Monday, 21 May 2018

What is HSCT?

I seem to be spending a lot more clinic time explaining to my patients about HSCT. What is happening and why?






HSCT = hematopoietic stem cell transplant

HSCT is simply a rebranding of bone marrow transplantation or BMT. BMT was the term we used when the stem cells had to be harvested by doing a bone marrow aspirates, i.e. a thick needle was inserted into the bone and the marrow sucked out under pressure. This procedure is painful and is done under sedation. I remember it very well when I was a houseman and junior medical registrar, or trainee, I worked on a haem-oncology unit and had to do this procedure. Fortunately, the haematologists have now developed an effective way of mobilising and harvesting stem cells from the blood without having to tap the bone marrow. This is done by giving a small dose of chemotherapy followed by growth factors so that the stem cells spillover from the bone marrow into the blood. These stem cells are harvested and frozen and can then be given after immunoablation therapy. Immunoablation therapy refers to chemotherapy to get rid of your immune cells. 

Please note that all that these stem cells do is allow you to receive more potent chemotherapy and work by allowing your bone marrow to recover more quickly. There is nothing magic about this; HSCT in the treatment of MS is simply used to speed up bone marrow recovery, nothing more and nothing less. More rapid bone marrow recovery makes BMT safer. 

The stem cells in HSCT don't go to the brain and spinal cord to repair the damage. This is a common misperception. People think the haemopoietic stem cells are being given to repair the damage that has accrued from having MS. This is why HSCT, like other DMTs, is more effective when used early before MS causes too much damage. 

There are different intensities of bone marrow ablation therapy. So-called myeloablative therapy is aimed at wiping out your immune system completely and replacing it with a new immune system. Non-myeloablative therapy is less intense in that it simply depletes your immune system partially and allows it to be rebooted (partially). The non-myeloablative therapy is clearly less risky than the myeloablative therapy but less effective. In other words, more pwMS have a recurrence of their disease activity after non-myeloablative HSCT (NM-HSCT), when compared to ablative-HSCT (A-HSCT).  The chemotherapy that is used for NM-HSCT is less toxic. Many in the field believe that if you are going to treat MS with HSCT you need to go the more aggressive route and use the more toxic and risky A-HSCT. They argue that NM-HSCT is not really better than the current high-efficacy drugs we are currently using to manage MS, i.e. alemtuzumab and/or natalizumab and/or ocrelizumab. This is why we are proposing to do a trial comparing alemtuzumab with NM-HSCT to see if NM-HSCT is more efficacious than alemtuzumab and to see if the potential benefits of HSCT warrant the risks.

What are the risks of NM-HSCT? The chances of dying from the NM-HSCT is in the order of 0.3%-1%; i.e. 1-in-330 to a 1-in-100 chance of dying. Then there is the toxicity associated with the chemotherapy; nausea, vomiting, diarrhoea, hair loss, bleeding, infections, infertility and neurotoxicity to name a few. It seems that the more disabled you are the worse the neurotoxicity. If you have lost a lot of nerve fibres already and have reduced brain reserve you handle chemotherapy poorly. The chemotherapy worsens neurological function. This is why a large number of BMT units stopped using this therapy in people with more advanced MS and is the reason why most units have an upper EDSS limit as part of their inclusion criteria. 

Once your immune system recovers post-HSCT does not mean it is necessarily back to normal. There is evidence that HSCT may result in a rejuvenation of your immune system and changes the so-called repertoire of your B and T cells. At the moment we don't know if this is a good or bad thing and what it means for MS. What we do know is that HSCT destroys memory cells from your previous vaccinations. This is why you have to be revaccinated with all your childhood vaccines at ~2 years after HSCT to restore your immune responses to these common infections.  

What about secondary autoimmunity? There is data in the literature that pwMS treated with HSCT are at risk of developing secondary autoimmune diseases similar to that which occurs after alemtuzumab treatment. If this is the case I would find it hard to recommend NM-HSCT, over alemtuzumab, unless it was part of a controlled trial, or the person had already failed alemtuzumab.

What about A-HSCT? This now is a different beast compared to NM-HSCT in that the short-term risks associated with the intense chemotherapy needed to ablate the immune system are so much worse. Everything is worse; the diarrhoea tends to be bloody and protracted, mucositis is the norm (the lining of your mouth, throat and intestine slough), infections are more severe, and are potentially life-threatening, there is solid organ toxicity (liver, lungs, kidneys and heart), your bone marrow takes longer to recover and a result you are more likely to need platelet and blood transfusions. A-HSCT is not for the faint-hearted. A large number of HSCT enthusiasts in the autoimmune field are of the opinion A-HSCT is the way to go; the failure rate from NM-HSCT is too high. They argue that if you are going to take the risk, you might as well go for maximum efficacy.

The seemingly miraculous treatment effects with HSCT, for example of people in wheelchairs getting up and walking, is not unique to HSCT. We see these 'Lazarus effects' with other highly-effective DMTs. Provided you have sufficient reserve capacity in the brain and spinal cord you will see spontaneous recovery from relapse-related disability once inflammation is switched off and recovery mechanisms are allowed to proceed. Tragically these Lazarus-like examples create unrealistic expectations for pwMS with more advanced disease. Once you have fixed or progressive disability it is likely that you have lost your neurological reserve and hence even if you switch off inflammation with HSCT, or any other anti-inflammatory DMT for that matter, it is unlikely that there will be a significant recovery of function. This is one reason why so many progressive MS trials have failed in the past. Therefore the benefit:risk ratio changes with more advanced disease and its the reason why most HSC units have age and disability cut-offs for pwMS.

Would I refer pwMS for HSCT? Yes, I do. The situation where HSCT is indicated as part of routine clinical care is in the occasional patient with more malignant disease, who have failed licensed treatment options. In these patients, the benefits of HSCT potentially outway the risks of the disease. 

In practice, I find the main reason why pwMS say no to HSCT is the infertility risk. The risk of premature ovarian failure, or early menopause, is over 40% and a lot of women when they hear this figure they tend to say no. Similarly, for males, the cyclophosphamide hits the testes hard and if you want to start, or extend, your family you need to bank sperm.

Please remember the human brain is hard-wired to be optimistic. I like to use the gambler’s dilemma as an analogy. No gambler places a bet, or goes into a casino, to lose money; they always believe they are going to be the one that wins the jackpot. No person will sign-up to HSCT believing that they are going to die or develop complications. However, there will always be the unlucky ones who have the serious complications and occasionally die from the procedure, or develops serious delayed adverse complications. If you decide to have HSCT as part of a trial, or as part of routine care, you need to ask yourself the question what if I am the unlucky one? Am I am ready to leave my family and loved ones prematurely? If you answer yes, and yes, then you are ready to take the risks. In the same way, I always tell my patients who sign-up for alemtuzumab treatment that they should expect to develop a secondary autoimmune complication; if they don’t they should count themselves lucky. if they are not prepared to develop a second autoimmune disease then shouldn’t be treated with alemtuzumab.

The following are our local criteria for being referred for HSCT. 


ProfG    

50 comments:

  1. It is because the HSCTers are getting a lot of airtime on the BBC and in the newspapers.

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    1. I agree. But I did think Caroline Wyatt's piece was very well balanced.

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

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  2. Your infographic is misleading. It assumes all people treated with HSCT will improve. This is not correct. And what about those who succumb to the treatment and die? Don't you think you should include the complications as well?

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    1. Re: "Your infographic is misleading"

      Yes, you have a point. If and when I get time I will redraw this to be more balanced. Please note this is not our own infographic but has been taken off the web. It was originally used by by MD1 last year.

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  3. Why can't HSCT be offered as a first-line treatment under the NHS? Surely people with MS are capable of assessing the risks and benefits for themselves and make the decision to have the most effective treatment at a stage of their disease were they stand to gain the most from it. These guidelines are very paternalistic.

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    1. Re: "Why can't HSCT be offered as a first-line treatment under the NHS?"

      Dare I suggest that the neurologists who run this group and are hence the gatekeepers to the HSCT units are too conservative? I agree that if we are prepared to use alemtuzumab first-line we should be prepared to use and offer HSCT first-line. I see no reason why a well informed patient can assess the risks and benefits of HSCT and make the decision themselves.

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    2. I am rather stunned but so pleased at your reply, Gavin!
      As someone with PPMS, I was never offered any DMDs (thank goodness) and HSCT was a first-line treatment for me. I am happy to report that HSCT (in 2014) was successful in halting the progression of my PPMS, and I have many (bonus) symptomatic improvements, too!

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    3. Thanks for your positive insight, but I suspect there are people out there where their PPMS has not been halted too/

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    4. Please note that we still don't have class 1 evidence to allow payers to accept HSCT as a standard treatment for MS. They need to know the costs of the risks and the benefits before they will accept it as genuine treatment for MS. Until we have a blinded randomised head-2-head study HSCT will always remain on the fringes of MS therapy.

      Part of getting HSCT adopted as a treatment for MS we need data to allow it to be adopted.

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    5. Here in Brazil, in the state of São Paulo, there's a reference center in the country for treatment of MS, and they use, there is already long time, the HSTC for cases more aggressive of the disease.

      What we saw and see until is that the HSTC got hold well MS for the cases of pwMS as RRMS highly active, as for the cases of pwMS with SPMS and PPMS who made the HSTC the effectiveness was not the same, in almost all of them the disease continued to progress.
      Why this happens?

      I don't know, I am not medical and nor a scientist, but it's disturbing that this happen being the types of phenotypes, spectra of in the same disease.
      And more disturbing is still the HSTC be used against something that we don't know not what is the real cause.

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    6. I'm still to be convinced that HSCT would not have a similar effect as Ocrevus on progressive or long standing MS, but anything is possible.

      As a side issue, almost everything that HSCT is used for has an unknown cause - most cancers don't have a known 'cause' as such.

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  4. As always you do not provide the data that you base your points.

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    1. As alway you hide behind "anonymous" when you are a HSCT troll.
      Plesase be specific about what your refer to

      Delete
  5. After you switch off the inflammation, you need re-myelination. The video below suggests a method (I'll stop posting it now, I promise - just want it out there).
    https://stopms.mssociety.org.uk/annual-lecture.html

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    1. (I'll stop posting it now, I promise - just want it out there).
      https://stopms.mssociety.org.uk/annual-lecture.html

      No..don't stop.
      This is great new news to me.
      Thank you.

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  6. Thank you very much for such a clear and concise summary of HSCT and for not mincing your words as to what it entails, and what it achieves.

    This is pertinent to me as I have my MRI and Consultant appointment next month. I had an MRI a mere month after the second lot of Alemtuzumab infusions, that showed two new lesions. To follow your analogy, I've retained the gamblers optimism, I hope on good grounds. I've viewed Aaron Boster on Youtube, saying that he thinks an MRI should wait until 6 months post the complete induction.

    However, I know that if the result is further evidence of disease activity that the conversation will concern a second course of Alemtuzumab or HSCT. This post is both timely and of real benefit to me as I prep for the consultation.

    For the benefit of others, and the optimum use of consultations, I wish this summary was readily available to a whole lot of other PwMS.

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  7. Great article - I finally get HSCT.

    What are the documented benefits of A-HSCT so far? Does it outweigh high-efficacy DMTs in RRMS?

    Has the A-HSCT death risk been stratified by age or EDSS score?

    Lat, is chemotherapy a 1 time a silver bullet? if used to treat MS, can it be used again in the future to treat malignancy in the same patient?

    Thank you

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    1. Re: "What are the documented benefits of A-HSCT so far? Does it outweigh high-efficacy DMTs in RRMS?"

      We may be able to answer some of these sorts of questions in the next few years when various trials currently been performed or in planning report out.

      The best results in favour of A-HSCT are from the Canadian/Ottawa cohort and they are very good. But this was an open-label observational study; there was no comparison versus very-high licensed treatments.

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    2. Re: "Has the A-HSCT death risk been stratified by age or EDSS score?"

      Not really as the vast majority of cases who have received HSCT have received NM-HSCT. But applying general principles the older you are the less well you tolerate chemotherapy. In addition, the more disabled you are the more at risk you are of infections, in particular UTIs and pneumonia therefore are at greater risk for A-HSCT.

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    3. Responding to your comment regarding older patients and those with worse disability and the increased risk of infections as well as problems coping with the chemotherapy - I assume that Cladribine tablets are a considerably milder and less toxic chemo treatment than that used for the HSCT procedure? Have you seen your older patients and those with advanced disease struggle to tolerate Cladribine or even worsen considerably following treatment?

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  8. Is mitoxantrone good for PPMS?

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    1. Re: "Is mitoxantrone good for PPMS?"

      Yes and no. Yes, if you active MS, i.e. with Gd-enhancing lesions on MRI or an increase in the T2 lesion load. No due to the side-effect profile. At Barts-MS we have essentially stopped using mitoxantrone and replaced it with off-label parenteral cladribine and would like to include rituximab in the mix. Even better would be to get yourself treated with a licensed product; if you have PPMS at the moment there is only one show in town (ocrelizumab).

      Delete
  9. Great article. Clearly explained the treatment vis a vis other high efficiency DMDs.

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  10. is Tysabri as effective a DMT as HSCT and Alemtuzumab? I know there is something called PML, but I hear that if you are negative of the JC virus, its quite rare to get PML.

    it seems like these hard hitting options come with almost certain side effects, and not minimal ones.

    its such a pity the NHS is toying with peoples lives, by denying them the newest treatment, ocrelizumab when it seems to be the most effective/ lowest risk combined treatment, available.

    Can the Barts Team help with pushing this? this is peoples futures here. I am very grateful to your team, and the blog. its why I guess I look towards you, as I think influence needs to be applied to have the NHS answer for their denial of proving a proven and safe drug

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    1. Where have you heard that Ocrelizumab is safer? That's not my impression, e.g. concerns about malignancies. And perhaps the side effect profile of the drug is not yet fully established as it has only just been let loose on patients?

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    2. Much safer. Malignancies are treatable and the mortality rate is well within the expected rate for people with MS.

      Anti-CD20 therapies have a well worn and expanding safety profile. There is no way that they are more toxic than chemotherapy and alemtuzumab. I will grant you that in JCV negative people natalizumab has the edge over ocrelizumab in terms of safety and possibly efficacy.

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  11. Prof G you say that the chemotherapy used in hsct can make a person worse the more disabled they are. Does that also apply to alemtuzumab?

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    1. Alemtuzumab is not a chemotherapeutic agent; it is a biological. Saying that if somebody developed an infectious complication, post-alemtuzumab, they could easily be worse off. In this situation it would be the infection rather than the alemtuzumab that caused the worsening.

      Chemotherapy (chemical therapy) deterioration occurs because the chemo is actually toxic to nerve cells and damaged nerve cells are more sensitive. The oncologists refer to this as chemobrain or chemotherapy induced neuropathy.

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  12. So, why do pwMS need to be OCB+ to get HSCT at the London MS AHSCT (and elsewhere, I presume)? If MS is one disease, this seems rather odd. It would be nice if OCB- pwMS knew why we're excluded from this potential treatment. Has anyone OCB- tried A-HSCT before?

    Thanks

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    1. I think it is because a lot of us think OCB-ve MS is not MS and another disease. The ocrelizumab trial, for example, also excluded OCB-ve subjects.

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    2. pigeon-holing OCB-ve 'pwMS' as another disease flies in the face of recent posts advocating MS to be considered as a single disease with a range of therapies available irrespective of what the diagnosis is. So, if its not MS, what is it? Kinda interested as I'm OCB-ve. Does OCB-ve also preclude treatment with cladribine?

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    3. "Is chemo brain temporary?"

      Yes..if you go HSTC facebook pages people talk
      about worsening effects followed by recovery of function.

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  13. Could I ask when the data from the head-to-head trials are expected to be out?

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    1. Not sure for all of them. However, the UK one will hopefully report out in 2023/24.

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    2. 2023/24? I would be dead if I had waited that long! Luckily we live in a truly global age now and receiving HSCT overseas has been an extremely safe option for many years already. ✅

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    3. Believe there was a cardiac death in Russia..2 deaths in India and one from cardiac sepsis in nuetropenic phase in Mexico all in the last year or possibly last 2 years.

      Remember there is no FDA in Russia or Mexico..those clinics pretty much do what they want i.e treating progressive MS
      with HTSC even though you can't get that treatment in EU U.K.
      U.S. Canada NZ Australia etc.

      Delete
  14. Great post

    "HSCT destroys memory cells from your previous vaccinations. This is why you have to be revaccinated with all your childhood vaccines at ~2 years after HSCT to restore your immune responses to these common infections. "

    In this study myeloablative with totsal body iradiation(Tbi) ,antibodies

    levels didn´t drop

    Surprisingly, antibody levels did not drop substantially, in spite of the severe CD4 T and B lymphopenia during the first several months posttransplant. Consistent with that, oligoclonal immunoglobulins in the cerebrospinal fluid of most multiple sclerosis patients treated with autologous transplantation did not disappear [3,37,38]. As the half life of IgM and IgA is only ~5 days and that of IgG only ~23 days [39], the antibodies detected in the sera of our patients were continuously produced, presumably by plasma cells generated pretransplant. Plasma cells are radiation-resistant and long-lived [40–42]. The persistent antibody production does not appear to require posttransplant exposure of patients to the cognate antigens. Tetanus IgG levels in the first posttransplant year remained stable, even though the patients were not vaccinated in the first year and natural exposure to tetanus toxin in developed countries is extremely unlikely [43]. However, it is unclear whether this applies to other autologous transplant settings. In three studies presenting tetanus antibody levels after autologous transplantation for malignancies, the levels appeared to drop between pretransplant and 1 year posttransplant [44–46].

    Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases)

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956741/



    Obrigado

    ReplyDelete
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    1. Protection against infections is not just antibody mediated, but via T-cells as well. In addition, long-lived plasma cells are not that long-lived. We recently saw a case of measles encephalitis in a bone marrow transplant patient despite them still having detectable anti-measles antibody. In the UK our HSCT centres re-vaccinate their patients ~ 2 years post-HSCT. You are welcome to say no; as with all things in life it is a choice.

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    2. No they don't! Hammersmith Hospital CLEARLY tells their patients that they do not need to be revaccinated. I have followed 41 patients who have had HSCT for MS at Hammersmith. They have been told that there is no need to check their immune titres as non-myelo chemo does not wipe out vaccines. I have consistently questioned that statement, but what do I know?

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    3. PS. I now have 41 patients interested in where you got your revaccinating information from? 🤔

      Delete
    4. Neurologists are the only real doctors and they know EVERYTHING, do not question them when they dont provide sources.

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    5. Re: "I now have 41 patients interested in where you got your revaccinating information from?"

      From our haemoncology unit; it's part of their standard operating procedure. When you do a search on Google you find it is quite a common practice, both in the UK and abroad.

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    6. Revaccinations are part of our proposed NIHR HSCT vs. alemtuzumab study protocol. This part of the protocol was written with input from haemoncologists from three UK BMT Units.

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    7. Re: "Neurologists are the only real doctors and they know EVERYTHING..."

      Sorry, not neurologists on this occasion, but haemoncologists; we are just following their SOP (standard operating procedure).

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    8. Professor Giovannoni... please contact the lead Haematologist at Hammersmith Hospital who have been transplanting MS patients with HSCT for over 2 years now.

      All the patients at Hammersmith have been advised that they DO NOT need revaccinations. I will not name the haematologist at Hammersmith, because I know that will lead to this post being deleted. So please liaise with him yourself in order to be corrected on your assertion that all UK Centres revaccinated.

      Delete
    9. Ablative HSCT you need vaccinations because you have a new immune system, but non-ablative you don't.

      Delete
  15. Infections

    As expected, infections were frequent in the first month, when multiple components of immunity were abnormal. Surprisingly, infections between day 31 and 730 were infrequent in spite of the profound initial lymphopenia (in particular CD4 lymphopenia) (Table 1).

    No T cells insight

    Obrigado

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956741/

    ReplyDelete
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    1. No different to alemtuzumab Could alemtuzumab and HSCT be offering the same thing? I suspect yes. Let's do a head-2-head study.

      Delete
    2. Can we do something for the drug antibodies and the secondary autoimmunity in alem? Because it fails too often and it fails loudly

      Delete

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