ClinicSpeak: reflections on HSCT after the fallout of the BBC Panorama programme

Should we create the equivalent of the Ig Nobel prize for irresponsible journalism? #ClinicSpeak #MSBlog #MSResearch

“It is clear from our analytics (page views and comments) that HSCT (hematopoietic stem cell transplant) is a hot topic at the moment. The BBC Panorama programme and subsequent news coverage only told half the story and was in some respects misleading. I was at a meeting this weekend and Fred Lublin (Mount Sinai, New York) took me to task about how much clinic time the BBC story had cost him and did we not have some influence over how the media reported MS stories? He was particularly upset about claims of a cure with no mention of the real risks of the procedure. As with all good storytelling the BBC got the soft touches right, but as Fred pointed out they failed to discuss the risks of HSCT and more importantly alternatives treatments available to neurologists to treat MS."


"Where do I begin?”

“HSCT is in fact a rebranding of bone marrow transplantation or BMT. BMT was used when the stem cells had to be harvested from doing bone marrow aspirates; thick needles were inserted into the bone and the marrow sucked out under pressure. This procedure was very painful and had to be 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 help do this procedure. Fortunately, the haematologists now have a very 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 down to be given after immunoablation therapy. All that these stem cells do is allow you to receive more potent chemotherapy and work by stimulating 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.”

“What was not told in the BBC programme is that 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 be rebooted (partially). The non-myeloablative therapy is clearly less risky than the myeloablative therapy, but less effective. In other words more pwMS have recurrence of their disease activity after non-myeloablative HSCT, when compared to ablative-HSCT (A-HSCT). The treatment in the BBC programme was non-myeloablative HSCT (NM-HSCT). This is why the treated MSers didn’t look too bad. 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 (still to be launched). This is why we are proposing to do a ZEUS-type trial comparing alemtuzumab with NM-HSCT to see if NM-HSCT is more efficacious than alemtuzumab and to see of the benefits warrant the risks.”

“What are the risks of NM-HSCT? The chances of dying from the NM-HSCT is in the order of 0.5%-2%; 1-in-200 to a 1-in-50 chance of dying. Then there is the toxicity associated with the chemotherapy; nausea, vomiting, diarrhea, hair loss, bleeding, infections, infertility and neurotoxicity to name a few. It seems that the more disabled your 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 progressive MS. Once your immune system recovers it does not mean it is back to normal. There is evidence that HSCT causes premature immune senescence, or ageing of the immune system. This may not be important in young people but may be important later in life when you need your immune system to fight new and persistent infections and keep malignancies at bay. The premature ageing of the immune system has been linked to an increased incidence of secondary, or delayed, malignancies; this is a theoretical risk with all immunosuppressive therapies. None of this was explained in the BBC documentary. 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 likely to be 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. I could go on but I will stop, the picture is not a pretty one. A-HSCT is not for the faint hearted. Nothing was mentioned about the A-HSCT vs. NM-HSCT debate in the BBC programme. Why not? 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. If you are going to take the risk, you might as well go for maximum efficacy.”

“The seemingly miracle treatment effects of somebody in a wheelchair getting up and walking is not unique to HSCT. We see it 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 significant recovery. 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 trials will have age and disability cut-offs.”

“So would I refer pwMS for HSCT? No, not as part of routine clinical practice. I would however be prepared to refer my patients to participate in a well-designed clinical trial to compare current treatments with HSCT. As part of the trial I would not expect my patients to pay for their treatment. The situation where HSCT is indicated as part of routine clinical care is the rare patient with MS with malignant disease that has failed all licensed treatment options. In this patient the benefits of HSCT outway the risks of the disease.”

“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 alway 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 go into an HSCT trial, or receive HSCT 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.”

“If we have the equivalent of the Ig Nobel prize for bad and irresponsible journalism the BBC Panorama will get my vote in 2016. Biased reporting with a catchy title that has created false expectations and driven up medical tourism. What is happening to the BBC? I promised Fred on Saturday that I would do this post for him.”




CoI: multiple

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