HSCT is highly Effective

H

In this study the results of a randomisation non-ablative HSCT stem cell therapy compared to current DMT and it does better. Much better

This is not surprising we know that immune depleteion is effective.

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis A Randomized Clinical Trial Richard K. Burt, MD; Roumen Balabanov, MD; Joachim Burman, MD; Basil Sharrack, MD; John A. Snowden, MD; Maria Carolina Oliveira, MD; Jan Fagius, MD; John Rose, MD; Flavia Nelson, MD; Amilton Antunes Barreira, MD; Kristina Carlson, MD; Xiaoqiang Han, MD; Daniela Moraes, MD; Amy Morgan, APRN; Kathleen Quigley, RN; Kimberly Yaung, RN; Regan Buckley, RN; Carri Alldredge, RN; Allison Clendenan, APRN; Michelle A. Calvario, APRN; Jacquelyn Henry, APRN; Borko Jovanovic, PhD; Irene B. Helenowski, PhD

IMPORTANCE Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). OBJECTIVE To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. DESIGN, SETTING, AND PARTICIPANTS Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. INTERVENTIONS Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). MAIN OUTCOMES AND MEASURES The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. RESULTS Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, −1.7; 95% CI, −2.03 to −1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). CONCLUSIONS AND RELEVANCE In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00273364

They use T and B cell depletion (CY and the anti-thyocyte globulin kills B cells) and then protect people from infection with stem cells. This is compared in relapsing MS to other treatments and the conclusion is that this does better. I have no problem with this ,but what would you expect if you are comparing this with treatment with CRAB drugs. If you want HSCT and end up with a CRAB I wonder.

21 patients received natalizumab and 6 mitoxantrone which I can buy but 14 on dimethyl fumarate, 14 fingolimod, 9 glatiramer acetate, 7 interferon beta-1a and 1 teriflunomide you are biasing your results as these will have known less efficacy. This should have been compared with alemtuzumab.

Anyway I am sure it will create a alot of discussion

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17 comments

  • I think that aHSCT is now the gold standard for RRMS but will the lesser non induction therapies go quietly into the night? There’s too much money at stake for CRAB producers.

  • I think that aHSCT is now the gold standard for RRMS but will the lesser non induction therapies go quietly into the night? There’s too much money at stake for CRAB producers.

  • MD I think we all accept that HSCT is highly-effective. The issue is safety. This study was done in a highly-motivated protocol-driven unit with a focus on patient selection and safety. What will happen if HSCT is expanded to the ‘Joe Soaps’ of the BMT units and let the private sector money-making machine loose on the MS community? I doubt the safety and efficacy profile will remain the same. This is why we needed a blinded, albeit single-blinded, head-2-head study against licensed high-efficacy DMTs. The obvious choice is alemtuzumab, but I would accept a bask of DMTs including natalizumab and ocrelizumab. Please watch this space and let’s hope our ZEUS trial becomes a reality. How long ago did we propose this study?

  • For those patients with MS desiring and eligible for HSCT treatment who live in more remote areas of the UK such as Scotland, Wales and the far South West – apart from travelling a long distance to either London or Sheffield, are there any other hospitals in the UK that look likely to offer this promising HSCT? I would certainly prefer my family to be as nearby as possible whilst undergoing such a procedure so they could visit/provide crucial emotional support but for most families I imagine the main breadwinner would simply not be in a position to take weeks off work to accompany their loved one to hospital in London or Sheffield.

  • I would love to hear comments from MD about this bombshell publication and article if possible (https://multiplesclerosisnewstoday.com/2019/01/17/brain-volume-loss-ms-gray-matter-atrophy-study/). It is about the lack of effect of DMDs on progressive MS, in this case Tysabri just as Dr. Burt found in his HSCT trial.

    It is like we are “fitting a round peg into a square hole” and trying to make immunosuppressive agents work when clearly they are not in progression of MS. This excludes a pathetic < 25% above placebo by siponimod and ocrezulimab in clear selection bias designed trials.

    The attitude among researchers that you will get worse just ever so slightly slowly is unacceptable. Clearly there is another mechanism at hand causing neurodegeneration that is not or very minimally involving B or T-cells.

    It is clearly time for some innovation in progressive MS trials. I believe that Dr. Burt's trial and this publication show an uncoupling between relapsing MS and progression of MS.

    • So what is unexpected here? No one is saying that dmt stop progressive ms. Even where they are doing something there is still deterioration. The grey matter loss is because yhe nerve heads are dying why. Because they are being attacked or because the axons or nerve body is being attacked. In 1 mm squared in centre of lesion 11,000 nerves are being cut. If i cut you in half the head dies. However did these people wait for 2-3 years for the effect of tje dmt to show itself.

      As to other mechanisms and neurodegeneration. Absolutely agree. Relapsing and progression are different but they are part of the same condition

    • This idea that relapse and progression are distinct does not fit with the biology but is dangerous because it means it is OK to do monotherapy. The establishment buy this. I dont. Because it is not considered cost effective and complicated does not mean it is something we should do

  • I can imagine that it is more difficult to find participants for a trial of HSCT vs Alemtuzumab (e.g. RAM-MS). The MIST study had a cross-over option, which allowed patients in the control arm to get HSCT after a year when they showed disease progression. Due to the rebaseline term of >12 months for Alemtuzumab, I would say this is not an option. As far as I know, the RAM-MS trial has no cross over.

  • Sorry for the late comment, getting au fait with the new format.

    Mexico clinic (Caroline Wyatt) use Cyclophosphamide and Rituximab. If the stem cell harvesting is purely to quickly reboot neutrophils (the brochure suggests it does much more than that and reboots the entire immune system) then surely the only thing we are comparing is one DMT (eg Cyclophosphamide + Rituximab) v another.

    All the stem cells do is allow use of a bigger sledgehammer. Are the stem cells a red herring?

    Fact: most of the people travelling abroad for HSCT are on the SPMS / PPMS no-treatment heap and at the ‘what have I got to lose’ stage.

    • what do you lose…Sadly about 50-100,000 dollars.

      There are two approaches one is non ablative meaning that you can keep your immune system and here the HSCT allow you to use a bigger dose.of DMT.

      The other is ablative meaning that you have a clear out of your immune system and so you need vaccinations again.

      Therefore how much drug do they give CY will clear out.dividing cells but not those no dividing and the rituximab will hit B cells. So what gets rid of the t cells.

      Whilst cyclophosphamide can get in the brain, rituximab wont and so
      immune system in brain is not going to get touched so HSVT does not get rid of oligoclonal bands, so probably
      Less effective in spms ppms

  • I am a US patient following your blog. I’d love to hear more about why HSCT isn’t offered to more people. I was diagnosed 3 years ago and am on Ocrevus. While it seems to have stabilized a very active MS and I am lucky to be able to work and parent as I used to, I don’t understand why I am not given the option of the best treatment now, before damage is done. All the research says it works best if used in the first five years. I’m aware of the risks but personally I’d rather die young than live a lifetime of not being able to work or parent. Shouldn’t that be my choice? If I progress despite Ocrevus i am out of options. The only alternaivs is to spend over $100,000 in travel abroad and treatment expenses, which I of course do not have. Even if HSCT were offered in the US they would not consider me before I got irreversibly more disabled. This to me seems criminal and antithetical to the “do no harm” mentality. We don’t tell cancer patients they don’t need chemo because they’re feeling fine now do we? Why is this approach ok with MS for those of us who value quality of life more than length of life?

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