Monday, 19 March 2018

MS in the News HSCT poster doing the rounds

"Game changing" HSCT data is being reported in the media.

This is in response to data being presented at a meeting, which we commented on a few weeks ago.. I saw Roumen Balabanov last week and he wasn't aware that the abstract below was published.

We made a post where the authors had complained about Social media as inaccurate, but I made the point that the authors are happy to take the benefits of Social Media.


This story is being circulated by Social Media.
If you want to read the abstract

SS2-8 - NON-MYELOABLATIVE HAEMATOPOIETIC STEM CELL TRANSPLANTATION VERSUS CONTINUED DISEASE MODIFYING THERAPIES (DMT) IN PATIENTS WITH HIGHLY ACTIVE RELAPSING REMITTING MULTIPLE SCLEROSIS (RRMS)

Richard K Burt1, Roumen Balabanov2, John A Snowden3, Basil Sharrack4, Maria Carolina Oliveira5, Flavia Nelson6, Joachim Burman7 1Northwestern University, Division of Immunotherapy for Autoimmune Diseases, Chicago, IL, United States; 2Northwestern University, Department of Neurology, Chicago, IL, United States; 3Sheffield Teaching Hospitals NHS Foundation Trust, Department of Haematology, Sheffield, United Kingdom; 4Sheffield Teaching Hospitals NHS Foundation Trust, Department of Neurology, Sheffield, United Kingdom; 5University of São Paulo, Department of Internal Medicine, São Paulo, Brazil; 6University of Texas Health Science Center at Houston, Department of Neurology, Houston, TX, United States; 7Uppsala University, Department of Neuroscience, Uppsala, SwedenBackground: We previously reported (Journal of the American Medical Association, 2015) that non-myeloablative haematopoietic stem cell transplantation (HSCT) may be performed safely in patients with multiple sclerosis and is accompanied by long-term improvement in neurologic disability. We now report results on a randomized trial of non-myeloablative HSCT versus continued treatment with standard DMTs.
Methods: Patients on stable disease modifying therapy (DMT) with > 2 relapses in the previous 12 months were randomized (1:1) to treatment with either cyclophosphamide and rabbit anti-thymocyte globulin followed by haematopoietic stem cell infusion or to a control arm with continued treatment with standard DMTs. Evaluating neurologists scoring the Expanded Disability Status Scale (EDSS) were blinded to treatment arms. Patients in the control arm who had 6 month confirmed EDSS increase of > 1 point despite at least one year of treatment (defined as treatment failure) were allowed to crossover to HSCT.
Results: 110 patients were randomized, 55 to each arm. Three HSCT patients were withdrawn: two for failing enrollment criteria, one for recurrent infections occurring before transplant. Five control patients were withdrawn after soliciting transplants at other centers. All patients are at least one-year post enrollment. No deaths occurred and no CTC grade 4 non-hematopoietic toxicities occurred in the transplant arm. DMTs (number of patients) used in the control arm were: natalizumab (22), dimethyl fumarate (18), fingolimod (13) interferons (10), glatiramer acetate (8), mitoxantrone (5). During the first year after enrollment, one relapse occurred on the HSCT arm versus 39 on the DMT arm (P< 0.001). Mean EDSS improved from 3.5 to 2.4 after HSCT while it worsened from 3.3 to 3.9 on DMTs (P< 0.001). With a mean follow up of 3 years (range 1 to 5 years), treatment failure was 60% (30 of 50) for the control arm and 6% (3 of 52) for HSCT (P < 0.001). For the 30 patients who failed the control arm and crossed over to HSCT, by one year after HSCT, the mean EDSS improved from 5.2 to 2.6 (P< 0.001).
Conclusions: HSCT was statistically superior to continued DMTs in patients with RRMS with > 2 relapses a year
Clinical Trial Registry: NCT00273364, https://clinicaltrials.gov/ct2/show/NCT00273364
Conflict of interest: All the authors have nothing to disclose
Reporting of HSCT seems to attract the HSCT evangelists and dealing with this is rather trying, so please make points rather than sermons. Yes I can see it works very well.  You have asked us to make comment so I have.This is a study where people were randomised to HSCT or other treatment and the people on HSCT did better. This is not surprising as HSCT is the ultimate immune reboot. However, I am surprised that people were offered DMF, interferons, glaterimer acetate as Natalizumab would be better than them. Surely we need to see highly active verses non-ablative HSCT for this type of analysis to be meaningful. Pitting highly-active treatment against low-hanging fruit is what pharma do to market their product. It is not going to convince those that need convincing.The other question is what is the optimum treatment schedule? In this study anti-thymocyte globulin is used to kill T cells. Does this say MS is a T cell problem. Alternatively is the cyclophophphamide doing the business.Lastly is the EDSS 5.2 to 2.6 a miraculous recovery or is this the effect of the natural resolution of a relapse. In the BBC film of a person making a startling recovery, I am led to believe they had had a relapse and so they were going to get better anyway. This is not the same as being permanently at EDSS 5.2 recovering to 2.6. That would be amazing

40 comments:

  1. Ah yes, the old nuke & puke approach. Reminds me of the CCSVI craze

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    1. You obviously don't know anything about the simple venous angioplasty treatment for CCSVI if you equate it to HSCT. I just celebrated my 7-year "angioversary" for treatment of CCSVI and all of my improvements have held. You must be one of the naysayers who chooses to ignore the fact that Dr. Zamboni's trial concluded that that "The delayed effect of venous PTA 6 months after the procedure on the magnetic resonance biomarker suggests a possibility that PTA may produce benefit for a subgroup of patients with MS. This should be further analyzed and investigated." I am one of that subgroup and I know many others. No deadly chemotherapy involved!

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    2. I wouldnt do that. Something that has a track record and biology verses something that does not. Happy that you are doing well.

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  2. MD, thanks very much for presenting this. I find you to be very honest and genuine. Dr. Burt has also stated previous that HSCT worked very minimally in progressive patients. I do wish researchers like MD2 and yourself could get enough funding to move research in progressive MS forward as relapses should be feared much less than progression of the disease.

    If HSCT does not make barely a dent in progressive MS, what chance do cladribine, ocrezulimab or natalizumab stand??? HSCT is the ultimate immunosuppressant. Do you personally think that neuroinflammation trials will appreciably alter the course of progressive MS?

    As for HSCT comparing to low lying fruit (ie. CRAB drugs), this is the same pathetic dirty trick that pharma with its accompanying neurologists use. So HSCT is just comparing "apples to apples". This madness is supported by its employed neurologists and needs to end. No new drug should be approved by governing bodies until it compares to the best drug currently available. This way will further MS research rather than running around in circles while generating billions for pharma off the backs of sick MS patients.

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    1. The important point I think will be that effective HSCT will be associated with people not becomming SPMS. Not much good news for the people who are SPMS.

      ProfG has made the point that it may take time for the inhibition of the immune response to have its effect, so best not to say no effect on advanced MS.

      As to HSCT and progression. Next thing that needs to be said is that the immune conditioning and ablation may not do much to the inflammation in the CNS. Cyclophophamide may get in but it only kills dividing cells and I doubt microglia are deviding. the anti-T cell globulin won't get there. So we may be able to do better.

      However, our work suggests you need more than just blockade of lymphocyte function.

      Neuroinflammation is not just T cells it is microglial and astrocytes and I am hopeful that that can be targetted to show benefit..

      Yes the regulators by gaining a spine could push through change

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    2. I do not quite agree with this call for HSCT to be more stringently tested than any other DMT out there. I also note that PPMS Ocrelizumab trial was powered in a way as to succeed, not fail. One could argue Dr Burt's trial is doing the same.

      But more important than anything that I was going to say... I googled "claradbine trial" (I have this recollection that claradbine wasn't tested against other DMTs etc - unsure if it is correct or not). I accidentally clicked on 'images' to the google search and this is what came up lol:

      https://www.google.com.au/search?q=claradbine+trial&rlz=1C1GCEA_enAU785AU785&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi6hqTgyfnZAhVGxrwKHWfPA1YQ_AUIDCgD&biw=1920&bih=949



      I will forever think of the pot and kettle fondly, but I'm now beginning to feel like the pot and the kettle are stalking me?

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    3. I am quite confident that depleting the immune system out of sight is as efficacious or more efficacious than current DMT. The question is the risk/benefit that is why I think it should have gone against a highly active agent, to see how much better it is, and at what cost.

      Cladribine was tested in the era of placebo control....that era should have passed but time and time again we see this occurring. What are the ethical committees doing?

      However the consequence of having to run test drug against active drug means that trials won't get done because the drug costs for the active arm would be so high.

      By ocrelizumab being approved for PPMS, it makes it that much harder to do other studies

      The picture in the link is Mark Freedman from Canada

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  3. The Swedish control arm included only tysabri patients and compared it to hsct. The complete peer reviewed study will be published in May so then we can say more.

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    1. the extract is confusing - says there were 55 in each arm (less the drop outs)... but the dmt numbers when added up well exceed 55). dunno if there were dmt changes during the trial.

      Still, tysabri recipients seemed to comprise about 40 to 45% of the DMT group

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    2. Thanks would you like to prepare a guest post?

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    3. 55 treated with HSCT 55 treated with DMT, as you say natalizumab (n=22), dimethyl fumarate (n=18), fingolimod (n=13) interferons (n=10), glatiramer acetate (n=8), mitoxantrone (n=5) n=76.

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    4. In abstract is does say DMT in the the control arm. So I suspect is more a and in the he writing

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    5. At the Chicago arm patients in the control group were allowed to use any FDA approved drugs, although Dr. Burt suggested avoiding certain ones because of long or difficult wash-outs. The only excluded drug was Lemtrada. Patients got to choose their own drug (this was not a placebo trial).

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  4. I am at 2018 Ebmt Lisbon (day 3)

    Cart cells ,Cart cells ,cart cells,Cart cells...

    Dr burt presentation 2018 Ebmt Lisbon

    https://www.youtube.com/watch?v=jpEM6A5nCSw&feature=youtu.be

    Obrigado

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    1. Ebmt 2018 Lisbon day 3 Dr Burt presentation


      https://youtu.be/oTWTe3nZ4hE

      Obrigado

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  5. Just wanted to point out a possible error in your analysis of this abstract. By my reading, the patient population was made up of MSers already taking DMTs, thereby the variety in drugs being used. Doesn't look like the researchers decided to put patients on different drugs, they just looked for patients who had experienced at least two relapses in the previous 12 months while on their existing these modifying drugs.

    If this is the case, then this trial was looking at patients who were failing on their DMTs, so the deck was kind of stacked in the favor of HSCT. Not saying the HSCT results aren't impressive and provocative, just saying that comparison is HSCT versus patients failing on their existing DMTs, not HSCT versus patients doing well with highly active disease modifying drugs…

    Just to cut off any hysterical critiques, my position on HSCT is that if I were a patient with highly active relapsing remitting MS I would do whatever I could to undergo HSCT.

    Would love to see some hard trial data on patients with progressive MS getting HSCT. From retrospective studies it appears the efficacy drops off dramatically in patients with SPMS and even more dramatically in those with PPMS. But retrospective studies have their limitations. And I am fully aware of the anecdotal reports of HSCT working on PPMS patients, but, you know, anecdotal reports…

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    1. I would guess that the researchers consider HSCT as a salvage therapy for RRMS patients who are failing DMTs. The improvement in EDSS is impressive though.

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    2. Good point WK the people are failing their treatments and to keep going with failure rather than escalating to standard care next progression will be seen as a flaw. Let's see the paper it will surface soon.

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    3. I have no doubt that the resistance to HSCT will continue. I wish that they would stop saying that HSCT doesn't work on SPMS & PPMS as it clearly does. The goal of HSCT is to stop the disease, recovery is a bonus & is not a stated outcome of HSCT. No doubt that the sooner the better, which is why it is so important to make HSCT a recognized treatment that is covered by insurance & available to all.

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    4. Not being snarky here, but please, show me a study that shows HSCT effective in SPMS and PPMS patients. And please don't site the Fedorenko paper, as it's one of the worst medical papers I've ever read.

      Retrospective studies consistently show that SPMS and PPMS patients fare much, much worse than RRMS patients post HSCT treatment. The recent Swedish retrospective studies showed about an 80% no progression at five years mark for RRMS patients. This dropped to 38% for SPMS and 0% for PPMS patients.

      Honestly, I would love to see hard data showing HSCT effectiveness in progressive patients who don't show signs of active inflammation. Chances are, the above-mentioned SPMS patients that saw benefit had active inflammation in their CNS.

      I have read the anecdotal reports from individual progressive patients, but anecdotal reports simply don't hold water when put to the test in rigid scientific trials. This has been shown again and again. Many of the patients on Facebook groups claiming success have only been treated within the last two or three years, far too soon to declare any kind of long-term success. Progressive MS is notorious for confounding researchers due to its unpredictable rate of progression. Many a progressive MS study has been sunk because the placebo arm progressed far slower than researchers were expecting.

      As I stated in an earlier comment, I am 150% behind HSCT for relapsing patients, and if I were one of them I would fight my way to the top of the list for getting the treatment. Unfortunately, as a progressive patient who has been searching high and low for any objective evidence of real benefit from HSCT for purely progressive patients, I just have not found any, zilch..

      This is one of the few cases where I would absolutely love to be proven wrong. So please, prove me wrong…

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    5. The Fassas paper is actually a PPMS HSCT paper even if its not clearly categorised as such, with long term results.

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    6. Fassas paper says "HSCT is not a therapy for the general population of patients with MS but should be reserved for aggressive cases, still in the inflammatory phase of the disease,"

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  6. I have progressive MS. Following the article on the BBC news a couple of days ago about HSCT, I'm perplexed as to what to say to my family and friends who now think I will be able to have this 'miraculous' treatment. Is this irresponsible publicity, not giving all the facts and potentially giving much false hope to many, especially when you consider that the risky procedure is only available in London or Sheffield at the moment and you're only eligible after failing the most potent DMT's (apologies if I've got these facts wrong)? Is there any glimmer of hope that it may work just as well for people with progressive forms of MS?

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    1. You will find that the London MDT does treat both SPMS and PPMS with aHSCT

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  7. I would be very interested in seeing you one of your soldiers (MD2, 3, 4...) invest a bit of time integrating the results of this study in the now infamous meta analysis claiming that DMT stop working at the age of 40.5.

    Let's stick to the same methodology as laid out by the authors, to avoid any polemic with regards to lead/lag effect - so apples for apples. 3ys is a sufficient time frame.

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    1. MD 1, MD2. MD3 etc do not do meta analysis...sorry to disappoint...it's not our thang or interest.

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  8. I've just met a junior MS specialist who believes that the immunosupression is doing all the work and not the stem cells! he thinks the same results can be achieved sans stem cell injection...
    Any thoughts?

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    1. Thats about right. Stems cells are used for faster immune system recovery, so to minimize the potential dangers. There is at least one patient that I know of who has undergone just chemotherapy -same regimen- without the post stem cells, as she was out of any trial, with the same excellent results seen at that paper. The title of the treatment is a little misleading and HSCT scietists are discoussing about how it can change.
      Totally different treatment from the repairing mesenchymal stem cells.

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    2. Interesting - maybe that treatment should be re-branded to "complete wipe out, with the optionality of stem cells if situation permits"

      I imagine that the poster above is referring to this study? http://www.msbrainhealth.org/treatment-decisions/article/efficacy-of-ms-drugs-is-linked-to-age

      Their question is well formulated if so.

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    3. Interesting. Maybe we just need to be more aggressive in immune ablation in the periphery and inside the CNS and let endogenous repair via NPCs take place. No need for stem cells if they are already present and just waiting an immune friendly environment.

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    4. That would make the treatment much much more dangerous. The one week total isolation would need to be one month with many Neupogen injections. The new trial is actually adding intravenous immunoglobulin to make the treatment even safer.

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    5. this study is non ablative and the HSCT promotes anti-infection protection

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  9. Twelve months on

    Today, I quite often feel worse than I did before HSCT.

    I still need to rest frequently during the day, and when I use my energy for work, I have none left for anything else at all.

    But there are sunnier days when I feel a little better than I did immediately before the treatment, and then my hopes soar.

    Of the other HSCT patients with whom I keep in touch via several vital support groups on Facebook, some have seen improvements and are overjoyed.

    Once again, they can play a full part in family life, and work without exhaustion. Many train hard at the gym or at home, doing their best to regain limb function and balance that was lost over many years.

    Others report little change.

    And a few have said that they now feel worse than they ever did before HSCT, and wish they had never had the treatment.

    Some have had fresh relapses since their transplant, and wonder whether to have HSCT again, or re-start MS drugs. It isn't yet clear why there is such a wide variation in response.

    Much about the long-term impact of HSCT on auto-immune diseases, from MS to systemic sclerosis or Crohn's disease, is still unknown, and may remain unclear until the causes of these diseases are better understood.

    Soberingly, over the past year, some patients at international centres have died while having HSCT, making clear that it is not a treatment to be entered into lightly, however effective it can be in halting progression for some.

    Many patients have struggled after transplant with everything from migraines, headaches, swollen feet or agonising neuropathic pain in the hands and feet, to viruses or bacterial infections that affect the bladder.

    They can also develop other common infections that resurface in the body when the immune system is fragile, such as the Epstein-Barr virus, herpes or shingles.

    However, my latest MRI brain scan shows that so far, I have no new lesions on the brain.

    It's a sign, I hope, that I shall be among the lucky ones for whom the treatment does halt further MS progression for several years.

    I asked Professor Muraro of Imperial College London how long that benefit might last for those who respond to HSCT.

    “In the very long term we do not know,” he says. “We know the durability of effects is still good at five years, but the longer term is a question that could be addressed.”

    After his last study, he concluded that “with this procedure, we've shown we can ‘freeze’ a patient's disease – and stop it from becoming worse, for up to five years. However, we must take into account that the treatment carries a small risk of death, and this is a disease that is not immediately life-threatening.”

    So how close are researchers to finding the causes of MS?

    “I don't think anyone knows how close we are. It is clear we are making stepwise progress. The critical - small or giant - leap may happen at any time,” says Professor Muraro.

    “Studying HSCT by comparing the immune system before and after treatment provides a great opportunity to find out what may have gone wrong that is corrected by HSCT in the patient where clinical MS is shut down.”

    I know that I can't, as yet, repair all the damage done to my brain and central nervous system by decades of MS.

    But I am an optimist, and shall remain so while my immune system finishes reconstituting itself fully by the end of this year, some two years after I started treatment

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    1. I wonder if in part the variety of response reflects the variety of methods used.

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  10. My goal is to stay healthy enough in the coming years to be there for my wonderful parents as they age, and for my brothers, sister, nieces, nephews, great-nieces and friends.

    I'd love to be able to continue both to work and enjoy life, rather than sleep-walking through the rest of it in a haze of crushing fatigue.

    Whatever happens in the future, I am grateful to have had these two years of hope.

    By Caroline Wyatt

    http://www.bbc.co.uk/news/resources/idt-sh/caroline_wyatt_multiple_sclerosis

    Obrigado

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    1. When it's not possitive, it's not anecdotal.
      Immanouel Kant (1724-1804)

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  11. This is about Ahsct

    The same conference Prof.G was in switzerland about a month ago

    (Strange you did not report it)

    https://www.youtube.com/watch?v=6veBGHOT2Xw&t=287s

    Obrigado

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  12. People want to get rid of their disease and then move on with life, not sure why this is so difficult to understand, maybe the professors cannot let go of their patients, hit patients with HSCT or a mighty antibody right at the first sign of inflammation, everything else seems dodgy.

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