AHSCT: who should have access?

Who should control access to AHSCT as a treatment for MS? The patient, the healthcare provider or the healthcare system? Have your say!

Please don’t shoot the messenger. If push came to shove if I had MS I would probably choose AHSCT (autologous haematopoietic stem cell transplant) as a first-line treatment. 

Photo by What Is Picture Perfect on Unsplash

Several people have been accusing me of preventing the patient I discussed in the case study on the 16th of September from having AHSCT. All I said is that I would not recommend she goes abroad for treatment. I am a strong supporter of the principles that (1) healthcare is a basic human right and (2) those that underpin the founding of the NHS; i.e. healthcare should be both equitable and free at the point of care. Advising a patient to go abroad and spend £40,000+ to have AHSCT undermines these principles.

It is important to remember that AHSCT is not generally offered as a first-line therapy on the NHS. At the moment AHSCT is only considered as a 2nd or 3rd-line treatment in the most active patients. The following are our criteria for AHSCT in London. 

MS Clinical Criteria adopted by the London MS-AHSCT Collaborative Group

The eligibility criteria are broadly based on the consensus protocol agreed for a Phase 3 trial of AHSCT in MS (Saccardi et al, 2012). Justification for the criteria is further provided by evidence from AHSCT trials and observational studies (as referenced).

Referral criteria:

I.     Diagnosis of MS made by a neurologist

II.     Able to walk, need at most bilateral assistance to walk 20mt without resting

III.     In RMS, failed at least one highly active approved therapy (currently MITOX, FTY, NTZ, ATZ) because of demonstrated lack of efficacy

IV.     New MRI activity within last 12 months

Inclusion criteria:

1.     Age 18 to 65 years

2.     Disease duration <=15 years from diagnosis of MS

3.     Diagnosis of MS according to McDonald’s criteria

4.     For PPMS, CSF OCB+

5.     For RMS, failed at least one highly active approved therapy (currently MITOX, FTY, NTZ, ATZ) because of demonstrated lack of efficacy (relapse, MRI activity as defined at point 7 after being on DMT for at least 6 months, EDSS increase)

6.     EDSS score 0-6.5

7.     Inflammatory active MS as defined by ≥1 Gd+ (>3mm) lesion(off steroids for one month) or ≥2 new T2 lesions in MRI within last 12 months detected at interval comparison with previous MRI

8.     Approved by the MDT

Exclusion criteria:

a.     Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic stem cell transplantation

b.     Contraindication to MRI including but not limited to metal implants or fragments, history of claustrophobia or the inability of the subject to lie still on their back

c.     Presence of any active or chronic infection

d.     Any significant organ dysfunction or co-morbidity that the Investigators consider would put

the subject at unacceptable risk

e.     Poorly controlled depression or recent suicidal attempt

f.     Inability to give written informed consent

g.     Unable to walk 20mt with or without support, or wheelchair dependent

h.     Eligible for an ethically approved clinical trial where AHSCT is offered as one of the treatment arms

Many of my critics accuse me of being responsible for the fact that access to AHSCT is not universal and very patchy across the country. I agree that there are only a handful of MS centres that are prepared to refer their patients for  AHSCT. This means that access to AHSCT is not equitable and may explain why an increasing number of pwMS are having to travel abroad, at great personal cost, to receive this therapy. I think this is unacceptable, but I only have so much bandwidth and it should fall on the MS community as a whole to drive the adoption of AHSCT as one of the treatment options for MS. 

The block in access to AHSCT 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 AHSCT on their patients with MS. However, the latter is unlikely to happen unless the local MSologist champions AHSCT as a procedure and get their local haematology unit on board. 

Another factor that has changed in the last 10 years is the strength of the evidence-base, which now shows how effective AHSCT is as a treatment for MS. The most recent MIST trial, the first large randomised controlled trial, and several meta-analyses of AHSCT confirm that AHSCT is a very effective therapy. At the same time, the risks associated with AHSCT have improved and the mortality in most BMT units is now below 1% for MS.  This is now tipping the scales in favour of AHSCT becoming a mainstream treatment for MS.

There is however resistance from the MS community about AHSCT been offered as first-line therapy. Why? I suspect because the risk-benefit profile of AHSCT has yet to be compared in a head-2-head study against our most effective licensed treatment. This is why we are doing a head-2-head study of alemtuzumab/ocrelizumab vs. AHSCT in the hope of generating this evidence. We know already that AHSCT will be less expensive than alemtuzumab and ocrelizumab, but will it be more effective and as safe? I don’t think we should try and second guess the results of this trial; I would not be surprised if there is no difference between alemtuzumab and HSCT in terms of efficacy.

Please remember that most of the proponents of AHSCT as a treatment for MS recognise that the major benefits from treatment will only be derived if AHSCT is used early in the course of the disease. This explains why most BMT units don’t offer AHSCT to pwMS with more advanced, or progressive, MS.  However, this does not stop private, fee-for-service, units offering AHSCT 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. This is wrong and is unlikely to happen in the NHS when AHSCT eventually becomes widely available. We have to be honest with our patients about the risks and the benefits and why we will limit AHSCT to those who benefit the most. In fact, there is evidence that more advanced patients may actually be made worse by AHSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up neuronal loss. In addition, infections are common when you have AHSCT and infections are well known to worsen MS disability in more advanced disease.

Please be aware that AHSCT 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 AHSCT first-line? I think not. If we are prepared to offer alemtuzumab, with its risk profile as a first-line treatment, why not AHSCT? 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 AHSCT as my treatment is to reframe the DMT debate, particularly in relation to access to highly effective DMTs. By focusing on AHSCT as a first-line treatment it should at least consider what your treatment objectives are in MS.

Framing is another 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 AHSCT as a 1st-line therapy 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 high or very high efficacy therapies. 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 AHSCT. 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 AHSCT within the frame may nudge patients and their neurologists to move up the treatment ladder and choose a high efficacy DMT.

Unfortunately, AHSCT 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.

When you have a disconnect between the needs, or implied needs, of the MS community, and the position of the NHS and/or the HCPs a Citizens’ jury is a potential solution to the problem. This is when a group of people from the general public (not people with MS or vested interests) decide policy on behalf of pwMS and HCPs; in other words, citizens decide if the NHS and/or HCPs are right to withhold an effective treatment from pwMS based on its costs and/or safety profile. At the moment most HCPs feel HSCT is too risky to be a mainstream treatment for MS.

I propose the NHS and MS Society set up a Citizens’ jury that looks into the question of whether or not AHSCT should be available for pwMS, who have active MS, as a first-, second- or third-line therapy. If the jury says ‘yes’ then the NHS should create the necessary capacity to deal with the needs of the MS community. I  think the NHS may support the results of a Citizens’ jury as it is a win-win for them. Firstly, they will be viewed as being proactive in supporting the wishes of pwMS and if they have to make AHSCT widely available as a treatment for MS it will save the NHS money. From a person with MS’ perspective it will also be a win-win; i.e. (1) they will have the option of being treated with potentially the most effective DMT under the NHS and (2) they won’t have to cover the private expenses of having to travel abroad to have AHSCT. Accessing HSCT under the NHS will also make it more equitable. What about HCPs and/or neurologists? Is it a win-win for them? Or a lose-lose for them?

So please don’t shoot the messenger. I am an active proponent of AHSCT as a treatment of MS in the NHS, but I am not prepared to refer patients abroad or to the private sector for the procedure. For me, it is about the principle of inequitable access.

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The MS-Selfie case study from the 18th of September is about a patient with secondary progressive MS who needs a systematic and holistic approach to his management and not just a focus on disease-modifying therapies.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.