Tuesday, 27 June 2017

#EAN2017 & #ClinicSpeak: immune reconstitution therapies

Should access to healthcare, for example HSCT, be equitable? #EAN2017 #ClinicSpeak

As promised the following is my presentation from the Excemed MS Symposium held on Sunday night at the EAN in Amsterdam. I had feedback from several people about how appealing selective immune system depletion followed by reconstitution is as a a treatment strategy for MS. However, the efficacy of all of our licensed DMTs remain a long way off that of what is being reported with HSCT. 

Giovanni Mancardi gave a wonderful meta-analysis in the session on the result of AHSCT and how the safety profile has improved. The most recent mortality is less than 0.3%, i.e. less than 3 in a 1,000 treated patients. I am therefore not surprised that a lot of pwMS who are not concerned about the risks associated AHSCT are frustrated about the lack of access to it as a treatment option. I really hope the NIHR will fund a AHSCT trial in the UK. We need randomised controlled data for AHSCT to become routine; otherwise it will remain a lottery with some pwMS being able to access AHSCT whilst others not being able to access AHSCT. The latter brings up the ethical dilemma about whether of not access to healthcare should be equitable. 


CoI: multiple

30 comments:

  1. Prof G equitable access to healthcare is one of the found principles of the NHS and underpins almost all socialist healthcare models. It is essential that we fight to maintain this principle. I am concerned that when we leave the EU we will not have access to the EU courts to fight for this fundamental right for British Citizens.

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    1. Yes, I agree with the principle of equitable access but there many factors at play when it comes to this. For AHSCT it is about adoption; most neurologists don't even consider this as a treatment option so their patients will never get referred. To change this we need it licensed. This is why we need trials and the regulators and payers to come on board and accept that HSCT is a treatment option for MS.

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    2. Any idea when ocrelizumab will be available in Europe for PPMS? It isn't fair that the FDA has approved the drug and we are still waiting and losing brain.

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  2. Great post... AHSCT needs to be an option on the table for the right patients, especially for those out of options with a bad prognosis... If we were talking about cancer there would be no discussion, many will need aggressive therapy, period, but in MS you can argue it takes way more time to deteriorate the quality of live of the patients, this is an excuse, a bad one. In my case after diagnosis I was put on DMF, even thought I wanted alemtuzumab or AHSCT from the start... Its my brain, my life

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    1. I agree. It is not clinicians, but patients who should be taking the risks. They are the ones with the disease.

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  3. ... 1 month later I had another big relapse and i was finally "a candidate" for alemtuzumab, AHSCT off the table unless I pay out of pocket, no insurance or social care would pay for it... That was 2 years ago, after alemtuzumab, 0 relapses and I'm back on competitive sports, but I still carry some sensory problems in my toes from that relapse. Its not fair that you need to suffer permanent neurological damage to recieve treatment, it makes no sense, in every disease you need to prevent damage, for some reason many neuros, laws and treatment policies treat un with MS differently, that needs to change.

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  4. But my understanding from reading this blog over a number of years now is that HSCT and best in class drugs (Tysabri, Alemtuzumab...) offer the ARR and brain atrophy rates!

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    1. Yes, that is correct. But is HSCT superior to alemtuzumab, natalizumab, ocrelizumab and cladribine?

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    2. *Errata: "offer the SAME ARR and brain atrophy rates"

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    3. if its secondary immunity is less than that of lemtrada, if it's an induction treatment rather than a bandaid relying on re-treatment every 28 days and a risk of rebound should one dare want to change (but why would you change) - then does it really matter if it's superior?

      your claradbine is not superior and you seem to think there is a role for it.

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    4. Yes, that is correct. But is HSCT superior to alemtuzumab, natalizumab, ocrelizumab and cladribine?
      I think it is
      Table 3.3 Comparisons of natalizumab, alemtuzumab and HSCT.
      Natalizumab Alemtuzumab HSCT
      Follow-up time
      (months) 24 24 47
      AAR baseline 1.44 1.7 4.1
      AAR on study 0.34 0.26 0.03
      Freedom from
      relapses 54 % 65 % 87 %
      Freedom from
      disease no data 32 % 68 %
      Mortality 0 % 0.59 %
      (pooled data)
      0 %
      (pooled data 0.76 %)
      PML 0.2 % per annum
      (post-marketing data) n/a n/a
      This table compares data from the SENTINEL125 and CareMS-2126 trials with data
      from the Swedish experiences of HSCT for MSI. Pooled alemtuzumab data are from
      the CAMMS223,128 CareMS-1129 and CareMS-2126 studies, whereas pooled HSCT
      data are derived from the studies in table 3.1 and 3.2.

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  5. Nice to see Barts-MS getting behind HSCT. It is about time. Some more information about HSCT would be helpful instead of your endless waffle on cladribine and alemtuzumab.

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    1. If there are published papers we report them.

      The James Lind Alliance asks about the influence of early and aggressive treatment as an MS Society priority. Should they act?

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    2. We have never not been interested in HSCT. The problem was the risks. The fact that the mortality has dropped makes this a real entity. The downside is the ovarian and testicular toxicity of cyclophosphamide. There is a significant risk of infertility associated with HSCT that depends on the intensity of the conditioning regimen.

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    3. https://www.ncbi.nlm.nih.gov/pubmed/28148635
      https://www.ncbi.nlm.nih.gov/pubmed/28241268
      https://www.ncbi.nlm.nih.gov/pubmed/27316394
      https://www.ncbi.nlm.nih.gov/pubmed/17942513
      https://www.ncbi.nlm.nih.gov/pubmed/27071689
      https://www.ncbi.nlm.nih.gov/pubmed/27430119
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956741/
      https://www.ncbi.nlm.nih.gov/pubmed/25602998
      https://www.ncbi.nlm.nih.gov/pubmed/27291994
      Etc...

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  6. Dr.G do you se ocrelizumab as maintenance terapi or IRT ?

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    1. Re: "Dr.G do you se ocrelizumab as maintenance terapi or IRT?"

      Both. It will be up to us the 'MS Community' to test the hypothesis of how good ocrelizumab is as a IRT.

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  7. How big would a trial need to be to prove out AHSCT in the U.K.? What would the non AHSCT arm of the trail be?

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  8. There will be problem of blinding. The only comparisons would be alemtuzumab or ablative verses non ablative. You have to have people willing to have any treatment so they can be randomised.

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  9. Still people look to blasting their immune system to kingdom come in the hope of fixing MS.

    Granted, with PPMS, my perspective is skewed by the fact it was always - since the recognised beginning of my MS journey - too late for me to be a good candidate for (surviving) HSCT.

    My hopes are more in the region of Pender's research - a truly intelligent form of immune therapy - and EBV.

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  10. "In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS."

    https://www.ncbi.nlm.nih.gov/pubmed/28241268

    I'm just wondering - how good is this really? I remained clinically progression free for almost 10 years since the first bout / showing of what turned out to be PPMS in the end. With no treatment at all.

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    Replies
    1. Unfortunately, MS is not a condition that lends itself to n=1 studies. It is too variable. Yes, we all have anecdotes about being stable before problems develop. There is a good chance that whilst you were inactive MS was gradually chewing up your reserve.

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  11. I'm still not doing too bad, thanks. Maybe better than if I'd had some toxic treatment that does nothing for progression? I'm not being cocky - I don't know the future, none of us do - and you're right, I am just one.

    I actually just wanted to say that this particular statistic - "almost half of them remained free from neurological progression for 5 years" - doesn't sound so great for such a risky treatment. No doubt / hopefully there are better results out there, for those for whom the treatment is suitable.

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    1. Efficacy and outcome
      Thirty-one patients have been followed for more than 2 years
      after AHSCT. Median follow-up of patients alive was 8.4 years
      (range 2

      16), 5.9 years for RRMS patients, and 9.6 years for
      SPMS patients (Table
      3).
      The annualized relapse rate (ARR) dropped to 0 in the
      first year, 0.22 in the second year, then remained stable at
      this rate until year 5, and then fell to 0.05 in years 6 and 7
      (50% of patients reached 7 years of follow-up after
      AHSCT). A reduction of 92% in the ARR 2 years after
      AHSCT was observed by comparing the ARR in the pre

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  12. With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new
    T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy
    controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained
    improvement in their Expanded Disability Status Scale score

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2816%2930169-6/abstract

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  13. I hate to keep returning to what may be a dead horse, but what does the failure of HSCT to treat progressive MS tell us about that flavor of the disease? The Swedish longitudinal study found that overall rates of progression free survival at five years were 50%, but broken down by subgroup, RRMS patients had approximately an 80% progression free rates, while SPMS patients only had a 35% number. PPMS patients fared even worse, but that cohort was very small.

    I suspect that the SPMS patients that responded still had active inflammation in their CNS.

    If HSCT, perhaps the most draconian immunosuppression/immune reconstitution therapy available does not significantly alter the progression of inflammation free SPMS and PPMS patients, this must offer some clues as to what's going on in those patients. Obviously, the peripheral immune system isn't playing a role in their disease course, but can the progression be explained by immune activity sequestered within the CNS alone? Or are there as yet undiscovered neurodegenerative processes at work in these patients?

    These are vital questions, especially to those of us who are watching themselves slowly succumb to the grip of quadriplegia.

    Thanks in advance for any insights provided.

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    1. TWK the observation of greater efficacy in progressive MS vs. relapsing-remitting disease is what we see with other DMTs and can be explained by loss of reserve, therapeutic lag and asynchronous progressive MS hypothesis. All these are underpinned by our length-dependent axonopathy hypothesis.

      The one other factor regarding HSCT is the neurotoxic effects of the chemotherapy used as part of the conditioning. The more underlying the damage the greater the chances of experiencing neurotoxicity (chemobrain). In addition, bladder dysfunction ups your risk of infections when you are neutropaenic.

      In summary, HSCT is likely to work in progressive disease, but less well, with increased risks. Therefore the risk:benefit ratio is very different between the two scenarios.

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  14. Thanks for the response, Dr. G.

    Does therapeutic lag really apply here, as the Swedish longitudinal study (and other long-term outcome HSCT studies) look at results at 5+ years, so the therapeutic lag effect should be accounted for by the length of the studies.

    The crux of the question is this: is the presence of enhancing lesions perhaps the most important selection criteria for patients considering undergoing HSCT? As you point out, the risk/benefit ratio for progressive patients make this treatment option less viable, however, if the presence of enhancing lesions improves the chances of a positive outcome, this would be a major factor in calculating that risk/benefit profile.

    As you stated, Full-scale HSCT trials (such as the HALT MS trials) are urgently needed, and these must include patients with progressive disease. As I'm sure you're aware, there is a burgeoning medical tourism industry offering HSCT to patients of all stripes, and I fear that many patients are traveling to far-off destinations and paying upwards of a minimum of $50,000 for a treatment that is potentially harmful and not likely to improve or stabilize their conditions. I'm referring specifically here to patients with late SPMS or PPMS. I think patients with active RRMS are very well served by seriously considering the HSCT option.

    On a side note, any thoughts on the failure of the Innate Therapeutics phase 2 trial of their experimental drug MIS 416 for SPMS? Seems to be another example of strong anecdotal evidence going down in flames once the therapy faces double blinded trials…

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    1. My personal view, backed by no data that I have seen is that in theory one can continue to progress after induction immune modulating if not resetting therapy, and still see some effect from the treatment. If disability is caused in part by the immune process and in part by neurodegenerative proceses,and they can't definitively say in any given person how much (of 100%) of today's disability is caused by focal inflammation and how much by other process, then you will never know the expected outcome in any given individual. The therapeutic lag theory does talk about protecting future CNS departments, rather than ones which are currently 'beyond repair'(ie.preserving future function, not today's).

      The question whether the risk and the side effects of something like HSCT outweigh the possible benefits of someone with progressive or advanced MS remains notwithstanding and I'm not
      qualified to venture a guess.

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  15. "Given the moderate effects of Ocrevus on even progressive patients with active inflammatory markers, a treatment modality that can put a halt to progression for years at a time warrants robust investigation."

    http://multiple-sclerosis-research.blogspot.com/2017/06/hsct-in-progressive-ms.html#comment-form

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