is a must? #MSBlog #MSResearch #CrowdSpeak
“This is another open-label descriptive study of HSCT (hematopoietic stem cell transplantation) in MS. At first glance the results are impressive and would appear better than one would expect from natural history studies. Fortunately, there were no deaths in this study. Until the community get together to plan, and perform, a proper randomised blinded study how can we, the MS community, assess the risk:benefit ratio of HSCT? HSCT is not benign and has a significant mortality associated with it. In the UK at present we really can’t refer MSers for this procedure because it is not licensed for treating MS and most HSCT units have no experience with using the procedure in MS. HSCT is close to the ultimate induction therapy and is underpinned by a very good scientific rationale. I have proposed developing the so called ZEUS trial to address the evidence gap.”
“As you can see the ZEUS trial is comparing HSCT to Alemtuzumab the only licensed induction therapy. I have suggested using a non-inferiority design simply because trying to show that HSCT is superior to Alemtuzumab will take too many MSers and be impossible to do. Before doing this study we are going to have to do a lot of enabling work to see if it feasible and whether or not MSers are prepared to take the risks associated with HSCT. I am aware that our recent survey suggests there is an appetite for the HSCT people who read and follow this blog are not average MSers and tend to be more informed. The following is a list of questions we have proposed that need answering:
- Do MSers understand the immediate risks associated with HSCT?
- Do MSers understand the undefined risks associated with HSCT?
- Would MSers be prepared to be randomised to receive alemtuzumab or HSCT?
- Would British Neurologists be prepared to refer patients for a HSCT trial?
- Do haematology units in the UK have enough capacity to handle a large national MS-HSCT trial?
- What are the economics of HSCT? How do they compare to alemtuzumab treatment?
- Would a non-myeloablative or a myeloablative protocol be best?
- What is the optimal trial protocol?
- Would we only target DMT failures or MSers naive to DMTs?
- Would eligible MSers have to have highly active MS or just active MS?
- Would the NIHR or MRC be prepared to discuss funding a trial of this nature?
- Should the study be limited to MSers with relapsing disease or should it include MSers with progressive MS?
- Should there be an age cut-off?
- Should MSer only be eligible if they have failed several other DMTs?
- Who should be the principal investigator?
- What should the primary outcome be? Relapse rate? MRI activity? Disease progression? Disability improvement?
- Should we allow retreatment if MSers breakthrough with activity as we do with alemtuzumab?
“At present we would not recommend HSCT to any of our patients. HSCT should only be done as part of clinical trials.”
Epub: Shevchenko et al. Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician’s and patient’s perspectives. Ann Hematol. 2015 Feb.
Background: High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (AHSCT) is a promising approach to treatment of MS.
Objective & Methods: In this paper, we present the long-term outcomes of a prospective single-centre study with the analysis of the safety and efficacy of HDIT + AHSCT with reduced-intensity BEAM-like conditioning regimen in 99 MSers: mean age-35 years old; male/female-39/60; median Expanded Disability Status Scale (EDSS) = 3.5; 43 relapsing/remitting MS, 56 progressive MS.
Results: No transplant-related deaths were observed. The mobilization and transplantation procedures were well tolerated. At 6 months post-transplant, neurological improvement or stabilization was observed in all the MSers except one. Cumulative incidence of disease progression was 16.7 % at 8 years after HDIT + AHSCT. Estimated event-free survival at median follow-up of 48.9 months was 80 %: 83.3 % in relapsing/remitting MS vs 75.5 % in progressive MS. Sixty-four MSers who did not progress during the first 3 years post-transplant and were monitored for more than 3 years were included in long-term outcome analysis. At the median long-term follow-up of 62 months, 47 % of MSers improved by at least 0.5 points on the EDSS scale as compared to baseline and exhibited improvement during the entire period of follow-up; 45 % of MSers were stable. No active, new, or enlarging lesions on magnetic resonance imaging were registered in MSers without disease progression. AHSCT was accompanied by a significant improvement in quality of life.
Conclusion: Due to the fact that MSer selection was quite different to the other studies and that the information about disease activity prior in the disease course and its treatment was inhomogeneous, comparison with the results in the literature should be done with caution. Thus, the risk/benefit ratio of HDIT + AHSCT with reduced-intensity BEAM-like conditioning regimen in our population of MS MSers is very favorable. The consistency of our long-term clinical and quality of life results, together with the persistence of improvement, is in favour of the efficacy and safety of this treatment approach in MS.
CoI: This group accept international referrals and charge for the procedure.
“Please note that the ZEUS Trial is one of the studies we have put forward as part of our exploration into crowdfunding. The crowdfunding survey is still open; if you haven’t done so already please feel free to complete the survey. Thank you.”
“Please note that the ZEUS Trial is one of the studies we have put forward as part of our exploration into crowdfunding. The crowdfunding survey is still open; if you haven’t done so already please feel free to complete the survey. Thank you.”
One question I would be interested in as a potential participant is why the results of HSCT aren't consistent for everyone i.e. If you are ablating everyone's immune system with the same treatment protocol, why don't all patients have long term remission.
Why would you expect the same effect on everyone? That is not what happens when these types of drugs are used to treat say Hodgkins lymphoma, some people go into remission and some do not. It could be that whatever is causing MS survives the treatment, or the new cells are affected again by the same problem as the first time. You see people who had Hodgkins getting it again 10 to 20 years later and it is a new case of the disease not a reawakening of the old one. If MS is an interaction between a virus and the person genetics HSCT is likely to work for a limited time until the mutation occurs again.
Almost everyone with RRMS and reasonably low EDSS (<6) does respond if you go with complete lymphoablation (i.e. erasing them all). Unfortunately, this is extremely toxic and involves TBI (total body irradiation) or some pretty nasty high intensity chemo which can have serious side effects, and a relatively high mortality risk. The "reduced intensity" treatments used today (BEAM, or Cyclophosphamide + ATG/Rituximab) ablate a significant chunk but not all of the lymphocytes, but are much safer and easier to tolerate. This appears (from the data available so far) to be enough in the majority, but not all patients.
"2. Do MSers understand the undefined risks associated with HSCT?"What are the undefined risks? It seems to me erasing your immune system may be a reasonable approach to treat an autoimmune driven disease in the short term but what are the concerns in the long run?
There's some (relatively small, but not irrelevant) risk of complications from chemo (peripheral neuropathy, secondary cancer, cariotoxicity, hepatic toxicity, etc.), and you've obviously got to be very careful whilst your immune system is down as you're susceptible to neutropenic sepsis.They mitigate this well with isolation & prophlaxis (short term), prophlaxis and monitoring (medium term) and regular monitoring (long term), but it's still a risk you need to be comfortable with.A lot of the risks you can mitigate yourself through lifestyle choices (e.g. good hand hygeine, avoiding risky foods/crowds of sick people, don't smoke, don't get sunburned in the first 24 months, etc.). The biggest risk of infection during the early period is actually from within yourself (reactivation or proliferation of opportunistic bacteria/viruses), but they monitor you very closely in that period and fill you full of anitvirals, antibacterials, and antifungals, and check your BP and temperature at regular intervals throughout the day.Collectively, it's worth noting that mortality with the current protocols (particularly non-myeloablative) in autoimmune patients is very very rare in experienced centres. I guess in the long term the risks (or probably actually questions more than risks) are:1) Will we all present back with SPMS in 10-15 years?2) Will MS reactivate in the long term because it wasn't truly entirely wiped out by HSCT?3) If MS is completely eradicated by HSCT, will it eventually retrigger through the environmental trigger reoccurring?
Actually as you age the thymus begin to be less productive such that new T cells aren't produced. It is suspected this may be the reason why cancer becomes more prevelant as you age. If you wipe out your immune system this could be problematic for cancer surveillance down the road: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750859/
This study contained progressive MSers, and appears to buck the trend of no effect. Is this correct?
Not sure that trend is so apparent in recent studies. I know it was there in the early days when they were using mega-strong protocols with TBI and/or Bulsophan essentially as a salvage treatment for those with very high EDSS, and terrible prognosis. But a number of recent studies seem to suggest an effect upon progressive disease.I believe some of Dr Burt's earlier (published) studies showed some positive effect upon progression in progressive disease, but not so much in reversing EDSS (which seems to be the endpoint he's focusing upon). Indeed, even in his latest study, 20% of the cohort were SPMS – so doing the maths based upon the reported 80% success rate (event free survival), either it worked for 100% of RRMS patients and none of the SPMS group (unlikely), or it worked for some SPMS patients too.Dr Federenko and co have published similar results including SPMS & PPMS previously, as have Uppsala Universtiy in Sweden (the Burman paper) where there was no statistically signifcant difference in response rate between RRMS & SPMS patients.That being said, all based on small patient populations and all open label.Would definitely be good to get it confirmed in a big study like Zeus.
Hi Prof Matt and Mouse This would surely suggest hsct as a possible treatment for progressive Ms? 75% chance of improvement?Especially in early orogressive Ms where we know inflammation often occurs?
Roughly how much would the zeus and charcot 2 trials cost?
I had hsct moscow 2009 ppms and totally halted progression. With ends improvement:)
Can you be more specific on your experience, symptoms and current status?
Can you give us details
Just a note of caution folks, that due to the nature of the internet, there is no guarantee of the veracity of assertions that are made here, particularly if posted anonymously.
Hi Md2 I know that but it's nice to see if we can get any proof to back up what claims they have
proper reputable studies
As the old saying goes,"Anecdotal evidence, is no evidence".
These I believe are often fee for service studies
Are we classing the above study as a reputable source? In which case surely surely it's an option as a treatment for ppms
Well it's open label for a start.
Fee for service..could be an advert..so buyer beware.
I was wondering this tooBut then wouldn't yhay apply to most studies regarding purchasable drugs of treatmentsWhat is your HONEST opinionThere's mot a lot else out therefor someone with early aggressive progressive Ms
What relevance is that? It has to be open label with stem cells surelyWhat I'm getting at is are the results correct, if so they represent a great chance albeit chance for people with ppms to slow disease until something better if needed comes along
Can someone explain the long term follow up figures theyve confused me