Thursday, 22 January 2015

Stem cell transplantation results very similar to alemtuzumab

Is hematopoietic stem transplantation cheaper and more effective than alemtuzumab treatment? #MSResearch #MSBlog

"The following open-label study on non-myeloablative hematopoietic stem transplantation (aka as bone marrow stem cell transplant) is very encouraging and not too dissimilar to that found with alemtuzumab treatment in the mid to late 90s. If you use the procedure in early RRMS, when you still have reserve capacity, you better outcome with a high likelihood of becoming NEDA (no evident disease activity) and seeing an improvement in disability. Unfortunately, the results in SPMS are a familiar one (see excerpt below)." 

Excerpt from the paper: Scores on the EDSS did not improve significantly for patients with secondary progressive MS (n = 27), in those with a disease duration of longer than 10 years (n = 32), or in those with sustained peritransplant fever of greater than 38.5°C (n = 31). In the mixed-effects analysis, both the difference in duration of disease (>10 years vs ≤10 years) and type of disease (secondary-progressive MS vs relapsing-remitting MS) were associated with a significantly (P = .05) increased post-transplant EDSS score.

"These results are almost identical to alemtuzumab, which is why it is going to be very difficult to justify this procedure in the UK when alemtuzumab has a 1st-line license for active RRMS. The good news that in this study there were no deaths related to the procedure."

"This study confirms what we already know; early highly-effective treatment gives you the best option of becoming NEDA and having a confirmed improvement in your level of disability. If you wait too long then you miss out the benefits of early treatment. These results need to be put into context of end-organ damage and quality of life. I think we are entering an era when MSers will have the option of front loading risk for the maximum benefit from the more effective treatments. Delay taking on the risk of treatment for when your disease has progressed will be the real gamble; time is brain and you can't turn back the clock. In addition, all DMTs get less effective the longer you wait. I suspect all the critics of the early-effective approach will say well what about all those MSers who will turnout to have benign MS. The problem with this statement is that it is very difficult to call benign MS upfront; if you give MS sufficient time the number of MSers who turnout to have benign MS is very small. Our treatment aim should be to increase the odds of you having benign MS. Another point is that highly-effective therapies don't have to be risky; we can de-risk them and develop new therapies that are safer. That is our challenge; how can we give highly effective therapies as early as possible with very little risk to the individual? If we can crack this nut then we will see a massive impact."

"Other questions that needs answering is whether, or not, non-myeloablative hematopoietic stem transplantation is cheaper, and safer, than alemtuzumab therapy? May be a pragmatic comparator trial comparing these two approaches needs to be done? It would be in the interests of payer to fund this study as the treatment costs of DMTs continue to soar."


Burt et al. Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis. JAMA. 2015 Jan 20;313(3):275-284.

Background & importance: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability.

Objective: To determine the association of non-myeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS.

Design, Setting, and Participants: Case series of RRMSers (n = 123) or SPMSers (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014.

Interventions: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells.

Main Outcomes and Measures: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan.

Results: Outcome analysis was available for 145 MSers with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, −0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128).

Conclusions and Relevance: Among RRMSers, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.

CoI: multiple

22 comments:

  1. Yawn, this is such an old story.

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    1. Yorkshire Lad in a WheelchairThursday, January 22, 2015 12:51:00 pm

      I agree. This blog has just become a mouthpiece for risky drugs that may or may not make a difference. There's no real breakthrough here.

      You can't reverse damage according to Prof G, but I ask why not? So much money and time has been invested and yet we're still badgering on about only being able to cater for those newly diagnosed. That sucks. What can you offer those that are disabled and getting worse? Nowt!

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    2. It is easier to stop things happening rather than waiting until the horse has bolted.
      That is a message we need to shout about this study confirms what we have been saying for some time.
      you can reverse some damage and most effort is beingplaced on existing MS

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  2. If I had highly active disease, I would want myeoblative HSCT. Maybe the non-meyoblative HSCT protocol is equivalent to alemtuzumab in your view but this is not the case for the meyoblative flavor:

    "Nevertheless, 78.4% of the study participants achieved NEDA at 3 years, compared to 39% of patients receiving alemtuzumab at the 2-year follow-up in the CARE MS1 trial"

    http://www.msdiscovery.org/news/new_findings/16252-stem-cell-transplants-risky-effective

    Regardless, If the non-myoblative treatment does not have the same risks such as secondary autoimminuty that alemtuzumab produces, it is a no brainer which would be the choice. I think the future of MS treatment will be HSCT.

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    1. There is indeed a risk of secondary autoimmunity

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    2. Immune complications were about 22% in people treated with Alemtuzumab verses about 7% in anti-thymocyte antibody

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  3. Well, it was new to me and definitely of interest!

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  4. HSCT treatment for early SPMS appears to be effective in ensuring progression free survival in a number of early studies, Saccardi, Burt, and others. Burt decided to abandon further studies of HSCT on progressive patients because he decided to focus on disability improvement, of which there is little in SPMS. But the question about efficacy in stopping progression in SPMS has not been answered. At five years, early, low EDSS SPMS was stopped for up to 48 months (Saccardi). Basically, emerging evidence is showing that HSCT may be effective in early SPMS, even more so with an inflammatory component. The key appears to be the level of disability. An EDSS of 6.5 or more has the poorest prognosis because possibly at that point, enough axons have been lost and a cascade of neurodegeneration (of unknown reasons) continues to cause progression.

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  5. If cure is defined as stopping disease progression then maybe we are close. But if a cure is defined by repair and decreased EDSS maybe this is possible in early stages of MS but progressive disease may not be amenable to endogenous repair alone.

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    1. I don't really care too much about definitions of "cure" - nirvana would be reversal of disability, but for me right now and into the future, just stopping progression would be quite nice, thank you very much.

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    2. Which is the prime focus of our research.

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  6. Team G,

    There's been a lot of discussion and confusion about this post over on the various forums. Could Dr G elaborate on how this is identical to Alemtuzumab please?

    In the HSCT trial, at 2 years:
    Event free (i.e. NEDA): 80%
    EDSS Improvement >=1.0: 50%

    Keep in mind that of the cohort of patients in which these results were seen, 20% of patients were SPMS, 100% had tried and failed at least 2 DMDs, less than 55% had an EDSS >4 (with 12.4% being >EDSS 6.0).

    By comparison, of the CARE-MS1 cohort, 0% had SPMS (100% RRMS), 0% had tried and failed even 1 DMD (let alone 2), 0% had an EDSS <4 (with 0% being > EDSS 6.0).

    So it's fair to say that the patient population is FAR more favourable in the CARE-MS1 study.

    Despite this, by comparison, event free (NEDA) in CARE-MS1 was 39% at 2 years in CARE-MS1 (vs 80% in HSCT), and average EDSS score improvement was 0.1 (vs 1.0 in HSCT).

    So by those stats, here's the facts. Non-myeloablative HSCT - despite a much less favourable patient population - is more than twice as effective as Alemtuzumab at inducing NEDA at 2 years, and leads to 10x the improvement of disability.

    If you factor in your belief that SPMS patients do not respond (and that they made up 20% of the HSCT cohort), then excluding them from the HSCT results would substantially NEDA even further (presumably by ~20%). The alternative is that a significant proportion of SPMS patients do respond to HSCT. Both cannot be true.

    So, in summary, hardly "almost identical". And are we really saying it is hard to justify a treatment which is more than TWICE as effective at achieving NEDA than the most effective treatment on the market, with a similar safety profile, that you only need to do once, and that is substantially cheaper over the course of the disease?

    What a silly post.

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  7. *** Sorry - coupe of corrected typos on this version. Doh! ***

    Team G,

    There's been a lot of discussion and confusion about this post over on the various forums. Could Dr G elaborate on how this is identical to Alemtuzumab please?

    In the HSCT trial, at 2 years:
    Event free (i.e. NEDA): 80%
    EDSS Improvement >=1.0: 50%

    Keep in mind that of the cohort of patients in which these results were seen, 20% of patients were SPMS, 100% had tried and failed at least 2 DMDs, 55% had an EDSS >4 (with 12.4% being >EDSS 6.0).

    By comparison, of the CARE-MS1 cohort, 0% had SPMS (100% RRMS), 0% had tried and failed even 1 DMD (let alone 2), 0% had an EDSS >4 (with 0% being > EDSS 6.0).

    So it's fair to say that the patient population is FAR more favourable in the CARE-MS1 study.

    Despite this, by comparison, event free (NEDA) in CARE-MS1 was 39% at 2 years (vs 80% in HSCT), and average EDSS score improvement was 0.1 (vs 1.0 in HSCT).

    So by those stats, here's the facts. Non-myeloablative HSCT - despite a much less favourable patient population - is more than twice as effective as Alemtuzumab at inducing NEDA at 2 years, and leads to 10x the improvement of disability.

    If you factor in your belief that SPMS patients do not respond (and that they made up 20% of the HSCT cohort), then excluding them from the HSCT results would presumably increase NEDA substantially further (presumably by ~20%). The alternative is that a significant proportion of SPMS patients do respond to HSCT. Both cannot be true.

    So, in summary, hardly "almost identical". And are we really saying it is hard to justify a treatment which is more than TWICE as effective at achieving NEDA than the most effective treatment on the market, with a similar safety profile, that you only need to do once, and that is substantially cheaper over the course of the disease?

    What a silly post.

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    1. When you assess NEDA you need to rebaseline after the drug works. With Alemtuzumab the NEDA rates after year 1, i.e. in year 2 & 3 are in the order of 70-80%. I have asked Genzyme to publish the data with rebaselining. I suggest you look at this paper for long-term remission rates:

      http://multiple-sclerosis-research.blogspot.com/2014/05/alemtuzumab-long-term-follow-up-for-up.html

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    2. I suspect HSCT works quicker than alemtuzumab because the induction protocol is more aggressive; this does not mean it will work better over 10-15 years.

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    3. Please remember the Alemtuzumab trials were blinded and controlled. The HSCT were not; this affects how activity is measured. Results alway get worse when you move from open-label to blinded assessments. HSCT is no different.

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    4. Seems to me that there are some elements of the old troubles that occurred in early Interferon trials, which although blinded, found that participants could tell if they were on the drug or not, simply because of the side effects that the drug/s caused. I don't see HSCT as the sort of procedure which can really be done blinded - you're not exactly going to be able to fake all of that chemotherapy intervention and then have a fake stem cell transplant.

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    5. You can fake a stem cell transplant easily. It looks like you're being given a bag of blood- it could be a bag of blood , it could be a bag of stem cells.

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    6. The stem cells are a distraction. It's unfortunate that HSCT is titled as it is, because it has very little to do with stem cells, and everything to do with chemotherapy. Complete misnomer.

      A patient is going to know if they've had chemotherapy or not (unless you sneak in on the placebo group whilst they're asleep and shave their hair off). Thinking about it, that could be the answer :)

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  8. Matt Perry said it clearly - 39% NEDA at 2 years for Alemtuzumab V's 78.4% at 3 years for HSCT. Even with a favourable cohort for the CARE-MS1 trial! And where are the NEDA stats at 7 years for the CARE-MS1 trial?! My guess is if they were 39% at 2 years, they're probably non-existent by 7 years! The only resistance towards HSCT is coming from big pharma & anyone who profits from them.

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  9. Fair comments. Couple of thoughts...

    1) To keep it fair, you would need to take the same re-baselining approach to HSCT, either with a second transplant or HSCT followed by immunoablative "top ups". You can't compare multiple hits of one induction with a single hit of another, and call it like-for-like. So - has this ever been done for HSCT? Indeed it has. In Dr Burt's MIST Phase II, when you include patients who relapsed and had chemo "top-ups" post HSCT, 100% of treated patients were in remission. Small patients population, but 100% is 100%.

    2) Re how durable the effect is, there are a number of patients now who are 10 years+ and NEDA. I won't bring in anecdotal evidence here but it may be worth you speaking with Dr Burt (Chicago), Saccardi (Florence) or Federenko (Moscow) on this. Regardless, if you believe the method of action in Lemtrada to be wiping out autoreactive lymphocytes and rebooting a naive immune system, surely it makes logical sense that a treatment which wipes out the autoreactive population more completely would be at least as durable (if not considerably more so). Dr Muraro's studies have shown the long term impact on T-Cell epitope post HSCT, so this isn't really speculation.

    3) Agree re blinded and controlled. Dr Burt's Phase III MIST trial is currently mid-way through, and is partially blinded (doctor only, as you can't really blind a patient as to whether or not they're having chemo) and controlled against Tysabri. The UK are participating in this trial (under Dr Sharrack and Snowden at Hallamshire). I've heard the interim reulsts show a success rate is close to 90% for RRMS. Perhaps it's worth reaching out to them to talk on this blog?

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