Thursday, 3 August 2017

#ClinicSpeak: do you need a sledgehammer to crack a nut?

Why high-dose cyclophosphamide is a not a treatment option for MS? #ClinicSpeak #MSBlog

Yesterday someone made the comment that cyclophosphamide, as part of the AHSCT (autologous hematopoietic stem cell transplant) conditioning and induction protocol, was the most effective treatment for MS. I disagree. Firstly, AHSCT does not use cyclophosphamide as monotherapy; most HSCT regimens include alemtuzumab, ATG (anti-thymocyte globulin) and other chemotherapy agents (e.g. BEAM - BiCNU/carmustine, Etoposide, Ara-C/cytarabine and Melphalan). Some newer protocols use follow-on rituximab as a maintenance treatment. Therefore you can't make the claim that cyclophosphamide is responsible for the efficacy of AHSCT.    

About 6 months ago one of my patients, a 34-year woman, with rapidly involving severe MS failed alemtuzumab therapy with a breakthrough spinal cord relapse at ~7 months post her second course of alemtuzumab. As we don't have funding in place in the NHS to give a 3rd course of alemtuzumab we had to consider other options. One of the options included HSCT (she was eligible under our the London AHSCT guidelines), however, when she was informed that the chances of her becoming infertile from the cyclophosphamide were over 40% she declined HSCT. That is the problem with cyclophosphamide; in high-doses it is seriously toxic to both the ovaries and testes and patients have to bank eggs (oocytes) and sperm. Cyclophosphamide is a potent immunosuppression so infections are a major risk. It also causes hair loss, mucositis, enteritis, hemorrhagic cystitis, nausea, vomiting, etc. I did my house job in a haemoncology ward and have personal experience with both allogeneic and autologous bone marrow transplantation and believe me we things go wrong they can go seriously wrong. Several of my patients died from the complications of bone marrow transplantation. I agree that things have improved markedly in the last 30 years, but there are still risks associated with HSCT that need to be carefully considered and this is why we are hoping to do a trial of AHSCT vs. alemtuzumab in the NHS to define the risk:benefit profile better. 

The high-dose cyclophosphamide proponents may be interested to hear that the John Hopkins group had a relatively large programme of high-dose cyclophosphamide as a treatment for highly-active MS. This treatment was called Revimmune. They have now stopped using Revimmune in MS because of the risks and because most of the patients had recurrence of disease activity about 18-24 months after the treatment. The latter is similar to our experience with mitoxantrone another chemotherapy agent used to treat highly active MS. So based on the above, and from the experience of the John Hopkins group, we would not recommend cyclophosphamide monotherapy to treat MS. We have also stopped using mitoxantrone for similar reasons and now offer off-label cladribine instead. 


So in an era of safer, more targeted, therapies why would anyone want to take the risks of their immune system and body being hit by a sledgehammer? These issues are likely to become major factors in how DMTs play out in the future; in particular the debate of continuous (fingolimod/natalizumab/ocrelizumab) vs. intermittent immunosuppression (alemtuzumab/cladribine/AHSCT) and non-selective (alemtuzumab/AHSCT) vs. selective immune reconstitution therapies (cladribine)

Dezern et al. Repeated treatment with high dose cyclophosphamide for severe autoimmune diseases. Am J Blood Res. 2013;3(1):84-90.

High dose cyclophosphamide (HiCY) without stem cell rescue has been shown to induce remissions in patients with severe autoimmune disorders (SADS). However, up to 80% of these patients ultimately relapse. Here we review the outcomes of seven patients treated with two cycles and one patient treated with three cycles of HiCY. The diseases re-treated were scleroderma, multiple sclerosis, three patients with severe aplastic anemia (SAA), and three patients with myasthenia gravis (MG). All but two patients with SAA had received standard immunomodulatory therapy for their disease up front and had been refractory. All patients had complete hematologic recovery. Overall survival in this cohort was 100%. All patients relapsed after the initial cycle but event free survival thereafter was 93.3%. All are still in remission except two MG patients, one of whom relapsed after a severe GI infection requiring hospitalization, and the other relapsed 3 years after the second treatment and she did not respond to the third treatment. This shows that HiCY can be safely re-administered in patients with SAA and refractory SADS. The quality and duration of second remissions appears to be equal or superior to the first remission.

CoI: multiple

22 comments:

  1. Contradiction Alert!
    "However, up to 80% of these patients ultimately relapse."

    Neither sledgehammer is capable of cracking a nut.

    ReplyDelete
  2. Interesting post. I agree cyclophosphamide isn't ideal without being part of a HSCT regime, although I know of regimens that use only cyclophosphamide and rituximab.


    You note a risk of infection. I think we need to be realistic here. HSCT only needs to be done once, and then the immune system almost fully recuperates. This is not the case with any low efficacy, ongoing treatment. If you look at the occurrence of infection for a lifetime of, say, tecfidera, versus an induction treatment with HSCT, I would say the tecfidera patients will get more infections. This is the same with every so-called 'safe', low efficacy MS drug.

    Now, compare HSCT to the relatively high efficiacy MS drugs. Ocrelizumab, natalizumab, alemtuzumab. Well, we know natalizumab isn't safe, because it causes PML at alarmingly high rates. We know ocrelizumab can also cause PML and we know it probably causes cancer too. We know the immune system never fully reconstitutes from alemtuzumab, we know T cells are suppressed for a lifetime after its use, and we know it gives the majority of people treated with it other autoimmune diseases.

    Cladribine has none of these problems but it just doesn't work as well as even ocrelizumab or alemtuzumab.

    So I'd say when you look at risks you have to look at them over the course of a lifetime. Cyclophosphamide is not a targeted therapy, but it only needs to be done once! Then you have no poisonous chemicals in your body ever again.


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    1. Re: "....only needs to be done once!"

      But once is enough to fry your gonads and the cancer causing mutation that will come back and bite you in the future. Thanks, but no thanks.

      HSCT is also not a cure, NEDA rates are about 70% at 3-years and will drop off with time. What happens then?

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  3. Dear Prof G,

    Regarding the point, that newer protocols maintain with Rituxan. Since MS is a B cell disease, and rituxan targets the B cells, how do we know that the HSCT is working? Could it be that just the rituxan on its own would yield the same results?

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    Replies
    1. Maybe not

      Case report. Results: 30 year old man with aggressive multiple sclerosis was diagnosed in 2010 and presented to University of Colorado in 10/2013 in a wheelchair. He was treated with Tysabri from 10/2013 until 8/2014. He was JCV+ and was then treated with 1 gram of rituximab in 9/29/14. He was showing gradual improvement and was beginning to ambulate with a walker (leg strength went from 2/5 to 4/5) when he died on 1 November15. He had received two additional 500mg doses with the last dose on 15 September. His peripheral CD19/20 counts stayed undetectable. His last MRI Brain on 3 July 2015 was stable.

      http://multiple-sclerosis-research.blogspot.com/2017/04/aan2017-b-cells-remain-in-brain-after.html

      Delete
  4. I thought that Team G rated mitox?

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    Replies
    1. We did and used it in our tolerance study, but when the leukaemia rate after mitox increased we felt that we should not be using it.

      Delete
  5. But why would you choose HSCT when you could be treated with cladribine? It is clearly safer, and possibly as effective, as HSCT?

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    Replies
    1. It is simply not as effective as HSCT.

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    2. Has Cladribine been use for 20 years min Ms?

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  6. Prof Giovannoni do you have Ms?

    If so do you pay for a 56 000$ a year for a "hi efficacy" Pharma drug?
    Do you EVER gonna feel inside of you what is like to live with Ms ?

    ReplyDelete
  7. Porf G and cyclophosphamide

    Love Me ,Love Me not....

    On this blog we have been actively promoting off-label prescribing for over two year. The motivation for doing started on my sabbatical in 2014 when I visited South Africa and saw first-hand how pwMS were not being treated with DMTs because of their high price. My position on this only got stronger when I visited other resource poor countries, in particular India. We have now generated a list of 9 off-label treatments; 5 of which are on the WHO list of essential medicines. The latter is important in that this ensures they are available in almost all resource poor countries.

    Azathioprine*
    Cladribine
    Cyclophosphamide*
    Fludarabine*
    Leflunomide
    Methotrexate*
    Mitoxantrone
    Rituximab*
    HSCT/BMT

    *on the 19th WHO Model List of Essential Medicines (April 2015)

    ReplyDelete
    Replies
    1. We don't live and work in a resource poor environment. One of the reasons that our Essential Off-Label DMT list has not been widely adopted is because clinicians working in countries where DMTs are needed feel that this list treats their patients as second-class citizens. This is something we are acutely aware of.

      Why can't I have access to the most innovative treatments that have been shown to work and have a well-defined risk-benefit profile?

      Why should I be forced to take cyclophosphamide when I really want to be treated with natalizumab?

      This situation will hopefully change when teriflunomide and fingolimod come off-patent!

      Delete
    2. That's actually amusing Gavin, because your resource-poor DMT list contains compounds far better than any drug currently used on-label for MS (cladribine, cyclophosphamide, mitoxantrone, rituximab).

      I am thankful that here in Australia there are no restrictions on off-label prescribing (except if access to the PBS is desired). That decision is left up to the doctor.

      Delete
    3. Another issue in the UK is that the NHS does not want to go to battle with Pharma. The NHS has stopped us using rituximab to treat MS as there are licensed treatments. The latter happens at a systems level because rituximab is expensive. If the drug is cheap, as is the case for generic cladribine, we can get away with it because nobody asks questions.

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    4. In a constantly resource poor system like the NHS it's amazing that such amounts are being wasted propping up drug companies.

      Imagine if we banned drug companies and instead used all the money currently spent on paying for their expensive molecules doing government research and development (including clinical trials), with the resulting drugs being made free for all.

      Government, with very limited resources, already does all the basic research and even some of the early stage development for drugs. I don't see why we can't extend the model into clinical trials.

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    5. You clearly don't understand how the larger economy works. The classic neoliberal model is that it is important that the GDP of a modern economy grows each year. A large part of GDP growth is related to healthcare, in particular Pharma. If you kill pharma you stunt GDP growth. Drug companies know this, politicians know this, but the average Joe on the street doesn't. However, the average Joe on the street probably has a private pension that relies on Pharma to continue making profits. The profits pay dividends and the dividends pay his pension, or future pension.

      The pharma gravy train is very long and getting longer.

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    6. And the gravy train includes a large number of vested interests who have no interest in having chronic conditions cured, but would rather they were just treated (so ensuring an on-going revenue stream) - as they're not living WITH them, but living ON them (or the revenue they genererate).

      Or perhaps I'm just being cynical....

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    7. Re: "..who have no interest in having chronic conditions cured..."

      I am not sure you are correct. I think IRTs (immune reconstitution therapies) such as alemtuzumab, cladribine and HSCT may offer some people a cure or at least long-term remission. These treatments are not given continuously and hence there is no guaranteed future income stream so you need to give credit where it is due.

      Some of us are also trying to prevent MS, with an EBV vaccination programme. The latter will require big pharma investment.

      I think the knee-jerk response to be cynical about Pharma and the people engaged with Pharma is unhelpful. We are all trying to do our bit with the tools and systems at hand.

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    8. Gavin, you have done more for people with MS than almost anyone else in the world. I admire you immensely for this and thousands of other people do too, although you will never get the true thanks that you deserve.

      However, pharma is a different story, and they refuse to actually dig into the underlying cause of MS. It's so much easier to put people on essentially random lifeling immunosuppressive treatments.

      The NIH does dozens of times more good with $30 billion a year than pharma do with several times that. You yourself encounter resistance from pharma all the time when actually trying to do good for people with MS - whether it is repurposing drugs like antiretrovirals or getting access to critical trial data about new treatments.

      Delete

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