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expert reaction to trial of stem cell transplantation (with chemotherapy) and multiple sclerosis

A paper published in the Lancet journal has looked at treatment of multiple sclerosis and reports the efficacy of chemotherapy to ablate the immune system followed by a stem cell transplant.


Dr Payam Rezaie, Reader in Neuropathology, The Open University, said:

Impact and value of the study

“This is a well-conceived, detailed and long-term follow-up trial, with clear exclusion and inclusion criteria, a strong rationale and sound methodological approach. The complete suppression of clinical relapse and the lack of development of new brain lesions in 23 of the 24 patients, after long-term follow-up of autologous Haematopoietic Stem Cell Transplantation (HSCT), and in the absence of any disease-modifying drugs, is a remarkable finding.

“Although evidence for this will need to be corroborated, the lack of new Gd+ lesions in this study potentially indicates the complete suppression or ‘arrest’ of active inflammatory lesions within the brain over an extended period (>3 years and up to 13 years; median 6.7 years). By selecting CD34+ progenitors from bone marrow extracts, this study has ensured that the cell population that is infused after chemoablation did not include mature cells, and thus avoided reintroducing autoreactive cells to the host (theoretically a subpopulation of the transplanted cells may have included the autoreactive cells that led to development of lesions in the first place). This is a clear advantage.

“There is greater need to relate treatment activity and outcome with disease profile and severity in MS. This is particularly relevant since MS is classified into four main subtypes: relapsing remitting (RR), secondary progressive (SP), primary progressive (PP), and progressive relapsing (PR). The vast majority (> 80 %) of patients have a relapsing remitting profile characterised by relapses that result from inflammation, followed by incomplete or complete remission, and this can progressively worsen (within 5-15 years about half of the patients progress onto a secondary progressive course). This study has shown improved measures across both relapsing remitting (12 patients) and secondary progressive (12 patients) disease course profiles.


“While this study does add considerable weight to the use of autologous HSCT as a therapeutic approach for MS, it is difficult to make a more generalised inference on its use, based on this study alone. As the authors of the study have acknowledged, aside from the small sample population (24) and the lack of appropriate controls, the complications (treatment-related risks) and mortality associated with this more aggressive chemoablation regimen (necessary in order to ensure a more complete renewal of immune cells) does limit widespread adoption. The risks need to be carefully weighed when compared with the beneficial outcomes. The present study indicates a need to examine this further.

“It is hoped that the remarkable outcomes of this long-term study (showing relapse prevention and improvement in the quality of life for a significant proportion of individuals with this devastating illness), will encourage more extensive trials to explore and develop strategies that will improve the long-term effectiveness and safety of autologous HSCT (perhaps in conjunction with alternative combinatorial strategies that limit neurodegeneration).


“Autologous HSCT appears to be a plausible treatment strategy for MS patients, but larger studies are required to better evaluate risk (of toxicity and immune complications of conditioning) versus benefit (neurological and quality of life) of conditioning regimens, and to identify whether selectively targeting different stages (particularly early stage) of the illness could be advantageous. The study shows that long-term follow-up after transplantation is essential for managing the health of MS patients. Consideration should continue to be given to patients’ medical condition (age, performance, disease status) and disease-specific prognostic factors.

Background – mechanism of disease context

“There is no cure at present for multiple sclerosis (MS). ‘Conventional’ treatments target specific symptoms, and most are designed to prevent the progression of disability through suppressing immune cell activation and inflammation – characteristically associated with this debilitating disorder. Haematopoietic stem cell transplantation (HSCT) has been anticipated, for more than twenty years, as a credible means of treating this devastating illness. Support for this therapeutic approach is derived from experimental (animal) models where the proposed strategy has been to reconstitute cells of the immune system, in order to override the ‘autoimmune attack’ of the central nervous system – the fundamental pathological substrate underlying MS.

“Although the precise details of the pathological mechanisms involved are still being unravelled, it is widely agreed that a certain class of immune cells, circulating in the blood (autoreactive T cells), which have been dysfunctionally primed to attack the brain’s white matter, cross over into the brain and trigger a cascade of events (neuroinflammation) that ultimately leads to the development of brain lesions and the progressive neurodegeneration that is characteristic of multiple sclerosis. These cellular ‘infiltrates’ are abundantly visible within the brain both in experimental models and in patients with MS. Pathological changes, particularly at more advanced stages of the disease, also correlate progressively with devastating neurological disability (including movement, co-ordination, cognitive impairment and memory loss).

Background – clinical trials using this approach

“Of the clinical trials using the HSCT approach, only a few of these have specifically used the individual’s own (i.e. ‘host-derived’ or ‘autologous’) stem cells. The rationale for this approach is sound, as it is proven to bypass graft-versus-host disease (causing unwanted and widespread immune activation which is damaging, in cases where the donor and the host are mis-matched, as the host mounts a ‘defence’ against the donor’s transplanted cells, which are recognised as ‘foreign’ elements). The rationale for autologous HSCT for MS is based on use of chemotherapy with subsequent reconstitution of immune cells through a process that generates new ‘self-tolerant’ cells.

“Success in the treatment of patients with this approach has been reported primarily when strict inclusion criteria have been used. Bakhurayasah et al [1] give an excellent overview of the current clinical (therapeutic) usefulness of this approach for MS, as well as some drawbacks. The use of high-dose chemical ablation targeting the patient’s own immune cells is a necessary step, in order to suppress and get rid of the resident (mature) cells which include the autoreactive T cell population that targets the brain, before introducing the ‘fresh’ batch of progenitor cells (stem cells) intravenously via the bloodstream. This procedure essentially acts to ‘reboot’ the immune system and replenish the host’s immune cell population. However, doing this means that there is a window of vulnerability to infection or other immune deficiency-related complications, and it could take several weeks (and up to 6 months or longer), for the individual to recover from the chemotherapy, for the ‘engraftment’ to take hold, as the host’s haematopoietic (‘immune cell’) system is reconstituted. The recovery process can therefore take several months (usually between 3 and 6 months), as pointed out by the study’s senior authors a few years back (Atkins and Freedman [2]).

“Successful reconstitution is both dependent on the level of ablation achieved and the number of reconstituting HSCs introduced into the host’s circulation. An intense pre-conditioning regimen does increase the risk of treatment-related infection, could exert a toxic effect on the CNS, and increases the risk of mortality. Moderating the conditioning may prove to be a less toxic outcome for MS patients treated with HSCT, but clearly there is a fine balance to be met, with a conditioning that supports maximal reconstitution and improvement in neurological and quality of life measures, without unnecessarily jeopardising health concerns and risks associated with toxicity.”

[1] Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality?

Bakhuraysah et al. Stem Cell Research & Therapy (2016) 7:12

[2] Hematopoietic stem cell therapy for multiple sclerosis: top 10 lessons learned.

Atkins HL, Freedman MS. Neurotherapeutics (2013) 10: 68–76.


Dr Emma Gray, Head of Clinical Trials at the MS Society, said:

“This type of stem cell transplantation is a rapidly evolving area of MS research that holds a lot of promise for people with certain types of MS.

“In this latest trial patients were monitored post treatment for a longer period than previous studies, providing valuable information about the long term safety and effectiveness of HSCT as well as who might benefit.

“This treatment does offer hope, but it’s also an aggressive procedure that comes with substantial risks and requires specialist aftercare. If anyone is considering HSCT we’d recommend they speak to their neurologist.”


Dr Paolo Muraro, Clinical Reader in Neuroimmunology, Division of Brain Sciences, Imperial College London, said:

“The article by Atkins et al documents with unprecedented clarity a near-complete suppression of MS disease for several years following autologous haematopoietic stem cell transplantation (aHSCT) in patients with previously highly active MS. Although no direct comparisons are available with standard therapy, none of the drugs that are currently approved or in late phase clinical trials has been reported to achieve a similarly profound control of the disease [1].

“The next challenge for those working in the field will be to demonstrate whether aHSCT is truly superior in efficacy to approved therapeutics and acceptably safe for treatment of MS. Treatment-related mortality was 1 in 24 (4%) in this study and it is perceived as unacceptably high, but it is important to note that they utilised a high-intensity chemotherapy that included busulfan, a drug that can cause veno-occlusive liver disease. The busulfan-related death occurred early in the trial when only oral and not intravenous busulfan was available (the latter enables control of the actual dose absorbed by the body much more precisely, thus reducing risks). Clinical trials and analysis of a European registry data have shown a steady decrease over the years of treatment-related mortality, likely related to more appropriate patient selection criteria and increased use of low- and intermediate intensity chemotherapy schemes. Treatment-related mortality has decreased from 7.3% in 1995-2000 to 1.3% in 2001-2007 [2] and further decreased subsequently, with no treatment-related deaths reported to the European Blood and Marrow Transplant (EBMT) registry since 2012 out of 230 procedures [personal communication from Dr Riccardo Saccardi, Careggi hospital Florence and EBMT Autoimmune Disease Working Party].

“It is also important to consider that although the results suggest that AHSCT may stop or reduce worsening of neurological disability (often improperly termed “progression”) and, as some other studies have demonstrated, can result in improvements in patients with relapsing forms of MS, this therapeutic approach is not suitable for everyone.  It is not suitable for people with progressive forms of MS who have accumulated long-standing disability.  For these people, the risks outweigh any potential benefit.

“aHSCT is perhaps the most powerful anti-inflammatory therapeutic approach but there is no evidence to suggest that it can regenerate lost nerve cells in MS. For all these reasons I would reiterate that aHSCT should only be offered in clinical trials or otherwise rigorously selective clinical programmes in specialised environments, and that patients interested in AHSCT should seek expert advice rather than the un-selective access that we hear is provided, for a fee, at some overseas private facilities.”

[1] Sormani MP, Muraro PA, Saccardi R, Mancardi G.  Mult Scler. 2016 Apr 26. pii: 1352458516645670. [Epub ahead of print]  PMID: 27207454

[2] Mancardi G, Saccardi R.  Lancet Neurol. 2008 Jul;7(7):626-36. doi: 10.1016/S1474-4422(08)70138-8. Review.  PMID: 18565456


Prof. Siddharthan Chandran, MacDonald Professor of Neurology, MRC Centre for Regenerative Medicine, University of Edinburgh, said:

“This is an important and carefully conducted proof of concept study that demonstrates that powerful chemotherapy based treatment for a selected subset of MS patients with very aggressive disease is effective in preventing further disabling relapses and, in a proportion, appears to render them effectively disease free.

“However, the treatment regime has substantial risks and safety concerns that underlines the need for future studies with a larger sample size, control group and ideally identification of predictive markers to allow targeting of this treatment to those MS patients at greatest risk of rapid and severe decline.”


Dr Stephen Minger, stem cell biologist and independent consultant (Director of SLM Blue Skies Innovations Ltd), said:

“It’s important to stress that this is a very early study, though with impressive long-term follow-up of treated patients. Nevertheless the clinical results are truly impressive, in some cases close to being curative, though we need longer-term follow-up to know for certain whether the patients continue to do well or if there is a chance of relapse. And of course this trial will need replication by other groups too.

“For a life-long progressive disease like MS with few treatment options this is really exciting data – it offers the hope of having a long-lasting treatment which may halt disease progression, though again, this is a very invasive therapy and not without risks. Still I would consider it a breakthrough therapy and the clinical group and the patients should be congratulated for this success.”


‘Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicenter single-group phase 2 trial’ by Harold L Atkins et al. published in the Lancet on Thursday 9 June 2016. 


Declared interests

Dr Payam Rezaie: “I have no competing interests to declare.”

Dr Paolo Muraro: “I am involved in research on AHSCT and received grant funding to study the mechanism of action of AHSCT from the UK MS Society.”

Prof. Siddharthan Chandran: “Consultancy fees paid to Institution from Biogen, Novartis and Merck. Research collaboration grant from Biogen.”

Dr Stephen Minger: “Nothing to declare – have never met the investigators of this study.”

No others received.

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