Hematopoietic stem cell transplantation (HSCT) is highly effective in autoimmune diseases such as multiple sclerosis and systemic sclerosis, improving outcomes and patients' quality of life, although patient selection is critical, say experts discussing results from recent studies.
Speaking here at several presentations during the European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019, experts explained that the technique is also being tested in a number of other conditions, revealing some promising results.
John A. Snowden, MD, PhD, is director of Blood and Marrow Transplantation at Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom, and chair of the EBMT Autoimmune Disease Working Party.
He told Medscape Medical News that it has taken a long time for HSCT to arrive as an established therapeutic treatment, as the first transplants specifically for autoimmune diseases were performed back in the mid-1990s.
There were "mixed feelings" initially among colleagues in neurology, rheumatology, and gastroenterology when such transplants were first proposed for patients with autoimmune disorders.
"It's really a cross fertilization of high-dose chemotherapy and autologous blood stem cells, as used in oncology, into the inflammatory specialties," Snowden said, "so there was a lot of misunderstanding and also some very reasonable concerns initially."
In addition, the evolution of HSCT for the treatment of autoimmune disease occurred alongside the introduction of novel biological agents for many inflammatory conditions.
Snowden said that while some of these biological agents can be highly effective, "they don't always produce the long-term responses that clinicians would want" and can be extremely expensive.
Consequently, it has been recognized that autologous HSCT can be "not only an effective way of suppressing or producing long remissions in some resistant patient populations, but is also likely to be cost effective compared with some of the biological approaches."
Studies Show Improvement in Quality of Life
This increasing acceptance of the use of HSCT in autoimmune diseases was reflected in the breadth of research presented at the EBMT annual meeting.
In one study, Mathieu Puyade, MD, Service de Médecine Interne, CHU de Poitiers, France, and colleagues conducted a systemic review of health-related quality of life following autologous HSCT.
Focusing on systemic sclerosis, they identified eight studies, involving 414 patients eligible for qualitative synthesis. In all, 289 patients underwent autologous HSCT whereas 125 were treated with cyclophosphamide.
There were significantly greater improvements over baseline with HSCT vs cyclophosphamide among 275 patients who were assessed using the Health Assessment Questionnaire-Disability Index.
These improvements were seen in both randomized (P < .05) and nonrandomized (P < .001) studies, and continued out to 7.5 years in one analysis.
Autologous HSCT was also associated with significantly better improvements vs cyclophosphamide in scores on the Short-Form Health Survey Component Summary in several studies.
There were also improvements seen in the index-based utility score of the EuroQol 5 Dimensions scores vs cyclophosphamide, as well as nonsignificant increases in the general health visual analogue scale.
While acknowledging the limitations of the data, Puyade said that the study is "very encouraging because it's the first time we show such wonderful results."
He cautioned, however: "The studies were heterogeneous in terms of the inclusion criteria, and improvements of quality of life will require future research...in a multicenter randomized trial."
Other studies presented at the meeting included the Sheffield experience in using HSCT in the treatment of patients with stiff person syndrome (Abstract OS13-6), presented by Basil Sharrack, MD, PhD, Royal Hallamshire Hospital, Sheffield, UK, and data from the US in patients with neuromyelitis optica spectrum disorder (Abstract OS13-7).
'Rebooting' the Immune System
Alongside the clinical results, there were presentations on the mechanisms of immune reconstitution following autologous HSCT in multiple sclerosis.
For example, John Moore, MD, PhD, St Vincents Hospital, Haematology, Sydney, Australia, presented the latest work from his group on the hypothesis that transplant induces a 'rebooting' of thymic function, resulting in a functional, tolerant immune system (Abstract OS13-2).
The team collected peripheral blood mononuclear cells from 10 patients with multiple sclerosis at baseline and at 6, 12, 24, and 36 months following autologous stem cell transplant.
This revealed significant and sustained increases in markers of both recent thymic emigrants and of thymic function, in particular the Sj:b TREC ratio, between baseline and the 24-month specimens.
Moreover, greater increases in the Sj:b TREC ratio were observed in patients who had evidence of sustained disease remission, as opposed to those who had relapse.
This study complemented a presentation given by Paolo A. Muraro, MD, PhD, Department of Medicine, Imperial College London, UK, during a workshop on HSCT in autoimmune disease (Abstract W6-1).
He examined the current evidence and medical opinion over how autologous HSCT leads to immune reconstitution in patients with multiple sclerosis.
This, he said, starts with T cell, and some B cell, clonal renewal and the diversification of the cell repertoire following replacement of the immune system.
Over time, this is accompanied by reductions in inflammatory cell/molecular expression and the enhancement of immune regulation, alongside normalization of gene expression profiles.
While these findings, which have been shown over a number studies in recent years, point to the way in which HSCT appears to work in controlling autoimmune disease, Muraro underlined that considerable progress still remains in order to correlate these laboratory observations with clinical outcomes.
Mechanism of Action Studies
Indeed, with numerous studies on the horizon, the future points to further refinements of HSCT and its mechanism of action in autoimmune disease.
One is the UK STAR MS, a randomized controlled trial that grew out of the recent MIST trial by Burt et al comparing a conditioning regimen of cyclophosphamide and rabbit antithymocyte globulin (rATG) with a standard-of-care conditioning, as it was at the time.
This new study will compare the same conditioning regimen with alemtuzumab(Campath, Genzyme), a highly active modern biological monoclonal antibody therapy for multiple sclerosis.
"We're hoping that we can resolve the question of whether stem cell transplantation is not only more efficacious but safe to deliver compared to alemtuzumab," Snowden said.
There are several other investigations currently underway that will look at the place of autologous HSCT in relapsing remitting forms of multiple sclerosis, including the Scandinavian RAM-MS trial in patients who have breakthrough inflammatory disease activity in spite of ongoing standard immunomodulatory medication.
Consequently, Snowden believes "the future is going to be very interesting, because I think there will be some positive developments and fine tunings of this approach."
Allogeneic Transplants
HSCT for autoimmune disease most often uses autologous transplants, but some patients do have allogeneic transplants.
To examine outcomes with this alternative transplant, Raffaella Greco, MD, Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy, presented findings from a retrospective analysis (Abstract OS13-3).
She and her colleagues included 128 patients from the EBMT registry who had received allogeneic HSCT for autoimmune disease between 1997 and 2014, of whom 64 completed a detailed questionnaire on long-term outcomes.
The median age of the patients at HSCT was 12.7 years, and the median time from diagnosis to transplant was 3.8 years.
All patients had previously received immunosuppressive therapies and 18 (7%) had received a previous transplant, which was autologous in 15 cases.
Over a median follow-up of 49 months, the researchers determined that the relapse incidence was 18% at 3 years and 20% at 5 years, while progression-free survival (PFS) was 59.4% at 5 years.
Chronic graft versus host disease (GVHD) was seen in 27.8% of patients at 5 years.
By the final follow-up, 67.2% of patients had a complete clinical response and 6.3% had a partial response.
Multivariate analysis showed that relapse or progression was significantly more likely in adults than in children, and females had worse outcomes than males.
However, it also showed that rates of non-related mortality, PFS, overall survival, and GHVD had all improved significantly in recent years.
Greco said the survey "confirms the potential of allogeneic transplant to give long-term disease remission to refractory autoimmune disease, with good outcomes".
She added that the "message is that allogeneic HSCT in this setting may be a potentially curative treatment, but in carefully selected younger patients with severe or poor prognosis autoimmune disease."
The importance of patient selection was underlined by Snowden. He emphasized that patients need to have a degree of reversibility of their disease, or that their inflammation can be arrested to prevent irreversible damage.
"Because this is primarily an anti-inflammatory type of treatment, you don't want to select patients that are so far down the line, where the inflammation is no longer the main component and all they've got is permanent damage, or the degenerative component," Snowden said.
Patients also need to be physically fit enough to undergo HSCT, as it is intensive and they "need to be fit enough to come through it safely."\
Nevertheless, the impressive results with HSCT seen in autoimmune diseases and the increasing knowledge of its mechanism of action has led to a great deal of optimism and enthusiasm among patients.
Not all of them live in countries where transplants are readily available, however.
Snowden explained that a relatively large number of patients with severe disease, particularly those with multiple sclerosis, have consequently gone for treatment in centers abroad.
While he emphasized that he would not like to judge the standard of treatment in those centers, there have been "occasions where patients haven't been highly selected...and also where patients returned to their home country and there was little in the way of ongoing supervision of care or long term follow-up arranged."
"I think those are basic provisions that any transplant center should make if they're going to treat patients," he said.
Snowden continued: "We recognize that some patients are looking very hard for potential treatments that aren't easily provided in their home countries and indeed the treatment may be very appropriate in many patients.
"They're going to countries where this type of treatment is perhaps more affordable and some of them are getting benefits, which justifies the toxicity, but some patients aren't as well-selected and it may be that they're going through a procedure without any major clinical benefit."
He would like to see all patients treated in fully accredited transplant units and, once they have undergone the procedure, to receiving ongoing local follow-up so that any later complications are fully addressed.
However, Snowden said that "unfortunately, many of these patients are in a vulnerable position and not every clinician understands this approach to resistant severe inflammatory disease. Sometimes, this leads to patients taking decision making into their own hands, which isn't always the best pathway to take."
To help educate patients and their caregivers, the EBMT Autoimmune Diseases Working Party has developed a position paper that explains HSCT in plain language.
"The aim was really to improve patients' understanding and education of the area," Snowden said, "and also provide them and nonspecialist clinicians with some key references, which do support this type of treatment as being highly effective in some patient populations."
Snowden declares receipt of grant funding from the UK NIHR and honoraria for speaking from Sanofi, Janssen, and Jazz. Muraro declares speaking and travel support from Merck Serono, Biogen, Bayer, Novartis, and Merck.
European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019: Abstracts OS13-1, OS13-2, OS13-3 and OS13-6. Presented March 27, 2019.
Abstract W6-1. Presented March 26, 2019.
Abstract W6-1. Presented March 26, 2019.
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