“My post on bone marrow transplantation (BMT) yesterday generated some discussion about brain atrophy. The BMT procedure requires chemotherapy to ablate or wipe-out your immune system to allow stem cell transplantation. The chemotherapy drugs that are used are neurotoxic, i.e. they damage the brain. In MSers who already have pre-existing damage their nerve cells are more susceptible to chemotherapy damage. The following study I was involved shows that when SPMSers are given chemotherapy they undergo increased neuronal loss, which is associated with faster progression on the EDSS and greater brain atrophy. The data speaks for itself. The picture below is what we call a survival curve of EDSS progressions and you can see that the MSers who had high serum levels of the neuronal toxicity marker neurofilament were much more likely to progress than those who did not have raised neurofilament levels. Similarly, brain atrophy rates in SPMSers were in the order of 2.1% per year in those who had a BMT compared to only 1.2% per year in SPMSers who did not have a BMT; the upper limit of normal for brain atrophy in healthy adults is generally accepted to be 0.4% per year. The bottom line is that if you have SPMS BMT is likely to accelerate your disease progression. As a result of these observations and other data most MSologists have stopped doing BMT in SPMS and limit it to those with RRMS. However, with the advent of highly-effective DMTs such as alemtuzumab, natalizumab, fingolimod and the anti-CD20s in development it is hard to justify BMT in view of its risks.”
Petzold et al. Evidence for acute neurotoxicity after chemotherapy. Ann Neurol. 2010 Dec;68(6):806-15.
OBJECTIVE: Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients’ quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.
METHODS: This prospective study included MSers with secondary progressive multiple sclerosis (SPMS-BMT, n = 14) and hematological malignancies (HM-BMT, n = 17) receiving chemotherapy as preconditioning for bone marrow transplant. The control groups included SPMSers matched for demographic and clinical data (SPMS-PL, n = 14) and healthy controls (n = 14). Neurodegeneration was assessed at baseline and longitudinally (months 1, 2, 3, 6, 9, 12, 24, and 36), combining a clinical scale for disability (Expanded Disability Status Scale [EDSS]), a serum protein biomarker for neurodegeneration (neurofilaments, NfH-SMI35), and brain atrophy measures (magnetic resonance imaging).
RESULTS: Disability progression was significantly more acute and severe following chemotherapy compared to placebo. Immediately after starting chemotherapy, serum NfH-SMI35 levels increased in 79% (p < 0.0001) of SPMS-BMT MSers and 41% (p < 0.01) of HM-BMT patients compared to 0% of SPMS-PL MSers or healthy controls. In SPMS-BMT serum NfH-SMI35 levels were > 100-fold higher 1 month after chemotherapy (29.73ng/ml) compared to baseline (0.28ng/ml, p < 0.0001). High serum NfH-SMI35 levels persisting for at least 3 months were associated with sustained disability progression on the EDSS (p < 0.05). Brain atrophy rates increased acutely in SPMS-BMT (-2.09) compared to SPMS-PL (-1.18, p < 0.05).
INTERPRETATION: Neurotoxicity is an unwanted acute side effect of aggressive chemotherapy.
A very clear and interesting post; thank you. It leaves one realising that we simply have to prevent SPMS. Once you become progressive you are condemned.
Re: " It leaves one realising that we simply have to prevent SPMS."Yes, I agree that is why one of the Ps in the 4Ps refers to preventing SPMS. http://multiple-sclerosis-research.blogspot.co.uk/2014/01/2014-year-of-4ps-prevention-prevention.html.
Some context: 0.5% death rate on cladribine (Giovannoni, NEJM); 0.2% death rate BG-12 (Gold, NEJM); Fingolimod 0.2% death rate (Kappos; NEJM); Alemtuzumab 0.9% death rate (NEJM 2008);
Are these death rates in respect of the use of cladribine and alemtuzumab for MS patients, or in respect of their use for cancer as well? I just find it incredible that almost 1 in a 100 people who were treated with alemtuzumab have died
Is this drug included deaths or deaths of natural causes as well
Re: "Some context: 0.5% death rate on cladribine (Giovannoni, NEJM); 0.2% death rate BG-12 (Gold, NEJM); Fingolimod 0.2% death rate (Kappos; NEJM); Alemtuzumab 0.9% death rate (NEJM 2008)"Most of these deaths were not treatment related and hence are not directly comparable. The 0.5-1.0% rate refers to complications of BMT.
Not all HSCT protocols are the same. I don't have access to the paper, so it would be great if you can describe the protocols this study is based on.
Re: "Not all HSCT protocols are the same. I don't have access to the paper, so it would be great if you can describe the protocols this study is based on."The BMT conditioning regimen consisted of horse antithymocyte globulin at a dose of 15 mg/kg intravenously (i.v.) from days -7 to -3. On days -4 and -3, cyclophosphamide (60 mg/kg i.v.) was given combined with mesnum (15 mg/kg, 4 times daily). Total body irradiation was given in 2 fractions of 5Gy each at days -2 and -1. To prevent serum sickness, prednisolone (1 mg/kg twice daily) was given concurrently, and tapered after stem cell reinfusion. Supportive care included preirradiated prophylactic platelet and red blood cell transfusions when necessary.
Total body irradiation is no longer used, so might this be a cause for increased neurodegeneration? It seems cyclophosphamide and ATG are used in non-meyoblative protocols such as that used by Dr. Richard Burt. http://clinicaltrials.gov/show/NCT00273364 He restrcts his trial to patients who exhibit active disease.It would be of interest to know if non TBI protocol has the same effect on neurodegeneration in progressive types as there are facilties overseas who perform HSCT using these reduced intensity protocols and some have no restrictions for progressive disease.
Absolutely true, anonymous. TBI and busulphan, early aggressive chemo agents used in oncology, contributed to progression and the date above contradicts the many clinical outcomes for halting SPMS progression as long as EDSS remained below 6.0 (even Dr. Burt's earlier studies suggested that none of the 9 patients with EDSS <6.0 and SMPS progressed in four years. Therefore, I would take the above results with skepticism. In addition, many open label and prospective studies internationally refute progression of early SPMS with HScT
ProfG do you think it was drug induced neurotoxicity or because the immune system is a good guy and removing it removed some protective immunity
Re: "ProfG do you think it was drug induced neurotoxicity or because the immune system is a good guy and removing it removed some protective immunity."No I think it is because the cyclophosphamide and whole body radiation are damaging to nerve cells and their processes; particularly if these nerve cells are already sick and vulnerable from MS-related damage.
Prof G, I've been following you blog from the start. I bought into the highly effective early treatment early on and the concept of NEDA. I was fairly confident that such an approach might prevent SPMS and perhaps provide a cure i.e. Turn off the disease. Some of your recent comments give me a sense that you're now not so convinced. A comment a couple of weeks ago said that you wouldn't be surprised is MS turned out to be a primary neurodegenerative disease. Yesterday's post hinted that a large number on Tysabri may have moved on to SPMS (even though inflammation has been controlled). On the positive side, early effective treatment does stop relapse – still a big plus for the patient. However, if neurodegeneration still continues even though inflammation has been addressed ie the immune system has been rebooted, then we are in trouble. No doubt researchers will put in huge numbers of grant applications for research into neurodegeneration which will keep them busy for the next 30 years, but it will be a nail in the coffin for those with MS today. I'm a pessimist with this disease. The only positive – buy shares in airline which fly to Switzerland.
Re: "Yesterday's post hinted that a large number on Tysabri may have moved on to SPMS (even though inflammation has been controlled)."I am not sure about this; in my experience the MSers that become progressive are the ones that are treated to late. However, even these SPMSers seem to reach a plateau after 3-4 years, which is why I think the affect is delayed. I have proposed calling this the therapeutic lag:http://multiple-sclerosis-research.blogspot.co.uk/2014/01/therapeutic-lag-is-it-time-for-new.html
here have already been lots of grant applications on this very subject.You say inflammation has been controlled but we have to careful with the word inflammation it means different to different people. Tysabri may deal with one bit of inflammation(peripheral but not touch another bit of inflammation (e.g. microglial activation)
Re: "Some of your recent comments give me a sense that you're now not so convinced."I simply don't know and would not want to raise people's expectations about a cure to only dash them when the data comes in. What I can say is that if I had MS I would not wait for the results of the 15-20 year experiment to come in; I would go for an induction therapy and NEDA as soon as possible into the course of the disease with the hope that MS is an autoimmune disease that can be cured. As you can see I am a risk-taker and this approach is not for everyone. We need to respect that and view.
"I would go for an induction therapy and NEDA as soon as possible into the course of the disease with the hope that MS is an autoimmune disease that can be cured"Fortunately for you there is no way we can test that hypothesis. If you had MS, your stand against it would be totally different. There is no way you can put your self in the shoes of an MSer."However, even these SPMSers seem to reach a plateau after 3-4 years"Did it ever pass your mind that this plateau may be due to the decreased mobility of SPMSers?
Prof G,I'm a risk taker and am 8 years post 2nd alemtuzumab infusion. Doing well and disease appears to be inactive. My niggling doubt is that something else may be going on – you've referred to slow burn inflammation and Mouse has eluded to other types of inflammation. However, there's no treatment option i.e I'd like to take a neuroprotective drug as an insurance policy. If one of the current trials of neuroprotective treatments (UCL) came good, could these be an add on to people like me, or will we face the usual 10 years of further trials and licensing?
You have made an excellent point. If pharma have their way they would argue that you have to follow the same rules and the phase ii will need to be followed by two phase iii and then licensing. In this respect the academic neuros have not thought this through if this is the case because they havent a hope in hell of doing this. First which agency charity has the resouurce to do this. There is no academic merit of doing the same thing twice so doing two phase iii is out of the question? Then there is the licensing. Academics do not have the knowledge or the resource to do this on the whole. Just to talk to the european regulators for a formal response costs £30,000 to go to the uk regulators cost £3,000 but that only lets you get through in one country. This is going to take years. The system created is only accessible to pharma I have asked the question before. In the modern era name a drug that has been developed by an academic without pharma.The government and the wellcome trust are asking for repurposed drugs but they have not thought it through because they have only thought as far as the trials and not the licensing. Who will hold and pay for the license. This costs£100,000 a year. This is why we need the big pharma alternative to encourage ansdincentivise pharma to do studies with repurposed drugs. Is this cloud cuckoo land or some form of utopia. After a trial are neuros going to drop their reserve and say to hell with it and prescribe in the absense of any licence and importantly without the evidence that pharma has to provide. This the hope but is this realistic. Well we have created a letigious society who gets sued when an unwanted side effect pops up but hey who would be monitoring this phsse IV activity because it aint pharma doing the treating. Now add to the mix that one drug gets a licence will your neuro be forced to switch drug because they will be exposed should something go wrong. Am I talking hogwash or do we really need to think this through and get our academic heads out of the clouds becuase if we dont we may be missing opportunities and we may be creating false hopes and wasting time.Prof G does surveys all the time to seek opinion from msers but maybe he should do one for neuros and ask will the prescribe a neuroprotective drug without the proper evidence. Will tyey do it aftrr a phase ii one phase iii two phase iii will they do it off label. Maybe ask where neuro is. This argument needs to be thought through with proper answers. Otherwise we will be wastingmour and your time money and hope. The path to prescription needs to be clear before walking down the path not after you have spent seven years walking down the path to find the gate is closed at the end of this.Is this nonsense? Ask what you are doing about the simvastatin phase ii data. Waiting for a phase iii? Is there going to be one? Even if there was. Then what? If there is no real and realistic pathway to prescription then it is unethical to start these studies.This is the debate and solution thatt needs to be addressed and made clear from the highest eschillons. This would be a good ECTRIMS ACTRIMS the non pharma pathway to prescription. I think there is a repurposing session.
To answer your question if you are neda you could say why do you need more treatment.However you ask a very sensible question whatmif the firenhas not been put out. Post lemtrada would be ideal becuase you would not need to worry abbout drug drug interactions. For example carbamazepine an anti elipelptic sodium chanel blocker induce liver enzeymnes that cause the drug to be broken down so you have to escalate the dose. So what if you are takinfg an immunosuppressive drug dos this stop the immunosuppressive drug working becuase the liver enzymes are activated. If a pharma company were doing the study with they would think about this and would want to know the answer especiallycif they make the immunosuppressive drug as they want to sell you a drug that works. If an academic group does the study they will not have the resource to look at drug drugninteractions.
However thinking about this, you have given me an idea for a neuro project. Would you a (CAMPATHer) be willing to have a lumbar puncture to get an idea if the fire is smouldering?If it is then surely you would want a neuroprotective when it becomes available, if it is not there is more piece of mind.Can we detect the fire, maybe maybe not…but you won't know unless you look
"Prof G does surveys all the time to seek opinion from msers but maybe he should do one for neuros and ask will the prescribe a neuroprotective drug without the proper evidence."Neuros may prescribe, but the insurance companies would have the final say.
I'm very confused, as are many neuroimmunologists, at this BMT data. First, as mentioned above, the irradiation protocol is not used anymore. Second, it contradicts many BMT treatment centers' outcomes with both SPMS and PPMS. Karussis and Slaving with their non-myeloablative treatment in Israel posted 65-70%PFS in SPMS patients TEN years post transplant. How does this jive with the brain shrinkage? The truth is, none of these SPMS patients have been followed up with atrophy measurements, only silent inflammation. To my knowledge, there is no EDSS comparative study between pre/post HSCT treatment in progressive MS patients to suggest an increase in disability or progression. Most studies have shown that the preponderance of short term atrophy is due to resolution of edema. And it wouldn't just be a BMT phenomenon. Cyclophosphamide alone has shown good effectiveness in slowing disability progression in SPMS, >65%, the only limitation being the high drop out rate due to side effects. And what about Mitoxantrone? Great effect in stabilizing SPMS and yet it is neurotoxic as well. But in 3 years time, it has stabilized disability progression, not increased it. So these atrophy studies need to be grounded in objective EDSS terms, not just volume correlates with MRI. And followed up for many years, not just immediately after HSCT. I don't believe this has been done and contradicts, again, many centers' experience with clinical follow up, QOL measurements, etc after BMT
Yes mousedoctor, having been part of the simvastatin trial and on the active drug I am disappointed not to be able to continue on that level of dose. I have no idea what is happening but have assumed, perhaps wrongly, that there will be some sort of follow up trial. Any ideas?
Not about the statin trial. The MS smart trial is about to start so having the energy for getting a regulatory statin trial in addition to a four arm study may be a problem.
I have a 277 patient case series of tysabri treated MSers (obviously not all my own patients), and I am studying post-tysabri relapses. I haven't processed the data, but I can tell you subjectively that a lot of patients in my series transitioned from RRMS to SPMS in their 40s and 50s while on tysabri despite NEDA while on the drug. This supports the idea that progressive MS is a secondary degenerative process related to prior inflammatory injury. It remains to be seen whether or not earlier drug-induced NEDA delays SPMS. Biogen is studying this currently. I'm with Dr. G though-If I had newly diagnosed MS, my goal would be NEDA or bust; I wouldn't even bother with copaxone/betaseron/extavia/rebif/avonex/tecfidera/aubagio as they are very unlikely to achieve NEDA over an extended period. It's not really about being a risk taker; It's just an understanding that the long term prognosis in MS is not great. Even the short term benefit of lower risk of EDSS 3.0 early in the disease would be worth the risk to me.
I suggest you process and publish the results. We the transition all people with neda whilst on tysabri or did thry hsve disease brea,kthrough. I could put the arguement that rsthrr thsn suggesting to prior infammation could be independent of it. I hope not
Sòrry rubbishy keyboard on my phone
Anon,are you in a position to give a rough idea of how long the patients in your series have been on Tysabri versus the time since initial diagnosis? Roughly speaking, is it a short or long gap from diagnosis to treatment with Tysabri?Thanks
If you are right which i think will be the case the writing is on the wall with regard to the ascend trial. It will not stop progression the best could be a change of slope. Which I think was probably the best hope when the trial was conceived. However you are right tysabri has been on the go for some years and they may be ablemto say how early is early with regard affecting the onset of progression.Also the question now posed is NEDA real was there beta interleukin 1 activity left in the brain.a
I assume that we can't take much from this in the UK as those on Tysabri will have been the more active patients with more established disability. Is this likely to be the clinical experience elsewhere where those patients so far treated with more effective drugs are also those most likely to have accrued a lot of damage already?I for instance can't understand why the likes of fingolimod is reserved for those with 'highly active' disease in the UK – what possible justification is there for this apart from some sort of money saving exercise? The side effect profile doesn't seem bad enough to justify this.
"Apart from some sort of money saving exercise?"Nail and Head springs to mind