Sunday, 17 May 2015

HSCT for multiple sclerosis

Hematopoietic Stem Cell Transplantation for Multiple Sclerosis
Burt et al. JAMA Neurol 2005:62:6




Hematopoietic stem cell transplantation (HSCT) was proposed as a treatment for multiple sclerosis (MS) in 1995 based on favourable results in animal models including experimental autoimmune encephalomyelitis.These initial or first-generation trials were developed by medical oncology subspecialists, used malignancy-specific myeloablative transplantation regimens, and selected patients with secondary progressive MS with rapid progression of disability. In general, these trials suffered from higher than anticipated toxic reactions including treatment-related and disease-related mortality, continued loss of brain volume as seen on magnetic resonance imaging (MRI), and, at least in some patients, continued progressive disability despite marked attenuation or absence of gadolinium-enhancing lesions on MRI. Learning from these experiences, second-generation transplantation trials for MS are using MS-specific nonmyeloablative transplantation regimens and selecting for active relapses despite the use of interferon treatment in patients with less accumulated disability. While still preliminary, results using second-generation nonmyeloablative HSCT regimens are encouraging with minimal treatment-related morbidity and improvement in Expanded Disability Status Scale (EDSS) scores. The following 3 variables seem important in predicting the benefit and minimizing the toxic effects from an autologous stem cell transplantation in patients with MS: the selection of patients who still have inflammatory disease (ie, gadolinium enhancement on MRI and/or frequent active relapses), treatment early in the course before the onset of significant irreversibly progressive disability, and the use of a safer lymphoablative but nonmyeloablative HSCT conditioning regimen.

The first partial misconception that HSCT is a high-risk procedure needs to be placed in perspective with the drug regimen utilized, as well as with the risks of current FDA-approved disease-modifying therapies. There are three variables that determine the safety of HSCT: 1) the regimen (drugs) used; 2) patient selection; and 3) a center effect (experience with transplant for MS).It is important to recognize that the terminology ‘autologous hematopoietic stem cell transplantation’ is in reality a misnomer. There is no transplant, only the infusion of an autologous supportive blood product, analogous to a surgeon collecting before and then reinfusing autologous packed red blood cells after an operation. Before receiving the stem cell infusion (transplant), patients with autoimmune diseases receive a ‘conditioning regimen’ of drugs (chemotherapy, biologics, and/or radiation). The early and late toxicity from HSCT depends upon the specific drugs in the conditioning regimen and not the infused autologous blood product, i.e. hematopoietic stem cells.

BACKGROUND
The current therapies for MS consist of immune-modulating agents, such as interferons or glatiramer acetate, and anti-inflammatory and immune suppressive drugs such as glucocorticoids, methotrexate, and mitoxantrone (Novantrone; Immunex Corporation, Seattle, Wash).Autologous HSCT (either myeloablative HSCT or nonmyeloablative HSCT) is a form of immune suppressive therapy in that immune suppression is maximized to the point of transient immune ablation. In theory, the transplantation conditioning regimen ablates the aberrant disease causing immune cells while hematolymphopoietic stem cells (HSCs) regenerate a new and antigen naive immune system. Therefore, all of the toxic reactions and efficacy of an autologous HSCT (either myeloablative HSCT or nonmyeloablative HSCT) is likely a consequence of the conditioning regimen.

MOBILIZATION


The most common method of collecting HSCs is by mobilization from the peripheral blood. Since negligible HSCs are detectable in the peripheral blood during the steady state, either a hematopoietic growth factor such as granulocyte colony-stimulating factor or chemotherapy (usually cyclophosphamide) with or without granulocyte colony-stimulating factor is necessary to mobilize HSCs into and subsequently collect HSCs from the blood. Hematopoietic growth factors used to mobilize HSCs also have immune-modulating effects and unlike malignancies may exacerbate disease depending on the growth factor. Granulocyte colony-stimulating factor may precipitate clinical flares of MS sometimes with significant and irreversible neurologic deterioration.Colony-stimulating factor–induced MS flare may be prevented by either administration of corticosteroids or mobilization using the combined therapy of cyclophosphamide and granulocyte colony-stimulating factor.

COLLECTING STEM CELL
Most mononuclear cells collected by peripheral blood apheresis are immune cells such as lymphocytes and monocytes not HSCs. While the true identity of human HSCs remains elusive, either purified CD34+ or AC133+ hematolymphopoietic progenitor cells are sufficient for hematopoietic and immune reconstitution. In general, a minimum number of 2 × 106 CD34+ cells per kilogram of recipient weight will ensure engraftment. Hematopoietic stem cells may be positively selected or enriched ex vivo using antibodies to CD34+ or AC133 or purified by negative selection by using antibodies to remove lymphocytes. In practice, the most common method of purging lymphocytes is via CD34-positive selection using either the Miltenyi CliniMACS (Bergish Gladbach, Germany) or the Baxter Isolex (Deerfield, Ill) cell separator device. Whether enriching the graft for CD34+ HSC is necessary or even superior to infusion of an unmanipulated graft remains unclear. CD34+ selection by removing lymphocytes is perhaps best viewed as another method of immune suppression. For an intense conditioning regimen, CD34+ selection may be unnecessary or even detrimental by increasing the risk of treatment-related infection.#The rationale for autologous HSCT of MS is to regenerate an antigen-naive immune system from the patient’s own HSCs. Therefore, the goal of the conditioning regimen is lymphoablation not myeloablation. The autologous HSCT regimen should be based on immune suppressive drugs that are well tolerated at conventional nontransplantation doses and are expected to remain safe and nonmyeloablative at higher transplantation doses. The regimen must also avoid further damage to already injured axons and oligodendrocytes. By definition, myeloablative agents are lethal to HSCs and, apart from their myeloablative effect on bone marrow, may be similarly cidal to tissue-specific stem cells such as oligodendrocyte progenitor cells or neural stem cells. In animal models, cranial irradiation impairs the mechanism of CNS repair by neural stem cell apoptosis, alteration in cell cycle progression, and/or destruction of the neural stem cell niche or milieu through invasion of macrophages and microglia. This raises concerns about using total body irradiation based, or any other stem cell ablative regimen, in the treatment of MS.

Nonmyeloablative HSCT regimens that are as immune suppressive as myeloablative regimens but without myeloablative adverse effects may be designed by using agents or combinations of agents such as fludarabine, cyclophosphamide, antilymphocyte antibodies such as Alemtuzumab or anti-thymocyte globulin, and/or by the use of CD34+ selection of the graft. Fever-related deterioration of neural function in MS, termed “pseudoexacerbations,” due to conduction blocks in marginally functioning demyelinated axons should be avoided during transplantation by minimizing pyrogenic agents in the conditioning regimen. Similarly, the risk of infection-related fever should be minimized during transplantation by use of prophylactic antibiotics.

In summary, for MS the rationale behind the HSCT conditioning regimen should be to (1) dose-escalate agents that work as conventional therapy, (2) maximize immune suppression without myeloablation, (3) avoid conditioning regimen agents that may cause injury to already disease-affected and damaged CNS tissue, (4) avoid injury to tissue-specific stem cell compartments that may be important for CNS repair, (5) minimize the risk of fever, and (6) design regimens that are justified for the risk of the disease being treated.

The current ongoing Multiple Sclerosis International Stem cell Transplant (MIST) trial (www.clinicaltrials.gov NCT00273364) randomizes patients with two or more steroid-treated relapses within 12 months despite first-line therapy with interferon or copaxone to either HSCT (cyclophosphamide/ATG) or best available approved second-line therapy (Novantrone, Tysabri, or Gilenya) with a target of n=110. 

So if positive what next? Will the regulators say: HSCT in place of current second line? (it would be cheaper in the long-run), HSCT in addition to second line; great but where is the second trial to confirm the results as we wouldn't want to favour academics over pharma or you are comparing apples with pears its obvious that HSCT is better than compound X in the standard second line or will they say the trial isn't properly done, like they did initially with Alemtuzumab (recently "We recognize that blinding during the first year will be compromised by patient hair loss but efforts will be made to mask hair loss by covering the heads of study patients during their first year neurology assessments" was removed from clinical trials .gov. Did they give up blinding the assessor?). If you agree to be randomised to HSCT and don't get it, do you loose the placebo effect. all sort of thng to think about.

I personally hope the regulators say yes this can be another treatment option choice.....(it will be approved for RRMS....will progressive MSers seek it a a base on which to layer neuroprotection and repair?).

However, I suspect there will be a lot of pharma out there who will not be so happy. Alternatively will it take so long to get HSCT approved, especially if more trials are needed the landscape will have changed by the time this happens.

If you do a trial against Alemtuzumab, in the two years to get the trial off the ground Ocreluzimab will probably come along. Will people therefore want Alemtuzumab? Will this be available as standard care, because if not, you will need to buy the drug for a trial of 110 people (based on the powering of MIST) the costs with be about £10-15,000,000 plus the costs of the HSCT and monitoring so who can fund a trial at this cost?
Nobody only Pharma?

Food for thought.

32 comments:

  1. I have brought this up before but I think maybe a consortium of the payees seems like the obvious choice. If the insuance companies as well as those government entities responsible for paying for the current drugs may be a source for funding.

    As it is now, pharma is continuing to escalate the costs of MS medications regardless of an increasing number of therapy options which means it is not based on economic principles.

    I think if the payers get together and fund a trial for HSCT it could get them out of the current situation.

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    1. If you are a government agency and you have been allocated 20 million for the whole of the countty and all the grants. Would you commit 5 million even if it would save the country thirty million in commiting. If the study cost 50 million to do would you entertain being part of it.

      This is the problem.The costs have got out of hand pharma then know no one can afford to do the necessary studies properly. It will take political will and some powerful people to make change

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    2. It'll never happen, MouseDoc.

      The will of the people just isn't there. Heck, the UK just voted for tax cuts and a brand new car over greater and better public services funded through higher taxation.

      The news is reporting that Big Pharma will not invest in researching new antibiotics because of money earning issues, meaning tax payers are obliged to pick up the costs.

      MS is so low down the priority for Big Pharma that MSers ought to be seriously scared. You yourelf have admitted that alemtuzmab may not be the beacon of hope Prof G has made it out to be and we need better alternatives, pronto.

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    3. It is a current beacon but in the future we will see.

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  2. The answer is don't do it in the UK. The MIST trial is not funded, so patients in the U.S. pay $150-200k each. In the vast majority of cases, insurance companies cover this. Which is how Dr Burt has got this off the ground without funding. Apparently he tried for 5 years to get pharma involved and got zero interest as there's no patent to be won.

    On a side note, Dr Snowden in the UK is treating some patients on the MIST trial and they're not self paying, so there must be a degree of funding from the NHS....

    Maybe we need to think multinational to spread the financial burden?

    Again, using MIST as the example, it's running in the U.S., Brazil, Sweden, UK, Australia (soon)... Maybe more...

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    1. Treating a few people can be down to funding by the local trust but to get UK wide approval is going to need the support of NHS England scotland wales northern ireland,

      MIST.. I hope the regulators won't see red mist. I look forward to the outcome

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  3. So where does your charcot project stand in all this?
    Would people who have had Hsct be able to
    Have HAART if proven succesful?
    Also as has been stated ppms has an inflammatory aspect at least early on in the process, so what is the harm in HSCT early in ppms followed by a neuroprotectiv? Especially is the toxicity risks are now lower

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    1. Anti-virals are irrelevant to the immune system issues but what is the harm of HSCT early in PPMS, according to someone who works on HSCT about 1 in 200 chance of death, however do we need that hammer or the nut we should be cracking.

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  4. I was told the risks were ALOT lower than that even now when you look at the amount of procedures that have been done
    Some centres are quoting upwards of 70% success rate for ppms? How is this not being taken seriously?
    This is a horrible position to be in when there are no options other than grasping at straws, I can't believe that in this day and age where we as a country pledge millions each year and pay aid to countries who no longer need it, we can't still look after our own! It's ridiculous
    This disease needs cracking, like polio, like whooping cough, like so many others that were once incurable

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  5. Also I agree with the hammer quote, but what other options are there? Ineffective injection therapies? I think it's a case specific decision
    What about the Greek study where some participants had remission and no progression for over 14 years with ppms after hsct
    I also believe in the therapeutic lag theory with ppms, the inflammation is not as easily measured so surely hsct would take care of that
    The disease is so immeasurable when mri doesn't correlate to disease

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    1. which study are you refedring to

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    3. I believe Kris is referring to this study, which demonstrated that 10% of patients who didn't display CNS inflammation before HSCT remained progression free 15 years after treatment, while 44% of patients who had active inflammatory markers prior to treatment remained progression free.

      http://www.ncbi.nlm.nih.gov/pubmed/21422458

      Seems to me that that 10% number isn't all that impressive, especially since a few PPMS patients do plateau and seem to stop progressing, or at least stop progressing rapidly, at some point during their disease course. The conclusion of the above study does state that HSCT is best indicated for patients with active inflammatory disease.

      As a PPMS patient myself, I of course would love to see some real evidence that HSCT is effective in at least slowing the progression of noninflammatory progressive disease. I had high hopes when I first read the abstract of the recent Russian study, but upon reading the actual paper was left quite disappointed. It seemed filled with statements that seemed almost contradictory, and provided very little background on the condition of patients prior to treatment.

      Dr. Burt in Chicago did seem to see some stability in SPMS and PPMS patients when he first started his HSCT experiments, but then switched over to exclusively treating patients with active inflammatory disease. I would love to know why he abandoned the treatment of later stage progressive patients. Anybody have any idea how to question him about this directly? I haven't found a way to contact him, and I'm planning on writing an article on the latest in HSCT for my Wheelchair Kamikaze blog. Getting the info straight from the horses mouth would put an end to a lot of the conjecture that's flying around the Internet…

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    4. BTW, that 70% number that Kris refers to in regards to PPMS is from the aforementioned Russian study…

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    5. Thanks , as this work wss published a few months ago it wont be digested yet let alone acted on to any extent that you will notice it, these things take time.

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  6. I think it was by vasilios kismikidis but I'll try get the study details asap
    There's also the Russian report albeit possibly biased as you suggested
    Then there's Dr Burts Initial study on spms where all 9 with short disease duration and edss below 6 had disease progression stopped at 48 month follow up average, surely this shows that it has the possibility to work in spms ppms early

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  7. There's also this on a different note
    http://www.clinsci.org/cs/128/cs1280111.htm

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  8. Kris-thanks for that link, fascinating. I'd love to see a study done on any epigenetic changes on cells outside of the immune system post HSCT. Would be interesting to see if genes activated in MS patients become deactivated after HSCT treatment. As for the Burt study on early SPMS and PPMS patients, I've no doubt there would be some affect if these patients had active inflammatory disease. Unfortunately, the majority of PPMSer's don't ever show signs of active inflammatory disease. Perhaps if caught early enough, though…

    Anonymous, thanks much for that email address. Let's see if the good Dr. responds…

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    1. Hi mark
      Thought you'd be interesred in that one
      There's a number of studies now that look like they show some level of improvement, some even state with triple does gadolinium that a larger percentage of ppms patients have enhancing lesions

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  9. Is the interest in HSCT here because of (a) ability to combat RRMS to add and induction therapy alternative to alemtuzumab (b) percieved ability to influence progressive MS?

    If the answer is (a) why would you not try alemtuzumab first and now if you are willing to try HSCT and if you are not willing to take alemtuzmab , i guess because of side effects would you try and induction therapy without the side effects first?

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  10. Hi MD
    I suppose if you can lower or remove the risks with lemtrada then you go for that maybe? But then hsct seems to have a better success rate? My only worry is i don't think you can repeat it or go back another therapy after? You'll know more on that
    HAART or your charcot should be interesting too i guess

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  11. Speaking strictly for myself, interest in HSCT (other than journalistic interests, i.e. my blog) is as a possible treatment for progressive MS. No real reason to think it would help in patients lacking active inflammatory markers, other than the anecdotal reports recounted on various Facebook pages and websites. Of course, these reports paint quite a rosy picture, but most are of short-term outcomes (1-2 years) which I would think are far too short to make any real objective judgments. Of course, there's also the placebo effect to contend with…

    I've also observed that many progressive patients are poor predictors of their own rate of progression. My wife likes to chide me that I've been saying I'm going to be bed ridden within six months for the last five years…

    As there is nothing else out there for PPMS, such anecdotal claims are compelling, but don't seem to be backed up by any research, or even solid rationale. However, there is low-level inflammation seen in most primary progressive patients, so there is that chance… Thoughts?

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    1. Come on Md what's your real thkughts on it?
      Take a situation as a young ppms patient with quite quick progression and relatively early in disease course? What do you do

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    2. My sleep habits are very strange. I generally keep the hours of a vampire…

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  12. What is the difference between using alemtuzumab as part of the conditioning regime prior to HSCT and using alemtuzumab as a treatment in its own right?

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    1. From what I understand in HSCT they may / sometimes use Alemtuzumab as one of the many (and I mean many) drugs to suppress your immune system after your bone marrow stem cells have been harvested.

      Alemtuzumab on its own suppresses your immune system to a less extent and your body rebuilds on its own, however in HSCT the immune systems is pretty much wiped out and your body rebuilds with the assistance of your stem cells.

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  13. What's the verdict on the ongoing Msc trial?
    The people involved seem very excited by it

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  14. Panorama next Monday will be looking at HSCT for MS. I'm really hoping this will reach the MS masses and push it forward as a treatment. There was a lot of talk about HSCT on this blog early last year but not anything since which is a shame. I don't remember a blog post ever getting so many responses or generating so much hope as your HSCT / Zeus talk did. I'm really hoping this program will raise awareness.

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  15. Unfortunately, Big Pharma makes customers they are NOT going to assist financially in a potential 'cure' or better treatment because it is NOT financially feasible for them to do so. HSCT threatens there pocket books. And I will make an educated guess that Pharma will try everything in there power to keep HSCT from coming to light. Personally as someone living with Progressive-relapsing MS I am beyond pissed! Not being able to obtain HSCT is like dangling a steak right out of the reach of someone who is famished. I'm trying to grasp that steak because I'm hungry. Yet, Big Pharma could care less if I starved to death!! It is what it is. Even though it should NOT be y'all!

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