Reinventing the Wheel. The Drugs used in HSCT are bad for you.

R

Whats the difference between a drum machine and a neurologist…..You only have to punch the information into a drum machine once!

This study says that if you look at someone who gets HSCT, that they suffer nerve damage as evidenced by a release of nerve proteins.

They say “the Canadian regimen is considered particularly intensive and involves high‐dose cyclophosphamide and busulfan as conditioning agents. These drugs are selected not only for their peripheral myeloablative and lymphoablative actions but also for their CNS penetrance and toxicity to microglia involved in MS pathogenesis……Now I have to ask what is the evidence for any influence of cyclophosphamide on microglia? Cyclophosphamide are only going to work on proliferating cells and the literature if anything says its effect is to activates microglia….Anyway they wonder if the early effect of brain volume loss seen on MRI relates to nerve loss. ProfG and sort of gave the answer to this question ten years ago but they used a different way to to the ablation They said the process resulted in nerve damage. With time you reap the benefit of this “cruel to be kind approach”. So you ask why is progress so slow? Well “speculation” is the stake/light/garlic to the vampire and it makes people say you haven’t shown this, so you have to prove it agian and again and again.

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis. Thebault S, Lee H, Bose G, Tessier D, Abdoli M, Bowman M, Berard J, Walker L, Rush CA, MacLean H, Booth RA, Narayanan S, Arnold DL, Tabard-Cossa V, Atkins HL, Bar-Or A, Freedman MS. Ann Clin Transl Neurol. 2020 Apr 18. doi: 10.1002/acn3.51045. [Epub ahead of print]

OBJECTIVE:

Accelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as ‘pseudoatrophy’, related to reduced inflammation. Treatment-related neurotoxicity may be contributory. We sought objective evidence of post-IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage.

METHODS:

Sera were collected from 22 MS patients pre- and post-IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single-molecule assay.

RESULTS:

Pre-IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12-month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL).

INTERPRETATION:

There is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.

About the author

MouseDoctor

7 comments

  • One of the biggest challenges remains as to how to define and differentiate pseudo-atrophy versus atrophy and what measures are universally accepted to define atrophy in the first place. Surrogate markers (peripheral blood) are acceptable for now but with quantitative metrics of brain atrophy available both for gray and white matter changes, one has to develop methodologies that will track changes before and after chemotherapy to document more precisely the changes that are being looked at. Identifying both global and focal changes of atrophy following drug use as noted in the article will probably help as well.

  • Results: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the
    busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively
    over approximately 2.5 years. There was no evidence that resolution of edema contributed to
    volume loss. The mean rate of long-term atrophy was −0.23% per year, consistent with the rate expected
    from normal aging.
    Conclusion: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely
    associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually
    slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can
    reduce secondary degeneration and atrophy.

    Brain atrophy after bone marrow
    transplantation for treatment of
    multiple sclerosis

    DOI: 10.1177/
    1352458516650992

    2016

    Nothing new

  • Hi mousedoc.
    its Simon Thebault, the person who wrote this paper. It sounds like you found it boring/repetitious; sorry for that and thanks for sharing your thoughts. To clarify though, the treatment here (chemoablation) is altogether to what ProfG reported neurotoxicity on 10 years ago (radioablation, Q: do people even do that any more? A: No, because its too toxic). Although I guess they both fall under the umbrella of ‘bone marrow transplant’, that is pretty much where the similarities end I think Luis here misses the point a bit as well: this study is supposed to be adjunct/development of to the brain atrophy paper which he quotes (and our group also wrote): the addition of the NfL data is the new bit: while we can infer toxicity from the MRI, you can measure it a little bit more directly with this protein.
    Cheers
    Simon

    • Don’t take it personally….after years of doing this nobody gets a “This is amazing and we are all made out of star dust” that is the standard tweet. The knowledge front moves forward and yes I was aware of that the method of treatment was different. It is relevant as it shows people that HSCT has some damaging aspects. This is important for people to know. As you know I’m a glass half empty mouse but if you want to write you own piece for the lay audience and send it to bartsmsblog@gmail.com you can do the glass half full approach, just send a picture and your conflicts…There are lots of people interested in HSCT that come to this site including the HSCT zealots. So next time you can do your own post.
      MouseDoc

      • Thanks. To be honest I’ve been jealous of your clinic blog for years, and totally get the need to try to interpret the literature for patients given the amount of misinformation out there, especially in MS. Privileged to have been included! No such thing as bad press.

        This was actually a tricky paper to write; you are walking a fine line when trying to report toxicity caused by a treatment that our group is one of the biggest proponents of. Equally, we didn’t want to overstate the “toxicity” we see here: we already had a anti-HSCT-zealot/Natulizumab-enthusiast reviewer holding this paper up as definitive evidence they had been waiting for of how terrible the treatment clearly is, probably looking for an editorial or something. I think the bottom line here is what you said: “cruel to be kind”- short term pain (which might include some seriously bad stuff like infertility, chemofog, hemorrhagic cystitis, infections etc) for long term treatment response without needing ongoing immunosuppressants, to be reserved for aggressive cases of RRMS/early SPMS with lots of inflammatory activity.

    • Nice to see an author (a real one not ananonymous)

      Defend their work ´
      Time and time again we ear just one side

      Thanks for your reply

      Obrigado

      Luis

  • I like the discussion, but would like to point out to the Mouse Doctor that the conditioning regimen we used in Canada is unique not for its use of cyclophosphamide, but for busulfan which we feel is key to the removal of microglia and thus the source of antigen-re-presentation. There is solid evidence that regimens for HSCT that include busulfan are capable of removing brain microglia is plentiful (albeit mouse data), and a nice paper showing that this is the one drug capable of eliminating the microglia so new ones can differentiate is the following: “Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation”, Proc Natl Acad Sci U S A. 2012 Sep 11; 109(37): 15018–15023. Published online 2012 Aug 23. doi: 10.1073/pnas.1205858109.

    The induction of long-lived immune tolerance, with no evidence of MS disease activity going on now for 20 years, probably speaks to the success of our conditioning regimen. In addition however, the busulfan has been linked to significant toxicity and we believe it is that drug that is responsible for the MRI and biomarker changes we report on in this recent paper.

    At the same time, we also believe that without busulfan, we would not have had the same success. In the early phases of the program, it was responsible for the one death we experienced, due to veno-occlusive liver disease – a complication of the oral formulation; as soon as we switched to the iv formulation we were better able to control the dosing and even lower the amount used and no longer experienced that serious side effect.

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