If push came to shove would you really choose HSCT as a first-line treatment to treat your MS?
When asked on the blog yesterday which DMT would I choose if I had MS, I chose HSCT. One of my patients, who I have been looking after for over a decade, sent me an email stating how upset she was that I had never offered her HSCT. I clearly need to explain my position so as not to upset anyone else.
Firstly, HSCT is not on offer as a routine NHS therapy. At the moment HSCT is only considered as a 2nd or 3rd-line treatment in the most active patients. Another problem is that it is not on offer across the country. There are only a handful of MS centres that are prepared to refer their patients for HSCT. This means that access to HSCT is not equitable and explains why an increasing number of patients are having to travel abroad, at great personal cost, to receive this therapy. Inequity of care is against one of the founding principles of the NHS and is unacceptable.
The block in access to HSCT seems to be at the level of the neurologist/MSologist. NHS England guidelines for bone marrow transplant (BMT) units allows them to use up to 15% of their procedures to treat autoimmune conditions, which includes multiple sclerosis. As BMT units exist across the country access to these units would simply require a referral from a neurologist to the unit to perform HSCT on patients with MS. However, the latter is unlikely to happen unless the local MSologist champions HSCT as a procedure and gets their local haematology unit on board. It always takes a local champion to make things happen and our Barts-MS champion is Dr Ben Turner.
Another factor that has changed in the last 10 years is the strength of the evidence-base showing how effective HSCT really is as a treatment for MS. The most recent MIST trial, the first large randomised controlled trial, and several meta-analyses of HSCT, which have been extensively discussed on this blog, have confirmed that HSCT is a very effective therapy. At the same time the risks associated with HSCT have improved and the mortality in most BMT units is now below 1% for MS. This is now tipping the scales in favour of HSCT becoming a mainstream treatment for MS. There is however resistance from the MS community about HSCT been offered as a first-line therapy. Why? I suspect because the risk:benefit profile of HSCT has yet to be compared in a head-2-head study against our most effective licensed treatment. This why we are planning to do a head-2-head study of alemtuzumab vs. HSCT in the hope of generating this evidence. We know already that HSCT will be more cost-effective than alemtuzumab, but will it be more effective and as safe? Don’t try and second guess the results of this trial; I would not be surprised if there is no difference between these two treatments in terms of efficacy.
Please remember that most of the proponents of HSCT as a treatment for MS recognise that the major benefits from treatment will only be derived if HSCT is used early in the course of the disease. This explains why most BMT units don’t offer HSCT to pwMS with more advanced, or progressive, MS. However, this does not stop private, fee-for-service, units offering HSCT to all-comers. If you have the money and are willing to travel abroad you will be able to find a BMT unit that will treat you. I think this is wrong and will not happen in the NHS when HSCT eventually becomes widely available. We have to be honest with our patients about the risks and the benefits and why we will limit HSCT to those who benefit the most. In fact there is evidence that more advanced patients may actually be made worse by HSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up neuronal loss. In addition, infections are common when you have HSCT and infections are well known to worsen MS disability in more advanced disease.
Please be aware that HSCT is not for the faint-hearted. It is a risky therapy with serious adverse events and quite a high mortality. Even a mortality rate of 0.3-0.5% is high when compared to other licensed DMTs. Should this stop us from offering HSCT first-line? I think not. If we are prepared to offer alemtuzumab, with its risk profile as a first-line treatment, why not HSCT? Most pwMS would agree that the decision regarding what is an acceptable risk to take should be taken by the patient and their families, and not the neurologist or other HCP. There is data showing that neurologists are much more risk-averse than pwMS. Neurologists need to acknowledge this bias, which is likely to be an unconscious bias, and let their patients make the decision.
What I am really trying to do by stating that if I had MS I would choose HSCT as my treatment is to reframe the DMT debate, particularly in relation to access to highly effective DMTs. By focusing on HSCT as a first-line treatment it should at least consider what your treatment objectives are in MS.
Framing is another a cognitive bias that was identified by Daniel Kahneman, the Nobel laureate, and his partner Amos Tversky. By moving the frame to the right, i.e to include HSCT as a 1st-line therapy, it makes it more likely for pwMS and their neurologists to choose more effective treatments. We now know that people who start on a low to moderate efficacy DMT do worse on average than those who start on a high or very high efficacy therapies do better. Despite this the majority of pwMS are not told this and are started on a low efficacy or platform DMTs without ever being given the option of a high efficacy DMT. Why? It is not due to lack of access to treatments as we now have several NICE and NHS England approved high efficacy DMTs available as first-line treatments.
So yes, if I had active MS I would want to have the full spectrum of high-efficacy DMTs available to choose from including HSCT. I would want to know about their relative efficacy and what the aim of the treatments are. I would certainly want to have a discussion about the possibility of a potential cure. Wouldn’t you?
By framing the spectrum of efficacy by having HSCT within the frame may nudge patients and their neurologists to move up the treatment ladder and choose a high efficacy DMT.
Unfortunately, HSCT as a first-line option is not going to happen any time soon, which is why I am trying to nudge the community to start debating the issue in earnest and why I want us to have a citizens jury on the issue.
Personally, I would’ve jumped at the offer of HSCT at diagnoses. Would be great to get rid of the disease before it truly starts. Currently on Natalizumab though and I can’t complain because it’s working well.
What about your brain volume loss?
Thank you for being so clear on this. You gave hit the nail on the head. It’s about ensuring that pwMS are given an informed choice.
We really do need to educate risk averse neurologists that’s facing a lifetime of deterioration, pain and disability does mean that their patients are likely to be prepared to take greater risks. It is their job to ensure their patients are fully informed, not to make the decision for them.
Can I ask you to revisit your view on HSCT as a “salvage” treatment. Anecdotally, I was SPMS, edss 6.5, aged 50 and Bmi ++. I was fully aware of the mortality risk and side effects prior to treatment. However, I was progressing extremely fast and I made the decision for myself that I wanted to have HSCT. I put my affairs in order before treatment, knowing that it would be tough and the odds of mortality could be against me. A decline into dependence was not something I could accept without fighting back.
The measure of success of the treatment really needs clarification. It is very clear to me that success is halting progression. The numbers in remission are looking good for progressive patients as more people have HSCT worldwide. To any of us any improvement is a massive bonus.
Of course as you are saying, ideally the majority should have the chance of treatment before disability is acquired. Wouldn’t it be great is SPMS became a thing of the past. It has to be eminently achievable.
Thanks so much prof G for this post. I couldn’t agree more.
I agree with a stronger approach, but why not start with high efficiency DMT (lemtrada, ocrevus…).
HSCT should, by now, be for more aggressive cases.
Once the HSCT evolves and becomes more “safe”, then, and only then, it could be first line !!
What about brain volume loss?
Let’s say your house was on fire and I offered you two options for dealing with it:
1. Slows the blaze down considerably
2. Puts the fire out
Which would you choose?
Lemtrada comes with its own unpleasant profile – Dr Burt calls it ‘liquid HIV’
The mortality rate for HSCT is 0.3% The likelihood of MS progression once it reaches a progressive phase is 100%
Patients should be allowed to make this choice for themselves with a view to getting the chance to halt their progression- not slow it down, HALT it.
I totally agree with you!!!
Yes, I am not disagreeing with you but to get the community to adopt any new treatment paradigm you have to have evidence, i.e. facts, and not anecdote or hearsay. We need trials. The open-label studies in SPMS tell a different story and the mortality rates are also much higher. I have a disclaimer here; I don’t run a BMT unit and I don’t sit on the London MS HSCT MDT. Ben Turner is our representative.
I’m going to be very clear here. Ben Turner put my husband through for HSCT at King’s. We went to see him and he agreed to represent us to the MDT.
Now here’s the thing – my husband was / is SPMS 6.5. He had NO active lesions and NO new T2 lesions. He was clearly SPMS. He didn’t fit the current criteria but slipped through the MDT net right before Panorama aired. He wouldn’t stand a chance now.
But his progression has stopped. We are 3 years down the line.
I appreciate that peer reviewed evidence is needed, but it baffles me how you can just dismiss the evidence from literally hundreds of patients treated in Mexico and Russia. They have FAR more experience of treating MS with HSCT than we do in the UK, yet their data is NOT GOOD ENOUGH. The arrogance of that statement is simply breathtaking.
You should be bending over backwards to work with these doctors and learn from them. You simply cannot keep burying your heads in the sand.
Approximately 100 patients have been treated in the UK – and there have been three deaths. Compare that with the mortality rates in Mexico and Russia.
As far as Doctor Burt goes, he is interested in reversing disability – that does not mean that he doesn’t have data that shows the halting of progression in SPMS – he does. I’ve seen him present it live twice and suggest that the fact that the EDSS was the same 5 years later (compared to a RRMS patient whose EDSS dropped by 2 points in the same period) means it’s not successful for SPMS. Ludicrous.
Come on Gavin, work with AIMS and let’s get things changed!
It is not me you have to convince but the wider MS community. This more social science than science, but it needs data that is acceptable to scientists, clinicians, pwMS, payers, healthcare administrators, regulators and politicians. It is a slow process. We launched our Brain Health initiative 4 years ago and we still haven’t got it adopted.
If you have the time I would recommend you read the Diffusion of Innovations, by Everett Rogers. This provides the background of what it takes to get a community to adopt an innovation. We are still at the very left of the curve with the innovators and early adopters.
I will read that, Gavin, and I’m not suggesting that it’s you that needs convincing- I am saying work with AIMS to strengthen this movement. If you would have HSCT yourself if you were diagnosed with MS, then put your money where your mouth is and let’s meet! Yes?
Re: “Lemtrada comes with its own unpleasant profile – Dr Burt calls it ‘liquid HIV’”
Not sure what this comment is based on. He seems to forget that HSCT has a very similar profile to alemtuzumab, including secondary autoimmunity, but a much higher mortality rate and almost certainly it will have a higher secondary malignancy rate, not to mention the infertility risk. Let’s wait to see who wins on the risk:benefit analysis, i.e. number-needed-to-treat to benefit minus the number to harm when we complete the head-2-head study.
I may have understood that HSCT has 2/3rd less secondary autoimmunity than Lematrada?
What is the secondary malignancy rate on HSCT? is it limited to blood-related cancers? can it be de-risked
Tony
You seem to be overlooking or avoiding the fact that MS is does immense harm and proscribing effective treatments is likely more harmful than the side effects of HSCT.
Quality of life can not be ignored in your risk benefit analysis
I agree. Of all the licensed DMTs alemtuzumab’s QoL data is the best. So HSCT is going to have a tough time beating it. I suspect the fertility issue would have clinched it in favour of alemtuzumab when it comes to QoL, but I doubt any women wanting to start or extend their families would volunteer to be randomised to HSCT or alemtuzumab when they could get alemtuzumab under routine care.
Gavin, this is what Dr Kazmi has to say about fertility after HSCT – can we not scaremonger about the impact on fertility after HSCT, please?
“For females that don’t regain hormone function post-HSCT, this is treatable with daily medication. The risk of experiencing infertility in non-myeloablative HSCT is age dependent with females below age of 30 unlikely to become permanently infertile but this risk increases with age over 30.
Anyone wishing to preserve their fertility should plan ahead in case a later IVF procedure is required. HSCT will not prevent a woman from having a healthy pregnancy or from bringing a baby to a healthy full term delivery.”
Please will you clarify. Who are the “wider MS community” to whom you refer ?
To Pedro LaCosta Pinto
I respectfully disagree with your statement and think Prof G is saying the exact opposite. You have repeated exactly what patients keep hearing from their neurologists. Why is it up to the neurologists to decide if it needs to wait til it’s safer? Shouldn’t each patient have the right to make that call for themselves? Delaying hsct until it’s more aggressive means by definition waiting until more irreversible damage has occurred, some patients feel like they’d rather risk mortality than more permanent disability. Sorry but your answer is exactly I think the epitome of the very problem prof g is trying to change. Some patients may agree with your POV and choose to be more cautious but the point is given the fact this disease isn’t curable and we can’t really predict how it will progress in each patient we should allow patients the right to make this decision for themselves taking into account guidance from their physician.
O transplante de medula ja evoluiu a muito tempo
Ablative vs Non-ablative?
The MIST trial ProfG refers to was non-myelo.
Can i ask? If you now had spms, would you go go for hstc regardless or would you do nothing?
Please remind me success rate at hstc stopping ms.
You may want to watch Burt’s presentation here: https://www.atthelimits.org/multimedia/msatl-2018/
I think the challenge is knowing who is SPMS vs RRMS is the absence of disease activity.
Thank you.
What would you say to the ones saying that by undergoing HSCT, you would be replacing your MS progression risk by a significantly increased cancer risk?
Has the cancer risk really spiked in the long term follow on studies of a patient who have undertaken the procedure? Can this be de-risked through monitoring of some sort?
Tony
47.1 Definitions
Secondary neoplasia (SN) after HSCT includes
any malignant disorder occurring after HSCT,
irrespectively, if related or not to transplantation.
For an individual patient, a clear relationship
between HSCT and SN often cannot be
provided. In this chapter, post transplant lymphoproliferative
disorders are not discussed
(see Chap. 45).
47.2 Types of Secondary
Neoplasia After HSCT
A. Tichelli (*)
Department of Hematology, University Hospital
Basel, Basel, Switzerland
e-mail: tichelli@datacomm.ch
47
Therapy-related myeloid
neoplasms (t-MN)a Donor cell leukemia (DCL)b Second solid neoplasms (SSN)c
Definition t-MDS or t-AML after exposition
chemo or radiation therapy
Hematologic neoplasms
occurring in grafted donor cells
Solid cancers of any site and
histology occurring after HSCT
Occurrence Mainly after auto-HSCT
Not excluded after allo-HSCTd
After allo-HSCT only After allo-HSCT and auto-HSCT
Appearance Within the first 10 years mainly Variable Increasing incidental rate with
longer follow-up
Prognosis Poor Poor Depends
47.3 Pathophysiology
47.3.1 Therapy-Related Myeloid
Neoplasms
t-MN are mainly associated with cytotoxic chemotherapy
and radiation therapy that the patient
has received either before HSCT or as conditioning.
The causal role of ionizing radiation in the
development of myeloid neoplasms has been
demonstrated in atomic bomb survivors of
Hiroshima/Nagasaki and in medical radiation
workers employed before 1950.
Responsible cytotoxic drugs:
• Alkylating agents, anthracyclines, and topoisomerase
II inhibitors.
• To a lesser extent antimetabolites and purines
analogs.
• Controversy exists on the role of azathioprine,
methotrexate, hydroxyurea, and
6-mercaptopurines
used for the treatment of
malignant and nonmalignant diseases.
t-MN occur mainly after auto-HSCT, where
the healthy HSC has been exposed to cytotoxic
effect. Rarely t-MN can be observed after allo-HSCT,
despite the donor cells have not been
exposed to cytotoxic agents. Persistent microchimerism
with few exposed residual recipient cells
may explain the development of t-MN after allo-HSCT.
The incidence of t-MN after allo-HSCT
might increase, since chimeric states are observed
more frequently after RIC-HSCT.
Today, increasingly cytotoxic drugs are
applied after the allo-HSCT, either as GVHD
prophylaxis (post transplant CY) or to prevent
disease recurrence (post transplant maintenance).
We do not yet know whether these procedures are
at risk for t-MN after allo-HSCT.
47.3.2 Donor Cell Leukemia
The cause of donor-derived hematological malignancies
remains speculative. Two different mechanisms
may be involved (Sala-Torra et al. 2006;
Wiseman 2011):
• Malignant clone transmitted from the donor to
the recipient
• Malignant transformation in the recipient
Malignant clones transferred to the recipient
are mainly of lymphoid origin, observed in older
donors, and may evolve into a lymphoid neoplasm
in the immunosuppressed host. Myeloid
clone transfer has not been reported. However,
systematic NGS analysis might allow to detect
myeloid clones transmitted to the recipient.
Malignant transformation in the donor cells is
probably of multifactorial causes:
• Premature aging of the donor hematopoiesis
in the recipient, more inclined to develop a
leukemia
• Abnormal microenvironment
• Genetic predisposition
• Acquired environmental factors
47.3.3 Second Solid Neoplasms (SSN)
Little is known about pathogenesis of SSN after
HSCT. An interaction between cytotoxic treatment
<genetic predisposition, environmental factors,
viral infections, GVHD, and its
immunosuppression may play a role.
Two main types of SSN (Rizzo et al. 2009):
• Radiation-related SSN
–– Proven for thyroid, breast, and brain
cancers
–– Occur after a long latency (≥10 years after
radiation)
–– Is dose related
• GVHD/immunosuppression-related SSN
–– Squamous cell carcinoma of the skin and
oropharyngeal area
–– Short latency
–– Can occur at different localizations
Association with viral infection
• HCV infection associated with hepatocellular
cancer
• HPV associated with cervix cancer
Table 47.1 Frequency and risk factors
Type of SN Frequency Risk factors
t-MN Great variability on the CI of t-MN after auto-HSCT
• In lymphoma patients between 1% at 2 years up
to 24% at 43 months
• Lower CI for patients treated for breast cancer,
germ cell tumor, and multiple myeloma
• Rare n-MN after HSCT for AID
CI depends mainly on pretransplant cytotoxic
therapy and the use of TBI
CI of t-MN after allo-HSCT: 0.06-0.67% at 3 yearsa
• Quantity of pretransplant chemotherapy
(see pathogenesis) and local
radiotherapy
• Conditioning with TBI
• Older age at HSCT
t-MN are mainly observed after HSCT for
lymphoma (NHL, HL)
DCL Rare complication, with a CI <1% at 15 years
Possibly underestimated (difficulty to prove donor
type of malignant cells)
Could represent up to 5% of post transplant leukemia
“relapses”
No clear risk factor defined (too few,
heterogeneous DCL)
Possible risk factorsb
• Malignant donor clone in the transplant
• G-CSF therapy
• In vivo T cell depletion
• Multiple transplantations
SSN
Breast, thyroid,
bone,
melanoma,
connective
tissue, brain,
BCC
Breast cancer: 11% at 25 yearsc
Thyroid cancer: SIR 3.2 compared to general
populationd
BCC: 6.5% at 20 yearse
Radiation before HSCT or TBI
Younger age at radiation
Longer follow-up
Light-skinned patients (BCC)
SSC of skin,
oral cavity, and
esophagus
SCC of the skin: 3.4 at 20 yearsf Chronic GVHD
Prolonged GvHD therapy
IS including azathioprine
Male sex
Unrelated with radiation
At any time after HSCT
Hepatocellular
carcinoma
Patients with HCV infection: CI 16% at 20 yearsg HCV infection
Cirrhosis
Lung cancer SIR 2.59 after BuCyh Conditioning with Bu-Cy
Smoking prior to HCT
Cervix cancer HPV reactivation
Melanoma T cell depletion
BCC basal cell
https://www.ebmt.org/education/ebmt-handbook
I have personally heard several accounts of PWMS stabilising on Natalizumab, which I think you regard as a safer DMT than Alemtuzumab and of nearly equal efficacy(?). I would be interested to know the oldest age of your Natalizumab patients; if a patient remains largely stable, JCV negative and can take the drug with extended dosing periods, at what stage of elderly life would you recommend stopping – when other health problems linked with older age emerge making it too risky to continue? To avoid rebound, would it be essential to move onto a safer maintenance therapy before stopping treatments altogether?
What about brain volume loss?
I was on tysabri since March/2008, but ms never stopped… started LEMTRADA last.month.
Lemtrada and natalizumab are very different, you can’t compare them, they “work” in different ways.
“I have personally heard several accounts of PWMS stabilising on Natalizumab”
Tysabri does not halt grey matter atrophy and convertion to SPMS is still seen.
This is what HSCT and possibly Alem. bring to the treatment landscape of MS. Those two seem to normalise brain atrophy rates.
HSCT often halts progression in PMS patients too, where Tysabri only offers a modest slowing. The reason why this result is not achieved to all but some PMS patients is still unknown.
I don’t think we can claim HSCT or alemtuzumab stabilises advanced MS. If anything the data suggests the opposite, which is why alemtuzumab has not gone into progressive MS and why most BMT units, including Richard Burt’s, don’t treat progressive MS with HSCT. The ones that do tend to be fee-for-service units.
Seriously ! There are hundreds of progressive patients, including some treated on the nhs in London, for whom HSCT has ‘stabilised’ progression – actually it has stopped progression.
Please stop with the slating of clinics abroad. You’ll find that Moscow and Mexico have a significantly better safety record than the UK, not to mention a great deal more experience.
Where is the highest mortality rate from HSCT for MS – oh yes, London !
Are there mortality tables published anywhere (or a registry of some kind)?
Yes, they are kept by the European BMT registry and are published intermittently.
https://www.ebmt.org/research
The EBMT does not seem to be accessible by the general public.
So for someone with worsening MS and thinking about Dr K’s hoped for Chariot trial – Cladribine seems to be the only DMT that offers real hope for more advanced patients??
Cladribine is inferior to HSCT and Lemtrada. If ProfG claims HSCT cannot halt progression of SPMS (which actually does in about half of PMS patients treated), Cladribine can do less.
Actually many neurologists give Alem. to SPMS paients as a last hope DMT and this data is unpublished and only anecdotal reports exist (that report a very positive outcome).
Inferior..where is the evidence…we offered to do a trial to put this too the test but the regulators didnt want to pay for yhr i
Confused. I thought you are of the opinion that MS is one disease? Surely Alemtuzumab and HSCT will help to stabilise some worsening patients? Please show us where the data is that suggests the opposite. Thankyou.
Watch this:
Given your overall, admittedly cautious, positive response and opinion of HSCT as an effective treatment I guess the main question that comes to mind is what is being done by people in your profession to actively promote discussion about making this proven treatment more widely available within the NHS?
People with MS just don’t have ten years to wait while the Neuro profession and the NHS pulls its finger out and gets proactive for the benefit of its patients. MS sufferers who’ve made the decision to go abroad for treatment have educated themselves as best as possible and are aware of the potential risks and likely outcomes. It’s not something undertaken lightly I can assure you but given the option of having exactly the same treatment here in the UK I would suggest they would all still go ahead with it. If the NHS, and by that I include all aspects of the organisational tree involved with the treatment of MS, was truly interested in offering proven effective treatments for patients then surely it makes sense, both medically and financially, to be offering HSCT more widely. If Neuros believe in HSCT as an option you need to be banging the drum more loudly to get people’s attention. Use your profile to make decision makers sit up and take notice.
Rod Jones yes! This! We do not have ten years to wait. Despite higher efficacy dmds it’s still incurable and a devastating disease. To me it’s unconscionable that a different treatment option exists, yet it’s not being made available as an option to patients who can’t afford to travel. This would never happen in cancer.
Thank you for pushing this topic Prof.
If I had the chance maybe I would have said yes 15 years ago. In terms of what it might have cost the NHS, if it had worked to help delay progression and allow me to continue working, my income tax would have paid for it. Instead I am now struggling to make ends meet and my body isn’t doing well either.
It feels like us progressives doomed to the disability bin. Hard to deal with that.
You are only doomed by UK Neurologists. In Mexico and Moscow they have data supporting hundreds of SPMS and PPMS patients. Neither location treats progressive just to get money; they already have more than enough RRMS patients to treat.
They treat progressive MS because it at least gives you a chance to halt your decline. Versus the 100% guarantee, that you will only get worse, presented by your UK Neurologists!
I was 20+ years MS (admittedly mostly benign) and an EDSS of 6.5 on arrival in Moscow. No active lesions, but declining every day. I’m now an EDSS of maybe 2.5/3.0 and on occasions have even been known to forget I ever had MS.
Research… leap of faith… done and dusted. #1 reason for going… my kids got their Mummy back!
“hey have data supporting hundreds of SPMS and PPMS patients. ”
Is this data published in any reputable peer reviewed medical journal?
I think we already know the answer.
You are only doomed by UK Neurologists. In Mexico and Moscow they have data supporting hundreds of SPMS and PPMS patients. Neither location treats progressive just to get money; they already have more than enough RRMS patients to treat.
They treat progressive MS because it at least gives you a chance to halt your decline. Versus the 100% guarantee, that you will only get worse, presented by your UK Neurologists!
I was 20+ years MS (admittedly mostly benign) and an EDSS of 6.5 on arrival in Moscow. No active lesions, but declining every day. I’m now an EDSS of maybe 2.5/3.0 and on occasions have even been known to forget I ever had MS.
Research… leap of faith… done and dusted. #1 reason for going… my kids needed their Mummy back!
Prof Burt says in the video posted above – no inflammation, no response. How are the benefits you describe to be accounted for if you had no active lesions?
Because active lesions may or may not be seen on MRI – it has to be done on the right day or the activity isn’t visible. Just because lesions aren’t enhancing on MRI, does not mean that there is no inflammation.
Active lesions last between 30-40 days. Think of them as open wounds. T2 lesions are more like scars, so they’ll show up if there has been new activity, even though the scan might not pick it up at the right time. HOWEVER, in the case of progressive MS there is likely to be hidden inflammation which won’t show up on a scan at all because it’s beyond the blood brain barrier (there is quite a lot of recent research on this). Just because inflammation isn’t visible in a scan doesn’t mean there isn’t any inflammation. I believe this is an area in which Ben Turner has expressed an interest.
Thanks Mindy – I shall take look.
I agree with you. Look at me, I’m 64 with SPMS, EDSS 6.5 and no hope of employment. Its not a case of being doomed, its like being condemned. I’m on the sidelines or scrapheap watching this disease called multiple sclerosis consume and dominate my life. To date no one has found anything to slow down or prevent progress that is available in the UK. Is progressive MS not sexy enough or not worth the investment to find a cure because because people say the wonder drug for the newly diagnosed has been found. Nonetheless I believe advanced MS will be around or many many years. Throw some money at advanced MS, column inches would be appreciated and give us some hope.
I’m so sorry Patrick. I feel your pain.
I wish neuros could understand the compulsion that develops when there is no hope offered by the NHS. Two years ago I was looking into going to Mexico and I thought I’d ask my UK neuro about HSCT instead. I think it is financially more difficult for me now but if a neuro could say honestly that it would be the best then I’d go. There is a fine line between those NHS guidelines and delivering something that is the best for the patient.
Aaron Boster does not agree with you on this one. He strongly prefers Lemtrada to HSCT.
And we all know that he ain’t a dinosaur.
Me too; alemtuzumab’s risk profile is better than HSCT. Why take a risk on frying your patients ovaries and testes and having a higher risk of secondary malignancy when you can prescribe alemtuzumab first-line. For HSCT you would have to wait for your patients to fail at least one and in some cases two DMTs. Waiting for them to become eligible for HSCT may cost them a lot of brain and/or spinal cord. Isn’t it better to flip the pyramid earlier rather than later?
What I am describing is the current reality of working in the NHS.
Really? Really?!
As a stand alone drug, the clinical data has shown Lemtrada to be only 70% as effective compared to HSCT in treatment of relapsing MS (this was stated at the last HSCT Symposium in Sheffield – you can find the audio files in the UK HSCT Facebook group files) And Lemtrada has not been found to be at all effective in the treatment of progressive forms of MS as HSCT has been found very effective to halt all forms of MS, including (SP, PP) progressive MS. Lemtrada has a well documented treatment profile that is NOWHERE near as safe as HSCT. Lemtrada is responsible for fatal cytopenias in patients, and Lemtrada treatment comes with a shocking 30% rate of initiating a secondary autoimmunity. This compares with extremely low incidence of fatal cytopenia in HSCT (this is because of the use of a stem cell graft in transplantation to reinitiate hematopoiesis), and HSCT only has a risk of initiating a secondary autoimmunity in the 1-2% range. Lemtrada and HSCT are not comparable, as HSCT is both a safer and more effective treatment compared to Lemtrada.
“HSCT has been found very effective to halt all forms of MS, including (SP, PP)”
Prof G – is this true?
So much conflicting information…
What do you think? Can I suggest you read my posts on (1) getting worse despite being NEDA and (2) smouldering MS. You will then be in a better position to make your own mind up.
“alemtuzumab’s risk profile is better than HSCT”
Across a population – this is probably true for now. But at the individual level I have suffered three critical autoimmune side-effects post alemtuzumab (ITP, Graves, and haemolytic anaemia). Interestingly, HSCT has been mentioned as a potential treatment for my various alemtuzumab driven autoimmunities if they don’t settle down with repeated courses of rituximab and time.
I think neurologists might be well served by consulting more with the haematology community on this – they are familiar with the agents involved from years of experience, what’s their view?
I think the main point is that pwMS need to be appraised of the facts to facilitate making their own informed decision.
Doctors will never reach perfect concensus and they are not in a position to make decisions for any individual.
Prof G, why don’t any neurologists acknowledge and accept the results of Mexico and Russia?
Their results equal Dr Burts MIST trial.
How can you accept results that aren’t published?
Those facilities have put statements out saying what their results are though.
They look very good. Their treatment seems easier to tolerate especially Mexico. I’m trying to raise the money to go to Mexico as everyone in the group says it’s the best. and it’s number one in the world. It’s not worth even applying for the NHS as it’s not as safe and is too hard and too long to be accepted.
Not good enough; we need scientific rigour and peer-review.
It would make sense to communicate with Drs Fedorenko and Ruiz. I’m sure they would be delighted to work with others to take global research forward. They have a great deal of experience which would undoubtedly be of benefit to haematologists with little or no experience of HSCT for AI diseases.
Below are Moscow’s PUBLISHED results. They were actually issued in March 2015 , while I was out there being transplanted. A huge celebration was also held, to honour the results of EIGHT years of HSCT for MS. You see Russia’s study results were published over 3 years before Dr Burt’s…
https://www.ncbi.nlm.nih.gov/m/pubmed/25711670/
https://hsct-russia.com/international-conference
Anyone at a loose end on 22 & 23 Nov 2019? Prof Giovannoni? Mouse Doctor?
Come and meet Dr Federenko!
Some readers maybe interested in reading a post by ProfG from January last year:
‘Is HSCT for everyone, or not?’ That post generated over 70 replies.
Do you think your view of HSCT has sifted significantly from this prior post and do you think that the cognitive damage associated with the chemotherapy is now not as critical an issue? Being told at the point of disease break I will become eligible for a third round of lemtrada or HSCT, I told my neuro my choice would be Alemtuzumab because at 55yrs of age already, and knowing that brain volume is more pertinent to disability progression than the number and location of lesions, I didn’t wish to risk the imposed loss of neurons with HSCT.
Thank you for this post.
I am glad to see a high profile UK neurologist speaking positively about HSCT as a possible first line treatment for MS and especially glad to see that you agree that patients need to be better informed and more involved in their treatment decisions.
What I’m also seeing here is the suggestion that hitting MS hard with high efficacy treatment, early in the disease progression is better for pwMS in the long run. This makes a lot of sense.
Why do so many neuros not see this? Is there no sharing of information, research and thinking at a national level? It seems that unless we live in London, we are stuck with neuros with who believe in the old fashioned escalation model of treatment, which ultimately leaves us more disabled and costs the NHS and society more. How can this be changed?
Someone called Mindy has posted some results from Russia above and now I am very confused. I thought that Mexico and Moscow do the same treatment and they gave the same results.
But the treatment isn’t the same. There’s no mention of the type of chemo and rutiximab that Mexico use.
Why would people say they were the same if they are not? Does this mean that I should wait go to Moscow not Mexico? Or is there more than one hospital in Russia doing the treatment?
What do you think? Can I suggest you read my posts on (1) getting worse despite being NEDA and (2) smouldering MS. You will then be in a better position to make your own mind up.
Both Mexico and Moscow use cyclophosphamide and rituximab.
I think what the poster was pointing out s that those results from Russia are not from the treatment that they are using now.
It’s an old treatment using different chemo. So those results are not relevant to anyone going to Russia today.
https://www.ebmt.org/ebmt/news/position-statement-providing-general-information-patients-and-carers-considering-hsct
https://www.ebmt.org/sites/default/files/2019-02/General%20information%20for%20patients%20and%20carers%20considering%20HSCT%20for%20ADs_BMT%202019.pdf
The scientific peer reviewed knowledge of the efficacy of rituximab in the treatment of MS is based on a phase II trial and real life data. In spite of this, the medicine has for years routinely been utilized as a DMT in countries like Sweden and Norway, both having health care systems where only scientifically proven medical procedures are to be employed. If i am correct, the scientific evidence for the efficacy of HSCT now exceeds that of rituximab, but alas HSCT is barely offered to any patient here in Norway. I am centenary not eligible even with disease breakthrough on rituximab; the catch 22 is that my neuro says that having been treated with rituximab really exacerbates the risk of developing both acute and late onset life threatening neutropenia post HSCT. So his opinion is that I never will be eligible, even if I stand on my head and scream! If rituximab treatment puts a full stop for HSCT – constitutes a serious contraindication – I guess the same would apply for ocreluzimab. Any comment?
Do you have a reference for this statement : “In fact there is evidence that more advanced patients may actually be made worse by HSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up neuronal loss.” I would love to read more about this.
I had 2 sons. One developed leukaemia and had to have a bone marrow transplant. The other developed MS a few years later. The bm transplant followed a myeloablative protocol. Although every care was taken he still developed sepsis and was lucky to survive. He was treated in London in a first class unit. He had a private room and bathroom and a dedicated team, but heavy chemo is toxic to many of the organs of the body, including thinning the gut wall that allowed bacteria in that would normally not have got into his bloodstream. So no matter how careful you are regarding cleanliness, adverse events can still happen, especially when you are neutropenic. Getting into this unit was difficult with far more patients from a wide area of the south east wanting access for treatment of their haematological cancers. I just can’t see how these expert haematology units could cope with an influx of MS patients without a lot more funding. A non-myeloablative protocol would possible not have the same life threatening risks, but would it be as effective?
My other son was diagnosed fairly quickly at a specialist neurological centre. He was seen by the head of the team- not an MS specialist. This was 9 years ago. When I mentioned campath(as it was then known) he said lots of people had died on it. When I mentioned stem cells, the ultimate immune system re booter, he thought I was talking about just injecting cells, not a transplant,and said he’d be struck off if he did. He said talk to the MS nurse about starting a DMT, and he would be happy to give steroids for the next 20 years as and when my son relapsed. He started on Rebif which was useless and moved to London. He saw a new consultant who offered nataluzimab, but again we asked for campath as we were put off by PML. This was before alemtuzumab had received its final ok. This consultant wouldn’t offer it, but told us the names of consultants who would. We got in touch with one of them and 6 months later he got alemtuzumab. Since then he has been NEDA and has his life back (hopefully). I could kiss the feet of the consultant who agreed to treat him before his MS caused too much damage, but he was lucky- living in London, and being informed and articulate he was able to argue his case.
Yes I’d have taken it as first line but it wasn’t on the table so I pushed for lemtrada. lemtrada has worked well for me but I’d still take HSCT now given the opportunity. If I could afford to pay for it privately I would and that’s with me being NEDA for the last 4 years with an EDS of 1. I’ve never underestimated what ms can do to me.
I’d be interested to know how much of the 15% HSCT budget you mention is actually used for autoimmune diseases.
Speci
fi
c advice to patients considering HSCT
for their AD
We recommend that before starting treatment, patients
should inform themselves
fi
rstly about current disease and
treatment guidelines, secondly about the professional com-
petence of the clinicians and thirdly the experience and
accreditation status of the transplant centre.
The European Society of Blood & Marrow Transplan-
tation (EBMT) has published a number of guidelines and
recommendations for the use of HSCT in ADs [
11
–
13
].
Other organisations and individual health professionals
have also made recommendations in speci
fi
c diseases
[
14
–
17
]. Whereas these guidelines are primarily intended
for a professional readership and therefore written in a
technical language, they are openly accessible to all.
Timing of HSCT is central to decision-making. The
severity of the autoimmune disease, its treatment-resistance
and availability of other treatment options are essential con-
siderations. However, HSCT needs to be considered before
organ damage caused by the autoimmune disease becomes
irreversible (limiting bene
fi
ts) and before the risks of HSCT
are signi
fi
cantly increased by compromised vital organ
function. Balancing potential bene
fi
ts and risks for individual
patients is often complex and requires disease specialists and
transplant clinicians to work closely together.
The EBMT recommend that patients ask their transplant
and disease specialists to explain any aspect of the guide-
lines, including whether treatment is in line with the pub-
lished recommendations.
Treating clinicians should be active in the EBMT and/or
other national and international professional societies,
which means that they should follow published guidelines,
report their outcomes to the EBMT (or equivalent profes-
sional society) and maintain their professional competencies
in this highly specialized
fi
eld. EBMT membership infor-
mation is available from
http://www.EBMT.org
and accreditation
status on
http://www.JACIE.org
websites.
https://www.ebmt.org/sites/default/files/2019-02/General%20information%20for%20patients%20and%20carers%20considering%20HSCT%20for%20ADs_BMT%202019.pdf
Treatment abroad
Patients should do their best to enquire whether treatment is
available within their own health service, and, if not, they
should question why. It may be that treatment is available
under speci
fi
c circumstances that do not cover speci
fi
c types
of AD or a disease specialist may not consider it a best
option. If treatment is planned outside of their home country
patients should think carefully about their decision, as it
may not only have
fi
nancial implications, but there may be
exposure to unnecessary risks to their health and well-being.
If treatment is unavailable in a patient
’
s home country, it is
more satisfactory if they travel and receive treatment with
the full support of a disease specialist and transplant spe-
cialist who knows them well and is familiar with the
centre providing the treatment, or at least their general
practitioner. This may enable direct communication with
transplant and disease specialist teams undertaking the
transplant. Independent self-referral by patients is strongly
discouraged.
Even if the initial phase of the transplant is a success,
patients should be aware that risks of treatment, such as
infection and organ damage, last for many months and, in
some cases, years after the transplant procedure. As with
HSCT in other settings, ongoing follow-up and support is
recommended, along with the need for rapid self-referral to a
locally available transplant or other specialist haematology
unit in case of infections or other emergencies. The follow-up
should include the provision of monitoring for
‘
late effects
’
of
HSCT. These aspects of essential care may be compromised
if initial HSCT treatment is delivered outside of their home
country, especially if communication between clinicians is
limited. It is, therefore, important that patients speci
fi
cally
address these issues prior to HSCT treatment as they may
require ongoing engagement with clinical services near their
home (in both planned or unplanned settings, i.e., emergency
or urgent care).
Following return to home, some health services may not
support monitoring and follow-up following HSCT,
and this may lead to further
fi
nancial commitment from
the patient. The EBMT therefore recommend that before
proceeding to transplants, patients carefully assess
arrangements and support for medium- and long-term
monitoring and follow-up in their locally available health
services
General information for patients and carers considering
haematopoietic stem cell transplantation (HSCT) for severe
autoimmune diseases (ADs): A position statement from the EBMT
Autoimmune Diseases Working Party (ADWP), the EBMT Nurses
Group, the EBMT Patient, Family and Donor Committee and the
Joint Accreditation Committee of ISCT and EBMT (JACIE)
https://www.ebmt.org/sites/default/files/2019-02/General%20information%20for%20patients%20and%20carers%20considering%20HSCT%20for%20ADs_BMT%202019.pdf
56.2.2 Gonadal Dysfunction
in Women Following
Chemoradiotherapy
Women are born with a finite number of eggs
which can be fertilized for pregnancy and depleted
over time as a result of physiological apoptosis or
else menstruation. Chemoradiotherapy depletes
further the number of follicles by (1) activating
apoptotic pathways, (2) causing fibrosis of stromal
blood vessels, (3) activating resting (antral)
follicles, leading to a ‘burn-out’ effect (Meirow
and Nugent 2001; Kalich-Philosoph et al. 2013).
The degree of ovarian damage is related to the
dose and type of chemotherapeutic agent used,
and baseline ovarian reserve which in turn is
dependent on age and previous treatment.
Manifestations of premature ovarian failure range
from premature menopause to varying degrees of
infertility. Alkylating agents have the highest ageadjusted
odds ratio of ovarian failure (Meirow
2000). A combination of BU and CY is particularly
gonadotoxic to females, but younger patients
who receive CY only may have some gonadal
function preserved and pregnancies following CY
are well described (Salooja et al. 2001). TBI is
also potentially sterilizing. The estimated median
lethal dose of radiation for the human oocyte is
less than 2 Gy (Wallace et al. 2003). The effective
sterilizing dose (ESD) decreases with increasing
age, and whilst estimated as 18.4 Gy at 10 years
of age, the ESD is approximately 14.3 Gy at
30 years of age, and only 6 Gy in women over age
40 (Wallace et al. 2005).
56.2.3 Gonadal Dysfunction in Men
Following
Chemoradiotherapy
In male patients, spermatogenesis is impaired,
but testosterone levels generally remain normal
because of the relative resistance of testosterone
producing Leydig cells to chemoradiotherapy. As
a result, secondary sexual characteristics remain
normal for male patients and typically testosterone
levels and luteinizing hormone (LH) levels
are in the normal range. Spermatogonia are very
sensitive to irradiation, and it takes approximately
2 years for sperm counts to recover to pre-irradiation
levels after a single dose of 1 Gy
(Meistrich and van Beek 1990). With higher
doses, azoospermia persists longer or may be
permanent. Following HSCT conditioned with
TBI, the majority of men will be azoospermic.
Chemotherapy only regimens are also associated
with azoospermia but to a lesser degree (Rovo
et al. 2013). Following BU, for example, approximately
50% will be azoospermic, whilst after CY
alone, recovery of spermatogenesis is more
frequent.
https://www.ebmt.org/education/ebmt-handbook
More recent data suggests that ‘high-intensity’
regimens, incorporating BU, have higher rates of
PFS but potentially greater toxicity, including
TRM (Atkins et al. 2016). Retrospective registry
data suggest that graft purging has no added benefit
to the transplant outcome (Snowden et al.
2012).
Currently, auto-HSCT is considered to be
most effective in patients with relapsing MS, who
are not older than 45 years, have had the illness
for less than 10 years, are not very disabled
(EDSS ≤6) and have very active disease with evidence
of enhancement on their MRI (Muraro
et al. 2017). An international randomised controlled
phase III trial is currently being conducted
to compare auto-HSCT with currently available
MDTs (MIST Study, ClinicalTrials.gov
Identifier: NCT00273364) and is anticipated to
report in full in 2021.
https://www.ebmt.org/education/ebmt-handbook
I have spent the last 5 days reading the EBMT handbook – thank you Prof G and Luis Fernando for the reference. I have focused on risks, and to my understanding:
-Autologous HSCT (hereby “HSCT”) has a marginally lower secondary autoimmunity risk compared to alemtuzumab
-HSCT has a significantly higher risk of mid-term and long term secondary malignancy compared to alemtuzumab. No plateau was seen to cap this risk neither.
-HSCT has a significantly higher short-term infection risk, and a marginally higher long term infection risk to alemtuzumab
-The HSCT procedure is double-edged: the chemotherapy may do immediate harm.
-The HSCT procedure may require 10 to 160 days of hospital stay in a glass room (30 to 60 days seems to be the case for most).
-Neither Mexico nor Moscow published any information on long term follow-ups.
-I have not found much published on transitioning strategies out of tysabri to HSCT or mitigant to the IRIS risk.
-Private online forum posts on HSCT are anecdotal at best and suffering from cognitive dissonance and survivorship bias.
Could we invite seasoned cross-discipline (Haematology, Oncology…) HSCT practitioners to discuss the risks on this blog? We could start with Basil Sharrack I guess.
“The HSCT procedure may require 10 to 160 days of hospital stay in a glass room (30 to 60 days seems to be the case for most).”
This doesn’t seem right …I believe Moscow, Mexico and UK suggest 7-10 days in isolation.
Moscow and Mexico are not reliable I am affraind.
“In a recently published Canadian study, the hospital stay after transplantation lasted 10 to 160 days, depending on any side effects experienced.”
source: https://www.nationalmssociety.org/Research/Research-News-Progress/Stem-Cells-in-MS/Bone-Marrow-Stem-Cell-Transplant-%E2%80%93-HSCT
Ah, I think the Canadian study used myeloablative HSCT.
This is not what is on offer in Moscow, Mexico or indeed the UK (either privately or on the NHS). It is much more risky than non-myeloablative and I certainly wouldn’t consider it.
The MIST trials also used non-myeloablative HSCT.
True, it doesn’t seem right. This is either for myelo-abletive HSCT or chemotherapy without stem cells.
Basil was asked to comment on his BBC programme and HSCT…not that informative
https://onlinelibrary.wiley.com/doi/10.1111/ene.13866
Safety and efficacy of autologous hematopoietic stem‐cell transplantation following natalizumab discontinuation in aggressive multiple sclerosis
I hope you are coming to the International Conference on HSCT on 22-23 November, Moscow, Russia 😀
For me, it’s clear that HSCT is worth the very small risk.
It’s not like the side effects of DMD’s are small either.
I got diagnosed mid-January 2019 with RRMS, my only relapse was in November 2019. I have not taken any MS medications.
I’m currently in Moscow doing the no-myeloablative aHSCT, feel free to check my blog for progress if you are interested in a patients point of view! Cheers 🙂 Link https://fighting.ms
On a side note:
Why are neurologists and organizations getting donations/paid by companies like Novartis?
Why hasn’t the clinical trials comparing lemtrada to HSCT gotten enough funding to actually finish their studies?
I know the Norwegian/Danish/German study is at a halt because of funding, not willing patients.
https://clinicaltrials.gov/ct2/show/NCT03477500
It smells like corruption to me, if I’m being honest.
Would love to hear your thoughts on this.
“it’s clear that HSCT is worth the very small risk”
You seem well versed in the subjected. How small is the secondary malignancy risk do you reckon?
The problem we face is about risk management and statistics.
The evidence-based medical system works well with large numbers. Compare it with car insurance. There are so many people with a car who need insurance and there is so much data about accidents (which group, what vehicle involved) that it is fairly easy to estimate what the chance is that someone with a certain profile will claim damage. If you serve a sufficiently large population, as an insurer you can properly assess your financial risk and determine the premium for your customers. But now there is a zoo that wants to insure itself against damage caused to visitors by escaped animals. In that case, an insurer will not be able to rely (completely) on the statistics. He won’t say either. Gosh. Just come back if there are enough lions escaped in zoos around the world to make a good estimate. No, based on available knowledge about how to keep animals in cages, the insurer will conduct an in-depth study at the zoo and try to calculate the odds in a risk assessment. Yes It will look at what happened earlier in other zoos. And what the damage was. But it will also look at the specific design of the zoo.
An MS treatment plan cannot be made solely on the basis of large numbers. Very simple because for promissing treatments it is too diffucult to get the number of comparable cases is too limited for statistics.
What you have in the current frame is that we always prefer the best available option according to the (relatively) large numbers, over a treatment option that has been applied with fewer large numbers but shows superior results there.
This is not right. You can, on the basis of substantive knowledge about what a treatment does and about knowledge from related research domains, arrive at a treatment strategy that takes all uncertainties into account.
What further obscures the risk assessment within the current system is that: 1. The pharmaceutical industry does not have to publish all the results of their trials. Negative results are kept out of the ‘big numbers’. 2. The real long-term effects that we can expect based on knowledge of the system – are only partially taken into account when considering new medical treatments on the market.
It is very typical that often highly skilled (medical) people who experience MS themselves – come up with a different treatment strategy than those that their professional brothers would draw up based on the existing protocols. The treatment is more integrated: Nutrition, sports and mindfulness suddenly play a central role in addition to DMT. These are issues that are very difficult to examine in “big numbers” investigations (comparing an MS group with a control group), but based on all knowledge about the functioning of the body, can be very meaningful in coping with a desease . You here see the parallel with the real estate case from Freakonomics that shows that real estate brokers behave differently when they sell their own house then if they sell a house for a client.
It is my opinion – as a Risk Manager – that is enough evidence to discuss HSCT as a first line treatment.
Thank you, Gavin, for – once again – combining your comprehensive knowledge with persistence and courage. I absolutely agree on having such a debate
Hi Prof G,
May I know what you understand under “more advanced MS”?
I have EDSS 3 – 3,5
I have had MS for 21-22 years. I have had multiple relapses (mostly optic neuritis and sensory issues) and alot of lesions on my brain (no black holes), one on my spine (C3-C4)
I wonder if I have the more advanced MS or if I still can have HSCT…
I am sorry but profG can not give individual advice, people with active lesions are those people most likely to benefit from HSCT and other current DMT
What ive read & seen with HSCT.. suggest it’s the chemo treatment that causes post health issues.. this is the same for cancer patients.. & reading the mortality rates & secondary illnesses with post cancer patients.. seems a reliable result table..to look at, before choosing HSCT.. combining this data..with MS HSCT.. should be included.. & probably decides if HSCT, will become a foremost treatment.. The fact that chemo, reduces life expectancy, by 30% should make most ppls minds up.. & any failure to disclose this.. suggests the MS community is being used as lab rats..
Urge all MS sufferers, to look at post chemo survival & health issues.. HSCT isn’t a miracle cure.. while chemo is involved in removing B cells from our system.. maybe they could remove or lower B cell count through some sort of sterilising dialysis… out of the body..so there are no chemo hazards ..