Health Policy Advisory Committee on Technology New and Emerging Health Technology Report

Transcription

1 Health Policy Advisory Committee on Technology New and Emerging Health Technology Report Stem cell therapy for non-haematological (autoimmune) indications March 2015

2 State of Queensland (Queensland Department of Health) 2015 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 2, 15 Butterfield St HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD [email protected] Telephone: For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, [email protected], phone (07) Electronic copies can be obtained from: DISCLAIMER: This Report is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Report is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Report. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Report is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Report was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Report was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This Report was prepared by Prof Paul Scuffham, Dr Tracy Comans, Nicole Moretto and Tom Elliott from The Centre for Applied Health Economics, School of Medicine, Griffith University

3 Table of contents HealthPACT Advisory... iii Executive summary... iv Background... 1 Patient indication... 1 Description of the technology... 1 Reason for assessment... 4 Stage of development in Australia... 4 Licensing, reimbursement and other approval... 4 Impact... 5 Multiple Sclerosis... 6 Systemic Sclerosis Systemic lupus erythematosus Current technology Diffusion of technology in Australia Cost infrastructure and economic consequences Cost analysis Ethical, cultural, access or religious considerations Evidence and Policy Safety and effectiveness for multiple sclerosis Haemopoietic stem cell transplantations for multiple sclerosis Mesenchymal stem cell therapy for multiple sclerosis Safety and effectiveness for systemic sclerosis Haemopoietic stem cell transplantations for systemic sclerosis Safety and effectiveness for systemic lupus erythematosus Haemopoietic stem cell transplantations for SLE Mesenchymal stem cell therapy for SLE Economic evaluation Ongoing research Stem cell therapy for non-haematological (autoimmune) indications: March 2015 i

4 Summary of findings References Search Strategy HTA sites Number of studies included Appendices Appendix A Estimation of the number of patients with relapsing remitting multiple sclerosis failing interferon beta and alemtuzumab, or alemtuzumab only Appendix B Profiles of all included studies for HSCT and MSCT for multiple sclerosis Appendix C Cochrane risk of bias assessment of the direct randomised trials of HSCT for systemic sclerosis Appendix D Profiles of included observational studies for SSc Appendix E Profiles of included studies for SLE Appendix F MS Australia statement on Autologous Hematopoietic Stem Cell Transplant (HSCT) treatment Appendix G MS Australia s statement on stem cells Appendix H NHMRC warns of the risks associated with unproven stem cell therapies in Australia and overseas Stem cell therapy for non-haematological (autoimmune) indications: March 2015 ii

5 HealthPACT Advisory This report was commissioned by HealthPACT in response to jurisdictions noting an increase in the number of patients seeking stem cell transplantation treatment overseas outside of clinical trials, especially in response to extensive press coverage. Many of these patients have not exhausted all of the available medical options to treat their condition and therefore would not fit the selection criteria for stem cell transplantation clinical trials conducted in Australia. Patients seeking this treatment need to be fully informed as to the potential risks and benefits, including that stem cell transplantation is not considered curative but rather aimed at ameliorating disease. It should be noted that although both mesenchymal and haemopoietic stem cells are being used in the treatment of immunological conditions including multiple sclerosis, systemic sclerosis and systemic lupus erythematosus, the use of haematopoietic stem cells is more effective in comparison to mesenchymal but associated with more adverse events. The evidence base for the treatment of severe systemic sclerosis is the most mature and is now an accepted treatment option for this disease based on data from two randomised controlled trials. One of these trials has confirmed a clear benefit of long term mortality for haematopoietic stem cell transplantation in systemic sclerosis. Trials to refine clinical protocols for use in systemic sclerosis are likely to continue. HealthPACT recommends that the treatment of patients with multiple sclerosis and systemic lupus erythematosus with stem cell transplantation should only be conducted under the auspices of an ethics approved controlled trial with informed consent Careful selection of patients for such clinical trials is required, with only those patients who are currently in an active inflammatory phase of the disease, and are therefore most likely to benefit from stem cell transplantation, being considered for enrolment in units with expertise in stem cell transplantation for autoimmune disease. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 iii

6 Executive summary This new and emerging health technology report was prepared for HealthPACT with the aim of providing a brief overview of the evidence on the safety, effectiveness and feasibility of stem cell transplantation for (non-haematological) autoimmune diseases within an Australian context. The focus of the report was haemopoietic stem cell transplantation (HSCT) and mesenchymal stem cell therapy (MSCT) for patients with multiple sclerosis (MS), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Both autologous (auto) and allogeneic (allo) forms were assessed. The reason for assessment was the increasing evidence base for autologous haemopoietic stem cell transplantation (auto-hsct) as a treatment for SSc, mounting pressure from the public for stem cell transplantation for MS and the potential for a major cost impact on the public health system. Description and estimate of patient numbers Multiple sclerosis MS is a chronic autoimmune disease of the central nervous system which can lead to a considerable level of disability. The most common subtypes of MS are relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS) and relapsing progressive multiple sclerosis (RPMS). There are also other rare variants of the condition. The prevalence of MS in Australia in 2010 was estimated to be 95.6 per 100,000 population in Australia. It is postulated that of the estimated 850 new cases of RRMS each year, approximately 125 to 187 patients would be refractory to interferon and alemtuzumab, or alemtuzumab only and may be assessed for eligibility for auto-hsct across Australia. It is difficult to estimate the number of patients with SPMS with inflammatory disease that may be suitable for auto-hsct. Systemic sclerosis SSc, also known as systemic scleroderma, is recognised as the most severe connective tissue disorder. SSc affects many different systems throughout the body with the most severe form involving major organs including the pulmonary, cardiac and renal systems. SSc carries a highly increased mortality risk with the major cause of mortality being cardiopulmonary events including interstitial lung disease and pulmonary arterial hypertension. 1 The median survival for patients with SSc related interstitial lung disease is 5 to 8 years. 2 The true prevalence of SSc is difficult to determine with international estimates ranging from three to 24 per 100,000 people. A systematic review of epidemiology suggests an incidence of SSc in Australia of 15 to 23 persons per million per year using data from three Australian sources covering 1993 to Based on Australian registry data and epidemiology of SSc, approximately 30 to 65 patients per year may be a reasonable approximation of the likely demand for stem cell treatment for SSc. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 iv

7 Systemic lupus erythematosus SLE is a chronic autoimmune disease characterised by inflammation across multiple organ systems, a clinical pattern of flares/relapses and remissions, and the presence of autoantibodies. Most patients with SLE have symptoms of the skin and joints, although lifethreatening manifestations can arise in the kidney, lungs, the central nervous system, gastrointestinal system, ophthalmic system, cardiovascular system and haematologic system. Inflammation of the kidney can cause lupus nephritis which can lead to significant illness and can even be fatal. The incidence of SLE in Australia is not well reported although a number of studies have reported the prevalence in population subgroups. The prevalence of SLE in Aboriginal peoples ( cases per 100,000 population) has been reported to be higher than in non-aboriginal peoples ( cases per 100,000 population). 3 Lupus nephritis is a severe form of SLE affecting renal function and therefore would be likely to be the main population requiring stem cell transplantation. The prevalence of lupus nephritis in Australia was found to be 5.5 per 100,000 population. Based on the current population, about 1,200 to 1,300 people would be living with the severe form of SLE in Australia. It is unclear how many of these people would be likely to benefit from stem cell therapies. Diffusion of technology in Australia In Australia, auto-hsct is widely used as a treatment for disorders of the blood and immune system and as supportive treatment for blood-related cancers. There have been over 60 auto-hsct for autoimmune disease performed at St. Vincent s Hospital since The use of allogeneic-hsct for the treatment of autoimmune diseases has been extremely limited. 4 The major concern with allogeneic transplants is the potential for graft-versus-host disease, a severe and potentially life threatening complication which has limited the diffusion of the technology. The technology to produce and use mesenchymal cells for therapy is available in Australia and has been used to treat a variety of conditions. There has been limited use of MSCT for the treatment of autoimmune disease in Australia with one small study published in Crohn s disease. There have been attempts to engage in early phase trials of mesenchymal stem cell therapy in MS in Australia. Cost infrastructure and economic consequences Little economic information was available on stem cell therapies for autoimmune diseases in Australia. This is likely due to the lack of mainstream use of stem cell therapy for autoimmune diseases. It was estimated that the direct cost to government for health and community care for MS in 2010 was $10,721 per patient, with an additional cost of $4,384 and $3,697 attributable to residential care and direct patient out-of-pocket costs, respectively. 5 No cost of illness estimates were available for SSc in Australia. An estimate of the cost for SSc in Canada in a cohort of 457 people with SSc found the direct healthcare Stem cell therapy for non-haematological (autoimmune) indications: March 2015 v

8 cost of $5,038 per patient (2007 Can$) 6. This cost, converted to 2013 Australian dollars using the OECD a purchasing parity index, 7 was $6,328. The Canadian cohort in this study included a wider range of patients than those likely to benefit from HSCT therefore the cost of patients with severe disease would be higher than this estimate. No cost of illness studies were found that reported costs for SLE in Australia. A UK report estimated the cost of a patient with severe SLE as 4,652 per annum equivalent to AUD $10,963. According to the selection criteria of the SLE studies, $10,963 would be a reasonable estimate of the yearly cost of a patient eligible for HSCT as only severe SLE patients are considered for stem cell transplantations. A cost analysis was performed for the purposes of this report only. The average national cost of a primary auto-hsct for MS was estimated to range from AUD $30,364 to $50,765. It was assumed that the same procedure is similar across the three autoimmune diseases. This estimate was based on the cost of undergoing an auto-hsct in one major transplant centre in Australia and may not reflect the cost of undergoing the procedure in other centres throughout Australia. Costs may also differ depending on the types of medications used in the protocol, the severity of patients, and the type of autoimmune condition. For example, there are biosimilar medications for the granulocyte-colony stimulating factor, such as pegfilgrastim, which are less costly than filgrastim. The cost estimate in this report was based on the medications used in a current clinical trial in Australia. The average cost per patient with different autoimmune conditions is relatively similar; however, patients with SSc require an extra day in hospital for the insertion of specialised central venous catheter. For the MSCT procedure, an additional cost of $10,000 to $20,000 per treatment course for the manufacture of mesenchymal stem cells in an accredited facility. However, the costs associated with chemotherapy, in-patient and support costs are less than HSCT. Based on the incidence rates of the three autoimmune diseases and the recommended patient selection for auto-hsct, it is unclear whether there would be capacity within existing hospitals across Australia to accommodate the anticipated increase in demand for stem cell therapies these diseases. However, there would be a significant increased burden on hospital staff. The strong centre effect observed in the European registry and American registry data, which demonstrates that more experienced centres are associated with improved safety and clinical outcomes, highlights the need to limit the procedure to a few specialised sites across Australia. a OECD = Organisation for Economic Co-operation and Development Stem cell therapy for non-haematological (autoimmune) indications: March 2015 vi

9 Review of the clinical evidence A literature search was conducted for each of the three conditions, MS, SSc, and SLE, for HSCT and MSCT. For MS, fifteen studies based on HSCT and four studies based on MSCT, published between 2009 and 2014, were included in this report. For SSc, three randomised controlled trials (RCTs) and six other relevant observational trials, published between 2007 and 2014, were included. For SLE, six studies published between 2009 and 2014 were included for HSCT which consisted of four case series and two comparative studies with concurrent controls. A further six case series studies, published between 2010 and 2014, were found for MSCT for SLE. Summary of multiple sclerosis Interpreting the evidence for stem cell transplantations for MS is challenging as the studies contain different treatment protocols, conditioning regimens, sources of stem cells and definitions for clinical outcomes. There is also limited long-term follow-up data. Most of the fifteen studies of HSCT for MS included in this report used autologous stem cells derived from peripheral blood. The median follow-up ranged from 31 months to 11.3 years. For the case series, the 100-day treatment-related-mortality (100 day TRM) ranged from zero per cent to four per cent and the treatment-related-mortality (TRM) ranged from zero to 14 per cent. For the retrospective analyses, the 100-day TRM and TRM ranged from two to four per cent and from 2.7 to 3.8 per cent, respectively. This reflects the European experience, 8 which reported a fall in mortality associated with autologous HSCT from 7.3 per cent from 1995 to 2000 down to 1.3 per cent from 2001 to This may have been due to improved patient selection and a reduction in the high-intensity conditioning regimens. Progression-free survival was estimated to be between 47.6 to 100 per cent at three years, 45 to 82 per cent at five years, 29.2 to 65 per cent at six years, 48 per cent at nine years and 25 per cent at 15 years. Disease free survival was estimated to be between 62 to 78.4 per cent at three years and 68 per cent at five years. Relapse-free survival was estimated to be 76 per cent to 86.3 per cent at approximately three years and between 85 to 87 per cent at five years. Only three studies reported magnetic resonance imaging (MRI) event-free survival which was estimated to be 100 per cent at 6-12 months, 92 per cent at two years, 100 per cent at three years and 85 per cent at five years. Disability at baseline, as measured by the median score on the Kurtzke expanded disability status scale (EDSS), ranged from 3.1 to 8.0. Disability progression was observed in zero to 58 per cent of patients whilst stabilisation or improvement was shown in 42 to 100 per cent of patients. New gadolinium-enhanced (Gd+) and/or T2 lesions were observed in zero to 24 per cent of patients at follow-up post-transplantation. Quality of life was found to significantly improve as early as six months post-transplantation (p<0.05) and improvements were observed in most of the domains at follow-up. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 vii

10 Stem cell transplantation is more efficacious in patients in the inflammatory stages of the condition (i.e. RRMS, and SPMS with episodes of relapsing remitting). As the condition progresses to SPMS, the disease shifts to a neural degenerative disorder and the treatment is no longer effective. According to updated guidelines, 4 the ideal target patient indications for auto-hsct for MS, are patients with MS in the relapsing remitting phase (characterised by clinical manifestations of high inflammatory activity and the presence of Gd+ enhancing lesions and/or new T2 lesions on MRI imaging scans) with aggressive progression failing one or more lines of treatment. Patients with severe malignant MS would also be suitable candidates for the procedure. Patients with SPMS who have evidence of some inflammatory disease activity and who have deteriorated may also be considered for auto-hsct. If the disease has progressed to a point where the patient have lost the ability to walk (approximately EDSS >6), auto-hsct is no longer a suitable treatment option (except for malignant forms of MS). Only four small case series for MSCT for MS met criteria for inclusion in this report. All included studies used autologous stem cell transplantation using mesenchymal stem cells derived from bone marrow. Common adverse events were fever, headaches, difficulty walking/standing and infections with no deaths reported across any of the four studies. Disease progression, as measured by the EDSS, significantly reduced in one study and was shown to improve in 34 per cent (13 patients), stabilise in 55 per cent (21 patients) and worsen in 11 per cent (4 patients) of patients in the other three included studies at six months with nearly 80 per cent improved or stable at 12 months. At follow-up, new T2, enlarging lesions or Gd+ lesions were found in zero to 71 per cent of patients. There is some research emerging on the combined effects of multiple therapies including stem cell transplantations in conjunction with other therapies as treatment for MS. For example, recent studies have explored the combination of non-myeloablative HSCT with a consolidation therapy of mitoxantrone, 9 HSCT with infusion of mesenchymal stem cells, 10 and failed non-myeloablative HSCT followed by natalizumab. 11 This area of research is still in its infancy, however may provide possible treatment options in the future. MS is generally not considered to be a fatal disease unlike the severe forms of SSc and SLE and the current TRM of auto-hsct for MS at one to two per cent remains a significant concern. Auto-HSCT remains a relatively experimental treatment for MS and should only be performed in a clinical trial setting, under the guidance of a human research ethics committee and with full informed consent. The safety and efficacy of stem cell therapies for autoimmune disorders and its benefits compared to existing standard therapies needs to be demonstrated through RCTs prior to becoming an accepted treatment option. Currently this level evidence is only available for SSc. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 viii

11 Summary of systemic sclerosis The results in trials to date support HSCT as an effective treatment for severe SSc. Patient selection is critical with high TRM in patients with cardiopulmonary involvement and in current and previous smokers. From the available evidence, auto-hsct had a worse short term safety profile than the comparison (cyclophosphamide) with more short term mortality and serious adverse events, particularly haematologic, respiratory, cardiovascular and common viral infections. TRM ranged from 0 to 23 per cent across the RCTs and observational studies. Auto-HSCT has a clear benefit on long term mortality. In the one RCT (van Laar et al. 2014) 12 reporting a comparison of mortality, a significant benefit was found for auto-hsct at five years despite the increased early mortality due to treatment. Mortality at around five years was similar in the RCTs to the observational studies at around 20 per cent. This compares favourably to estimates of mortality in SSc with major organ involvement of around 40 to 50 per cent at five years. 13 The results of longer term follow up support the hypothesis that HSCT is safer if baseline cardiac assessment is favourable and HSCT should be instituted before the SSc has caused cardiac abnormalities in order to maximise the benefit. The transplantation procedure used to treat patients with SSc has undergone changes since it was first implemented, primarily related to the increased screening of patients for cardiac complications to reduce TRM. In order to appropriately ascertain risk, screening should include echocardiogram, confrontational right heart catheterisation, including a fluid challenge test and cardiac MRI, however screening will increase the cost of the procedure. 14, 15 The improved procedures should have an impact on reducing the early mortality associated with auto-hsct therefore making it a safer treatment option. Summary of systemic lupus erythematosus HSCT and MSCT are both promising treatments for SLE, though they are still in the naïve stages of being proven clinically effective. The evidence available for this report came from six HSCT studies and six MSCT studies. Only two studies included an alternative treatment, a conventional treatment, which diminished the ability of this report to comment on the effectiveness of the treatments. 16, 17 No RCTs comparing HSCT or MSCT to standard treatment were found. The safety of HSCT and MSCT differed greatly across the 12 studies, supporting the claim of a strong centre effect / learning curve being involved in stem cell transplantation therapies. 18 The 100-day TRM of the HSCT studies varied from zero per cent in Song et al. (2011) 17 to per cent in Farge et al. (2010). 19 Only Farge et al. (2010) 19 judged deaths within their study to be by TRM. Song et al. (2011) 17 was unable to prove that HSCT was superior to conventional treatment with respect to overall survival. It was shown that Stem cell therapy for non-haematological (autoimmune) indications: March 2015 ix

12 progression free survival was significantly improved in the HSCT group, suggesting patients stay in remission longer due to HSCT. 17 The MSCT studies did not judge any death to be TRM, although Wang et al. ( and ) reported a 100-day TRM of 2.5 per cent and 2.29 per cent, respectively. The MSCT studies had an overall mortality range of 0.0 per cent (follow-up of 8.25 and 17.2 months) to 7.5 per cent (follow-up of 12 months). A number of parameters were used to demonstrate the decrease in disease activity after HSCT or MSCT. In both HSCT and MSCT studies, each study which reported the systemic lupus erythematosus disease activity index (SLEDAI) analysis, found the average SLEDAI score to significantly decrease after transplantation. Decreasing SLEDAI scores represent diminishing disease activity, with remission reached at SLEDAI scores < three. The MSCT studies found 24h proteinuria, serum albumin levels and anti-dsdna levels to positively change, representing statistically significant decreases in disease activity after treatment. There is no economic information available on SLE and stem cell transplantations in Australia. No Australian data exists to estimate number of potential SLE patients that would meet the treatment criteria, and be able to estimate the cost per annum. Cost-effectiveness analysis A search of health technology assessment (HTA) databases revealed stem cell transplantations for each of the relevant conditions, revealed three health technology assessments for MS, one health technology assessment for SLE, and no health technology assessments for SSc. Of these, only one publication was available which reported on an exploratory cost-effectiveness analysis in the UK evaluated the incremental costeffectiveness of auto-hsct versus mitoxantrone in the treatment of patients with SPMS. The results of the cost-utility analysis revealed auto-hsct as cost-effective compared with mitoxantrone at a threshold accepted by policy makers in the UK. These results are not generalisable for auto-hsct as a treatment for other subtypes of MS (e.g. RRMS) due to different comparators, other autoimmune diseases, or other types of stem cell transplantations (e.g. MSCT). Ongoing research Stem cell transplantation is an intervention currently of high interest to research teams with a large volume of research currently underway. For MS, 42 studies were found on clinical trial registries on stem cell transplantation for MS of which 30 studies are registered as active/recruiting/complete; 12 studies (HSCT), 21 studies (MSCT), and 3 studies (other). One multi-centre RCT (MIST phase) based in USA, Sweden, Brazil and the UK comparing auto- HSCT versus standard of care treatment is currently underway and will provide pivotal evidence on the outcomes of HSCT. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 x

13 There are 22 studies on stem cell transplantation for SSc of which 15 studies are registered as active/recruiting, three trials registered as complete and four trials registered as either terminated or withdrawn. Two RCTs are underway with results expected in For SLE, 14 studies on stem cell transplantation were found. Most of the current trials were based on HSCT. There are no RCTs registered for HSCT for SLE. There is one double blind RCT comparing MSCT versus cyclophosphamide which will be first clinical trial with the ability to judge the efficacy of MSCT in SLE patients. Stem cell therapy for non-haematological (autoimmune) indications: March 2015 xi

14 Background Register ID WP 194 Technology name Patient indication Stem cell therapy for non-haematological (autoimmune) indications Patients with multiple sclerosis, systemic sclerosis and systemic lupus erythematosus Description of the technology Stem cells are a type of cell that are defined by their ability to multiple themselves (selfrenew) and change into different types of specialist cells (differentiate). There are two main groups of stem cells: tissue stem cells and pluripotent stem cells (Table 1). Tissue stem cells are (multipotent) have the ability to differentiate into a limited number of cell types. Tissue stem cells include adult stem cells, cord blood stem cells and fetal stem cells. Pluripotent stem cells are able to differentiate into any type of cell and include embryonic stem cells and induced pluripotent stem cells. Table 1 Classification and types of stem cells Group Description Type of stem cells Source of stem cells Adult stem cells Part of human body (e.g. bone marrow) Tissue stem cells Differentiation into a limited number of cell types Cord blood stem cells Umbilical cord blood Fetal stem cells Aborted fetuses Pluripotent stem cells Differentiation into any type of cell Embryonic stem cells Induced pluripotent stem cells Embryos Part of human body (e.g. skin) The current report will focus on treatment involving tissue stem cells, specifically adult stem cells, which can be isolated from the bone marrow. These are sub-classified into haemopoietic and mesenchymal stem cells. Stem cell therapy refers to transplanting stem cells into the body (stem cell transplantation) and drug therapies that target stem cells in the body. Stem cell transplantations have been proposed as a treatment for severe autoimmune diseases. The objective of the treatment is remove the autoreactive immune cells and to introduce stem cells (either from the patient or a donor) to reset or replace the patient s immune system. The two main types of stem cell transplantations for autoimmune diseases are haemopoietic and mesenchymal (Figure 1). Haemopoietic stem cell transplantation (HSCT) refers to the transplantation of multipotent haemopoietic stem cells derived from bone marrow, peripheral blood, or umbilical cord blood. Mesenchymal stem cell therapy (MSCT) refers to the transplantation Stem cell therapy for non-haematological (autoimmune) indications: March

15 of multipotent mesenchymal stromal cells derived from bone marrow, umbilical cord, adipose tissue, placenta, teeth and menstrual fluid. 7, 22 For stem cell transplantations, stem cells may be obtained from the patient (autologous), a matched donor (allogeneic), or an identical twin (syngeneic). Stem cell transplantation / stem cell therapy Haemopoietic stem cell transplantation (HSCT) Mesenchymal stem cell therapy (MSCT) Autologous Allogeneic/syngeneic Autologous Allogeneic/syngeneic (auto-hsct) (allo-hsct) (auto-msct) (allo-msct) Figure 1 Common types of stem cell transplantations in autoimmune diseases The autologous haemopoietic stem cell transplantation (auto-hsct) procedure is outlined in Figure 2 and involves the following steps: 1. Mobilising - Mobilising of haemopoietic stem cells from bone marrow or peripheral blood, typically with granulocyte-colony stimulating factor and cyclophosphamide. 2. Collecting or harvesting - Collecting or harvesting the haemopoietic stem cells by leukaphersis/plasmapheresis and selection for CD34+ cells. - Purifying and concentrating of the haemopoietic stem cells in the laboratory. - Freezing or cryopreserving the cells in the laboratory. 3. Conditioning and reinfusing - Immunoablative conditioning (chemotherapy) to destroy the immune system, typically with cyclophosphamide with or without anti-thymocyte globulin. - Reinfusing the thawed haemopoietic stem cells into the patient. Stem cell therapy for non-haematological (autoimmune) indications: March

16 Figure 2 Illustration of autologous haemopoietic stem cell transplantation procedure 23 The conditioning regimens include myeloablative conditioning (cyclophosphamide with total body irradiation or busulfan) and nonmyeloablative conditioning (cyclophosphamide with or without anti-thymocyte globuline. Myeloablative conditioning is associated with higher treatment-related-mortality (TRM) and is less suitable for patients with autoimmune disease. The auto-hsct procedure is relatively similar across multiple sclerosis (MS), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Allogeneic haemopoietic stem cell transplantation (allo-hsct) involves mobilisation, collection, and the harvest of haemopoietic stem cells from a human leukocyte antigen matched healthy donor. MSCT using bone marrow derived mesenchymal stem cells involves the aspirate of a small volume of bone marrow and then the isolation and culture expansion of the mesenchymal stem cells in an accredited manufacturing facility. Administering the mesenchymal stem cells to the patient can be via injection using the following methods: intravenous (vein); intrathecal (space around spinal cord); or intraparenchymal (brain). Company or developer Not applicable. Stem cell therapy for non-haematological (autoimmune) indications: March

17 Reason for assessment The technology of stem cell transplantations for autoimmune diseases has been assessed in this new and emerging health technology report for a number of reasons including: - increasing evidence for auto-hsct as superior to the current treatment for severe SSc; - mounting pressure from the public for stem cell transplantation to be made available to treat patients with MS; and - results of the current phase III trial for auto-hsct for MS which are expected to be released over the next few years. If the results are considered to have significant health benefits in a subgroup of patients with MS, it is likely that there would be a major cost impact on the public health system as multiple sclerosis is a large patient group associated with significant morbidity. Stage of development in Australia Yet to emerge Experimental Investigational Nearly established Established Established but changed indication or modification of technique Should be taken out of use Licensing, reimbursement and other approval The Therapeutic Goods Administration (TGA) is the regulatory authority for all devices, drugs and biological in Australia and is responsible for the regulation of the importation, manufacture and supply of stem cells. Stems cells intended to be used for therapeutic purposes are required to be listed on the reference database of the TGA, the Australian Register of Therapeutic Goods. Under the Therapeutic Goods Act 1989, Therapeutic Goods (Excluded Goods) Order No. 1 of 2011, human tissues and cells intended for use in humans are exempt from regulation by the TGA for medical practices with registered medical practitioners under specified medical conditions. b In partnership with the Australian Health Practitioner Regulation Agency, the Medical Board of Australia is responsible for the regulation of medical practice in Australia. Before new stem cell treatments are made available to the public, clinical trials should be used to establish their safety and efficacy. In Australia and overseas, clinical trials should be b Human tissue and cells, intended for use in humans, are declared not to be therapeutic goods if they are collected from a patient who is under the clinical care and treatment of a medical practitioner registered under a law of a State or an internal Territory; and manufactured by that medical practitioner, or by a person or persons under the professional supervision of that medical practitioner, for therapeutic application in the treatment of a single indication and in a single course of treatment of that patient by the same medical practitioner, or by a person or persons under the professional supervision of the same medical practitioner. For more information, see the Therapeutic Goods Administration website at Stem cell therapy for non-haematological (autoimmune) indications: March

18 registered with World Health Organization (WHO) approved clinical trial registries. According to the National Health and Medical Research Council (NHMRC), HSCT is the only stem cell treatment that is recognised as a safe and effective treatment to re-establish the blood and immune system for specific medical conditions. 24 The NHMRC has released information guidelines 25 for medical practitioners on stem cell treatments in Australia in which it states that there are some medical practitioners in Australia and overseas that are providing stem cell treatments that may not have been shown to be effective. Australian Therapeutic Goods Administration approval Yes ARTG number (s) No Not applicable Technology type Technology use Speciality Technology setting Procedure Therapeutic Haematology Specialist hospital Impact Alternative and/or complementary technology Additive and substitution (i.e. technology can be used as a substitute in some cases, but may be used in combination with current technologies in other instances). Stem cell therapy for non-haematological (autoimmune) indications: March

19 Patient Indication and Setting Multiple Sclerosis Disease description and associated mortality and morbidity Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (i.e. the brain, spinal cord and optic nerves). It is characterised by demyelination caused by the body s immune system attacking its own myelin sheaths (covering that surrounds the axons of the nerve fibres). The resulting inflammation and damaged myelin and axons lead to a disruption of the transmission of electrical signals to the brain. The symptoms of MS are dependent upon the areas of the central nervous system involved and can vary significantly between patients. Symptoms include numbness, tiredness, muscle weakness, sensitivity to heat, problems with balance and co-ordination, bladder and bowel symptoms, cognitive changes, and visual disturbances. The cause of MS remains largely unknown, however it has been proposed that autoimmunity (auto-reactive T and B cells), genetics and environmental factors (such as Epstein-Barr virus, human herpes virus 6, low vitamin D levels, smoking, and sun exposure) may all play a role. The most common subtypes of multiple sclerosis are outlined in Table 2 below, and include: relapsing remitting multiple sclerosis (RRMS); secondary progressive multiple sclerosis (SPMS); primary progressive multiple sclerosis (PPMS); relapsing progressive multiple sclerosis (RPMS); and other rare MS variants (e.g. Marburg s disease (malignant MS), Balo s concentric sclerosis, Schilder s diffuse sclerosis, relapsing optic neuritis). The latest diagnostic criterion for MS is the revised 2010 McDonald criteria (previously Poser and Schumacker criteria). It is estimated that approximately 75 per cent of patients with multiple sclerosis are female. The average age of onset of MS in Australia is usually between 20 to 40 years of age. Stem cell therapy for non-haematological (autoimmune) indications: March

20 Table 2 Overview of types of multiple sclerosis Type of MS Features Disease course Relapsing remitting multiple sclerosis (RRMS) Fluctuation of symptoms with periods when symptoms worsen (relapses) and periods when symptoms improve (remission). 85 per cent of patients are initially diagnosed with RRMS. Secondary progressive multiple sclerosis (SPMS) Initial RRMS disease course, followed by steady worsening of disease with or without occasional relapses and remissions. Primary progressive multiple sclerosis (PPMS) Steady worsening of disease without any remissions. PPMS is less common. Relapsing progressive multiple sclerosis (RPMS) Steady worsening of disease from onset with relapses (with or without partial recovery). In 2012, a total of 149 deaths (53 males and 96 females) were registered with MS being the underlying cause and 249 registered deaths (83 males and 166 females) were associated with multiple causes, including MS, in Australia. 26 In general, MS is not considered to be a fatal condition and does not significantly reduce life expectancy. 27 MS can often lead to a considerable level of disability. The Kurtzke expanded disability status scale (EDSS) 28 is a scale used to measure the severity of the disability in neurological impairment in people with MS. The EDSS scale is based on eight functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral and other) and ranges from 0 (normal function) to 10 (death) with higher scores representing greater levels of disability (Figure 3). The scale has 0.5 unit increments. An EDSS score of 1.0 to 4.5 refers to fully ambulatory patients whilst patients with impairments in walking are indicated by a score of 5.0 to 9.5. Stem cell therapy for non-haematological (autoimmune) indications: March

21 Figure 3 Kurtzke expanded disability status scale (EDSS) (MS Decisions) 29 Number of patients The 2009 Australian Bureau of Statistics (ABS) Survey of Disability, Ageing and Carers estimated the number of people living with MS in Australia to be 23,700 individuals (0.1% of the population) with the true prevalence estimated to be between 21,150 and 26,250 individuals. 30 Of the estimated 23,700 Australians with MS in 2009, core-activity limitation was reported as profound (19.8%), severe (28.2%), moderate (11.9%), mild (15.5%), or no disability (22.7%). It is estimated that the number of people diagnosed with MS will increase by four per cent per year. 31 The prevalence of MS in Australia in 2010 was estimated to be 95.6 per 100,000 based on pharmaceutical prescription data for MS prescription medications which is similar to an estimate of 89.3 per 100,000 based on client membership of the Multiple Sclerosis Society database. 5 Based on the pharmaceutical data, the number of people living with MS in Australia in 2010 was estimated to be 21,283 people (Table 3). The number is likely to be underestimated as not all people diagnosed with MS may be on medication due to being in remission. Table 3 Number of people with multiple sclerosis in Australia, 2010, based on prescriptions, by state NSW Vic Qld SA WA Tas ACT NT TOTAL Number of people with MS 6,268 6,637 3,179 1,760 2, ,283 Percentage of cases of MS by State 29.5% 31.2% 14.9% 8.3% 10.9% 3.4% 1.7% 0.2% 100% Abbreviation: MS: multiple sclerosis A recent Australian study 32 used pharmacoepidemiology of MS disease-modifying drugs for RRMS between 2005 and 2008 to estimate the overall prevalence of MS (all subtypes) to be 68.4 per 100,000 people and the prevalence of RRMS in Australia to be 31.1 per 100,000 Stem cell therapy for non-haematological (autoimmune) indications: March

22 (Figure 4). This data supports a latitude gradient effect with the prevalence lower in the northern states of Australia and higher in the southern states of Australia. Mean prevalence of treated RRMS (per 100,000 people) Figure 4 Map of Australia illustrating the mean prevalence of treated RRMS by state, 2005 to MS is a disease of the nervous system (International Classification of Diseases, ICD-10 code G35) and (ABS code 607). In , the number of separations (episodes of care) of patients with a primary diagnosis of MS admitted to Australian hospitals was 19, According to updated guidelines, 4 the ideal target patient indications for auto-hsct for MS, are ambulatory patients (i.e. approximately EDSS <6) patients with: - rapidly progressing RRMS refractory to one or more lines of treatment; - SPMS with inflammatory activity who have deteriorated; and - severe malignant MS. Based on an incidence of 1,000 new cases of MS (all subtypes) per year, 85 per cent would be diagnosed with RRMS. It is estimated that of the 850 new cases of RRMS, approximately 125 to 187 patients would be refractory to interferon and alemtuzumab, or alemtuzumab only (Appendix A) and may be assessed for eligibility for auto-hsct across Australia. A proportion of these patients who are referred by their neurologist for auto-hsct, who met all of the inclusion/exclusion criteria, and agree to undergo the procedure, may be eligible for the auto-hsct treatment. It is difficult to estimate the number of patients with SPMS with inflammatory disease that may be suitable for auto-hsct. Stem cell therapy for non-haematological (autoimmune) indications: March

23 Systemic Sclerosis Disease description and associated mortality and morbidity Systemic sclerosis (SSc), also known as systemic scleroderma, is part of a group of conditions known as scleroderma and is recognised as the most severe connective tissue disorder. The aetiology of SSc remains unknown. SSc is an autoimmune disorder that involves endothelium dysfunction and excessive production of collagen due to altered fibroblasts. 34 This results in fibrosis of the skin and internal organs which in severe cases leads to organ failure and death. 35 SSc is sub-categorised depending on the extent of skin involvement: limited cutaneous SSc affects mainly the fingers, toes and face and the diffuse form affects large areas of the skin including the torso. A third subset with no skin involvement, sine scleroderma, is sometimes used. Figure 5 outlines the types of scleroderma. Scleroderma Localised scleroderma Systemic sclerosis Morphea Linea scleroderma Limited cutaneous systemic sclerosis Diffuse cutaneous systemic sclerosis Figure 5 Types of scleroderma Localised forms of the disease affect only the skin and related tissues, and will not progress to the systemic form. These localised forms, while they can have a severe impact on quality of life depending on the extent of skin involvement, are not life threatening. Similar to other autoimmune disorders, SSc is more common among females with around 4:1 females to males. 36 SSc affects many different systems throughout the body. Complications of SSc include digital vasculopathy (Raynaud s phenomenon, digital ulcers), pulmonary arterial hypertension, interstitial lung disease, scleroderma renal crisis and gastrointestinal disease. 37 Less than one third of those with this form of the disease will go on to develop the severe form. 36 Stem cell therapy for non-haematological (autoimmune) indications: March

24 SSc carries a highly increased mortality risk. Scleroderma renal crisis develops in 10 to 15 per cent of patients and was a major cause of mortality before ACE inhibitors c became widely available in the 1980s. 36 Renal crisis is currently managed well with optimal medical therapy. The major cause of mortality is now attributable to cardiopulmonary events including interstitial lung disease and pulmonary arterial hypertension. 1 The median survival for patients with SSc related interstitial lung disease is 5 to 8 years. 2 Interstitial lung disease occurs in both diffuse and limited cutaneous forms of the disease 38 and is found in around 40 per cent of patients with SSc. 34 Long term data shows a 2.5 times higher risk of death compared to the general population based on 40 years of observational studies. 35 This risk has remained relatively stable over time although there is a trend towards longer survival of patients in the last few decades due to the improvement in the treatment of renal crisis. 39 Number of patients The true prevalence of SSc is difficult to determine with international estimates ranging from three to 24 per 100,000 people. 40 There are no estimates for the prevalence of SSc in Australia; however, there are an estimated 100,000 people with SSc in the United States. 36 The Australian Rheumatology Association maintains the Australian Scleroderma Interest Group (ASIG) database. This database recruits patients from 12 sites across Australia and has over 1,000 Patients with SSc enrolled. 41 As of 2011, 88 per cent of patients were female and 26 per cent had diffuse disease. Twenty-four per cent of the cohort had significant interstitial lung disease and 11 per cent had pulmonary arterial hypertension using gold standard right heart catheterisation. 41 A systematic review of epidemiology suggests an incidence of SSc in Australia of 15 to 23 persons per million per year using data from three Australian sources covering 1993 to Based on the current population of 23.7 million people, this predicts that there will be 356 to 545 new cases of SSc diagnosed yearly in Australia. Based on the proportion in the Australian registry approximately 85 to 130 of these new cases will develop significant interstitial lung disease. Given that a proportion will respond well to current therapies and a proportion would be ineligible due to major organ involvement precluding stem cell treatment or for other medical reasons, it is estimated that between 30 to 65 patients may be a reasonable estimate of likely demand for stem cell services per year. c ACE inhibitors = angiotensin-converting-enzyme inhibitors Stem cell therapy for non-haematological (autoimmune) indications: March

25 Systemic lupus erythematosus Disease description and associated mortality and morbidity There are two main types of lupus; discoid lupus erythematosus (DLE) and SLE. DLE is the most common form of the condition confined to the skin. SLE is a chronic autoimmune disease characterised by inflammation across multiple organ systems, clinical pattern of flares/relapses and remissions, and the presences of autoantibodies. Most patients with SLE have symptoms in the skin and joints, although life threatening manifestations can arise in the kidney, lungs, the central nervous system, gastrointestinal system, ophthalmic system, cardiovascular system and haematologic system. Inflammation of the kidney can cause lupus nephritis which can lead to significant illness and can even be fatal. The vast variation in clinical and serological manifestations, led by a series of dysregulated immune processes, makes SLE a very heterogeneous disease which can affect any combination of organs in an individual. Due to the complexity of the disease, the primary causes of SLE remain unclear. A number of contributing factors have been identified as: 42 generalised T-cell dysregulation causes immune activity through multiple pathways; various B-cell defects cause damage to host tissue by means of loss of immune tolerance, dysregulation of cytokines and production of autoantibodies; the response of the innate immune system to pathogens, which leads to increased effects of interferon-α; and defects in the complement system and/or programmed cell death impair the clearing of immune debris, and in so doing, prolong inflammation. Epidemiological studies on SLE show marked variations in gender, age and race, as well as hormonal, genetic and environmental disease triggers. There are striking gender disparities in SLE burden, with the disease generally affecting females in 80 to 90 per cent of the cases. In 20 per cent of patients with SLE, symptoms arise prior to the age of 16 years. Childhoodonset SLE is known to confer a worse prognosis than adult disease in terms of disease activity, organ damage and mortality. 43 Studies of racial tendencies showed that SLE more frequently affects non-caucasian individuals than Caucasian individuals. The literature on mortality and morbidity of SLE in Australia is limited and primarily reported in comparison studies of Caucasian and non-caucasian population groups. A small study reported Aboriginal peoples (n=18) to have a mortality rate of 11.1 per cent compared to zero per cent for Caucasians (n=6). 3 Multiple reports have shown Asian patients with SLE are more affected then their Caucasian counterparts with respect to disease severity, renal involvement, photosensitivity, laboratory characteristics and flares No study has been able to confirm a difference in mortality rates of SLE between Asian Australians and non- Asian Australians. Several adverse effects of SLE on pregnancy have been reported including 47, 48 maternal or fetal complications and poor fetal outcomes. Stem cell therapy for non-haematological (autoimmune) indications: March

26 Number of patients The incidence of SLE in Australia is not well reported although a number of studies have reported the prevalence in population subgroups. The prevalence of SLE in Aboriginal peoples ( cases per 100,000 population) has been reported to be higher than in non-aboriginal peoples ( cases per 100,000 population). 3 Mackie et al. (2014) reported the first incidence data for paediatric SLE (younger than 16 years) in Australia and found 0.32 cases per 100,000 population per annum. 43 Lupus nephritis is a severe form of SLE affecting renal function and therefore would be likely to be the main population requiring stem cell transplantation. The prevalence of lupus nephritis in Australia was found to be 5.5 per 100,000 population. The prevalence of Caucasian lupus nephritis was lower (4.0 per 100,000 population) compared to Asian lupus nephritis (27.9 per 100,000 population). 49 Based on the current population, about 1,200 to 1,300 people would be living with the severe form of SLE in Australia. It is unclear how many of these people would be likely to benefit from stem cell therapies. Stem cell therapy for non-haematological (autoimmune) indications: March

27 Current technology Multiple sclerosis Disease modifying therapies for MS are medications aimed at decreasing the frequency and severity of relapses/attacks and reducing the disability progression of the disease. Disease modifying therapies are only available for clinically isolated syndrome (i.e. first episode of neurologic symptoms), RRMS and relapses in SPMS. The type of treatment used depends on the disease course and the treatment response. Currently, there are nine therapies listed on the Pharmaceutical Benefits Scheme (PBS) in Australia and three therapies approved by Pharmac in New Zealand (Table 4). Table 4 Therapies approved for multiple sclerosis in Australia and New Zealand Drug (trade name) Listed on PBS (Australia) Approved by PHARMAC (New Zealand) Dose / frequency CIS Approved indications RRMS Relapses in SPMS Interferon-b 1a IM 30μg weekly Interferon-b 1a S/C 44μg 3 times / week Interferon-b 1b S/C 250μg alternate days Glatiramer acetate 20mg daily Natalizumab 300mg every 4 weeks Fingolimod 0.5mg daily Teriflunomide 14mg daily Dimethyl Fumarate 240mg twice daily Alemtuzumab mg two courses Abbreviations: CIS: clinically isolated syndrome; IM: intramuscular; IV: intravenous; PBS: Pharmaceutical Benefits Scheme; RRMS: relapsing remitting multiple sclerosis; S/C: subcutaneous; SPMS: secondary progressive multiple sclerosis. Treatments for MS include immunomodulators, corticosteroids and immunosuppressants. The therapeutic approaches to disease modifying therapies for MS in adults have been reviewed by the Multiple Sclerosis Neurology Group of the Australian and New Zealand Association of Neurologists The first-line treatments for MS are immunomodulators including: interferon beta - RRMS: moderate reduction in relapses and disability in the short-term. - SPMS: slight reduction in change of experiencing relapses. - PPMS: not effective in preventing disability from getting worse. glatiramer acetate - RRMS: slightly reduces the chance of relapse. - RRMS/SPMS/PPMS: does not prevent disability getting worse. Second-line treatments for MS may include immunosuppressants such as natalizumab and fingolimod. Due to the potential serious risks of drug-induced leukaemia and cardiotoxicity associated with chemotherapy treatment, this treatment is reserved for aggressive MS refractory to therapy. The escalation of treatment beyond the first-line treatments are more Stem cell therapy for non-haematological (autoimmune) indications: March

28 potent and may have a greater effect on the disease; however, there are more serious side effects, higher costs and limited evidence on long-term outcomes and the types of MS that may benefit. Alemtuzumab was recently approved by the TGA in December 2013 as a firstline treatment option for active RRMS and is awaiting listing on the PBS in Australia. Alemtuzumab has been shown to be superior to interferon beta in reducing the frequency of relapses and delaying the progression of disability in some patients with active MS. It is not recommended for patients who are stable on their current treatment or who have inactive disease. Side effects of alemtuzumab include infusion-associated reactions, lowered blood cell counts, infections, overactive or underactive thyroid gland, and immune thrombocytopenic purpura (ITP). As this can be fatal, monitoring is required for the early detection and treatment of ITP. Other promising disease-modifying therapies in late phase development for MS have been published. 53 Systemic sclerosis Due to the involvement of multiple organs and systems in SSc, many different therapies are used in the management of this condition. No current therapy is curative. A large range of vasodilators, vasoactive therapies, immunomodulators and antifibrotics have been used to treat the symptoms of SSc. 37 Table 5 lists the most common complications and recommended therapies from the European league against rheumatism (EULAR) scleroderma trials and research group. 37 This list includes the therapies that have the most evidence available but is not a comprehensive list of all therapies available. Table 5 Recommended therapies for treatment of major systemic sclerosis complications Systemic sclerosis complication Therapy Evidence Digital vasculopathy (Raynaud s phenomenon, digital ulcers) Calcium antagonists (nifedipine), prostanoids (intravenous iloprost) Bosentan if failure of calcium antagonists and prostanoid therapy Bosentan, sitaxentan, sildenafil Intravenous epoprostenol for severe symptoms Pulmonary Arterial Hypertension Skin involvement Methotrexate Improves skin score Interstitial lung disease Cyclophosphamide Improves lung function Scleroderma renal crisis ACE inhibitors Prevent renal crisis Gastrointestinal disease Proton pump inhibitors, prokinetic drugs and rotating antibiotics Source: Topal and Dhurat (2013) 37 Abbreviations: ACE inhibitors = angiotensin-converting-enzyme inhibitors Reduces the frequency and severity of Raynaud s phenomenon attacks Heals digital ulcers Prevention of digital ulcers Improves exercise capacity, functional class and some haemodynamic measures Poor evidence available but may improve symptoms of reflux, ulcers and strictures, gastric motility and reduce bacterial overgrowth causing malabsorption Treatments used for SSc lung involvement (the most frequent cause of mortality) have included prednisone, azathioprine, cyclophosphamide, rituximab and mycophenolate mofetil. 2 Oral cyclophosphamide is the only treatment to have been tested in randomised controlled trials (RCTs) and shown to have some benefit in the treatment of SSc interstitial Stem cell therapy for non-haematological (autoimmune) indications: March

29 lung disease. In a systematic review including three RCTs, a meta-analysis found that cyclophosphamide significantly improved the diffusing lung capacity of carbon monoxide (3.74, 95% CI [0.09, 7.40]) and showed a positive trend to improving forced vital capacity (4.15, 95% CI [-0.51, 8.80]). 54 These benefits were modest and below what could be considered clinically relevant. Cyclophosphamide treatment carries considerable risk of toxicity and close monitoring of haematological status is required. Myelosuppression can lead to leukopenia, neutropenia, thrombocytopenia (higher risk of bleeding events), and anaemia. Immunosuppression can cause serious and sometimes fatal infections. Renal, cardiac and pulmonary systems can also be affected with severe consequences. Secondary malignancies, sterility and genotoxicity are also possible. The usual dose for immunosuppressive therapy as used for SSc is 1 to 3mg/kg orally depending upon response and toxicity. 55 In conclusion, there is no one therapy available to treat all aspects of the disease process. Systemic lupus erythematosus The current treatment methods have created a dramatic improvement in prognosis for patients with SLE, though improving the prognosis of refractory patients with SLE continues to be an obstacle. The guidelines presented by the EULAR recommend the use of antimalarial and/or glucocorticoids on patients not displaying major organ involvement. 42 Glucocorticoids are still the foundation of SLE treatment, despite their well-known sideeffects. 56 In non-responsive patients or those requiring a higher than acceptable use of steroids, immunosuppressive agents are recommended. Lupus nephritis is a common and challenging manifestation of SLE. This variety of SLE is treated in two phases; aggressive immune suppression (induction phase), and a long term, less aggressive immune suppression (maintenance phase). The aim of the induction phase is to get the life threatening SLE flare under control with limited side-effects. The most common induction phase therapies include the use of cyclophosphamide or mycophenolate mofetil, often with concurrent use of corticosteroids. The maintenance phase regimens consist of continued less frequent use of cyclophosphamide, mycophenolate mofetil or azathioprine. The aim of biological treatments is to use the knowledge of the different dysregulated immunological pathways involved in SLE to develop target specific therapies. There are many biological therapies in clinical trials or development. Only two biological therapies are being used as treatments; belimumab and rituximab. Belimumab has current TGA approval for add-on therapy in adult patients with active, autoantibody-positive SLE with a high degree of disease activity. It also has United States Food and Drug Administration (FDA) approval. It is not currently listed on the PBS and therefore will currently have very limited use in Australia. Rituximab is not approved in Australia or the United States for use in SLE; Stem cell therapy for non-haematological (autoimmune) indications: March

30 Rituximab is used off-label in the United States for patients with refractory SLE in addition to immunosuppressive treatment; however, RCTs have failed to find a clinical benefit. The current therapies in use for SLE are summarised in Table 6. Table 6 Current therapies used in the management of systemic lupus erythematosus Severity of SLE Therapy type Common medications Evidence Mild Antimalarials Hydroxychloroquine First-line treatment effective in treatment of and preventing future mild manifestations but is ineffective against severe SLE manifestations. 57 Mild to moderate Glucocorticoids Prednisone Methylprednisolone Supresses SLE fever. 58, 59 Treatment of pulmonary manifestations of SLE with Glucocorticoids showed per cent survival rates. Ineffective as sole therapy for gastrointestinal, neurological, ophthalmologic and haematologic manifestations of SLE. 56 Serious adverse events with long term use including osteoporotic fractures; symptomatic coronary artery disease; cataracts; diabetes; pulmonary fibrosis; cognitive impairment/psychosis Moderate to Severe Maintenance for mild Moderate lupus arthritis Severe lupus nephritis Severe lupus nephritis Immunosuppressing agents Azathioprine Methotrexate Cyclophosphamide Mycophenolate mofetil Azathioprine has superior efficacy to corticosteroids in the treatment of lupus nephritis, but less effective than other immunosuppressing agents. 57 Treatment of joint involvement especially for lupus arthritis. Two clinical trials have shown an association between methotrexate therapy and articular improvement. 63, 64 Side effects mild and controllable. Does not have a place in the treatment of SLE with major organ involvement. Has been first-line treatment for lupus nephritis, often in conjunction with steroid therapy. Predominantly used in the induction phase due to its aggressive side effects. Long-term exposure to cyclophosphamide can cause bladder cancer, bone marrow suppression, haematologic malignancies, infections, myelodysplasia and premature gonadal failure. 65 Newer treatment for lupus nephritis equal in efficacy and with fewer side effects then cyclophosphamide Moderate to Biological treatments Belimumab Two phase III trials showed superiority on the SLE responder index, severe SLE however the overall effect size was modest. 69, 70 Adverse events across the treatment groups were not noticeably different. Severe SLE (active central nervous system or nephritis) patients were not included in the clinical trials so benefit is not clear in this group of patients. Severe SLE Rituximab A clinical trial failed to show benefit in primary and secondary endpoints. 71 Several open-label or retrospective studies suggest that adding rituximab to standard treatment regimen is beneficial. 72 Common side effects are mild Infusion infection, while neutropenia and severe infections were reported in 10 per cent of treated patients. 73 Abbreviations: SLE: systemic lupus erythematosus. The high morbidity of cyclophosphamide and the building evidence of mycophenolate mofetil efficacy are creating a considerable push for mycophenolate mofetil to be the firstline immunosuppressant in the induction and maintenance phase therapy for lupus nephritis. Studies have shown that as a treatment for lupus nephritis, mycophenolate mofetil is at least equal in efficacy and has fewer side effects than cyclophosphamide Stem cell therapy for non-haematological (autoimmune) indications: March

31 The adverse events associated with mycophenolate mofetil are primarily mild, consisting of gastrointestinal events and infections. 57 Although mycophenolate mofetil may become the appropriate first-line treatment for lupus nephritis and therefore be the main comparator to stem cell transplantation, in the relevant clinical trials the inclusion criteria was primarily failure of cyclophosphamide treatment. Diffusion of technology in Australia Haemopoietic stem cell transplantation Autologous haemopoietic stem cell transplantation In Australia, auto-hsct is widely used as a treatment for disorders of the blood and immune system (e.g. leukaemia and lymphoma) and as supportive treatment for blood-related cancers. To date, less than 40 patients with MS have undergone auto-hsct across several sites in Australia including St Vincent s Hospital in Sydney, the Sir Charles Gairdner Hospital in Perth and the Canberra Hospital in Canberra. 74 St Vincent s Hospital is currently the only site providing auto-hsct for patients with MS and other severe autoimmune diseases (including SSc and SLE) in Australia where the procedure is being performed as part of phase II clinical trials using strict eligibility criteria. There have been over 60 auto-hsct for autoimmune diseases performed at St. Vincent s Hospital since Information on blood stem cell transplants performed in Australia and New Zealand are collected by the Australasian Bone Marrow Recipient Registry, which is hosted at St. Vincent s Hospital. Allogeneic haemopoietic stem cell transplantation The use of allo-hsct for the treatment of autoimmune diseases has been extremely limited. 4 The major concern with allogeneic transplants is the potential for graft versus host disease, a severe and potentially life threatening complication which has limited the diffusion of the technology. Mesenchymal stem cell therapy Autologous and allogeneic mesenchymal stem cell therapy For allogeneic bone marrow derived mesenchymal stem cells manufactured in Western Australia (WA) under TGA license, there have been approximately 400 infusions performed in about 90 patients throughout Australia. There have been 10 clinical trials originating from WA using mesenchymal stem cells to treat a variety of conditions. There has been limited use of MSCT for the treatment of autoimmune disease in Australia with one small study published in Crohn s disease. 75 There have been attempts to engage in early phase trials of mesenchymal stem cell therapy in MS in Australia. Stem cell therapy for non-haematological (autoimmune) indications: March

32 Cost infrastructure and economic consequences Estimate of the ratio and number of patients eligible for autologous haemopoietic stem cell transplantation Data from the European Group for Blood and Marrow Transplantation (EBMT) registry shows that the majority of auto-hsct treatments reported to the registry from 2005 to 2007 were severe cases of MS (49%), whilst SSc and SLE accounted for 25 per cent and five per cent of cases, respectively (Table 7). Other autoimmune conditions such as rheumatoid arthritis, juvenile idiopathic arthritis and haematologic immune cytopenia accounted for the remaining 21 per cent of auto-hsct treatments during that period. Recent data suggests that auto-hsct is now rarely used for rheumatoid arthritis as newer biological treatments have proved effective. Updated registry figures of the total number of HSCTs registered with the EBMT by condition have been published; 4 however, the relative progression in the number of procedures over time cannot be elicited. Table 7 Number and proportion of autologous haemopoietic stem cell transplantation performed for severe autoimmune diseases reported to the European Group for Blood and Marrow Transplantation registry from 2005 to 2007 Year MS SSc SLE Other a Total number of auto-hsct /80 (44%) 17/80 (21%) 6/80 (8%) 22/80 (28%) /99 (53%) 22/99 (22%) 4/99 (4%) 21/99 (21%) /61 (49%) 21/61 (34%) 2/61 (3%) 8/61 (13%) 61 Total 117/240 (49%) 60/240 (25%) 12/240 (5%) 51/240 (21%) 240 Abbreviations: auto-hsct: autologous haemopoietic stem cell transplantation; MS: multiple sclerosis; SSc: systemic sclerosis; SLE: systemic lupus erythematosus; a other conditions include rheumatoid arthritis, juvenile idiopathic arthritis, haematologic immune cytopenia and other autoimmune diseases. It is likely that Australian patients would share similar characteristics with a European cohort and therefore it is reasonable to assume that these MS, SSc and SLE would represent around 80 per cent of auto-hsct for autoimmune (non-haematological diseases) required in Australia. Cost analysis Limited economic information was available on stem cell treatments for autoimmune diseases in Australia. This is likely due to the lack of mainstream use of stem cell transplantations for autoimmune diseases. It was estimated that the direct cost to government for healthcare and community care for MS in 2010 was $10,721 per patient, with an additional cost of $4,384 and $3,697 attributable to residential care and direct patient costs, respectively. 5 If hospitalised for MS, the relevant diagnosis-related groups (DRGs) are B68A/B for MS and cerebellar ataxia, at a cost of $11,136 and $1,731 with (+CC ) and without (-CC) Stem cell therapy for non-haematological (autoimmune) indications: March

33 complications and comorbidities, respectively ( data). 76 There is no DRG registered for SSc or SLE. No cost of illness studies were found that reported costs for SSc in Australia. An estimate of the cost for SSc in Canada in a cohort of 457 people with SSc found the direct healthcare cost of $5,038 per patient (2007 Can$) 6. This cost, converted to 2013 Australian dollars using the OECD d purchasing parity index, 7 was $6,328. The Canadian cohort in this study included a wider range of patients than those likely to benefit from HSCT therefore the cost of patients with severe disease would be higher than this estimate. No cost of illness studies were found that reported costs for SLE in Australia. A paper by Khamashta et al. (2013) 77 reported the cost (standard deviation) associated with a patient with severe SLE in the UK as 4,652 ( 2,265) per annum. The cost (standard deviation) in Australian dollars using the 2013 OECD purchasing parity index was $10,963 ($5,338). According to the selection criteria of the SLE studies, $10,963 would be a reasonable estimate of the yearly cost of a patient eligible for HSCT, as only severe patients with SLE are considered for stem cell transplantations. The estimated cost for a primary auto-hsct for MS has been valued for the purpose of this report and is presented in Table 8. The auto-hsct method is similar across the three autoimmune disease indications. The cost per auto-hsct treatment is estimated to be $75,082. This estimate was based on the cost of undergoing an auto-hsct in one major transplant centre in Australia with an average length of stay of 27 days and may not reflect the cost of undergoing the procedure in other centres throughout Australia. However, when national data is used the average length of stay ranges from 6.9 to 21.6 days for the DRG AO8B and AO8A, respectively (autologous bone marrow transplant without and with catastrophic complication and/or co-morbidity, respectively). Using the 2015 National Efficient Price as defined by the Independent Hospital Pricing Authority of $4,971 this would result in a national average price for each service ranging from $16,068 to $36,469. This would result in an overall total estimated cost, inclusive of mobilisation, stem cell collection and follow-up visits, of $30,364 to $50,765. d OECD = Organisation for Economic Co-operation and Development Stem cell therapy for non-haematological (autoimmune) indications: March

34 Table 8 Estimated cost per autologous haemopoietic stem cell transplantation for multiple sclerosis Costs Reference Cost per patient Based on 27 days ALOS a Cost per patient Based on National ALOS A Auto bone marrow transplantation (A08A) IHPA 78 $60,785 b $16,068 to $36,469 B Chemotherapy (R63Z) IHPA 78 $1,768 b $1,768 b C Mobilisation (filgrastim 10 mcg/kg administered at home for 8 days) c PBS 79 $2,776 $2,776 D Stem cell collection (outpatient haematology) IHPA 78 $658 b $658 b E Rehabilitation (Z60A/Z60B) 6 days) IHPA 78 $4,485 b $4,485 b F Follow-up visits (7 visits in first year after treatment) IHPA 78 $4,609 b $4,609 b G Total cost of HSCT (A+B+C+D+E+F) $75,082 $30,364 to $50,765 Abbreviations: mcg/kg: micrograms per kilogram of body weight; LOS: Length of stay; IHPA: The Independent Hospital Pricing Authority; PBS: The Pharmaceutical Benefits Scheme; AUD: Australian Dollars; HSCT: haemopoietic stem cell treatment; a The average length of stay of 27 stays was based on the current average length of stay of patients with multiple sclerosis undergoing an auto-hsct in one major transplant centre in Australia. b Adjusted from 2012 AUD to 2014 AUD using medical and hospital services inflation. c The cost of stem cell mobilisation was based on the daily administration of filgrastim subcutaneous injections by the patient or a nominated other at home for 8 days (range 7 to 9 days). The average body weight of an Australia adult was weighted to the proportion of females/males (3:1) with multiple sclerosis and was calculated to be 75kg. The estimated daily dose required for a 75kg adult at 10mcg/kg would be 750mcg. Using this estimate, the amount of filgrastim required over the treatment period would be 10 packs of 480mg syringes plus 10 packs of 300mg syringes would be required. The average cost per DRG for an autologous bone marrow transplant with catastrophic complications and comorbidities (+CCC) (A08A) e sourced from Independent Hospital Pricing Authority (IHPA) national hospital data was used as the baseline cost. 78 This cost is based on malignant disease and according to a transplant specialist with experience in this area, patients with autoimmune diseases are general more sick and stay longer in hospital on average for this procedure compared to patients with malignancies. In addition, these patients require an additional five to seven days of rehabilitation post-procedure. As such, the baseline cost was amended to account for longer hospital stays, chemotherapy, stem cell mobilisation, stem cell collection, additional rehabilitation and follow-up visits within the first year after transplantation. Costs may also differ depending on the types of medications used in the protocol, the severity of patients, and the type of autoimmune condition. For example, there are biosimilar medications for the granulocyte-colony stimulating factor, such as pegfilgrastim, which are less costly than filgrastim. The cost estimate in this report was based on the medications used in a current clinical trial in Australia. e The DRG for an autologous bone marrow transplant +CCC (A08A) (length of stay 22 days) was considered a more appropriate baseline cost estimate of the procedure compared to the DRG for auto bone marrow transplant -CCC (A08B) (length of stay 8 days) due to the increased length of stay experienced by patients with autoimmune diseases (average length of stay days). Stem cell therapy for non-haematological (autoimmune) indications: March

35 This cost estimate is based on a primary auto-hsct procedure only does not account for repeated stem cell transplantation procedures or combined therapies that may be required. There is limited evidence available for the need for subsequent stem cell treatments. The average cost per patient with different autoimmune conditions is relatively similar; however, patients with SSc require an extra day in hospital for the insertion of specialised central venous catheter. Costs associated with MSCT include the manufacture of mesenchymal stem cells in an accredited facility, which is estimated at $10,000 $20,000 per treatment course. The costs associated with chemotherapy, in-patient and support costs are significantly less than HSCT. Capacity for autologous haemopoietic stem cell transplantation for autoimmune diseases in existing hospitals in Australia It is unclear whether there would be capacity within existing hospitals across Australia to accommodate the anticipated increase in demand for stem cell therapies if they were to be extended to these autoimmune diseases (MS, SSc and SLE). However, there would be a significant increased burden on hospital staff. Staffing requirements for auto-hsct under a larger clinical trial would include staff specialists for haematology and neurology, clinical trial nurses, nurses, research scientists and project staff. The strong centre effect observed in the European registry and American registry data, which demonstrates that more experienced centres are associated with improved safety and clinical outcomes, highlights the need to limit the procedure to a few specialised sites across Australia. Stem cell therapy for non-haematological (autoimmune) indications: March

36 Training and accreditation HSCTs are generally performed in haematology departments of specialist hospitals. Unlike HSCTs, MSCT requires access to a TGA approved laboratory. Several hospitals across Australia are accredited by the Australian Bone Marrow Donor Registry to perform allogeneic stem cell transplantations with an unrelated donor. Ethical, cultural, access or religious considerations Auto-HSCT remains a relatively experimental treatment for MS and should only be performed in a clinical trial setting, under the guidance of a human research ethics committee and with full informed consent. Currently, there is a registered phase II clinical trial for auto-hsct for patients with MS being conducted in Australia. Patients with MS are required to have accessed, and be unresponsive to, multiple standard therapies prior to enrolling in this clinical trial. Some patients in Australia that do meet the inclusion and exclusion criteria for the clinical trial, and/or who do not wish to wait until all of the standard therapy options have been exhausted, have chosen to seek treatment overseas. There are some international centres providing stem cell treatments, which, despite some having comparable safety and efficacy outcomes, are not part of registered clinical trials. Patients who have undergone stem cell treatments may not be eligible to participate in registered clinical trials in the future. MSCTs require access to a TGA approved laboratory facility; however, the procedure for both HSCT and MSCT are not subject to TGA approval, making it difficult to regulate. MS is generally not considered to be a fatal disease unlike the severe forms of SSc and SLE, therefore the current TRM of auto-hsct for MS at one to two per cent remains a significant concern. 8 Auto-HSCT may be confused with treatment and research involving embryonic and fetal stem cells. Some people object to the use of embryonic and/or fetal material for such purposes. A clear differentiation in use of terminology would help to minimise this potential confusion. Providing publicly funded stem cell transplantations for these conditions may lead to therapies being offered in the private sector. These facilities may not be of comparable standard to a specialist centre and therefore the outcomes may be inferior. A private facility may not generate the number of patients needed to ensure that staff members are experienced and the highest quality service is provided. The safety and efficacy of stem cell transplantations for autoimmune disorders and its benefits compared to existing standard therapies needs to be demonstrated through randomised clinical trials prior to becoming an accepted treatment option. Currently, SSc is the only autoimmune condition in this report which has this level of evidence available. Stem cell therapy for non-haematological (autoimmune) indications: March

37 Evidence and Policy Safety and effectiveness for multiple sclerosis Haemopoietic stem cell transplantations for multiple sclerosis Fifteen studies, published between 2009 and 2014, were eligible for inclusion in this report. To be eligible for inclusion, studies were required to have 10 or more participants and report on the safety and/or efficacy of haemopoietic stem cell treatment. Of the 15 studies included, eight were non-comparative case series, two were retrospective observational studies, four were retrospective cohort studies of patient registries, and one was a descriptive study. The profiles of the included studies of HSCT for MS are detailed in Appendix B. It should be noted that there may be considerable overlap in patients analysed in the retrospective cohort studies of the patient registries. Study Description A description of the treatment characteristics for each of the 15 included studies for HSCT for MS is presented in Table 9. Nash et al. (2014) 80 recently published 3-year interim findings of the HALT-MS study, an ongoing, prospective, multicentre, phase II clinical trial designed to evaluate the safety, efficacy, and durability of high-dose immunosuppressive therapy and auto-hsct for 25 patients with RRMS. Patients with RRMS receiving disease-modifying therapies during the 18 months prior to the procedure who experienced relapses with loss of neurologic function were eligible to participate in the study. The follow-up period was five years and the primary outcome was event-free survival. Adverse events were also reported. An observational study by Burman et al. (2014) 81 used retrospectively collected data from follow-up surveys of 48 patients with MS (RRMS=40; SPMS=5; PPMS=2; and PRMS=1) who were treated with auto-hsct in Sweden. A total of 41 patients with MS had at least one year of follow-up (mean follow-up 47 months) in which relapses, disease progression, survival and adverse events were recorded. The long-term outcome of a large, international, retrospective cohort study of auto-hsct for patients with MS was published in a recent abstract by Muraro et al. (2013). 82 The study was conducted by the Center for International Blood and Marrow Research and the European Group for Blood and Marrow Transplantation between 1995 and Data was collected data from 281 patients (RRMS=46; SPMS=186; PPMS=32; PRMS=17) in 13 countries. The median EDSS (a measure of severity of the disability in neurological impairment) at baseline was 6.5 (range ) and the follow-up period was 6.6 years (range years). Stem cell therapy for non-haematological (autoimmune) indications: March

38 A review study by Pasquini et al. (2012) 83 examined the characteristics and safety of patients with autoimmune diseases, including 143 patients with MS (RRMS=8; SPMS=62; PPMS=23; and unknown/not reported=50), from a patient database of the Center for International Blood and Marrow Transplant who had an auto-hsct in North and South America transplantation centres between 1996 and The median follow-up of survivors was 31 months (range < months) in which survival and mortality was reported. A prospective phase II, open-label single-centre study in Russia conducted by Shevchenko et al. (2012) 84 investigated the safety and efficacy of high-dose immunosuppressive therapy and auto-hsct in 95 patients with MS (RRMS=42; SPMS=35; PPMS=15; and PRMS=3) who underwent early, conventional, and salvage/late transplantation. f The mean long-term follow-up was 46 months (range months) in which survival, disease progression, quality of life outcomes and adverse events were recorded. A review of the patient registry of the EBMT was conducted by Mancardi et al. (2012) 85 of all patients (n=74) with MS treated with the same conditioning regimen (BEAM/anti-thymocyte globulin) in Italy during 1996 to The median follow-up was 48.3 months (range months). In a study by Bowen et al. (2012), 86 the long-term safety and effectiveness of high-dose immunosuppressive therapy and auto-hsct was assessed in 26 patients with advanced MS. Data was collected from 2005 to The design, conditioning and outcomes have been published previously. 87, 88 Of the 26 patients, 17 had SPMS, 8 had PPMS and 1 had RRMS with a median age of 41 years (range years). Patients had a median disease duration of 84 months (range months). The mean EDSS score was 7.0 (range ). Patients were followed-up for a median of 48 months (range 3 72 months) posttransplantation. Chen et al. (2012) 89 conducted a retrospective analysis of the safety and long-term clinical outcomes of 25 treatment experienced patients with MS who underwent an auto-hsct in China between 2000 and Of the 25 patients, 19 patients had SPMS, 1 had PPMS, 2 had PRMS and 3 had RRMS. At the time of transplantation, the median disease duration was 48 months (range months) and the median EDSS score was 8.0 (range 3-9.5). Patients were followed-up for a mean of 59.6 months (range ). Fourteen of the 25 patients were assessed as having active lesions according to the pre-transplantation MRI scans. Xu et al. (2011) 90 assessed the clinical outcomes of auto-hsct in a sample of 36 patients with SPMS, of which 15 had MS of the conventional subtypes (CMS) defined in this report and 21 patients had opticospinal MS, which is considered a variant of MS. The average f Early referred to patients with an EDSS score between with auto-hsct soon after diagnosis in primary refractory disease or poor prognosis; conventional: patients who had an EDSS score of with secondary refractory disease; and salvage/late: patients who had an EDSS score of with high disease activity and rapid neurological deterioration in late stages of the disease. Stem cell therapy for non-haematological (autoimmune) indications: March

39 follow-up was 48.9 months (range 10 91). The average duration of disease at transplantation was 72.4 months (range months). The average EDSS score was 6.6 (range ). Patients were followed-up for an average of 48.9 months (range months). In a phase I/II study in a single centre, Fassas et al. (2011) 91 evaluated the long-term effectiveness of auto-hsct in 35 patients with aggressive MS (SPMS=19; PPMS=11; RPMS=3; ARPMS=1; and RRMS=1) between June 1995 and May The treatment protocol was previously described. 92 The median EDSS score at baseline was 6 (range 4.5 8). Twelve out of 30 patients (40%) had active disease as indicated by single-dose Gd+, or new or enlarging T2 lesions on the MRI at baseline. Patients (n=33) were followed up for a median of 11.3 years ( ). In an observational study, Farge et al. (2010) 19 performed an analysis of 900 patients with autoimmune diseases treated with auto-hsct and were reported to the EBMT registry between 1996 and Of the 900 patients, 345 patients had MS. Patients with MS underwent an auto-hsct using peripheral blood stem cells, with or without bone marrow (95%) or stem cells from bone marrow only (4.7%). Patients were categorised according to the type of conditioning regimen; low intensity (6%), intermediate intensity (81%) and high intensity (45%). Primary outcomes were overall survival, progression-free survival and transplant-related mortality at 100 days. Average follow-up was 31 months ( ). A prospective multi-centre study by Hamerschlak et al. (2010), 93 analysed two groups of patients with MS treated with different conditioning regimens; BEAM/horse anti-thymocyte globulin (n=21) between 2001 and 2004, and cyclophosphamide/rabbit anti-thymocyte globulin (n=20) between 2004 and The majority of patients had SPMS (n=33; 80.4%), RRMS (n=4; 9.8%), and PPMS (n=4; 9.8%).The median EDSS score at baseline was the same in both groups (median=6.5, range 5-7). There were differences in the MRI activity at baseline, with more active disease activity in the BEAM/horse anti-thymocyte globulin group than the cyclophosphamide/rabbit anti-thymocyte globulin group (35.0% vs 5.3%, p=0.04, respectively). Patients were follow-up until November A descriptive study by Guimaraes et al. (2010), 94 investigated the impact of auto-hsct on health related quality of life in 34 patients with MS treated with auto-hsct between 2003 and 2008 in Brazil. Two primary outcomes measures, Medical Outcomes Study 36-Item Short-Form Health Survey and the EDSS, were administered at admission, hospital discharge and 1 year following the transplantation. Most cases had SPMS (64.7%) followed by RRMS (20.6%) and PPMS (14.7%). A single-centre study by Krasulova et al. (2010) 95 assessed the long-term safety and effectiveness of auto-hsct in 26 patients with MS (RRMS=11; SPMS=15) in the Czech Republic between 1998 and Patients had a median EDSS score of 6 (range ) Stem cell therapy for non-haematological (autoimmune) indications: March

40 and median disease duration of 7 years (range 2 19 years). The median follow-up period was 66 months (range months). In a phase I/II study in USA, Burt et al. (2009) 96 analysed the safety and efficacy of auto-hsct in 21 patients with RRMS who were non-responders to interferon beta between 2003 and Progression-free survival and neurological disability (as indicated by the EDSS scores) were assessed at baseline, six months, one year and then annually. The mean follow-up was 37 months (range months). Safety Common adverse events were reported in 10 of the 15 included studies for HSCT for MS and are presented in Table 10. Five of the studies did not report adverse events. 19, 82, 83, 91, 94 The most frequent adverse events in the included studies were events related to acute toxicity, neutropenic fever, engraftment syndrome, hepatic toxicity, sepsis, infections, diarrhoea and severe mucositis. These are commonly reported events with immunosuppressive therapies. The adverse events were usually of low grade, however, the grading of adverse events were not consistently reported in the studies. It was difficult to compare the rates of adverse events between studies due to the different methodologies. Mortality Mortality was reported differently across the included studies. Where possible, 100-day treatment-related-mortality (100-day TRM) was extracted as per reporting guidelines (Table 11). For the case series, the 100-day TRM ranged from zero per cent to four per cent and the overall TRM ranged from zero to 14 per cent. For the retrospective analyses, the 100-day TRM and TRM ranged from two to four per cent and from 2.7 to 3.8 per cent, respectively. Stem cell therapy for non-haematological (autoimmune) indications: March

41 Table 9 Treatment characteristics of all included studies of HSCT for multiple sclerosis Study Treatment Mobilisation Graft Manipulation Conditioning regimen Post-transplantation Nash et al (2014) 80 Auto-HSCT (PB) G-CSF (n=24) and CY (n=1); and prednisone CD34+ selection BEAM/rATG Prednisone Burman et al (2014) 81 Auto-HSCT (PB) CY and G-CSF No manipulation BEAM/ATG (n=41), or CY/ATG (n=7) NR Muraro et al (2013) 82 Auto-HSCT NR NR NR NR Pasquini et al (2012) 83 Auto-HSCT (PB or BM) G-CSF - CY + ATG (with or without TBI) a NR Shevchenko et al (2012) 84 Auto-HSCT (PB) G-CSF No manipulation BM (n=60), or minibeamlike (n=30) b (±horse ATG), and G-CSF Mancardi et al (2012) 85 Auto-HSCT (PB) CY and G-CSF - BEAM/rabbit ATG NR Bowen et al (2012) 86 Auto-HSCT (PB) rhg-csf e CD34 selection Fractionated TBI, CY and equine ATG (ATGAM) NR Chen et al (2012) 89 Auto-HSCT (PB) CY and G-CSF CD34+ enrichment CY/TBI (n=1), or BEAM (n=24) rabbit ATG, methylprednisolone Xu et al (2011) 90 Auto-HSCT (PB) G-CSF CD34+ selection (n=28) Modified BEAM c NR Fassas et al (2011) 91 Auto-HSCT (PB) CY and G-CSF CD34+ selection (n=10) BEAM (n=15), BEAM plus ex vivo CD34 cell selection (n=10), or busulfan (n=10) Farge et al (2010) 19 Auto-HSCT (PB, BM or both) CY and G-CSF; or G-CSF alone Hamerschlak et al (2010) 93 Auto-HSCT (PB) CY and G-CSF, and methylprednisolone CD34+ selection 92%); negative purging (8%) No manipulation rabbit ATG (during pretransplantation) Chemotherapy alone (93%) or TBI (7%) d ATG (55%) Group 1: BEAM with horse ATG (n=21), Group 2: CY and rabbit ATG. (n=20) e Guimaraes et al (2010) 94 Auto-HSCT NR NR NR NR Krasulova et al (2010) 95 Auto-HSCT (PB) CY and G-CSF In vitro purging (n=13) (50%) BEAM NR Rabbit polyclonal ATG (n=15); double purging (n=2) Burt et al (2009) 96 Auto-HSCT (PB) CY and G-CSF - CY with intravenous mesna, and G-CSF (filgrastim) alemtuzumab with methylprednisolone m Abbreviations: auto-hsct: autologous haemopoietic stem cell transplantation; ATG: anti-thymocyte globulin; BM: bone marrow; CY: cyclophosphamide; rhg-csf: recombinant human G-CSF; TBI: total body irradiation; PB: peripheral blood; a most patients with autoimmune disease had CY/ATG (with or without TBI); b BM consisted of BCNU/CCNU and melphalan, minibeamlike consisted of BCNU/CCNU, etoposide, Ara-C and melphalan; c Modified BEAM consisted of tiniposide, melphalan, carmustin, and cytosine arabinoside; d Combinations of chemotherapy alone (93%), included CY-based (52%), busulfan-based (4%), and BEAM-based (carmustine, cytarabine, melphalan, and etoposide) (34%); e rabbit anti-thymocyte globulin instead of alemtuzumab (n=4). Stem cell therapy for non-haematological (autoimmune) indications: March

42 Table 10 Common adverse events of all included studies of HSCT for multiple sclerosis Nash et al Burman et al Shevchenko Mancardi et Bowen et al Chen et al Xu et al Hamerschlak Krasulova et Burt et al (2014) 80 (2014) 81 et al (2012) 84 al (2012) 85 (2012) 86 (2012) 89 (2011) 90 et al (2010) 93 al (2010) 95 (2009) 96 N (%) N (%) N (%) N (%) N (%) a N (%) N (%) N (%) N (%) N (%) Adverse events Events related to acute toxicity b - Majority 95 (100%) 59 (80%) 1 (4%) c /39 (46%) d 14 (56%) d - Neutropenic fever - 17 (35%) 30 (32%) 52 (70%) e - 12 (48%) 53% (24%) Engraftment syndrome 1 (4%) /18 (72%) Hepatic toxicity grade I and II (42%) Mild hepatic function damage % Transient neurological dysfunction (27%) (5%) Pneumonia (2%) /40 (20%) - - Sepsis a (3%) 22 (30%) (40%) - Urinary tract infection (25%) 8 (31%) - - 7/40 (18%) 7 (28%) - Diarrhoea and severe mucositis (15%) Diarrhoea / gastrointestinal disorders 9 (36%) % - 16 (64%) 1 (5%) Severe mucositis (grade II-III) - 4 (8%) (44%) - Allergy thymoglobulin / lymphoglobulin /40 (13%) - - Bacteraemia - 22 (46%) g (15%) Typhlitis - 5 (10%) Infection reactivation cytomegalovirus (7%) 4/9 (44%) Bacterial infection (52%) Transient elevation of liver enzymes (24%) Tachycardia % Transient deterioration of neurological function % Herpes zoster reactivation - 8 (17%) Infections 14 (56%) (5%) (20%) - Metabolism, grade III, grade IV 8 (32%), 3 (12%) Headache 3 (12%) Deep vein thrombosis 3 (12%) 1 (2%) (8%) Note. This table includes adverse events that occurred in 10 per cent or more of patients; a reported in Nash et al. (2003) 87 ; b Events related to acute toxicity, for example, alopecia, anaemia, thrombocytopenia, transient idiopathic thrombocytopenic purpura, leukopoenia, neutropenia, febrile neutropenia, fatigue; c thrombocytopenia / transient idiopathic thrombocytopenic purpura only; d neutropenia / febrile neutropenia only; e 37 out of 74 cases (50%) experienced worsening of neurological symptoms; f engraftment syndrome refers to fever with/without a skin rash; g bacteraemia included α-haemolytic streptococci, other streptococci and coagulase-negative staphylococci. Stem cell therapy for non-haematological (autoimmune) indications: March

43 Table 11 Mortality of all included studies of HSCT for multiple sclerosis Study 100-day TRM TRM NTRM Overall mortality Nash et al (2014) 80 0/24 (0%) 0/24 (0%) 2/24 (8.3%) 2/24 (8.3%) Burman et al (2014) 81 0/48 (0%) 0/48 (0%) 0/48 (0%) 0/48 (0%) Muraro et al (2013) 82 NR NR NR NR Pasquini et al (2012) 83 NR NR NR 11/143 (7.7%) ADs (n=4); bleeding (n=2); infection (n=1); myelodysplasia b (n=1); organ failure (n=1); TTP (n=1); unknown (n=1) Shevchenko et al (2012) 84 Mancardi et al (2012) 85 Bowen et al (2012) 86 0/95 (0%) 0/95 (0%) 0/95 (0%) 0/95 (0%) 3/74 (4.1%) encephalopathy (n=1) (56 days); engraftment failure (n=1) (24 days); ICH (n=1) (56 days) 1/26 (4%) EBV-PTLD (n=1) (53 days) 2/74 (2.7%) encephalopathy (n=1) (56 days); engraftment failure (n=1) (24 days) 1/26 (4%) EBV-PTLD (n=1) (53 days) Chen et al (2012) 89 0/25 (0%) 2/25 (9.5%) pneumonia (n=1) (4.5 months); VZVH (n=1) (15 months) 1/72 (1.4%) post traumatic intra-cerebral haemorrhage (n=1) (56 days) 3/25 (12%) pneumonia (n=3) (724; 940; 2645 days) 3/74 (4.1%) 4/26 (15.4%) 0/23 (0%) 2/25 (9.5%) Xu et al (2011) 90 0/36 (0%) 0/36 (0%) 0/36 (0%) 0/36 (0%) Fassas et al (2011) 91 1/35 (2.9%) aspergillosis (n=1) (2 months); 2/35 (6%) aspergillosis (n=1) (2 months); pulmonary haemorrhage (n=1) (2.5 years) Farge et al (2010) 19 NR/NR 2% 13/345 (3.8%) infection (n=5); cardiac toxicity (n=1); haemorrhage (n=2); interstitial pneumonitis (n=2); secondary malignancy (AMK) (n=1); other (n=2) Hamerschlak et al (2010) 93 Guimaraes et al (2010) 94 Krasulova et al (2010) 95 NR CY/rATG: 0/20 (0%) BEAM/hATG: 3/21 (14%) sepsis (n=1); cardiac toxicity (n=1); alveolar haemorrhage (n=1) 3/22 (9%) prostate cancer (n=1) (12 years); MSrelated complications (n=2) (10 years, 14 years) 8/332 (2.4%) MS-related complications (n=8) CY/rATG: 0/20 (0%) BEAM/hATG: 0/18 (0%) 22/345 (6.4%) unknown (n=1) 3/21 (14%) NR NR NR NR 0/26 (0%) 0/26 (0%) 2/26 (7.7%) peritonitis (n=1) (30 months); glioblastoma multiforme (n=1) (60 months) Burt et al (2009) 96 0/21 (0%) 0/21 (0%) 0/21 (0%) 0/21 (0%) Abbreviations: auto-hsct: autologous haemopoietic stem cell transplantation; ADs: autoimmune diseases; AMK: acute myeloid leukaemia; BEAM/hATG: BEAM/horse anti-thymocyte globulin; CY/rATG: rabbit cyclophosphamide/anti-thymocyte globulin; EBV-PTLD: Epstein-Barr virus related posttransplantation lymphoproliferative disorder; TTP: thrombotic thrombocytopenic purpura; TRM: treatment-related-mortality; VZVH: varicella-zoster virus hepatitis; a mortality was higher in centre that performed 15 or fewer auto-hsct for autoimmune diseases compared to patients from centres that performed more than 15 auto-hsct; b patient developed condition after auto-hsct then die from persistent myelodysplasia following allogeneic HSCT. Stem cell therapy for non-haematological (autoimmune) indications: March

44 Efficacy Progression-free survival (PFS) For the included studies, the effectiveness of auto-hsct for treatment of MS was reported as progression-free survival, defined as no sustained increase in EDSS score between baseline and subsequent follow-ups post-transplantation. Progression-free survival was reported in 13 of the 15 included studies and is presented in Table 12. Two studies did not 94, 97 report progression-free survival. At three years, Nash et al. (2014) 80 reported the progression-free survival to be 90 per cent of patients. In the study by Burman et al. (2014), 81 the progression-free survival (defined in this study as the absence of an increase in EDSS score 0.5 points) was 77 per cent at five years. Muraro et al. (2013) 82 reported the probability of progression free at five years was 49 per cent. The progression of MS was affected by age older than 37 years (HR=1.40, p=0.04), progressive versus relapsing forms of MS (HR=1.6, p=0.02) and more than two previous lines of therapy for MS (HR=1.6, p=0.005). Shevchenko et al. (2012) 84 estimated the progressionfree survival (defined in this study as no increase in the EDSS score of 0.5 points) to be 82 per cent at 5 years. At 5 years, progression-free survival was significantly higher in patients who underwent early treatment with auto-hsct (92%) compared to patients who underwent conventional or salvage treatment with auto-hsct (73%) (p=0.01). In the study by Mancardi et al. (2012), 85 the progression-free survival (defined in this study as an increase EDSS of 0.5 or 1 point, if baseline EDSS was > 5.5 or 5.5, respectively) was 66 per cent (standard error = 7%) at 5-years. Patients with MRI Gd-enhancing lesions at baseline had higher progression-free survival than patients without baseline MRI Gd-enhancing lesions (87% vs 46%, p=0.013). In addition, patients aged less than 40 years had a slightly higher progression-free survival than patients over 40 years (69% vs 52%, p=0.33), and patients with RRMS had a slightly higher progression-free survival than patients with SPMS at 5-years (71% vs 62%, p=0.28). Bowen et al. (2012) 86 reported progression-free survival to be 60 per cent at three years and 48 per cent at six years. Progression-free survival reported by Chen et al. (2012), 89 decreased from a rate of 74 per cent at 3 years down to 65 per cent at 6 years and subsequently 48 per cent at 9 years following the auto-hsct. In the study by Xu et al. (2011), 90 progression-free survival was 83.3 per cent at 91 months post-transplantation across both groups (malignant MS and conventional MS). In a long-term follow-up study by Fassas et al. (2011), 91 progression-free survival was 25 per cent at 15 years. At 15 years, patients with active MRI lesions at baseline showed higher rates of progression-free survival (44%; median 11 years) compared to patients with no active MRI lesions at baseline (10%; median 2.3 years; (p=0.01). For patients with SPMS, RRMS, and RPMS, the median progression-free survival time was higher at 5.4 years compared to 1.5 years in patients with PPMS; however, it was not significant (p= 0.338) possibly due to the number of patients in Stem cell therapy for non-haematological (autoimmune) indications: March

45 each MS patient category was small. The authors noted that patients aged less than 35 years and patients with shorter disease duration prior to auto-hsct had better outcomes. The type of MS, gender, conditioning regimen and baseline EDSS were found to no influence the rate of progression-free survival at follow-up. Farge et al. (2010) 19 reported the rate of progression-free survival of patients with MS to be 45 per cent at five years. Higher rates of progression-free survival were associated with the diagnosis (HR = 0.86, p=0.000), age <35 years (HR=1.37, p=0.004) and auto-hsct after December 2000 (p=0.001). In the study by Hamerschlak et al. (2010), 93 event-free survival g was estimated to be 59 per cent across both conditioning regimen groups with no significant difference between the BEAM/horse anti-thymocyte globulin group (48%) at three years and the cyclophosphamide/rabbit antithymocyte globulin group (70%) at two years (p=0.288). Krasulova et al. (2010) 95 found the progression-free survival to be 70.8 per cent at 3-years and 29.2 per cent at 6-years posttransplantation. In relation to the type of MS, progression-free survival was higher in patients with RRMS (n=11) compared to patients with SPMS (n=15) at 3 years (84% vs 60%, p=0.000). The odds ratio for the risk of progression increased from 5.1 at 3-years to 39 at 6 years. In terms of disease duration, patients with a shorter duration <5 years (n=6) had significantly higher progression-free survival (82%) than patients with 5 years (n=20) (62%) at 3-years. The odds ratio for the risk of progression increased from 8.25 at 3 years to 18 at 6-years. For EDSS scores, progression-free survival did not differ between the patients with lower scores of <6 points (i.e. mobility intact) (n=8) and higher scores of 6 points (i.e. loss of mobility) (n=18). With respect to age, progression-free survival was significantly higher in patients with under 35 years compared to patients 35 years and over (p=0.011), as 100 per cent of the older patients progressed before the four-year follow-up. In the phase I/II study by Burt et al. (2009), 96 progression-free survival, defined as no increase in EDSS score of least 1 point, was 100 per cent after a mean of 3-years after auto-hsct. Disease-activity-free survival Three of the 15 included studies reported event-free / disease-activity survival. Nash et al. (2014) 80 estimated the overall event-free survival, defined as survival without death or disease activity from loss of neurologic function, clinical relapse, or new MRI lesions to be 78.4 per cent at three years. In the recent study by Burman et al. (2014), 81 disease-activityfree survival, defined as freedom from all measurable forms of disease (i.e. no relapses, no new MRI lesions and no EDSS progression), was 68 per cent at 5-years. Disease-activity-free survival was higher in patients with MS who had gadolinium enhancing (Gd+) lesions on the MRI scans prior to auto-hsct compared to patients with MS without Gd+ lesions (79% vs 46%, p=0.028). There were no significant differences in the disease-activity-free survival associated with type of MS, duration of disease, conditioning regimen and EDSS, however, g Event-free survival was defined in this study as the probability of no disease progression (as indicated by EDSS in the last 6 months 1 point if patient range or 0.5 points if patient range ), no relapserelated events, and no new lesions on the MRI. Stem cell therapy for non-haematological (autoimmune) indications: March

46 some of the groups had small number of patients. In the study by Burt et al. (2009), 96 disease-activity-free survival was 62 per cent at 3-years which accounted for relapses (n=5) and new non-enhancing T1 or T2 lesions (n=3). Relapse-free survival Eight of the 15 included studies reported relapse-free survival which is presented in Table 12. For patients with MS, a relapse was defined as the by presence of new MS-related symptoms or the recurrence of previously recovered symptoms (for a period of 24 hours). Five studies reported results regarding relapse-free survival and/or annualised relapse rates. In the study by Nash et al. (2014), 80 clinical relapse-free survival was 86.3 per cent at three years. Burman et al. (2014) 81 reported a relapse-free survival of 87 per cent at 5 years and an annualised relapse rate (ARR) of 0.03 (i.e. one relapse occurred for every 33 years of follow-up). Shevchenko et al. (2012) 84 reported the majority of patients with RRMS (98%) were relapse-free at long-term follow-up. In the study by Mancardi et al. (2012), per cent of patients were relapse-free at five years with a higher proportion of relapses during follow-up in patients with RRMS compared to patients with SPMS (30% vs 10%, p=0.03). Krasulova et al. (2010) 95 reported a median annual relapse rate of 0 (1st quartile 0, 3rd quartile 1) at 2 years post-transplantation. MRI event-free survival Only three of the 15 included studies reported MRI event-free survival, defined as the absence of new lesions detected on MRI. Mancardi et al. (2012) 85 found no Gd-enhancing lesions at 6 to 12 months follow-up in 45 patients assessed with MRI scans. At 2 years follow-up, MRI-event free was 92 per cent (22/24 patients). Nash et al. (2014) 80 reported the MRI event-free survival as 100 per cent at three years. In the study by Burman et al. (2014), the MRI event-free survival was 85 per cent at 5 years. Overall survival Two studies reported the overall survival which was defined as time to death irrespective of the cause death. In the large retrospective cohort study, Muraro et al. (2013) 82 reported the overall survival rate to be 93 per cent at five years for auto-hsct performed between January 1995 and December Overall survival was reported by Farge et al. (2010) 19 to be 93 per cent at 3 years and 92 per cent at five years. Stem cell therapy for non-haematological (autoimmune) indications: March

47 Table 12 Patient response to transplantation of all included studies of HSCT for multiple sclerosis Study Follow-up time Progression-free survival [90*, 95% CI] Disease-free survival at 5 years [90% CI] Relapse-free survival [90% CI] MRI eventfree survival [90% CI] Overall survival [95% CI] Nash et al Interim: (2014) 80 median followup 186 weeks (IQR, weeks)(n=24) Burman et al (2014) 81 Muraro et al (2013) 82 Pasquini et al (2012) 83 Shevchenko et al (2012) 84 Mancardi et al (2012) 85 Bowen et al (2012) 86 Chen et al (2012) 89 Xu et al (2011) 90 Fassas et al (2011) 91 Farge et al (2010) 19 Hamerschlak et al (2010) 93 Guimaraes et al (2010) 94 Krasulova et al (2010) 95 Burt et al (2009) 96 Mean 47.4 (range ) months 90.9% [73.7, 97.1]* at 3 years Overall eventfree survival 78.4% [60.1, 89.0]* at 3 years 86.3% [68.1, 94.5]* at 3 years 100% [100, 100]* at 3 years 77% at 5 years 68% at 5 years 87% at 5 years 85% at 5 years NR 49% [43, 55] at 5 years Median 31 (range <1-144) months for all ADs Mean 46 (range 10-66) months Median 48.3 (range ) months Median 48 (range 3-72) months Mean 59.6 (range ) months Average 46.80±27.27 (CMS only group) Median 11.3 (range ) years; (n=33) Mean/median 31 ( ) months (MS group only) NR NR NR 93% [91, 95] at 5 years NR NR NR NR NR 82% [71.2, 89.1] at 5 years 66% (SE = 7%) at 5 years (n=74) 60% at 3 years; 48% at 6 years 74% at 3 years; 65% at 6 years; 48% at 9 years 83.3% at 91 months (n=35) (Both CMS and OSMS groups) NR 39/40 (98%) RRMS NR NR NR 52/61 (85%) at 5 years 45/45 (100%) 6-12 months; 22/24 (92%) at 2 years NR n=4 new lesions within 13 months. 1 patient during engraftment syndrome NR 16/21 (76%) at mean of 37- month follow-up NR 62.9% at 91 months (n=35) (Both CMS and OSMS groups); relapse without progression (n=2/15) (CMS only group) 25% at 15 years NR NR NR NR 55% [49, 61] at 3 years; 45% [38, 52] at 5 years NR BEAM/hATG: 47.6% at 3 years; CY/rATG: 70% at 2 years NR NR NR 93% [89, 97] at 3 years; 92% [88, 96] at 5 years NR NR NR NR NR NR NR NR NR NR Median 66 (range ) months Mean 37 (range 24 48) months (n=26); 70.8% at 3 years; 29.2% at 6 years 100% at 3 years 62% at 3 years (n=13) NR NR NR NR 5/21 (24%) relapsed average 11 months with remission after further immunosuppression Abbreviations: ADs: autoimmune diseases; BEAM/hATG: BEAM/ horse anti-thymocyte globulin; CI: confidence interval; CMS: conventional multiple sclerosis; CY/rATG: cyclophosphamide/rabbit anti-thymocyte globulin; IQR: interquartile range; MRI: magnetic resonance imaging; MS: multiple sclerosis; NR: not reported; OSMS: opticospinal multiple sclerosis; RRMS: relapsing remitting multiple sclerosis; SE: standard error. Disability progression (EDSS) Stem cell therapy for non-haematological (autoimmune) indications: March NR NR NR NR NR NR NR NR NR NR NR

48 Eleven of the 15 included studies reported disease progression, measured by the EDSS. According to the EBMT criteria, a patient with MS is considered to have responded to treatment if the progression of the disease is stopped (indicated by steady EDSS scores) or the inflammation is ceased (indicated by improved EDSS scores). In the most recent study by Nash et al. (2014), 80 the EDSS score significantly improved at 1- year (p=0.003), 2-years (p=0.004), and 3-years post-transplantation (p=0.007) compared to baseline. The median change from EDSS at baseline compared to 3 years post-hsct was (interquartile range, -1.5 to 0.0; p=0.007). Burman et al. (2014), 81 found that the overall median EDSS improved from baseline to the latest follow-up (6 vs 4, respectively). The median EDSS change was significantly better in patients with RRMS compared to patients with either RRMS or PRMS (-1.5 vs -7, respectively). Eight patients progressed (i.e. deterioration of at least 0.5 points sustained at subsequent follow-up visits) whilst the remaining 33 patients were stable or improved. In the study by Shevchenko et al. (2012), 84 the vast majority of patients experienced either an improvement in neurological symptoms (decrease 0.5 points h ) or stabilisation of the disease (41% and 58%, respectively) with only one patient (1%) showing deterioration (increase 0.5 points i ) at 6 months. In general, this trend remained relatively unchanged at 12 months follow-up with slightly more patients showing deterioration (43%, 53%, and 3%, respectively). At long-term follow-up (mean 46 months), the majority (84%) had experienced improvement or stabilisation (28 vs 31 patients, respectively) with the number of patients with deterioration increasing to 16 per cent (11 patients). Eight of the 11 patients with disease progression (73%) had progressive forms of MS and the other three patients (27%) had RRMS. Mancardi et al. (2012) 85 showed that 28 of 61 patients (46%) experienced an improvement at 1-year follow-up with significantly more patients with RRMS improving compared to patients with SPMS (31% vs 3%, respectively, p=0.009). Significantly more patients aged below 40 years showed improvement compared to patients over 40 years (p=0.03). A shorter disease duration (less than 5 years) compared to a longer disease duration (more than 5 years) was also shown to be associated with significantly greater improvements (p=0.03). After 5 years follow-up, a total of 66 per cent of patients remained stable or improved. After long-term follow-up of more than 7 years, 3 patients (17%) remained stable, 5 patients (27%) improved and 10 patients (56%) were worse. j In the study by Bowen et al. (2012), 86 of 26 patients assessed at last follow-up (median 4 h Improvement in neurological function was defined as decrease in EDSS score of 0.5 points compared to baseline on two consecutive visits 3 months apart. i Deterioration was defined as disease progression as defined by an increase in EDSS score of 0.5 points on a minimum of two occasions that were at least 3 months apart. j Sustained improvement defined as a decreased EDSS score at all time-points compared to baseline. Stabilisation defined as no change in EDSS over the follow-up period compared to baseline. Deterioration defined as increase in the EDSS confirmed after 6 12 months during the follow-up. Stem cell therapy for non-haematological (autoimmune) indications: March

49 years), four patients (15%) improved ( 0.5 point), 7 patients (27%) were stable, and 15 patients (58%) were worse ( 0.5 point). At 6 years, the estimated probability of a patient EDSS failure (increase 1 point) was 0.52 (95% CI, ) and EDSS failure (increase 0.5) was 65 per cent (95% CI, ). Of the 25 patients enrolled in the study by Chen et al. (2012), (40%) showed improvement, 7 (28%) remained stable and 8 (32%) were worse at last follow-up. k Of the 35 patients with OSMS and CMS in the study by Xu et al. (2011), 90 a total of 20 patients (57%) showed improvement, two patients (5.7%) were stable, 7 patients (20%) experience relapse without progression and 6 (17%) had relapse with progression. l For the CMS group only, 13 out of 15 patients (87%) improved and the remaining 2 patients (13%) experienced relapse without progression. Fassas et al. (2011), 91 reported that 16 of 35 patients (46%) with aggressive MS experienced improvement following HSCT lasting for a median of two years. Of the 16 patients that showed initial improvement, the EDSS scores of nine patients did not progress above baseline EDSS scores. In the study by Hamerschlak et al. (2010), patients (39%) improved (decrease 0.5 points), 9 (24%) were stable and 14 (37%) became worse (increase 0.5 points) following the HSCT with no difference between conditioning groups. In the study (n=34) by Guimaraes et al. (2010), patients (32%) improved, 16 patients (47%) stabilised and 7 (20%) patients got worse at 1 year follow-up. Burt et al. (2009) 96 reported there were significant improvements in EDSS scores after HSCT compared with baseline (p<0.0001). The mean follow-up was 37 months and it was shown that 19 patients (90%) improved (decrease EDSS 0.5%), two patients (10%) stabilised and no patients (0%) patients progressed at the most recent follow-up. The mean EDSS scores improved between 0.8 to 1.7 points from 6 months through to four years. k Disability progression was defined as increase 1 EDSS point (if baseline EDSS score 5) or an increase 0.5 EDSS point (if baseline EDSS was >5). l Neurological improvement defined as decrease EDSS score of 0.5 points (if baseline EDSS >5) and decrease by 1 EDSS points (if baseline EDSS 5) with no disease relapse. Neurological stabilisation defined as decrease of <0.5 EDSS points (if baseline EDSS was >5) and decrease by <1 EDSS points (if baseline EDSS 5) with no disease relapse or progression. Relapse without progression defined as neurological improvement and relapse occurred during the follow-up. Relapse with progression defined as increase of 1 EDSS points (if baseline EDSS 5) and increase by 0.5 EDSS points (if baseline EDSS >5) at any relapse event during the follow-up. Stem cell therapy for non-haematological (autoimmune) indications: March

50 Table 13 Evolution and changes in EDSS scores of all included studies of HSCT for multiple sclerosis Study Median baseline EDSS Median EDSS at 1 year Median EDSS follow-up > 1 year Median improvement in EDSS Evolution of EDSS a Nash et al Mean 4.4 (2014) 80 (SD=0.6); median 4.5 (range ) (n=25) Burman et al (2014) 81 Pasquini et al (2012) 83 Shevchenko et al (2012) 84 Mancardi et al (2012) 85 Bowen et al (2012) 86 Chen et al (2012) 89 Xu et al (2011) 90 Fassas et al (2011) 91 Farge et al (2010) 19 Hamerschlak et al (2010) 93 Guimaraes et al (2010) 94 Krasulova et al (2010) 95 Burt et al (2009) 96 All: 6 (range 1 8.5); RRMS: 5.5 ( ); PRMS: 6.5 (6 8) 6.5 (range, ) (n=62) At 1 year compared to baseline (p=0.003) RRMS: 3.25 (0 7); PRMS: 6.5 (6 8) At 2 years compared to baseline (p=0.004) All: 4 (0 8) at last follow-up (mean follow-up 47 months); RRMS: 3 (0 7) at 2 years; PRMS: 6.5 (6 7.5) at 2 year 0.50 (IQR, 1.5 to 0.0) at 3 years compared to baseline (p=.007) All: 0.75 (7 to 1.5); RRMS: 1.5 (7 to 1.5) NR NR NR NR 3.5 NR NR NR At 6 months: improved: 37/90 (41%); stable: 52/90 (58%); worse: 1/90 (1%) At 12 months: improved: 39/90 (43%); stable: 48/90 (53%): worse: 3/90 (3%) Mean follow-up 46 months: improved: 28/70 (40%); stable: 31/70 (44%); worse: 11/70 (16%) 6.5 (range = 3.5 9) 7.0 (range ). NR NR NR After 1 year, improved: 28/61 (46%) stable or deteriorated 33/61 (54%). At 5 years, stable or improved: 55%; worse 45%. After 7 years: 5/18 (27%) improvement; stable: 3/18 (17%); deterioration 10/18 (56%) NR NR NR Median follow-up 28 months: improved: 4/26 (15%); stable: 7/26 (27%); worse: 15/26 (58%) 8.0 (range 3 9.5) 5.5 (n=23) 7.0 at 6 years (n=10) All: Average 6.58 ( ); CMS: 6.77±1.05; OSMS: 6.45±1.34 NR NR NR Improved: 10 (40%); stable: 7 (28%); worse: 8 (32%) NR NR NR All: improved: 20/35 (57%); stable: 2/35 (5.7%); RWOP: 7/35 (20%); RWP: 6/35 (17%) CMS group only: improved: 13/15 (87%); stable: 0/15 (0%); RWOP: 2/15 (13%); RWP: 0/15 (0%) 6 (4.5 8) NR NR NR Improvement (lasting median 2 years): 16/35 (46%) NR NR NR NR NR 6.5 (4.5 7) NR NR NR Improved: 15/38 (39%); stable 9/38 (24%); worse: 14/38 (37%) NR NR NR NR At 1 year: improved: 11/34 (32%); stable: 16/34 (47%); worse: 7/34 (20%) 6.0 ( ) NR NR NR NR 3.1 ( ) NR NR Mean 0.8, 0.9, 1.5, 1.6, 1.7 points at 6 months, 1, 2, 3, 4 years. Improved: 19/21 (90%); stable: 2/21 (10%); worse: 0/21 (0%) CMS: conventional multiple sclerosis; EDSS: Kurtzke expanded disability status scale; IQR: interquartile range; OSMS: opticospinal multiple sclerosis; RRMS: relapsing remitting multiple sclerosis; RWOP: relapse without progression; RWP: relapse with progression: PRMS: progressive relapsing multiple sclerosis; SD: standard deviation; a at the most recent follow-up unless otherwise stated. Stem cell therapy for non-haematological (autoimmune) indications: March

51 Magnetic resonance imaging A major maker for inflammatory activity is lesions detected through magnetic resonance imaging (MRI), specifically Gd+ lesions and T2 lesions. Nine studies reported disease activity using MRI scans. Nash et al. (2014) 80 observed a reduction of Gd+ lesions within six months post-hsct compared to baseline. New brain Gd+ and/or T2 lesions were found in two patients between 3.5 to 4 years post-transplantation. In Burman et al. (2014), per cent (25 patients) had at least one Gd+ lesion at baseline. Following the HSCT, 12 per cent (5 patients) had new Gd+ and/or new T2 lesions. In Shevchenko et al. (2012), 84 a total of 11 patients had disease progression at follow-up. In the remaining patients without disease progression, no new, active or enlarging lesions were found. Mancardi et al. (2012) 85 found that of the 45 patients that underwent an MRI prior to the auto-hsct, 71 per cent (32 patients) had an active MRI with Gd+ lesions. No Gd+ lesions were found in 45 patients (0%) at 6-12 months follow-up and two patients (8%) had Gd+ lesions at 2-years. At pretransplantation, 7 of the 26 patients (27%) enrolled in the study by Bowen et al. (2012) 86 had evidence of Gd+ lesions on the MRI at baseline. Within 13 months of HSCT, 4 of the 25 patients able to undergo MRI evaluations (16%) had new or enhancing lesions. In Chen et al. (2012), 89 Gd+ active lesions were found in over half of the 25 patients (14 patients; 56%) at pre-transplantation. Of the 12 patients that were available for MRI following treatment, 10 patients (83%) had no active lesions and two patients (17%) had active lesions. Of the 10 patients with no active lesions following treatment, seven (58%) had active lesions at baseline whilst the other three patients experience disease progression post-hsct. The two patients with active lesions following treatment had no active lesions at baseline. Xu et al. (2012) 90 found longitudinally extensive spinal cord lesions (i.e. lesions longer than three vertebral segments) in 23 of the 36 patients (64%) across both groups. The group of patients with opticospinal MS had significantly more longitudinally extensive spinal cord lesions (7/21) compared to the patients with the conventional form of MS (6/15) (81% vs 40%, respectively, p=0.012). The phase I/II study by Fassas et al. (2011) 91 reported baseline MRI activity (Gd+, or new or enlarging T2 lesions) in 12 (40%) of the 30 patients with available MRI data. The number of Gd+ lesions significantly decreased between baseline and post-transplantation (87 vs 25, respectively, p<0.001), however, the number of new Gd+ lesions increased from 0/87 (0%) to 16/25 (64%). The volume of Gd+ lesions also significantly reduced from 9.5cm 3 at baseline to 0.2cm 3 post-transplantation. Stem cell therapy for non-haematological (autoimmune) indications: March

52 In the study by Hamerschlak et al. (2010), 93 baseline disease activity (Gd+) was found in 20 per cent of MRI scans at baseline (8/41) with significantly more cases with Gd+ in the cyclophosphamide / rabbit anti-thymocyte globulin conditioning group (7/21) compared to the BEAM/horse anti-thymocyte globulin conditioning group (1/20) (33% vs 5%, respectively, p=0.04). Following HSCT, there were no new or active Gd+ lesions found in all 35 patients who underwent MRI assessments across both conditioning groups. Burt et al. (2009), 96 reported that all of the patients had T1 and T2 lesions and the majority of patients also had Gd+ lesions prior to transplantation (16/21; 76%). During follow-up post-transplantation, three of the 21 patients (14%) had Gd+ lesions. The number of T2 lesions that were unchanged, increased and decreased were 14, 5, and 2 (67%, 24% and 10%, respectively). The number of T1 lesions that were unchanged, increased and decreased were 16, 2, and 3 (76%, 10% and 14%, respectively). Of the five patients that experienced a clinical relapse, the MRI show 3 patients had new Gd+ lesions, 3 had new T2 lesions and 1 had new T1 lesions. Cerebrospinal fluid Cerebrospinal fluid (CSF) IgG index and oligoclonal bands (OCB) are common laboratory tests used for diagnostic purposes in MS. Elevated levels CSF IgG index and oligoclonal banding are commonly found in patients with MS. Only two out of the 15 included studies report this indicator. All patients (n=26) in the trial conducted by Burman et al. (2014) 81 had evidence of oligoclonal bands in the cerebrospinal fluid at baseline (mean IgG index = 0.81) with 69 per cent of patients (11/16) retaining the oligoclonal bands after HSCT. In these patients, the mean value of IgG index significantly decreased at post-transplantation compared to baseline (0.63 vs 0.85, respectively, p=0.0007). Bowen et al. (2012) 86 evaluated the cerebrospinal fluid of 15 patients with baseline and 12- or 24- month follow-up data, 12 patients retained the same oligoclonal bands, two patients had a decrease and one patient had an increase in the number of oligoclonal bands. A further two patients with long-term follow-up data at 48- and 72- months retained their oligoclonal bands. Stem cell therapy for non-haematological (autoimmune) indications: March

53 Table 14 MRI and cerebrospinal fluid of all included studies of HSCT for multiple sclerosis Study Baseline MRI Follow-up MRI Baseline CSF Follow-up CSF Nash et al (2014) 80 Burman et al (2014) 81 Muraro et al (2013) 82 Pasquini et al (2012) 83 Shevchenko et al (2012) 84 Mancardi et al (2012) 85 Bowen et al (2012) 86 Chen et al (2012) 89 Xu et al (2011) 90 Fassas et al (2011) 91 Farge et al (2010) 19 Hamerschlak et al (2010) 93 Guimaraes et al (2010) 94 Krasulova et al (2010) 95 Burt et al (2009) 96 NR MRI activity: 25/41 (61%); No Gd+ lesions: 16/41; 1 Gd+ lesion: 25/41; (of 25 patients, >10 Gd+: 13/41; >30 Gd+ lesions: 6/41) New Gd+ and/or T2 lesions: two patients (3.5 to 4 years) New T2 and/or Gd+ lesions: 5/41 (12%) (13 lesions: 5 x new Gd+ lesions & 8 x new T2 lesions) Stem cell therapy for non-haematological (autoimmune) indications: March NR OB: 26/26 (100%); mean IgG index in CSF: 0.81 (±0.24) (n=26); mean IgG index in CSF: 0.85 (±0.25) (n=11) NR mean IgG index in CSF: 0.63 (±0.12) (n=11) NR NR NR NR NR NR NR NR NR Active MRI with Gd+ lesions: 32/45 (71%) (mean 4.4 lesions range, 0-28) Patients without disease progression: 0 At 6-12 months: Gd+ lesions: 0/45 (0%) At 2 years: Gd+ lesions: 2/24 (8%) MRI activity: 7/26 (27%) Within 13 months: 4/25 (16%) Gd+ lesions: 14/25 (56%) No lesions: 10/12 (83%); active lesions: 2/12 (17%) LESCL lesions: Both groups: 23/36 (64%); CMS: 6/15 (40%); OMSM: 17/21 (81%) MRI activity: 12/30 (40%); number of Gd+ lesions: 87; number of new Gd+ lesions: 0; volume Gd+ lesions: 9.5cm 3 NR NR NR NR NR NR Median +12 months follow-up: OB: same: 12/15 (80%); decrease: 2/15 (13%); increase: 1/15 (7%) NR NR NR NR Number of Gd+ lesions: 25; number of new Gd+ lesions: 16; volume Gd+ lesions: 0.2cm 3 NR NR NR NR MRI activity (all): 8/41 (20%) (i.e. BEAM/hATG: 7/21 (33%); CY/rATG): 1/20 (5%)) MRI activity (all): 0/35 (0%) NR NR NR NR NR NR NR NR NR NR Gd+ lesions: 16/21 (76%); T2 lesions: 100%; T1 lesions: 100% Gd+ lesions: 3/21 (14%); new T2 lesions: 5/21 (24%); new T1 lesions: 2/21 (10%) Abbreviations: BEAM/hATG: BEAM/ horse anti-thymocyte globulin; cm: centimetre; CMS: conventional multiple sclerosis; CSF: cerebrospinal fluid; CY/rATG: cyclophosphamide/rabbit anti-thymocyte globulin; Gd+: gadolinium-enhanced; IgG index: Immunoglobulin G index; LESCL: longitudinally extensive spinal cord lesions; MRI: magnetic resonance imaging; NR: not reported; OB: oligoclonal bands; OSMS: opticospinal multiple sclerosis; SESPC: longitudinally extensive spinal cord lesions. Quality of life Five of the 15 included studies measured and reported on quality of life (QoL), which can gradually decline in patients with MS and is therefore recognised as an important outcome parameter. These studies used the Multiple Sclerosis Impact Scale (MSIS-29) and the Medical Outcomes Study 36-Item Short-Form Health Survey (MOS SF-36). The MSIS-29 is a NR NR NR NR

54 used to measure therapeutic outcome in patients with MS. The 29 item scale consists of two components: dealing with limited abilities, and being bothered by symptoms or consequences of illness. Scores range from 29 to 145, with higher scores indicating a greater degree of disability. The MOS SF-36 is a self-report measure used to assess QoL. The 36 item instrument consists of eight domains, which make up two components: the physical health component (physical functioning, role limitations due to physical problems, bodily pain and general health perceptions) and the mental health component (vitality, social functioning, role limitations due to emotional problems and general mental health). Each domain is scored on a scale ranging from 0 (worst health state) to 100 (best state of health). This same instrument can be scored using different scoring algorithms for two of the eight domains (Bodily Pain, General Health) and the scale is then referred to as RAND-36. The results for these two domains are not comparable with the standard SF-36. Of the five studies that reported QoL, one study used the MSIS-29, 80 one study used the MOS SF-36, 94 one study used the RAND-36, 84 and two studies used the SF-36 surveys but did not specify the type of scoring used. 93, 96 Nash et al. (2014) 80 administered the MSIS to assess quality of life. At 3-years posttransplantation, QoL, as measured by the MSIS-29, improved compared to baseline (median change 15.0; interquartile range, to 0.6; p=0.02). In the study by Shevchenko and colleagues (2012), 84 there was a significant increase of all RAND-36 domains (except bodily pain and role-emotional functioning) compared to baseline (p < 0.05) at 12 months post-hsct with significant improvements registered in five of the eight SF-36 domains (except physical functioning, bodily pain and role-emotional functioning) as early as 6 months post-hsct (p < 0.05). All patients without disease progression had improved QoL parameters over the full study period. 99 In the study by Hamerschlak et al. (2010), 93 the physical aspect domains of the SF-36 improved significantly in the cyclophosphamide/ rabbit anti-thymocyte globulin group only (p=0.033) at 100 days post-hsct compared to baseline (n=20). The remaining domains were not statistically significant which may have been due to small sample size and a short followup period. General health domain was slightly improved in both the BEAM/horse antithymocyte globulin and cyclophosphamide/rabbit anti-thymocyte globulin groups (p=0.096 and p=0.073, respectively). Guimaraes et al. (2010) 94 reported that statistically significant improvements were observed in all domains of the MOS SF at 1 year post-hsct compared to baseline admission to hospital with no improvements evidence at hospital discharge (Table 15). Statistically significant negative correlations were found between EDSS score and the physical functioning domain of the MOS SF-36 at hospital admission, discharge, and 1 year post- HSCT. Stem cell therapy for non-haematological (autoimmune) indications: March

55 Burt et al. (2009) 96 reported a significant improvement in overall quality of life (26.7 points), as measured with the SF-36 questionnaire, at the most recent post-hsct assessment compared to baseline (78.9 vs 52.2, respectively; p<0.0001). There were statistically significant improvement in seven of the eight domains expect emotional role. Stem cell therapy for non-haematological (autoimmune) indications: March

56 Table 15 Quality of life outcomes of all included studies of HSCT for multiple sclerosis Guimaraes et al (2010) 94 Shevchenko et al (2012) 84 Burt et al (2009) 96 Hamerschlak et al (2010) 93 Baseline MOS SF-36 RAND-36 SF-36 a SF-36 a Hospital discharge 1-year post- HSCT Baseline, mean(sd) 12 months post- HSCT, mean(sd) p value Pre- Post- Mean diff HSCT HSCT (SD) p value Pre-HSCT, mean (SD) BEAM/hATG Post-HSCT, mean (SD) p- value (Post x pre) Pre-HSCT, mean (SD) CY/rATG Post-HSCT, mean (SD) p- value (Post x pre) Physical functioning Reference 0.09 < ± ± ±23 < ± ± ± ± Role limitations (physical health) Reference 0.76 < ± ± ±39.6 < ± ± ± ± Bodily pain b Reference 0.5 < ± ± ±22 < ± ± ± ± General health perceptions b Reference 0.12 < ± ± ± ± ± ± ± Vitality Reference 0.28 < ± ± ±21.7 < ± ± ± ± Social functioning Reference 0.99 < ± ± ± ± ± ± ± Role limitations (emotional) Reference ± ± ± ± ± ± ± General (mental health) Reference 0.48 < ± ± ± ± ± ± ± Dimension (physical health) NR NR NR NR NR NR ±19.3 < NR NR NR NR NR NR Dimension (mental health) NR NR NR NR NR NR ± NR NR NR NR NR NR Total SF-36 score NR NR NR NR NR NR ±18.6 < NR NR NR NR NR NR Abbreviations: BEAM/hATG: BEAM/horse anti-thymocyte globulin; CY/rATG: cyclophosphamide/rabbit anti-thymocyte globulin; HSCT: haemopoietic stem cell transplantation; mean diff: mean difference; SD: standard deviation; SF: short form; a scoring algorithm of SF-36 not specified; b these domains cannot be compared across the studies as different scoring algorithms are used. Stem cell therapy for non-haematological (autoimmune) indications: March

57 Mesenchymal stem cell therapy for multiple sclerosis Four studies, published between 2009 and 2014, were eligible for inclusion in this report. To be eligible for inclusion, studies were required to have 10 or more participants and report on safety and/or efficacy of mesenchymal stem cell therapy for MS. All four of the included studies were non-comparative case series. Study Descriptions Connick et al. (2012) 101 conducted an open-label, phase IIA, proof-of-concept study in the UK between 2007 and 2010 in which 10 patients with SPMS with optic nerve involvement underwent auto-msct. The study aimed to investigate the safety, feasibility and efficacy of auto-msct for patients with SPMS. An open-label, phase II study was conducted by Bonab et al. (2012) 102 in Iran between 2008 and 2010 which aimed to assess the safety, feasibility and efficacy of auto-msct in 25 patients with progressive forms of MS (SPMS=23; PRMS=2). General disability progression was measured using EDSS and MRI outcomes were evaluated at follow-up. Yamout et al. (2010) 103 conducted a phase I clinical trial of auto-msct to treat 10 patients with SPMS. Clinical outcomes and imaging were assessed at 12 month follow-up. A phase I/II, open pilot study performed by Karussis et al. (2010) 104 investigated the safety and feasibility of combined intrathecal and intravenous injection of bone marrow derived auto-msct in 15 patients with SPMS and 19 patients with amyotrophic lateral sclerosis (ALS). Adverse events were documented and clinical and imaging outcomes were assessed at six months follow-up. Table 16 Treatment characteristics of all included studies of MSCT for multiple sclerosis Study Treatment Mesenchymal stem cells Conditioning regimen Adminstration of stem cells (i.e. injection) Connick et al (2012) 101 Auto-MSCT (BM) In-vitro expanded MSCs Medications to reduce type I hypersensitivity reactions (i.e. chlorpheniramine, hydrocortisone, and metoclopramide) Intravenous Bonab et al (2012) 102 Auto-MSCT (BM) Ex-vivo expanded MSCs No conditioning regimen Intrathecal Yamout et al (2010) 103 Karussis et al (2010) 104 Auto-MSCT (BM) Ex-vivo expanded MSCs; 3/10 (30%) failed to grow adequate number of MSCs a No conditioning regimen Intrathecal and intracisternal Auto-MSCT (BM) Purified MSCs No conditioning regimen Intrathecal and intravenous Abbreviations: auto-msct: autologous mesenchymal stem cell therapy; BM: bone marrow; MSCs: mesenchymal stem cells; a Bone marrow aspiration failed twice in all three patients. Stem cell therapy for non-haematological (autoimmune) indications: March

58 Safety Common adverse events reported in the four studies of MSCT treatment for MS were fever, headaches, difficulty walking/standing and infections (Table 17). Table 17 Adverse events of all included studies of MSCT for multiple sclerosis Transient encephalopathy with seizures - - 1/7 (14%) - Abbreviations: MS: multiple sclerosis; a Infections included upper-respiratory tract infection and escherichia coli urinary-tract infection. Mortality Connick et al (2012) 101 Bonab et al (2012) 102 Yamout et al (2010) 103 Karussis et al (2010) 104 N (%) N (%) N (%) N (%) MS only (N=15) Macular rash 1/10 (10%) Scalp pruritus 1/10 (10%) Infections a 2/10 (20%) Nausea / vomiting - 2/25 (8%) - - Fever - Majority - 10/15 (67%) Headache - 3/25 (12%) - 10/15 (67%) Meningism /15 (7%) Rigidity /15 (13%) Leg pain and/or lower limb weakness - 2/25 (8%) - 1/15 (7%) Confusion /15 (7%) Neck pain and/or low back pain - - 1/7 (14%) 1/15 (7%) Difficulty walking/standing /15 (27%) No deaths were reported for MSCT for MS in the four included studies (Table 18). Table 18 Mortality of all included studies of MSCT for multiple sclerosis Study 100-day TRM TRM NTRM Overall mortality Mean follow-up Connick et al (2012) 101 Bonab et al (2012) 102 Yamout et al (2010) 103 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 7 months (range ) 0/22 (0%) 0/22 (0%) 0/22 (0%) 0/22 (0%) 12 months 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 3-6 months Karussis et al 0/15 (0%) 0/15 (0%) 0/15 (0%) 0/15 (0%) 25 months (2010) 104 Abbreviations: 100-day TRM: 100-day treatment-related-mortality; NTRM: non-treatment-related-mortality; TRM: treatment-related-mortality. Efficacy Clinical outcomes (EDSS) In the study by Connick et al. (2012), 101 the progression of general disability, as measured by the EDSS, was significantly reduced following auto-msct (difference in rate of change after treatment , p=0.028). Stem cell therapy for non-haematological (autoimmune) indications: March

59 In the study by Bonab et al. (2012), 102 the clinical course of the disease, as measured by EDSS, was found to be improved in three patients, remained stable in 16 patients and worse in three patients at 6 months. At 12 months, the clinical course of the disease was found to be improved in four patients, remained stable in 12 patients and worsened in six patients. The mean EDSS scores increased slightly from 6.1 (SD=0.6) at baseline to 6.3 (SD=0.4) at 12 months follow-up after MSCT. For the seven patients in the study by Yamout et al. (2010), 103 the clinical course of the disease was shown to be improved (by EDSS ) in 5 patients, remained stable in one patient, and worsened (by EDSS 0.5) in one patient at 3 6 months follow-up. At 12 months, 3 out of 6 patients improved (by EDSS 0.5) and 3 out of 6 remained stable. It should be noted that one of the patients that initially improved at 6 months worsened due to osteoporotic vertebral fractures. In the study by Karussis et al. (2010), 104 the clinical course of the disease significantly improved at 6 months after MSCT compared to baseline (6.7 (SD=1.0) and 5.9 (SD=1.6), p=0.001, respectively). Of the 15 patients, 11 patients improved (by EDSS of at least 0.5) and four remained stable at 6 months. Table 19 Patient response to transplantation of all included studies of MSCT for multiple sclerosis Study Connick et al (2012) 101 Bonab et al (2012) 102 Yamout et al (2010) 103 Karussis et al (2010) 104 Baseline EDSS Mean 6.1 (SD=0.3) (range, ) Mean: 6.1±0.6 Median: 6 (3.5-7) 6-month post MSCT EDSS 12-month post MSCT EDSS Rate of change EDSS before MSCT Rate of change EDSS after MSCT Clinical course of MS (EDSS) at 6 months a Clinical course of MS (EDSS) at 12 months a NR NR NR NR Mean: 6.2± 0.3 Median: 6.25 ( ) Mean: 6.3±0.4 Median: 6.5 (5.5-7) NR NR Improved (n=3/22); stable (n=16/22); worse (n=3/22) NR NR NR NR NR Improved (n=5/7); stable (n=1/7); worse (n=1/7) 6.7 (1.0) 5.9 (1.6), p=0.001 NR NR NR Improved (n=5/9); stable (n=4/9); worse (n=0/9) a Improvement refers to a decrease in EDSS score by at least 0.5 points; deterioration refers to an increase in EDSS score by at least 0.5 points. Imaging outcomes (MRI) Improved (n=4/22); stable (n=12/22); worse (n=6/22) Improved (n=3/6); stable (n=3/6); worse (n=0/6) In the study by Connick et al. (2012), 101 MRI scans revealed a decrease in T1 hypointense lesion volume and an increase in the magnetisation transfer ratio m after MSCT compared to baseline which was not statistically significant. No change in the rate of T2 lesion NR m Magnetisation transfer ratio is an imaging measure used to quantify changes in myelin in MS. Stem cell therapy for non-haematological (autoimmune) indications: March

60 accumulation or general brain atrophy was found after MSCT compared to baseline assessment. Bonab et al. (2012) 102 reported that MRI scans at 12 months post-transplantation revealed new T2 or Gd+ lesions in 27 per cent of patients and no change in 68 per cent of patients. Of the seven patients assessed at follow-up in the study by Yamout et al. (2010), 103 five patients (71%) had new or enlarging lesions and three patients (43%) had Gd+ lesions on MRI scans at 3 months. Magnetic resonance spectroscopy was used to assess the peak area ratio of N-acetyl aspartate over creatine (NAA/Cr ratio), which is a marker of axonal density and integrity. The NAA/Cr ratio decreased by a mean of 0.18 (n=6) at 3-months and was found to be remain stable in two patients and decreased in one patient at 12 months. These results indicate the progression of the disease, despite the clinical improvements and stabilisations which the author postulated could be attributed to failure of MSCT in preventing ongoing inflammation related to disease activity. Karussis et al. (2010) 104 reported no new or Gd+ lesions up to 6 months post-transplantation in all of the 15 patients with MS. Table 20 MRI and magnetic resonance spectroscopy of all included studies of MSCT for multiple sclerosis Study MRI MRS Baseline Follow-up NAA/Cr ratio Connick et al (2012) 101 T1 lesion volume: mm 3 ; T1 lesion magnetisation transfer ratio pu; T2 lesion volume mm 3 ; T2 lesion magnetisation transfer ratio pu; total brain volume % T1 lesion volume: 60.73mm 3 ; T1 lesion magnetisation transfer ratio pu; T2 lesion volume 20.90mm 3 ; T2 lesion magnetisation transfer ratio pu; total brain volume % NR Bonab et al (2012) 102 NR New T2 or Gd+ lesions: 6/22 (27%); no change: 15/22 (68%); missing data 1/22 (5%) NR Yamout et al (2010) 103 NR New or enlarging lesions: 5/7 (71%); Gd+ lesions 3/7 (43%) At 3 months: mean decrease by 0.18 (n=6) At 12 months: stable: 2/3; decrease: 1/3 Karussis et al (2010) 104 NR New or Gd+ lesions 0/15 (0%) NR Abbreviations: Gd+: gadolinium-enhanced; MRI: magnetic resonance imaging; MRS: magnetic resonance spectroscopy; NAA/Cr: peak area ratio of N- acetyl aspartate over creatine; NR: not reported. Stem cell therapy for non-haematological (autoimmune) indications: March

61 Safety and effectiveness for systemic sclerosis Haemopoietic stem cell transplantations for systemic sclerosis RCTs Three RCTs were found (known as ASSIST, ASTIS and SCOT) that compare haemopoietic stem cell transplantation to cyclophosphamide in the treatment of patients with SSc. The SCOT trial was listed on clinicaltrials.gov as having completed recruitment in however no final results from this trial were found in the systematic literature search or from relevant conference websites. Two publications 106, 107 were found that reported on aspects of the conditioning regimen used in the trial. The limited information, where available, from the SCOT trial has been included in the report. Observational studies were also included if identified as containing additional information relevant to longer term safety and effectiveness. Inclusion criteria were that studies contained at least 10 patients, were published in the last 10 years and contained longer term follow up (at least one year) with data on clinical effectiveness and mortality. Six studies were found with five of these reporting clinical outcomes and all six reporting mortality. Appendix D gives the key characteristics of the included observational studies. Study descriptions of the RCTs The ASSIST trial reported by Burt et al. (2011) 108 was a single centre trial in Chicago, USA that recruited 19 patients between January 2006 and November Patients were randomised one to one to receive either HSCT or cyclophosphamide. Patients were included in the trial if they were under 60 years of age with either diffuse SSc with internal organ involvement or limited SSc with coexisting pulmonary involvement. Patients were excluded if they had more than six months previous treatment with cyclophosphamide, lung capacity of less than 45 %, symptomatic cardiac disease, renal insufficiency, pulmonary hypertension or disease for more than four years. The ASTIS trial reported by Van Laar et al (2014) 12 was a multi-centre trial conducted in 10 countries in Europe. One hundred and fifty-six patients were randomised one to one to receive either HSCT or cyclophosphamide. Patients included were adults aged under 65 with diffuse SSc and major organ involvement and had not received more than a total dose of 5mg of cyclophosphamide intravenously. Patients with severe major organ involvement or pulmonary hypertension were excluded. No baseline information was available for patients recruited to the SCOT trial. Table 21 lists the key characteristics of patients recruited in Burt et al. (2011) 108 and van Laar et al. (2014). 12 Stem cell therapy for non-haematological (autoimmune) indications: March

62 Table 21 Key patient baseline characteristics of the randomised controlled trials of HSCT for systemic sclerosis Burt et al (2011) 108 van Laar et al (2014) 12 Baseline characteristics Auto-HSCT n=10 Control n=9 Auto-HSCT n=79 Control n=77 Age, years 45 (32 58) 44 (26 54) 44.2 (11.1) 43.3 (11.5) Sex, female (54.4) 49 (63.6) Disease duration from diagnosis, months 13 6 (2 33) 18 (6 36) 17 (14) 18 (17) Duration of skin involvement, years NR NR 1.7 (1.2) 1.7 (1.3) Major organ involvement Modified Rodnan skin score 28 (6 48) 19 (4 45) 24.8 (8.1) 25.8 (7.9) Gastrointestinal involvement n (%) 10 (100) 9 (100) NR NR Forced vital capacity % of predicted 62% (53 70) 67% (43 84) 82% (19) 81% (18) Lung involvement n (%) 7 (70) 8 (89) 68 (86) 67 (87) Heart involvement n (%) NR NR 6 (8) 7 (9) Kidney involvement n (%) NR NR 3 (4) 2 (3) Cardiac (abnormal electrocardiogram) n (%) 8 (80) 2 (22) 10 (13) [n = 76] 14 (19) [n = 74] EQ-5D, mean (SD) NR NR 0.46 (0.32) 0.47 (0.32) Burt et al. (2011) 108 reported values as median (range) and van Laar et al. (2014) 12 reported values as mean (sd); NR: not reported. The Burt et al. (2011) 108 and van Laar et al. (2014) 12 RCTs were well designed and risk of bias was generally low. The exceptions were performance and detection bias which were high due to the inability to blind participants to the treatment they were receiving and nonblinding of outcome assessors. Full risk of bias table according to the Cochrane risk of bias tool is in Appendix C. Treatment regimens Table 22 lists the treatment regimens used in the three RCTs. Stem cell therapy for non-haematological (autoimmune) indications: March

63 Table 22 Treatment characteristics of the randomised controlled trials of HSCT for systemic sclerosis Study Burt et al (2011) 108 van Laar et al (2014) 12 SCOT 107 Mobilisation Cyclophosphamide (2.0 g/m 2 ) G-CSF 10 μg/kg until apheresis Methylprednisolone 1000 mg infusion prior to each dose Cyclophosphamide (2 x 2.0 g/m2) G-CSF 10 μg/kg per day G-CSF 10 μg/kg Stem Cell Transplantation Conditioning IV cyclophosphamide 200 mg/kg in four equal daily doses IV rabbit ATG 1 x 0 5 mg/kg then 4 x 1 5 mg/kg IV cyclophosphamide 200 mg/kg in four daily doses; IV rabbit ATG 7.5 mg/kg administered in equal amounts over 3 consecutive days IV methylprednisolone 1mg/kg and hyperhydration Total body irradiation 800 cgy; Cyclophosphamide 2x60 mg/kg; Equine ATG 6 x 15 mg/kg Infusion NR Reinfusion of peripheral blood autologous CD34+ stem cells ( 2 106/kg) NR Control Control Six monthly IV cyclophosphamide 1.0 g/m2 12 monthly IV cyclophosphamide 750 mg/m2 1 cycle of IV cyclophosphamide 500 mg/m2; 11 monthly IV cyclophosphamide 750mg/m2 Abbreviations: ATG: anti-thymocyte globulin; G-CSF: granulocyte-colony stimulating factor; IV: intravenous; NR: not reported; ASSIST: Supportive care included oral lisinopril ( mg per day), subcutaneous filgrastim 10 μg/kg per day from 5 days after stem-cell infusion until engraftment, irradiated, leucocyte-depleted, and cytomegalovirus-safe blood products, antimicrobial prophylaxis with intravenous piperacillin-tazobactam or cefepime, and oral or intravenous acyclovir (for 12 months post) and fluconazole (for six months post). Oral trimethoprim-sulfamethoxazole three times a week or nebulised pentamidine inhaled once a month was used for prophylaxis of pneumocystis jirovecii for 6 months. Both Burt et al. (2011) 108 and van Laar et al. (2014) 12 used similar mobilisation and conditioning regimens. The SCOT trial used an alternative regimen including total body radiation and equine anti-thymocyte globulin rather than rabbit. The regimen used in SCOT has a higher risk of acute kidney damage. To mitigate this, the protocol used renal shielding techniques, 107 which may require additional training and incur additional costs over protocols used in other clinical trials. Outcome measures of RCTs The key outcomes measured in the included trials are in Table 23. Table 23 Key outcome measures used in the randomised controlled trials of HSCT for systemic sclerosis Outcome measures Burt et al (2011) 108 van Laar et al (2014) 12 SCOT 107 Primary outcome Mortality Event free survival a Survival without significant organ damage Secondary outcomes Disease improvement, disease progression b lung function c, mrss, SF-36 Treatment-related-mortality, toxicity, mrss, organ function, HAQ-DI, weight, SF-36, EQ-5D Treatment-related-mortality, toxicity, complications, SHAQ, SF- 36, mrss, Lung function, cardiac function, renal crisis a defined as death from any cause or development of persistent major organ (heart, lung or kidney) failure; b defined as a 25% decrease in mrss for patients with an initial score of >14 or >10% increase in forced vital capacity; c: increase in mrss of at least 25% for patients with an initial score of >14; c includes predicted forced vital capacity, predicted total lung capacity, volume of diseased lung on CT scan, predicted diffusing capacity carbon monoxide (DLCO); EQ-5D: European quality of life five dimensions; HAQ-DI: health assessment questionnaire disability index; mrss: modified Rodnan skin score; SF-36: short form health survey 36; SHAQ: modified scleroderma health assessment questionnaire. Stem cell therapy for non-haematological (autoimmune) indications: March

64 Safety of RCTs Van Laar et al. (2014) 12 reported the adverse events associated with auto-hsct for patients with SSc. The serious adverse events that affected more than 10 per cent of patients are presented in Table 24. Table 24 Serious adverse events for van Laar et al. (2014) of HSCT for systemic sclerosis Grade 3 or 4 adverse event van Laar et al. (2014) 12 HSCT Control p All, n (%) 51 (63%) 30 (37%) Respiratory, n (%) 15 (19%) 6 (7.8%) 0.06 Cardiovascular, n (%) 13 (17%) 8 (10%) 0.35 Gastrointestinal, n (%) 10 (12.7%) 11 (14.3%) 0.82 Haematologic, n (%) 10 (12.7%) 1 (1.3%) Renal, n (%) 8 (10.1%) 4 (5.2%) 0.37 Infection, n (%) 8 (10.1%) 4 (5.2%) 0.37 Abbreviations: HSCT: haemopoietic stem cell transplantation. Overall, significantly more adverse events were reported in the HSCT group compared to control (63% vs 37%, p=0.002). More grade 3 and 4 adverse events occurred in all categories although only haematologic events were significantly higher. It should be noted however that studies are not powered to detect differences in adverse events between groups. Viral infections were common with 28 per cent affected in the auto-hsct group with cytomegalovirus, Epstein-barr virus and herpes simplex the most common. Adverse events that resulted in death were however equivalent between groups (12 (15%) versus 13 (17%)). Burt et al. (2011) 108 reported limited safety data. In the auto-hsct group during the transplantation period, two patients had infections, two had cardiac arrhythmias and two had volume overload. There was one later cytomegalovirus infection and one cardiac event. In the control group, one patient had an infection and two experienced nausea, vomiting and diarrhoea. No statistical comparison of events was given. Efficacy of RCTs Burt et al. (2011) 108 was powered for a mortality outcome with 60 patients planned to be enrolled however the study was stopped early due to significant benefit in disease progression between groups. No deaths in either group had occurred when the trial was ceased and reported. The major outcomes of Burt et al. (2011) 108 are presented in Table 25. Stem cell therapy for non-haematological (autoimmune) indications: March

65 Table 25 Burt et al. (2011) key clinical outcomes of HSCT for systemic sclerosis Burt et al. (2011) 108 Outcome measure HSCT Control p Disease improvement n(%) 10 (100%) 0 (0%) <0.001 Disease progression n(%) 0 (0%) 8 (89%) <0.001 Lung Baseline 1 year Baseline 1 year Predicted forced vital capacity (%) 62 (15 0) 74 (15 7) 67 (17 0) 61 (19 8) Predicted total lung capacity (%) 76 (14 6) 80 (17 9) 83 (14 8) 74 (18 7) Predicted DLCO corrected for haemoglobin (%) 58 (21 8) 69 (18 6) 75 (27 5) 74 (37 0) 0.36 Volume diseased lung (ml) 823 (268 9) 551 (277 1) 877 (240 6) 985 (277 1) Skin Modified Rodnan skin score 28 (13 6) 15 (7 9) 19 (13 7) 22 (14 2) <0.001 Abbreviations: DLCO: diffusing capacity of the lung for carbon monoxide; HSCT: haemopoietic stem cell transplantation. At one year, there were significant improvements in lung function on all reported measures apart from diffusing capacity of the lung for carbon monoxide (DLCO) and significant improvements in the modified Rodnan skin score (mrss). For the composite measure of disease improvement, all patients in the HSCT group improved compared to none in the cyclophosphamide group. In addition, patients in the HSCT group showed a significant improvement in overall health as measures by the SF-36 of 17 (SD 20.59) points compared to a significant decline in the cyclophosphamide group of -10 (SD 18.03). After one year, patients in the cyclophosphamide group were able to cross over if they had treatment failure and seven of the nine patients subsequently received HSCT at a mean of 14 months post enrolment in the study. All of these patients had subsequent disease improvement. The major outcomes of van Laar et al. (2014) 12 are given in Table 26. The study had a median follow up of 5.8 years for the primary outcome measures of deaths and major events. Stem cell therapy for non-haematological (autoimmune) indications: March

66 Table 26 van Laar et al. (2014) key clinical outcomes of HSCT for systemic sclerosis van Laar et al (2014) 12 Outcome Measure HSCT Control Mean difference (95% CI) p Major event a 22 (27.8%) 31 (40.3%) NR 0.04 Deaths 19 (24.1%) 23 (29.9%) NR 0.03 Major event in the first year 13 (16.5%) 8 (10.4%) NR NR Secondary outcomes b Baseline to 2 years follow up N=67 N=64 Lung Skin Kidney Heart Predicted forced vital capacity (%) 6.3 (18.3) 2.8 (17.2) 9.1 ( 14.7, 2.5).004 Predicted total lung capacity (%) 5.1 (17.5) 1.3 (13.9) 6.4 ( 11.9, 0.9).02 Predicted DLCO 4.7 (13.7) 4.1 (17.6) 0.6 ( 4.9, 6.0).84 Modified Rodnan skin score 19.9 (10.2) 8.8 (12.0) 11.1 (7.3, 15.0) <.001 Creatinine clearance, ml/min 12.1 (29.7) 1.2 (24.1) 10.9 (1.5, 20.3).02 LVEF, % by cardiac echocardiography 2.2 (14.7) 1.9 (13.8) 0.3 ( 4.7, 5.2).91 Quality of life SF-36 physical component score 10.1 (15.8) 4.0 (11.2) -6.1 (-10.9, -1.4).01 SF-36 mental component score 3.1 (16.0) 3.4 (17.1) 0.3 (-5.51, 6.07).91 EQ-5D utility score 0.31 (0.50) 0.03 (0.44) (-0.45, -0.12) <.001 Abbreviations: DLCO: diffusing capacity of the lung for carbon monoxide; LVEF: left ventricular ejection fraction; NR: not reported. a defined as deaths and irreversible organ failures. b defined as the change in the area under the time response curve from baseline to 2 years. Auto-HSCT was significantly better than cyclophosphamide in long term overall and event free survival. It was also significantly better at improving lung and skin condition after two years. Kidney function was worse. No centre effect was observed for the deaths in this study with 62.5 per cent of these occurring in three of the four most active transplant centres in Europe. Quality of life was improved in the HSCT group with both the SF-36 physical component score and the EQ-5D utility score demonstrating significant improvements from baseline to two years compared to the control group. Sub-group analysis of the results demonstrated significant differences in outcomes based on smoking status. Seven of the eight patients who died from treatment-related causes were current or former smokers. Relevant observational studies of autologous haemopoietic stem cell transplantation for systemic sclerosis Study descriptions of the observational studies Six studies of level IV evidence were found that met the inclusion criteria. Burt et al. (2013) 15 followed up 90 patients for five years who received HSCT as part of a clinical trial (n=59) or for compassionate reasons (n=31). Eighteen of these were also part of the phase II randomised trial reported in Burt et al. (2011). 108 Moore et al. (2012) 109 followed an Stem cell therapy for non-haematological (autoimmune) indications: March

67 Australian cohort of 10 patients for up to 84 months post-treatment. Henes et al. (2012) 14 treated 26 patients with auto-hsct using a similar protocol to the European ASTIS trial with a median follow up of 4.4 years. Farge et al. (2010) 19 reported mortality from HSCT in SSc from the European registry data. Vonk et al. (2008) 110 reported long-term results on 26 patients undergoing HSCT. Nash et al. (2007) 111 enrolled 34 patients with a poor prognosis in a pilot study to assess the safety and efficacy of HSCT. The SCOT trial is the subsequent RCT to this pilot. Additional information is presented in Appendix D. Safety of the observational trials The key outcome of mortality from the additional observational studies is presented in Table 27. Table 27 Mortality of all included observational studies of HSCT for systemic sclerosis Study Median follow up (years) N 100-day TRM TRM NTRM Overall mortality Burt et al (2013) NR 5 (6%) NR 20 (22%) Moore et al (2012) (20%) 2 (20%) Henes et al (2012) (11%) 3 (11%) 4 (15%) 7 (27%) Farge et al (2010) NR (6%) 12 (7%) 23 (13%) 35 (20%) Vonk et al (2008) (4%) 1 (4%) 4 (14%) 5 (18%) Nash et al (2007) NR 8 (23%) 4 (12%) 12 (35%) Abbreviations: NR: not reported; NTRM: non-treatment-related-mortality; TRM: treatment-related-mortality. Burt et al. (2013) 15 reported that five patients (6%) had treatment related deaths with four from cardiac events and one as a result of septic neutropenia. The 5-year overall survival rate was 78 per cent. Thirteen patients relapsed, of these eight patients (six related to cardiopulmonary disease and two renal crisis) subsequently died of SSc complications. No TRM was recorded in Moore et al. (2012) 109 in an Australian cohort however two patients subsequently died from recurrence of disease. Henes et al. (2012) 14 reported that only one patient died of transplant related causes as two died from disease progression. Three patients died during or shortly after the mobilisation phase, one as consequence of SSc progression, one with infection and progression of SSc and a third from pulmonary failure. Seven patients had major disease relapses and four patients died during the follow up period from consequences of disease progression. After deaths and drop outs (n=2), 14 patients were still in remission with no signs of disease activity up to 13 years post-transplant. Stem cell therapy for non-haematological (autoimmune) indications: March

68 Farge et al. (2010) 19 report limited data from the European Group for Blood and Marrow Transplantation working party on autoimmune diseases. The five year mortality rate for SSc was 18 per cent. Vonk et al. (2008) 110 reported that only two patients (8%) of the five in total died from disease progression by 5 years. Event free survival was 64 and 57 per cent at five and seven years, respectively. Nash et al (2007) 111 reported a high TRM rate of 23 per cent. Seven of the deaths occurred in the first year and six of these were attributed to organ dysfunction associated with SSc. Renal dysfunction requiring dialysis occurred in four patients with three fatalities. One late fatality occurred 6 years post due to myelodysplastic syndrome attributed to the transplant. Several cardiac arrhythmias occurred with one fatality. The treatment team revised the treatment plan and inclusion criteria following this pilot to improve the selection of suitable patients for the subsequent SCOT RCT. 111 Overall the mortality rate in the observational studies is lower than that expected for patients with severe SSc who have an estimated mortality rate of 40 to 50 per cent at five years. 13, 112 Efficacy of the observational trials The key clinical outcomes of the mrss and forced vital capacity are presented for five of the included observational trials for auto-hsct for SSc in Table 28. Data has been extracted at six months unless indicated. Table 28 Key clinical outcomes of all included observational studies of HSCT for systemic sclerosis Study ID N mrss VC/FVC, % of predicted Pre Post Change p Pre Post Change p Burt et al (2013) NR < a 70.8 NR Moore et al (2012) 109 Henes et al (2012) 14 Vonk et al (2008) b NR <0.05 NR NR NR NR (SD 7.9) 11.2 (SD 7) NR < NR NR NR NR (9-51) 19 (3-51) c NR < (37-143) 84 (43-138) c NR ns Nash et al (-20.72, (2007) (3-48) NR < ) a NR Abbreviations: mrss: modified Rodnan skin score; SD: standard deviation; VC: vital capacity; FVC: forced vital capacity; a Burt et al. (2013) 15 reported forced vital capacity; b estimate from figure; c reported at one year. Burt et al. (2013) 15 found that the main outcome of mrss significantly improved at six months and maintained this improvement up to five years post-transplant. Forced vital capacity was significantly better at six, 12, 24 and 36 months but not at 48 or 60 months. Stem cell therapy for non-haematological (autoimmune) indications: March

69 The other outcomes of total lung capacity and DLCO did not significantly improve at any time point. Moore et al. (2012) 109 found significant improvements in mrss at all time points and also in health assessment questionnaire scores and visual analogue scales of disease and pain. Four of the 10 patients had recurrence of disease and two of these subsequently died. Significant mrss and lung function improvements occurred by six months post-treatment in Henes et al. (2012). 14 Recurrence of the disease occurred in seven patients. Vonk et al. (2008) 110 found that a significant improvement in mrss was observed up to seven years post HSCT. Cardiac and renal function remained stable and there was no significant change in lung function measured with VC, FEV1 and DLCO. All studies found statistically significant improvements in disease activity as measured by the mrss six to 12 months post transplantation indicating a favourable effect of HSCT on disease progression. Mesenchymal stem cell therapy for systemic sclerosis MSCT may offer another alternative that has improved short term safety over HSCT. 113 Limited evidence was available for the treatment of SSc with MSCT. Results from one case series of five Patients with SSc who underwent allogeneic mesenchymal stem cell therapy from related donors has been reported. 114 There was some evidence of pulmonary stabilisation and skin and digital ulcer improvement with no early adverse events above grade 1. One patient died at six months from a sudden cardiac arrest, and another at 23 months from sudden heart failure. A third patient required cardiac stenting. 114 RCTs are required in order to assess the safety and efficacy of this therapy. Stem cell therapy for non-haematological (autoimmune) indications: March

70 Safety and effectiveness for systemic lupus erythematosus Haemopoietic stem cell transplantations for systemic lupus erythematosus Six studies, published between 2009 and 2014, were eligible for inclusion in this report. To be eligible for inclusion, studies were required to have at least five patients and report on the safety and/or efficacy of haemopoietic stem cell treatment for patients with SLE. Two of the included studies were comparative studies with concurrent controls (Level III-2 evidence) and four were case series (level IV evidence, see Appendix E). Study Description A description of the treatment characteristics for each of the six included studies for HSCT for SLE is presented in Table 29. A non-randomised experimental trial was described in Song et al. (2011), 17 where the efficacy and safety of auto-hsct was compared with the conventional therapy. Seventeen patients with SLE were treated with auto-hsct in the same period as 20 patients with SLE who were treated with conventional therapy as the control group. The auto-hsct group were conditioned with the cyclophosphamide / anti-human thymocyte regimen and infused stem cells containing two million CD34+ cells per kg of body weight according to the treatment protocol. The control group were treated with monthly pulses of cyclophosphamide according to disease progression. The only significant difference between patients in the auto-hsct and conventional therapy group was that the auto-hsct group had both more refractory subjects and longer disease progression. The median follow-up time for this study was 89 months. Meng at al. (2011) 16 described a comparative study on patients with SLE previously treated with either auto-hsct or traditional immunosuppressive therapy, who fell pregnant while in remission. The study focussed on the rate of pregnancy complications and disease progression after pregnancy. The auto-hsct cohort of 11 females had a mean age of 29.8±.8 years and the traditional therapy cohort of 39 females had a mean age of 30±2.5 years. The subjects were examined for disease activity (SLEDAI), clinical measurable outcomes and laboratory data before, during and after treatment. The transplantation group and control group were not significantly different in age or disease activity (SLEDAI) prior to treatment. A retrospective survey by Alchi et al. (2013) 115 reviews the safety and efficacy of 28 patients with SLE who were treated with immunoablation and auto-hsct. Stem cells were harvested from peripheral blood in all patients who underwent mobilisation and conditioning regimens. The patient cohort had a median follow-up length of 38 months in which adverse events, SLEDIA analysis and disease progression were recorded. A case series study was performed by Su et al. (2013) 116 evaluating the outcomes of auto- HSCT in patients with severe paediatric SLE. Five patients were administered with Stem cell therapy for non-haematological (autoimmune) indications: March

71 autologous CD34+ cells and different conditioning regimens. Patients one through five were followed up for 83, 69, 66, 62 and 40 months respectively. An observational study on all first time auto-hscts that were reported to the European Group for Blood and Marrow Transplantation was described by Farge et al. (2010) 19. Of the 900 transplantations between 1996 and 2007, 85 were patients with SLE. Standard auto- HSCT techniques were used with conditioning regimens of low, intermediate and high intensity. The patients with SLE were followed up for an average of 25 months, where disease progression was monitored. A monocentric phase I/II clinical trial was reported by Alexander et al. (2009) 117, where seven patients with SLE were treated with immunoablation and auto-hsct. One patient died three months after transplantation, the remaining six were followed-up on average for 62 months. The patients were monitored for disease activity and immune system reconstitution. Table 29 Treatment characteristics of all included studies of HSCT for systemic lupus erythematosus Study Treatment Mobilisation / Graft manipulation Conditioning Regimen Post transplantation Alchi et al (2013) 115 Auto-HSCT (BM) CY and G-CSF: 26/28 (93%); G-CSF: 2/28 (7%) CD34+ positive selection: 10/28 (36%); No graft manipulation: 18/28(64%) Low intensity: CY: 9 (32%); Melphalan: 1 (4%) Intermediate intensity:cy+atg: 4 (14%); CY+ATG+MP: 7 (25%); CY+ATG+fludarabine: 3 (11%); CY+ATG+thiotepa: 3 (11%); CY+thiotepa: 2 (7%); CY+fludarabine+MP+alemtuzumab: 1 (4%) Immunosuppressive drugs or biological agents (60%) Prednisolone at last follow-up (85%) Song et al (2011) 17 Auto-HSCT (PB) CY and G-CSF CD34+ positive selection Intermediate intensity: CY+ATG Antibiotics (ciprofloxacin, acyclovir; fluconazole) and intravenous immunoglobulin to prevent infection Su et al (2013) 116 Auto-HSCT (PB) CTX and G-CSF CD34+ positive selection Patient 1: BEAM Patient 2&5: CY; ATG Patient 3: CY; ATG; Melphalan Patient 4: CY; ATG; Carmustine Antibiotics (sulfamethoxine; ganciclovir; fluconazole) to prevent infection; IVIG monthly for 6 months Meng et al (2011) 16 Auto-HSCT (PB) CY and G-CSF CD34+ positive selection Intermediate intensity: CY+ATG NR Farge et al (2009) 19 Auto-HSCT (BM=11) (BM+PB=74) CY and G-CSF CD34+ positive selection: 33 No selection: 45 Total body irradiation (n=13); CY (n=6); CY+other (n=18); Melpalan (n=3); Fluradinebased (n=3); Busulfan-based (n=2); BEAM (n=33); other chemotherapy (n=33) NR Alexander et al (2009) 117 Auto-HSCT (PB) CY and G-CSF CD34+ positive selection Intermediate intensity: CY+ATG+MP NR Abbreviations: Auto-HSCT: autologous haemopoietic stem cell transplant; BM: bone marrow; CY: cyclophosphamide; G-CSF: granulocyte-colony stimulating factor; ATG: rabbit anti-thymocyte globulin; MP: methylprednisolone; Beam: carmustine + etoposide + cytarabine + melphalan + ATG; IVIG: human immunoglobulin; CD34: cluster of differentiation 34; NR: not reported; PB: peripheral blood. Stem cell therapy for non-haematological (autoimmune) indications: March

72 Safety Alchi et al. (2013) 115 reported 31 adverse events from 23 patients with SLE. Three patients had severe immune responses: post-transplant Epstein-Barr-associated lymphoproliferative disorder (alive at six years); autoimmune haemolytic anaemia (died); and acquired haemophilia (alive at five years). Two patients had cardiovascular events. Song et al. (2011) 17 found no significant differences in the adverse events between conventional therapy and auto-hsct. Four adverse events were reported in the mobilisation phase of auto-hsct, including allergic reaction to cyclophosphamide, fever related to granulocyte-colony stimulating factor and bone pain. Post-transplant there was one case of allergy to anti-thymocyte globulin, eight cases of fever of unknown origin, eight documented infections, 17 cases of nausea and vomiting, and one case of transient elevation of liver enzymes. In the follow up there was one case of spinal tuberculosis. Su et al. (2013) 116 reported three patients having cytomegalovirus (CMV) infections and one patient having CMV and Epstein-Barr virus infection. During pre-treatment one patient developed anaphylactic shock one hour after the use of anti-thymocyte globulin. Table 30 Study Adverse events of all included studies of HSCT for systemic lupus erythematosus Adverse events HSCT Conventional therapy Alchi et al (2012) 115 Infections (n=15) Severe autoimmune events (n=3) Post-transplant EB-associated lymphproliferative disorder (n=1) Haemophilia (n=1) Cardiovascular events (n=2) Song et al (2011) 17 During mobilisation: allergic reaction to CY (n=1); fever related to G- CSF (n=3); bone pain (n=4) Treatment: allergy to ATG (n=1); FUO (n=8); documented infection (n=8); nausea and vomiting (n=17); transient elevation of liver enzymes (n=1). Follow up: spinal tuberculosis (n=1) Su et al (2013) 116 Low-grade fever from CMV (n=1) (14 days after HSCT); CMV infection (n=3)(28, 31 and 35 days after HSCT); EB virus infection (n=1)(36 days after HSCT) NA FUO (n=6) Documented infection (n=10) Nausea and vomiting (n=15) Elevation of liver enzymes (n=3) Ovarian failure (n=1) Meng et al (2011) 16 NR NA NA Farge et al (2010) 19 NR NA Alexander et al (2009) 117 NR NA Abbreviations: ATG: rabbit anti-thymocyte globulin; CY: cyclophosphamide; CMV: Cytomegalovirus; EB: Epstein-Barr; FUO: fever of unknown origin; G- CSF: granulocyte-colony stimulating factor; HSCT: haemopoietic stem cell transplant; NA: not applicable; NR: not reported. Mortality Five of the six studies reported 100-day TRM. The 100-day TRM was per cent, per cent and per cent in Alchi et al. (2012), 115 Farge et al. (2010), 19 and Alexander et al. Stem cell therapy for non-haematological (autoimmune) indications: March

73 (2009), 117 respectively. Only Farge et al. (2010) 19 reported the deaths as related to the treatment. Song et al. (2011) 17 reported the deaths in the HSCT group to not be related to treatment. Table 31 Mortality of all included studies of HSCT for systemic lupus erythematosus Study 100-day TRM TRM NTRM Overall mortality Alchi et al (2012) 115 3/28 (10.71%): infection (n=3) (1, 2 and 3 months) NR NR 5/28 (17.86%): secondary autoimmune haemolytic anaemia (n=1) (15 months); SLE disease progression (n=1) (24 months) Song et al (2011) 17 HSCT: 0/17 (0%) Conventional: NR HSCT: 0/17 (0%) Conventional: NR HSCT: 2/17 (11.76%): severe pneumonia (n=1)( 33 months); heart failure (n=1) (64 months) Conventional: NR HSCT: 2/17 (11.76%) Conventional: 5/20 (25%): pneumonia (n=3); renal failure (n=1); respiratory failure (n=1) Su et al (2013) 116 0/5 (0%) 0/5 (0%) 0/5 (0%) 0/5 (0%) Meng et al (2011) 16 Farge et al (2010) 19 Alexander et al (2009) 117 NR NR NR NR 11/85 (12.94%) 11/85 (12.94%) 18/85 (21.18%) 29/85 (34.12%) 1/7 (14.29%): uncontrolled invasive central nervous system aspergillosis (n=1) (3 months) NR 1/7 (14.29%) SLE-related pulmonary embolism (n=1) (38 months) 2/7 (28.57%) Abbreviations: SLE: systemic lupus erythematosus; HSCT: haemopoietic stem cell transplantation; TRM: treatment-related-mortality; NTRM: nontreatment-related-mortality; NR: not reported. Efficacy Overall survival, disease-free progression and progression-free survival The overall survival and disease/progression free survival of patients after auto-hsct was discussed in three studies (Table 32). Alchi et al. (2013) 115 reported the 5-year overall survival rate as 81 per cent. Five deaths were reported within two years after auto-hsct. The probability of disease free survival, which is defined as the time interval between auto-hsct and death or relapse, was 29 per cent. The probability of non-relapse mortality, defined as death in absence of relapse, was 15 per cent. The relapse incidence, which censors any patients who die from direct treatment toxicity and non-lupus related causes, was 56 per cent. The study found no relationship between these primary endpoints and disease duration length. No transplant related deaths occurred in the study by Song et al. (2011) 17 according to the Milan consensus, which stipulated that deaths within three months of the transplantation were deemed transplanted-related deaths. 118 The overall survival probability was not Stem cell therapy for non-haematological (autoimmune) indications: March

74 significantly different between auto-hsct and conventional therapy. The progression free survival (PFS) was significantly lower in conventional therapy compared to auto-hsct. This showed that auto-hsct has greater capability to induce sustained remissions compared to conventional therapy. Farge et al. (2010) 19 reported the 5-year overall survival, progression free survival and transplant-related mortality. The transplant-related mortality was 11 per cent. Table 32 Patient response to transplantation of all included studies of HSCT for systemic lupus erythematosus\ Study Treatment 5 (7) -year OS NRM RI DFS PFS Alchi et al (2012) 115 Auto-HSCT (PB) 81±8% 15±7% 56±11% 29±9% NR Song et al (2011) 17 Auto-HSCT (PB) 82.4%± 9.2% NR NR NR 64.7% ± 11.6% Conventional Therapy 66.7% ± 11.4% NR NR NR 24.7% ±10.3% Farge et al (2010) 19 Auto-HSCT (BM=11)(BM+PB=74) 76%, 95% CI[66%, 86%] NR NR NR 44% 95% CI[32%,56%] Abbreviations: Auto-HSCT: autologous haemopoietic stem cell transplant; BM: bone marrow; CI: confidence interval; NR: not reported; NRM: non-relapse mortality; RI: relapse incidence; DFS: disease free survival; PFS: progression free survival; OS: overall survival; PB: peripheral blood. Disease activity Five studies used the SLE disease activity index (SLEDAI) to measure overall disease activity before auto-hsct and through-out follow-up (Table 33). Meng et al. (2011) 16 only reported the baseline SLEDAI but not the follow-up values. SLEDAI is a global index developed to capture an overall measure of disease activity at a given time. 119 Decreasing SLEDAI scores represent diminishing disease activity, with remission reached at SLEDAI scores < three. 120 The study by Alchi et al. (2013) 115 reported 6/28 (21%) patients to have a SLEDAI score under three at the last follow-up. The change in SLEDAI from mobilisation to last follow-up was found to significantly decrease with a p-value = (Table 33). The SLEDIA of 17 auto-hsct patients were found to significantly decrease from before transplantation to 5-years post-transplant (p 0.01). The SLEDAI scores at 5-years follow-up in the conventional therapy group were also significantly decreased (p>0.01). Song et al. (2011) 17 did not statistically report on the relationship between changes in SLEDIA scores of conventional therapy and auto-hsct. Alexander et al. (2009) 117 reported on seven patients with SLE post-auto-hsct. All patients reached SLEDIA scores below three, five of whom remained with SLEDIA scores below three at the last follow-up, whilst two patients died. Meng et al. (2011) 16 compared auto-hsct and conventional therapy in patients with SLE who intended to become pregnant. Pre-conception, both the 17 patients with SLE in the Stem cell therapy for non-haematological (autoimmune) indications: March

75 auto-hsct group and 39 patients with SLE in the conventional therapy group had SLEDAI scores of 4. Four weeks post-delivery the non-transplant group s SLEDAI score was significantly higher than that of the transplant group (p<0.05). The non-transplant group was also found to have significantly higher rates of lupus nephritis and maternal hypertension (p<0.05). Auto-HSCT was shown to decrease the SLEDAI scores of five paediatric patients with SLE in a study by Su et al. (2013). 116 All five patients were alive at the end of follow-up and three no longer had any drug use. The study reported the patient s growth rate increased significantly post-transplant and were approximately on par with their age groups by the end of follow-up. Table 33 Disease activity after transplantation of all included studies of haemopoietic stem cell transplantation for systemic lupus erythematosus Study Treatment Baseline SLEDAI SLEDAI at end of follow-up SLEDAI preconception SLEDAI 4-weeks post-conception Alchi et al (2013) 115 Auto-HSCT 15.5, 95% CI [12%, 18.9%] 8.5, 95% CI [5.3%, 11.1%] NA NA Song et al (2011) 17 Auto-HSCT 32.3 ± ± 0.92 NA NA Conventional Therapy 18.2 ± ± 4.48 NA NA Su et al (2013) 116 Auto-HSCT Patient 1: 32 Patient 2: 18 Patient 3: 15 Patient 4: 38 Patient 5: 24 Patient 1: 0 Patient 2: 10 Patient 3: 0 Patient 4: 4 Patient 5: 0 NA NA Meng et al (2011) 16 Auto-HSCT 20±5 NA 4±1 4±2 Conventional Therapy 21±3 NA 4±1 7±2 Alexander et al (2009) 117 Auto-HSCT Patient 1: 25 Patient 2: 23 Patient 3: 30 Patient 4: 28 Patient 5: 26 Patient 6: 23 Patient 7: 19 Patient 1: <3 Patient 2: <3 Patient 3: Dead Patient 4: <3 Patient 5: Dead Patient 6: <3 Patient 7: <3 Abbreviations: Auto-HSCT: autologous haemopoietic stem cell transplant; SLEDAI: systemic lupus erythematosus disease activity index; CI: confidence interval; NA: not applicable. NA NA Stem cell therapy for non-haematological (autoimmune) indications: March

76 Mesenchymal stem cell therapy for systemic lupus erythematosus Six studies, published between 2010 and 2014, were eligible for inclusion in this report. To be eligible for inclusion, studies were required to have at least five patients and report on safety and/or efficacy of mesenchymal stem cell therapy. All six studies were noncomparative case series (level IV evidence, see Appendix C). No studies were found where MSCT was compared with another treatment method, hence the effectiveness of MSCT cannot be proved. All of these studies, except Wang et al. (2014), 20 recruited patients between March 2007 and July It cannot be confirmed that no patient overlap occurred between these five studies. Study description A description of the treatment characteristics for each of the six included studies for MSCT for SLE is presented in Table 34. In a clinical trial described by Wang et al. (2014), patients with SLE aged years who had a British Isles lupus assessment group (BILAG) grade B were enrolled. The patients had an intravenous infusion of one million umbilical cord mesenchymal stem cells (UC-MSC) per kilogram of body weight on days zero and seven, one patient did not receive the second infusion due to uncontrolled disease progression. The patients returned for follow-up at one, three, six, nine and 12 months after MSCT, where the determination of SLEDAI score, BILAG analysis and evaluation of organ function occurred. The 2013 study by Wang and colleagues 21 observed the long-term safety and efficacy of allogeneic MSC transplantation in treatment-resistant patients with SLE refractory to standard therapies who had SLEDAI scores eight (n=87) were administered with cyclophosphamide (10mg/kg/day) on days -4, -3 and -2 before receiving a single intravenous infusion of either BM- or UC-derived MSCs (1 million cells/kg of bodyweight per infusion). Patients returned at one, three, six, 12 month and yearly thereafter for follow-up where physical examinations, serological tests and SLEDAI analysis were recorded. The mean follow-up period was 27 months. Li et al. (2013) 121 reported on the MSCT of 35 patients with SLE with cytopenia refractory to standard therapies. A total of 15 patients received cyclophosphamide infusion for 2-4 days. The remaining 20 patients did not receive cyclophosphamide -pre-treatment due to severe baseline disease condition. Eight patients were infused with BM-MSCs of which three patients required an additional infusion of UC-MSCs at eight, three and four months respectively. One other patient who had a BM-MSC infusion required three additional infusions of UC-MSCs at 11, 19 and 20 months. Of the 27 patients who originally received the UC-MST infusion three required a second infusion of UC-MSC at two, four, three months respectively. Additional infusions were due to disease relapse and every infusion for both BM- and UC-derived MSCs was one million cells per kg of body weight. Patient s returned Stem cell therapy for non-haematological (autoimmune) indications: March

77 for follow-up at one, three, six, 12, 18, 24, 36 and 45 months after MSCT for physical examination, serological testing and SLEDIA analysis. An RCT was performed by Wang et al. (2012) 120 to observe whether double MSCTs were superior to single MSCTs in refractory patients with SLE. Fifty-eight patients with refractory SLE were randomly administered to receive either single (n=30) or double (n=28) MSCTs. All patients received cyclophosphamide intravenously prior to transplantation on days -4, -3 and -2. All patients retuned for follow-up at one, three, six and 12 months and the yearly thereafter for physical examination, serological testing and SLEDIA analysis. A single arm clinical trial was carried out by Sun et al. (2010) 122 which involved 16 refractory patients with SLE receiving UC-MSCT. Eleven of the patients received cyclophosphamide intravenously before UC-MSCT, the other five patients did not receive cyclophosphamide due to their poor medical condition. All patients received prednisone at 5-10mg/day and 13 patients also received cyclophosphamide ( gm per 2-3 months) as maintenance therapy. Both drugs were tapered down upon patient s condition improvement. All patients were followed up at one and three months, 10 patients were followed up at six months and two patients were followed up greater than one year. A study by Liang et al. (2010) 123 described an un-blinded clinical trial where 15 patients with persistently active SLE underwent MSCT. Patients all had one intravenous infusion of one million BM-MSCs/kg of body weight. All patients continued treatment with steroids until disease condition improved and then followed a withdrawal schedule. Each patient returned for follow-up at one-week, one, three, six, 12, and 18 months and then once every half-year thereafter for physical examinations, serological testing and SLEDAI analysis. Stem cell therapy for non-haematological (autoimmune) indications: March

78 Table 34 Treatment characteristics of all included studies of MSCT for systemic lupus erythematosus Study Treatment Mesenchymal stem cell source Conditioning regimen Maintenance treatment Wang et al (2012) 120 Allo-MSCT Single: BM (n=12); UB (n=18) Double: BM (n=9); UB (n=19) CY NR Li et al (2013) 121 Allo-MSCT BM (n=4); UB (n=24); BM and UB (n=3); BM and UBx2 (n=1); UBx2 (n=3) CY (n=15) No conditioning (n=15) NR Liang et al (2010) 124 Sun et al (2010) 122 Wang et al (2013) 21 Allo-MSCT BM and UC NR Prednisone and CY at 1 month post-msct; all continue steroids and taper from infusion 5-10mg every 2 weeks Allo-MSCT UC CY (n=11) No conditioning (n=5) Prednisone and CY post-msct; all continue steroids and taper from infusion 5-10mg every 2 weeks Allo-MSCT BM & UC CY Second MSCT infusion due to lupus relapse (n=18) Wang et al (2014) 20 Allo-MSCT Double: UC (days 0 and 7) NR Doses of steroids were tapered after transplant according to amelioration of disease Abbreviations: BM-MSCT: bone marrow mesenchymal stem cell therapy; UC-MSCT: umbilical cord mesenchymal stem cell therapy; CY: cyclophosphamide; MSCT: mesenchymal stem cell therapy; mg: milligram; NR: not reported. Safety The adverse events for all six studies are presented in Table 35. Wang et al. (2014) 20 reported no adverse events related to MSCT. Three patients died during the study as a result of uncontrolled disease activity and organ failure at seven, 192 and 256 days after MSCT. Wang et al. (2013) 21 reported five of 87 patients died after MSCT, of which none were judged to be treatment-related. A number of adverse events occurred though none were considered to be related to MSCT. Li et al. (2013) 121 reported none of the adverse events to be related to MSCT. Two patients died due to uncontrolled disease reoccurrence due to infection. During the four year follow-up, Wang et al. (2012) 120 reported seven patients from single MSCT and nine patients from double MSCT suffered infection events. All adverse events were not considered to be transplantation related. Sun et al. (2010) 122 reported no UC-MSCT related mortality or adverse events, with all patients reported to well tolerate the infusion. Stem cell therapy for non-haematological (autoimmune) indications: March

79 Liang et al. (2010) 123 reported no serious adverse events, including graft-versus-host disease. Adverse events during follow-up were usually mild infections, which were thought to not be due to the procedure. Table 35 Study Adverse events of all included studies of MSCT for systemic lupus erythematosus Adverse events Wang et al (2014) 20 Wang et al (2013) 21 Liang et al (2010) 124 Herpesvirus infection (n=3) (135, 187 and 291 days after MSCT) Tuberculosis infection (n=1) (326 days after MSCT) Diarrhoea (n=2) (3 and 4 months after MSCT) Herpes virus infection (n=2) (1 and 6 months after MSCT) Agranulocytosis and oral fungus infection (n=1) (7 days after CY pre-treatment) Tuberculosis infection in lung (n=1) (9 months after MSCT) Bone fracture in L3 in an accident (n=1) (2 months after 3 rd MSCT) Myocardial infarction (n=1) (14 month after MSCT) Upper respiratory tract infections Sun et al (2010) 122 Severe nausea (n=1) (during CY pre-treatment) Li et al (2013) 121 Agranulocytosis and oral fungus infection (n=1) (4 days after MSCT) Tuberculosis infection in lung (n=1) (9 months after MSCT) Wang et al (2012) 120 Single transplantation: upper respiratory tract (n=3); intestinal infection (n=3); oral fungi infection (n=1) Double transplantation: upper respiratory tract (n=4); intestinal infection (n=2); herpes zoster infection (n=1); pneumonia (n=1); pulmonary tuberculosis (n=1) Abbreviations: CY: cyclophosphamide; MSCT: mesenchymal stem cell therapy. Table 36 Mortality of all included studies of MSCT for systemic lupus erythematosus Study 100-day TRM TRM NTRM Overall mortality Wang et al (2014) 20 Wang et al (2013) 21 1/40 (2.5%): uncontrolled progressive disease and acute heart failure (n=1) (7 days) 2/87 (2.29%): acute gastroenteritis and heart failure (n=1)(3 months); progressive disease and acute heart disease (n=1)(7 day) 0/40 (0%) 3/40 (7.5%): respiratory disease (n=1) (192 days); right-sided heart failure (n=1) (256 days); uncontrolled progressive disease and acute heart failure (n=1) (7 days) 0/87 (0%) 5/87 (5.75%): disseminated pulmonary infection (n=1) (6 months); right sided heart failure (n=1)(8 months); pulmonary embolism (n=1) (9 months) Li et al (2013) 121 0/35 (0%) 0/35 (0%) 2/35 (5.7%): uncontrolled disease reoccurrence due to infection (n=2)(6 months) Wang et al (2012) 120 Sun et al (2010) 122 0/58 (0%) 0/58 (0%) 1/58 (1.72%): acute heart failure (n=1)(6 months) 3/40 (7.5%) 5/87 (5.75%) 2/35 (5.7%) 1/58 (1.72%) 0/16 (0%) 0/16 (0%) 0/16 (0%) 0/16 (0%) Liang et al 0/15 (0%) 0/15 (0%) 0/15 (0%) 0/15 (0%) (2010) 124 Abbreviations: TRM: treatment-related-mortality; NTRM: non-treatment-related-mortality. Stem cell therapy for non-haematological (autoimmune) indications: March

80 Efficacy Survival / Disease progression Three included studies reported on the overall survival, disease free survival or relapse rate of patients with SLE after MSCT. The overall survival reported by Wang et al. (2014) 20 was 92.5 per cent (37/40). The primary efficacy endpoints of this study were major clinical response (MCR) and partial clinical response (PCR). A MCR was achieved in 13/40 patients (32.5%) and a PRC was achieved in 11/40 patients (27.5%). Three patients with a PCR and four patients with a MCR experienced a disease relapse. The primary outcomes for Wang et al. (2013) 21 were overall survival and disease remission. The overall survival was 94 per cent (82/87) and the yearly rate of clinical remission and relapse can be found in Table 37. The overall rate of relapse was 23 per cent (20/87). The average time to disease relapse was 16 months (3-42). Eighteen patients with SLE underwent a second MSCT after relapse or no clinical response; two patients died; two achieved clinical remission; seven showed a response but didn t reach clinical remission and seven were refractory to multiple MSCT or had lupus relapses. No significant differences in overall survival or disease progression were found by Wang et al. (2012) 120 when comparing single and double MSCT. The survival rate was 100 per cent and 96.4 per cent for single and double MSCT respectively. The rate of complete remission was 53.3 per cent and 28.6 per cent for single and double MSCT respectively. The time and rate of relapse was 21 months with a rate of 26.7 per cent and 12 months with a rate of 22.2 per cent for single and double MSCT respectively. Table 37 Complete clinical remission and rate of relapse after MSCT in patients with systemic lupus erythematosus 21 Wang et al (2013) 21 Probability at year 1 Probability at year 2 Probability at year 3 Probability at year 4 Complete clinical remission 28% (23/83) 31% (12/39) 42% (5/12) 50% (3/6) Rate of relapse 12% (10/83) 18% (7/39) 17% (2/12) 17% (1/6) Abbreviations: SLE: systemic lupus erythematosus; MSCT: mesenchymal stem cell therapy Disease activity (SLEDAI) SLEDAI scores are used to measure changes in overall disease activity in six included studies. BILAG and SLEDAI were both used to measure disease activity in the study by Wang et al. (2014) 20. The mean SLEDAI scores at one month, three months, six months, nine months and 12 months were all significantly decreased compared to the baseline (p<0.01) (Table 38). The BILAG scores also showed a statistically significant (p<0.001) decreases at all timepoints compared to the baseline. Stem cell therapy for non-haematological (autoimmune) indications: March

81 Wang et al. (2013) 21 and Wang et al. (2012) 120 both reported a significant decrease in SLEDAI score after MSCT, although they did not report the SLEDAI values. SLEDAI analysis was measured by Li et al. (2013) 121 at 1, 3, 6, 12 and 24 months follow-up. All time points showed significant decreases (p<0.01) in SLEDAI scores compared to baseline (Table 38). Liang et al. (2010) 123 reported an improvement in the SLEDIA score across the 13 patients who were followed-up past 12 months (Table 38). The study described a significant difference (p<0.05) between all follow-up time-points (1, 3, 6, 12 and 24 months) and baseline. A significant improvement in SLEDAI scores was reported by Sun et al. (2010) 122 at one month, three months, six months and two years compared to baseline (Table 38). Table 38 Disease activity after transplantation of all included studies of MSCT for systemic lupus erythematosus Study Baseline SLEDIA 3 months 12 months 2 years Li et al (2013) ± ± ±2.1 (n=31) 3.5±2.0 (n=17) Liang et al (2010) ±3.3 (n=12) NR 3.2±2.8 (n=12) NR Sun et al (2010) ±1.1 (n=16) 7.9±0.8 (n=16) NR < 4 (n=2) Wang et al (2014) ± ± ±3.52 NR Abbreviations: SLEDAI: systemic lupus erythematosus disease activity index; MSCT: mesenchymal stem cell therapy; NR: not reported. Renal Function Five studies included patients with SLE who had renal involvement which were investigated through twenty-four hour (24 h) proteinuria as a measurement of disease activity. The study by Wang et al. (2014) 20 investigated 40 patients with SLE of which 38 (95%) had renal involvement. Along with the renal BILAG scores decreasing after two UC MCTs, the 24 h proteinuria levels decreased significantly (Table 39). The decrease in 24 h proteinuria was significantly lower than baseline at the nine and 12 month follow-ups (p<0.05). Seventy-three of the 84 patients with SLE had renal involvement in the study by Wang et al. (2013). 21 The study showed significant decreases from baseline in 24 h proteinuria at one, three, six, 12, 24 and 36 months follow-up (p<0.01) (Table 39). Wang et al. (2012) 120 investigated 26/30 (86.7%) from single MSCT and 24/27 from double MSCT (88.9%) who had renal involvement at baseline. Both groups reported a significant decrease in 24 h proteinuria after MSCT (p<0.001). The study pointed out that single MSCT decreased 24 h proteinuria significantly more than the double MSCT group (p<0.026). Stem cell therapy for non-haematological (autoimmune) indications: March

82 In the study by Sun et al. (2010), 122 renal involvement was measured in 15 of the 16 patients. The 24 h proteinuria at three months was significantly decreased as reported in Table 39 (p<0.001). Eight of the 15 patients had further decreases in 24 h proteinuria at the six month follow-up with (1,056.5 ± mg versus 3,237.4 ± 1,259.9 mg at baseline; n=8) (p<0.001). The two patients who had a follow-up longer than two years remained negative for 24 h proteinuria. Liang et al. (2010) 123 reported all 15 patients with SLE to have renal involvement and all showed reduced 24 h proteinuria after MSCT. A significant decrease was observed (n=12) at one week compared to baseline (1,430.7 ± vs. 2,538.0 ± mg, p<0.01). Table 39 Renal Function after transplantation of all included studies of MSCT for systemic lupus erythematosus Study 24h proteinuria (mg) at baseline 24h proteinuria (mg) at 3 months 24h proteinuria (mg) at 12 months 24h proteinuria (mg) at 4 years Liang et al (2010) 124 2,538.0±382.3 (n=15) 1,273.8±194.0 (n=9) 858.0±800.7 (n=12) NR Sun et al (2010) 122 3,121.5±1,191.4 (n=15) 1,338.0±910.3 (n=15) NR NR Wang et al (2013) 21 2,710±1,190 1,520±960 1,520±1,010 1,320±1,520 Wang et al (2014) 20 2,240±1,430 1,910±1,200 1,410±1,330 NR Abbreviations: MSCT: mesenchymal stem cell therapy; mg: milligram; h: hour; NR: not reported. Serological response Five included studies reported on serum albumin levels and anti-double stranded DNA levels post MSCT. Low serum albumin levels have been associated with higher SLE disease activity. Although anti-double stranded DNA is commonly used to monitor the progress of SLE, it has not been confirmed whether anti-double stranded DNA are innocent markers of disease or harmful agents. Wang et al. (2014) 20 measured both serum albumin levels and anti-double stranded DNA levels. The serum albumin levels significantly improved at each time point after MSCT compared to baseline as reported in Table 40 (p<0.05). The serum anti-double stranded DNA levels were significantly decreased compared to baseline at the 6 and 12 month followups (p<0.05) (Table 41). The serum albumin levels and anti-double stranded DNA were both reported in Wang et al. (2013). 21 The serum albumin levels were significantly higher at the three, six, 12 and 24 months compared to baseline (p<0.001) as shown in Table 40. The decreased anti-double stranded DNA levels after MSCT of which only three months (p<0.021) and six months (p<0.019) follow-up were statistically significant (Table 41). Stem cell therapy for non-haematological (autoimmune) indications: March

83 Both single and double MSCT were found by Wang et al. (2012) 120 to increase serum albumin levels and decrease serum anti-double stranded DNA. Liang et al. (2010) 123 only reported decreases in serum anti-double stranded DNA levels after MSCT. Eleven of the 15 patients had statistically significant decreases at one month (p<0.05) and three months (p<0.05) post-infusion compared to baseline. In the study by Sun et al. (2010) 122 the serum albumin levels increased after three months (p<0.001) and reached almost normal levels in seven patients at six months after MSCT (p<0.001) (Table 40). The serum anti-double stranded DNA levels decreased significantly for 13 patients three months after MSCT (p=0.03) (Table 41). Table 40 Serum albumin levels after transplantation of all included studies of MSCT for systemic lupus erythematosus Study Baseline (gm/litre) 3 months (gm/litre) 6 months (gm/litre) 12 months (gm/litre) 4 years (gm/litre) Sun et al (2010) ± ± ±0.175 (n=7) NR NR Wang et al (2013) ± ± ± ± ±.66 Wang et al (2014) ± ± ± ±0.78 NR Abbreviations: gm: grams; MSCT: mesenchymal stem cell therapy; NR: not reported. Table 41 Serum anti-double stranded DNA antibody after transplantation of all included studies of MSCT for systemic lupus erythematosus Study Baseline (IU/ml) 3 months (IU/ml) 6 months (IU/ml) 12 months (IU/ml) 24 months (IU/ml) Sun et al (2010) ± ±423.7 NR NR NR Wang et al (2013) ± ± ±125.6 NR 394.0±110.9 Wang et al (2014) ± ± ± ± NR Abbreviations: Anti-dsDNA: anti-double-stranded deoxyribonucleic acid; MSCT: mesenchymal stem cell therapy; IU: international unit; ml: millilitre; NR: not reported. Stem cell therapy for non-haematological (autoimmune) indications: March

84 Economic evaluation A search of the Centre for Reviews and Dissemination, University of York, for economic evaluations of stem cell transplantations for each of the relevant conditions, revealed three health technology assessments (HTAs) for MS, one HTA for SLE, 128 and no HTAs for SSc. Of these health technology assessments, only one publication 125 was available at the time of this report. An exploratory cost-effectiveness analysis in the UK evaluated the incremental costeffectiveness of auto-hsct versus mitoxantrone in the treatment of patients with SPMS. 11 An indirect comparison of patient-level data from two European MS registry databases n formed the basis of a decision-analytic Markov model to evaluate the lifetime costs and health outcomes associated with disability progression and MS relapse. The outcomes used from the registry databases were relative effectiveness of auto-hsct versus mitoxantrone and the incidence of MS relapse. Clinical studies provided estimates of TRM of auto-hsct. The setting was an inpatient secondary care setting with the perspective from the UK National Health Service and Personal Social Services. The utility estimates were sourced from a study of over 2,000 patients. 129 Costs and future benefits were discounted at an annual rate of 3.5 per cent. The lifetime of the patient was used as the time horizon of the model. The benefit measure was quality adjusted life years (QALYs) gained. The results of the cost-utility analysis revealed auto-hsct as cost-effective compared with mitoxantrone at a threshold accepted by policy makers in the UK. Analysis of three treatment duration scenarios varied considerably: Based on optimistic assumptions reflecting six-month sustained progression from any EDSS, the incremental cost-utility ratio for auto-hsct compared with mitoxantrone was 2,783 per QALY gained (i.e. auto-hsct generated additional costs of 3,883, over mitoxantrone, and additional 1.40 QALYs). Using pessimistic assumptions reflecting six-month sustained progression from baseline EDSS, auto-hsct dominated by mitoxantrone (i.e. auto-hsct was less effective and more expensive compared with mitoxantrone generating additional costs of 24,540, over mitoxantrone, and 1.02 fewer QALYs). When a middle ground scenario reflecting next-visit sustained progression from baseline EDSS, was adopted the incremental cost-utility ratio for auto-hsct compared to mitoxantrone was 74,210 per QALY gained (i.e. auto-hsct generated additional costs of 17,136, over mitoxantrone, and additional 0.23 QALYs). A sensitivity analysis revealed that the results were sensitive to changes in procedural costs and TRM of auto-hsct, suggesting that improvements in transplant related mortality may n European Group for Blood and Marrow Transplantation registry database and the Clinique de Neurologie, Lyon, registry database. Stem cell therapy for non-haematological (autoimmune) indications: March

85 improve the cost-effectiveness of auto-hsct considerable, especially in related to the middle ground scenario. This analysis was limited by the lack of data available from RCTs. It was concluded that auto-hsct could be a cost-effective treatment for SPMS, however, large, high-quality RCTs comparing auto-hsct versus mitoxantrone are required to confirm these results. These results are not generalisable for auto-hsct as a treatment for other subtypes of MS (e.g. RRMS) due to different comparators, other autoimmune diseases, or other types of stem cell transplantations (e.g. MSCT). Ongoing research Ongoing research for multiple sclerosis Searches of the Australian New Zealand Clinical Trials Registry, ClinicalTrials.gov registry and the WHO International clinical trials registry platform found 42 studies on stem cell transplantation for MS of which 30 studies are registered as active/recruiting, seven trials registered as complete, three trials registered as terminated and two was registered with an unknown status. Details of these studies are outlined in Table 42. The three trials that have been terminated were based on autologous HSCT (NCT , NCT ), and autologous MSCT (NCT ). Of the 30 current (active/recruiting/complete) trials, 12 studies are based on HSCT, 21 studies are based on MSCT, two studies are based on stromal vascular fraction, one study was based on bone marrow derived mono nuclear stem cells and one study based on bone marrow cellular therapy. All of the 12 studies of HSCT are autologous, except for one study which is allogeneic (NCT )., Of the 11 studies of autologous HSCT, there are two RCTs; MIST trial (NCT ) and the MIST-S trial (EUCTR SE), six phase II trials (NCT :HALT-MS, ACTRN , EUCTR IT:LIGHT, NCT , NCT , NCT ), two phase I trials (NCT , NCT ) and one observational trial (NCT :NISSC). - The MIST phase III trial (NCT ) is a multi-centre RCT based in USA, Sweden, Brazil and the UK. The trial will compare auto-hsct versus standard of care treatment approved by the FDA (i.e. interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) for patients with inflammatory (i.e. relapsing) MS failing alternate approved therapy. The primary outcome measure will be disease progression, defined as a one point increase in the EDSS on consecutive evaluations at least six months apart and not due to a non-ms disease process. Patients will be followed for a period of five years after randomisation. The estimated enrolment will be participants aged 18 to 55 years with an EDSS score of 2.0 to 6.0. Exclusion criteria includes a diagnosis of primary progressive MS and secondary progressive MS, and treatment with prior alemtuzumab which may in fact be a more Stem cell therapy for non-haematological (autoimmune) indications: March

86 appropriate treatment comparator. The study commenced in January 2006 and the estimated primary completion date is December 2016 with the final study completion date estimated to be December Australia may become part of this phase III clinical trial this year (2015). At the time of this report, the authors were informed that St. Vincent s Hospital in Sydney has been accepted, and intends to be part of the MIST phase III trial as a collaborative treatment centre in There are no phase III trials for MSCT for MS. All of the 21 studies of MSCT are autologous, except for two studies which are allogeneic using umbilical cord-derived stem cells (NCT , NCT ). Of the 19 studies of autologous MSCT, there are 13 RCTs (phase I/II) and six are single group (phase I/II) trials. It should be noted that there are a number of centres that are providing stem cell transplantation for MS that are not part of registered clinical trials, including the facility in Russia that has provided treatment to a number of patients from Australia in recent years. Stem cell therapy for non-haematological (autoimmune) indications: March

87 Table 42 List of registered clinical trials for stem cell transplantations for multiple sclerosis Clinical trial identifier Country Study Designs Trial Trial Status Interventions Primary Outcomes Follow up N Compl etion Date NCT (MIST) USA, Brazil, Multi-centre RCT Phase III Recruiting Auto-HSCT vs. standard EDSS 5 years 110 Dec-17 Sweden, UK EUCTR SE Sweden RCT Phase II Active Auto-HSCT vs. standard EDSS 5 years 20 NR (MIST-S) NCT (HALT-MS) USA Single group Phase II Active, not Auto-HSCT Time to treatment failure 5 years 25 Sep-15 recruiting NCT Canada Single vs. control Phase II Unknown Auto-HSCT vs. standard MS activity free survival 3 years 24 Dec-12 ACTRN Australia Single group Phase II Recruiting Auto-HSCT 100-day TRM, efficacy 5 years 30 a NR b EUCTR IT Italy NR Phase II Active Auto-HSCT Safety 2 years 12 NR (LIGHT) NCT USA NR Phase II Completed Auto-HSCT NR NR 34 May-11 NCT USA Single group Phase II Completed Auto-HSCT NR NR 10 Aug-05 NCT USA NR Phase I Completed Auto-HSCT NR 5 years 20 NR NCT USA NR Phase I Completed Auto-HSCT NR 2 years 35 NR NCT USA Single group Phase II Terminated Auto-HSCT Toxicity 5 years 1 Nov-13 NCT USA Single group Phase I/II Terminated Auto-HSCT EDSS 3 years 21 May-12 NCT USA Single group Phase I/II Active, not Allo-HSCT Stem cell engraftment 3 years 3 Dec-20 recruiting EUCTR DK Denmark RCT Phase II Active Auto-MSCT MRI activity 24 weeks 25 NR NCT Spain RCT Phase II Terminated Auto-MSCT vs. placebo Severe adverse events, MRI 12 months 9 Dec-13 activity NCT Iran RCT Phase I/II Completed Auto-MSCT vs. placebo MRI changes, brain atrophy, 12 months 22 Apr-14 severe relapses, EDSS, MSFC NCT Sweden RCT Phase I/II Recruiting Early auto-msct vs. delayed Safety IV therapy + auto-msct 48 weeks 15 Dec-15 MSCT NCT Spain RCT Phase I/II Recruiting Auto-MSCT vs. placebo Adverse events, MRI activity 12 months 30 Jul-16 NCT Italy RCT Phase I/II Recruiting Auto-MSCT vs. placebo Adverse events, MRI activity 48 weeks 20 Sep-14 NCT Jordan RCT Phase I/II Recruiting Primed auto-msct vs. unprimed Adverse events 18 months 30 NR auto-msct NCT Spain RCT Phase I/II Recruiting Auto-MSCT vs. placebo Safety, MRI activity 12 months 8 Dec-15 NCT Israel RCT Phase II Not yet auto-msct (IT vs. IV vs. both) MRI activity, immunological 12 months 36 NR recruiting response NCT Canada RCT Phase II Not yet Auto-MSCT vs. placebo Adverse events, MRI activity 24 weeks 40 Sep-17 recruiting NCT UK RCT Phase I/II Active, not Auto-MSCT vs. placebo Adverse events, MRI activity 36 months 13 Jul-15 Stem cell therapy for non-haematological (autoimmune) indications: March

88 recruiting EUCTR ES Spain RCT Phase I/II Active Auto-MSCT vs. placebo Safety, tolerability 48 weeks 8 NR NCT UK RCT Phase II Recruiting Early auto-msct vs. late MSCT Global evoked potentials 24 months 80 Oct-18 NCT Spain RCT Phase I/II Active, not High-dose auto-msct vs. lowdose Safety, tolerability 12 months 30 Dec-14 recruiting auto-msct vs. control NCT USA Multi-centre single Phase I Recruiting Auto-MSCT SCQ, MSIS-29, modified SF-36, 5 years 100 Nov-17 group physical evaluation NCT USA Observational NR Recruiting Stromal vascular fraction Quality of Life (MSQLI) 12 months 100 NR cohort NCT UK Single group Phase I/II Completed Auto-MSCT Adverse events 12 months 10 Dec-10 NCT Israel Single group Phase I/II Active, not Auto-MSCT Safety, migration of injected cells 12 months 20 NR recruiting NCT USA Single group Phase I Completed Auto-MSCT Feasibility of culturing MSCs, 1 month 24 May-14 safety NCT China Single group Phase I/II Recruiting Allo-MSCT (UB) EDSS 12 months 20 Dec-14 NCT USA Single group Phase I Active, not Auto-MSC-NP Adverse events 30 months 20 Oct-16 recruiting NCT Panama Single group Phase I/II Active, not Allo-MSCT (UB) Adverse events 12 months 20 Aug-17 recruiting NCT Mexico Single group Phase I/II Not yet Auto-MSCT Disability score, adverse events 6 months 10 Jan-17 recruiting NCT (SIAMMS-II) UK Single group Phase I Recruiting Auto bone marrow cellular Adverse events 12 months 6 Sep-16 therapy (BMCT) NCT India Single group Phase I/II Recruiting BMMNC Patient symptoms 6 months 15 Dec-16 NCT USA Single group Phase II Recruiting Auto-HSCT Toxicity 5 years 20 Jun- 17 c NCT (ASTRAD) Germany Single group Phase I/II Unknown Auto-HSCT Disease-free survival, overall survival 24 months null Start 1998 NCT (NISSC) EBMT ADWP, Observational NA Recruiting Auto-HSCT Progression free survival 2 years 50 Dec-17 France cohort NCT USA Single group NR Recruiting Auto-SVF Adverse events 10 years 3000 Mar-17 Abbreviations: Allo-HSCT: allogeneic haemopoietic stem cell transplantation; Auto-HSCT: autologous haemopoietic stem cell transplantation; EDSS: Kurtzke Expanded Disability Status Scale; NR: not reported; RCT: randomised controlled trial; TRM: transplant related mortality; Auto-MSC-NP: autologous bone marrow-derived mesenchymal stem cell-derived neural progenitor cells; Auto-MSCT: autologous mesenchymal stem cell therapy; MSC: mesenchymal stem cells; MSQLI: multiple sclerosis quality of life inventory; SCQ: Standard complication questionnaire BMMNC: bone marrow derived mono nuclear stem cell; UB: umbilical cord; a The number of participants with multiple sclerosis is not specified as it is anticipated that 30 patients were difference types of severe autoimmune diseases will be recruited; b The date of completion is not specified, however it is anticipated that recruitment will be completed at Dec-2015; c Date of primary completion. Stem cell therapy for non-haematological (autoimmune) indications: March

89 Ongoing research for systemic sclerosis Searches of the Australian New Zealand Clinical Trials Registry, ClinicalTrials.gov registry and the WHO International clinical trials registry platform found 22 studies on stem cell transplantation for SSc of which 15 studies are registered as active/recruiting, three trials registered as complete and four trials registered as either terminated or withdrawn. Details of these studies are outlined in Table 43. The four trials that have been terminated or withdrawn were based on HSCT; autologous (NCT , NCT , NCT ), and allogeneic (NCT ). Of the 18 current (active/recruiting/complete) trials, 14 studies are based on HSCT, two studies are based on MSCT (autologous; NCT , NCT ), one study is based on stromal vascular fraction for the fingers of patients with SSc (NCT ), and one study is large-scale non-interventional based study on the incidence of malignant myeloid haematologic disorders in donors involved stem cell transplantation treatments (NCT ). Of the 14 studies of HSCT, there are two RCTs of auto-hscst (NCT :ASSIST- IIb/DIScl2011, NCT :SCOT/SCSSc-01), eight single group studies of auto-hsct (EUCTR DE, NCT :ASTRAD, NCT , NCT , ACTRN , ACTRN , NCT :AST MOMA, NCT : STAT), two observational cohort studies of auto-hsct (NCT :NISSC, NCT :STAR Registry), and two studies on allo-hsct (NCT , NCT ). The single group study of auto-hsct (NCT ) builds on a case series of six patients 130 which investigated a less cardiotoxic conditioning regimen. The two RCTs of auto-hscst anticipate recruiting at total of 274 participants. Details of the RCTs include: - The ASSIST-IIb trial, Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial, is a phase III trial based in USA (NCT :ASSIST-IIb/DIScl2011) which aims to evaluate different nonmyeloablative conditioning regimens with auto-hsct in patients with SSc. Specifically, the trial aims to assess whether a reduced dose of cyclophosphamide (less cardiotoxic regimen) will be safer than, and as effective, as the standard dose of cyclophosphamide used in the ASSIST I trial regimen. The primary outcome measure is time to treatment failure at 12 months follow-up with survival assessed up to five years follow-up. The estimated enrolment is 160 participants. The study commenced in September 2011 and the estimated primary completion date is September 2016 with the final study completion date estimated to be September As mentioned in the evidence section above, the SCOT trial is a multi-centre phase II/III RCT based in USA and Canada (NCT :SCOT/SCSSc-01) which aims to Stem cell therapy for non-haematological (autoimmune) indications: March

90 Table 43 List of registered clinical trials for stem cell transplantations for systemic sclerosis Trial identifier Country Study Design Trial Trial Status Interventions Primary Outcomes Follow up N Completio n Date ACTRN Australia Single group Phase II Recruiting Auto-HSCT 100-day TRM, efficacy 5 years 30 Dec-15 a ACTRN Australia Single group Phase II Recruiting Auto-HSCT Safety, efficacy, QoL (HAQ, 10 years 25 Start 2008 VAS, modified RSS) NCT (AST Germany Single group Phase II Recruiting Auto-HSCT Overall survival 3 years 44 Sep-20 MOMA) NCT USA Parallel groups Phase I Recruiting Allo-HSCT Engraftment and toxicity 24 months 20 Jan-20 NCT (STAT) USA, Canada Single group Phase II Recruiting Auto-HSCT Event-free survival 5 years 30 Sep-19b NCT (ASSIST- USA RCT Phase III Recruiting auto-hsct vs. lowerdose Time to treatment failure 5 years 160 Sep-18 IIb) (DIScl2011) auto-hsct NCT (NISSC) EBMT, Observational cohort NA Recruiting Auto-HSCT Progression free survival 2 years 50 Dec-17 France NCT USA Parallel groups Phase II Withdrawn Allo-HSCT Event-free survival 5 years 0 Sep-17 b NCT USA Single group Phase I/II Recruiting Allo-HSCT Event-free survival 5 years 20 Sep-17 b NCT USA, Canada Multi-centre RCT Phase II/III Active, not recruiting Auto-HSCT vs. Cytoxan Global rank composite score 72 months 114 Jun-16 (SCOT/SCSSc-01) EUCTR Germany Single group Phase II Active Auto-HSCT Overall survival 36 months 44 Start 2012 DE NCT USA Single group Phase I Terminated Allo-HSCT Survival, DI, TTDP 5 years 8 Dec-12 NCT USA Single group Phase I Completed Auto-HSCT Mortality >5 years 20 May-11 NCT USA Parallel groups Phase I Terminated Allo-HSCT (donor/uc) Toxicity 1 year 1 Jul-08 NCT USA Parallel groups Phase I Terminated Auto-BMT Toxicity 24 months 15 Mar-07 NCT USA Single group Phase I Completed Auto-HSCT Not reported 2 years 24 Jun-04 NCT (ASTRAD) Germany Single group Phase I/II Active (2008) Auto-HSCT Disease-free survival, 2 years null Start 1998 overall survival NCT France Single group Phase I/II Recruiting Allo-MSCT Toxicity 2 years 20 Jun-19 NCT China Single group Phase I/II Recruiting Allo-MSCT mrss, HRQOL, SF-36 NR 20 Dec-11 NCT France Single group NR Completed Auto-SVF fingers/hand Functional index of Cochin 2 years 12 Mar-14 NCT (LTDFU) USA Observational cohort NA Recruiting Non-interventional MMHD from donors 5 years Oct-20 NCT (STAR USA Observational cohort NA Recruiting Telephone follow-up Death, renal and pulmonary 44 months 45 Sep-14 Registry) Abbreviations: ADs: autoimmune diseases; ADWP: autoimmune disease working party; auto-svf: stromal vascular fraction; Cytpxan: high-dose pulse IV cyclophosphamide; DI: disease improvement; HAQ: health assessment questionnaire; IV: intravenous; MMHD: malignant myeloid haematologic disorders; mrss: modified Rodnan skin score; RA: rheumatoid athritis; SSc: systemic sclerosis; TTDP: time to disease progression UC: umbilical cord; VAS: visual analogue scales; a anticipated date last participant recruited/enrolled; b primary completion date. Stem cell therapy for non-haematological (autoimmune) indications: March

91 evaluate high-dose immunosuppressive therapy using total body irradiation, cyclophosphamide, equine anti-thymocyte globulin, and autologous-hsct with CD34+ compared to intravenous pulse cyclophosphamide for the treatment of patients with severe SSc. The primary outcome measure is the global rank composite score at 54 months post-randomisation with secondary outcomes collected up to 72 months follow-up. The estimated enrolment is 114 participants. The trial completed enrolment in May 2011 and is estimated to finalise the data collection June 2016 with publication of results expected in Ongoing research for systemic lupus erythematosus Searches of the Australian New Zealand Clinical Trials Registry, ClinicalTrials.gov registry and the WHO International clinical trials registry platform found 14 studies on stem cell transplantation for SLE of which six studies are registered as active/recruiting, four trials are registered as complete and four trials are registered with unknown status. Details of these studies are outlined in Table 44. Most of the 10 current trials are registered as active, recruiting, or complete, eight were based on HSCT and two were based on MSCT. There are no RCTs registered for HSCT for SLE. Of the eight HSCT studies, six are single group trials based in either USA or Australia (ACTRN , NCT , NCT , NCT , NCT , NCT ), one is a parallel group study of both SLE and SSc (NCT ), and one is a multi-centre cohort study (NCT ). Both of the MSCT-based clinical trials are based in China. One of these trials is double blind RCT comparing MSCT versus cyclophosphamide (NCT ). This will be the first clinical trial with the ability to judge the efficacy of MSCT in patients with SLE. There is also an RCT from China, one two arm comparison trial from Germany and the remaining trials are single arm studies. The other trial is a single group study of allogeneic bone marrow derived MSCT which is registered as completed (ChiCTR-TNC ). Stem cell therapy for non-haematological (autoimmune) indications: March

92 Table 44 List of registered clinical trials for stem cell transplantations for systemic lupus erythematosus Trial Number Country Study Design Trial Status (last updated) Interventions Primary Outcomes Follow up N Completion Date* NCT USA Single group Recruiting Allo- HSCT Survival 5 years 10 Jul-17 NCT USA Single group Completed Auto-HSCT Relapse-free Complete Clinical Response 60 months 9 Oct-13 NCT USA Single group Recruiting Auto-HSCT Overall survival, Remission 5 years 40 Dec-16 NCT USA Parallel group (SLE & SSc) Recruiting Allo-PBSCT Engraftment and toxicity 2 years 20 Jan-20 NCT Germany Multi-centre cohort study Recruiting (2009) Auto-HSCT vs. Best available immunosuppressant SLEDAI 4 years 30 Aug-14 NCT USA Single group Completed Auto-HSCT Mortality 5 years 20 May-11 NCT China Double-blind RCT Recruiting UC-MSCT vs CY Efficacy and Safety 6 months 25 Mar-13 NCT China Single group Unknown MSCT Remission 2 years 20 May-10 ChiCTR-TNC China Single group Completed Allo- BM-MSCT 24-hour proteinuria, urine routine, renal function, glomerular filtration rate, serum albumin NR 50 NR NCT USA Single group Unknown Allo-HSCT Remission NR 15 Jul-10 NCT USA Single group Completed Auto-HSCT SLEDAI 5 years 52 Apr-12 NCT USA Single group Unknown PBSC Treatment 2 years 10 NR NCT USA Single group Unknown Auto-PBSC Treatment NR 10 NR ACTRN Australia Single group Recruiting HSCT transplant related mortality by 5 years NR NR day 100 Abbreviations: RCT: randomised controlled trial; SLE: systemic lupus erythematosus; SLEDAI: systemic lupus erythematosus disease activity index; SSc: systemic sclerosis; * estimated completion date; NR: not reported; Allo- HSCT: allogeneic haemopoietic stem cell transplant; Auto-HSCT: autologous haemopoietic stem cell transplant; PBSC: peripheral blood stem cell; HSCT: haemopoietic stem cell transplant; Auto-PBSC: autologous peripheral blood stem cell; Allo- BM-MSCT: allogeneic bone marrow mesenchymal stem cell therapy; CY: cyclophosphamide; UC-MSCT MSCT: umbilical cord mesenchymal stem cell therapy. Stem cell therapy for non-haematological (autoimmune) indications: March

93 Summary of findings Summary of multiple sclerosis Interpreting the evidence for stem cell transplantations for MS is challenging as the studies are highly heterogeneous, consisting of different treatment protocols, conditioning regimens, sources of stem cells and definitions for clinical outcomes. There is also limited long-term follow-up data. This report has reviewed the evidence of primary stem cell transplantations. Most of the studies of HSCT for MS included in this report used autologous stem cells derived from peripheral blood. In most of the included studies, mobilisation involved cyclophosphamide and granulocyte-colony stimulating factor with a few studies using granulocyte-colony stimulating factor alone or cyclophosphamide alone. Graft manipulation using CD34+ selection was performed in approximately half of the included studies. The majority of included studies used conditioning regimens which included either BEAM with horse/rabbit anti-thymocyte globulin or cyclophosphamide with horse/rabbit antithymocyte globulin. Some studies used modified BEAM regimens and some included the use of total body irradiation or busulfan. For the case series, the 100-day TRM ranged from zero to four per cent and the overall TRM range from zero to 14 per cent. For the retrospective analyses, the 100-day TRM and overall TRM ranged from two to four per cent and from 2.7 to 3.8 per cent, respectively. This reflects the European experience, 8 which reported a fall in mortality associated with autologous HSCT from 7.3 per cent during the period 1995 to 2000, down to 1.3 per cent in the period 2001 to This may have been due to improved patient selection and a reduction in the high-intensity conditioning regimens. Across the included studies for HSCT, the median follow-up ranged from 31 months to 11.3 years. Progression-free survival was estimated to be between 47.6 to 100 per cent at three years, 45 to 82 per cent at five years, 29.2 to 65 per cent at six years, 48 per cent at nine years and 25 per cent at 15 years. Disease free survival was estimated to be between 62 to 78.4 per cent at three years and 68 per cent at five years. Relapse-free survival was estimated to be 76 per cent to 86.3 per cent at approximately three years and between 85 to 87 per cent at five years. Only three studies reported MRI event-free survival which was estimated to be 100 per cent at 6-12 months, 92 per cent at two years, 100 per cent at three years and 85 per cent at five years. Overall survival was reported in two studies and was estimated to be 93 per cent at 3 years and 92 to 93 per cent at 5 years. For HSCT, disability at baseline, as measured by median EDSS, ranged from 3.1 to 8.0. Disability progression was observed in zero to 58 per cent of patients whilst stabilisation or improvement was shown in 42 to 100 per cent of patients. New Gd+ and/or T2 lesions were observed in zero to 24 per cent of patients at follow-up post-transplantation. Quality of life Stem cell therapy for non-haematological (autoimmune) indications: March

94 was found to significantly improve as early as six months post-transplantation (p<0.05) and improvements were observed in most of the domains at follow-up. Stem cell transplantation is more efficacious in patients MS in the inflammatory stages of the condition (i.e. RRMS, and SPMS with episodes of relapsing remitting). As the condition progresses to SPMS, the disease shifts to a neural degenerative disorder and the treatment is no longer effective. According to updated guidelines, 4 the ideal target patient indications for auto-hsct for MS, are patients with MS in the relapsing remitting phase (characterised by clinical manifestations of high inflammatory activity and the presence of Gd+ enhancing lesions and/or new T2 lesions on MRI imaging scans) with aggressive progression failing one or more lines of treatment. Patients with severe malignant MS would also be suitable candidates for the procedure. Patients with SPMS who have evidence of some inflammatory disease activity and who have deteriorated may also be considered for auto-hsct. If the disease has progressed to a point where the patient have lost the ability to walk (approximately EDSS >6), auto-hsct is no longer a suitable treatment option (except for malignant forms of MS). Only four small case series for MSCT for MS met criteria for inclusion in this report. All included studies used autologous stem cell transplantation using mesenchymal stem cells derived from peripheral blood. No conditioning regimes were used in these studies except for medication to reduce type I hypersensitivity. The administration of stem cells differed across studies from intravenous only, intrathecal only, or intrathecal with either intracisternal or intravenous. Common adverse events were fever, headaches, difficulty walking/standing and infections with no deaths reported across any of the four studies. Disease progression, as measured by the EDSS, significantly reduced in one study and was shown to improve in 34 per cent (13 patients), stabilise in 55 per cent (21 patients) and worsen in 11 per cent (4 patients) of patients in the other three included studies at six months with nearly 80 per cent improved or stable at 12 months. At follow-up, new T2, enlarging lesions or Gd+ lesions were found in zero to 71 per cent of patients. There is some research emerging on the combined effects of multiple therapies including stem cell transplantations in conjunction with other therapies as treatment for MS. For example, recent studies have explored the combination of non-myeloablative HSCT with a consolidation therapy of mitoxantrone, 9 HSCT with infusion of mesenchymal stem cells, 10 and failed non-myeloablative HSCT followed by natalizumab. 11 This area is still in its infancy, however may provide possible treatment options in the future. Summary of systemic sclerosis The results in trials to date support HSCT as an effective treatment for severe SSc. Patient selection is critical with high TRM in patients with cardiopulmonary involvement and in current and previous smokers. Stem cell therapy for non-haematological (autoimmune) indications: March

95 From the available evidence, auto-hsct had a worse short term safety profile than the comparison (cyclophosphamide) with more short term mortality and serious adverse events, particularly haematologic, respiratory, cardiovascular and common viral infections. TRM ranged from 0 to 23 per cent across the RCTs and observational studies. Auto-HSCT has a clear benefit on long term mortality. In the one RCT (van Laar et al. 2014) 12 reporting a comparison of mortality, a significant benefit was found for auto-hsct at five years despite the increased early mortality due to treatment. Mortality at around five years was similar in the RCTs to the observational studies at around 20 per cent. This compares favourably to estimates of mortality in SSc with major organ involvement of around 40 to 50 per cent at five years. 13 The results of longer term follow up support the hypothesis that HSCT is safer if baseline cardiac assessment is favourable and HSCT should be instituted before the SSc has caused cardiac abnormalities in order to maximise the benefit. It has been suggested that HSCT be limited to two patient groups who are not current smokers: 1. Diffuse cutaneous SSc less than five years from onset without only mild to moderate organ involvement; or 2. Limited cutaneous SSc with progressive internal organ involvement. 1 Recently, identification of cellular and molecular targets for therapy has been made. This may allow the development of novel new drug therapies that may offer far greater benefit than the currently available treatments. 131 This would potentially alter the place of stem cell therapies in treatment. The procedure in SSc has undergone changes throughout the implementation of the procedure. These have primarily related to increased screening of patients for cardiac complications to reduce the TRM. In order to appropriately ascertain risk, screening should include echocardiogram, confrontational right heart catheterisation, including a fluid challenge test and cardiac MRI. 14, 15 The improved procedures should have a impact on reducing the early mortality associated with auto-hsct therefore making it a viable treatment option. Summary of systemic lupus erythematosus HSCT and MSCT are both promising treatments for SLE, though they are still in the naïve stages of being proven clinically effective. The evidence available for this report came from six HSCT studies and six MSCT studies. Only two studies included an alternative treatment, a conventional treatment, which diminished the ability of this report to comment on the effectiveness of the treatments. 16, 17 No RCTs comparing HSCT or MSCT to standard treatment were found. Stem cell therapy for non-haematological (autoimmune) indications: March

96 The safety of HSCT and MSCT differed greatly across the 12 studies, supporting the claim of a strong centre effect / learning curve being involved in stem cell transplantation therapies. 18 The 100-day TRM of the HSCT studies varied from zero per cent in Song et al. (2011) 17 to per cent in Farge et al. (2010). 19 Only Farge et al. (2010) 19 judged deaths within their study to be treatment related. Song et al. (2011) 17 was unable to prove that HSCT was superior to conventional treatment with respect to overall survival. It was shown that progression free survival was significantly improved in the HSCT group, suggesting patients stay in remission longer due to HSCT. 17 The MSCT studies did not judge any death to be a TRM, although Wang et al. (2014) 20 and Wang et al. (2013) 21 had 100-day TRM of 2.5 per cent and 2.29 per cent respectively. The MSCT studies had an overall mortality range of 0.0 per cent (follow-up of 8.25 and 17.2 months) to 7.5 per cent (follow-up of 12 months). A number of parameters were used to demonstrate the decrease in disease activity after HSCT or MSCT. In both HSCT and MSCT studies, each study which reported SLE disease activity index (SLEDAI) analysis, found the average SLEDAI score to significantly decrease after transplantation. Decreasing SLEDAI scores represent diminishing disease activity, with remission reached at SLEDAI scores < three. 120 The MSCT studies found 24h proteinuria, serum albumin levels and anti-double stranded DNA levels positively changed, representing a statistically significant decrease in disease activity after transplantation. There is no economic information available on SLE and stem cell transplantations in Australia. The cost of a single HSCT treatment is $75,082. Unfortunately no data in Australia exists to estimate number of potential patients with SLE that would meet the treatment criteria, and be able to estimate the cost per annum. The efficacy of HSCT and MSCT is currently unclear based on current evidence. The upcoming RCT for MSCT will provide additional information to assist decision-makers on whether to fund stem cell transplantation for SLE. Stem cell therapy for non-haematological (autoimmune) indications: March

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105 121. Li, X, Wang, D et al (2013). 'Mesenchymal SCT ameliorates refractory cytopenia in patients with systemic lupus erythematosus'. Bone Marrow Transplant, 48 (4), Sun, L, Wang, D et al (2010). 'Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus'. Arthritis Rheum, 62 (8), Liang, J, Zhang, H et al (2010). 'Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study.[erratum appears in Ann Rheum Dis Jan;70(1):237]'. Ann Rheum Dis, 69 (8), Liang, J, Gu, F et al (2010). 'Mesenchymal stem cell transplantation for diffuse alveolar hemorrhage in SLE'. Nat Rev Rheumatol, 6 (8), Tappenden, P, Saccardi, R et al (2010). 'Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory costeffectiveness analysis'. Bone Marrow Transplant, 45 (6), (2010). High-dose immunosuppressive therapy with or without hematopoietic transplantation for the treatment of multiplesclerosis, HAYES, Inc, Lansdale 127. VTAP (2006). Bone marrow transplantation for treatment of multiple sclerosis, VA Technology Assessment Program (VATAP), Boston 128. (2009). High-Dose immunosuppressive therapy with or without hematopoietic transplantation for the treatment of rheumatic and mixed autoimmune diseases, HAYES, Inc., Lansdale Available from: 129. Orme, M, Kerrigan, J et al (2007). 'The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK'. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research, 10 (1), Henes, JC, Koetter, I et al (2014). 'Autologous stem cell transplantation with thiotepa-based conditioning in patients with systemic sclerosis and cardiac manifestations'. Rheumatology (Oxford), 53 (5), Antic, M, Distler, JH & Distler, O (2013). 'Treating skin and lung fibrosis in systemic sclerosis: a future filled with promise?'. Curr Opin Pharmacol, 13 (3), PBAC (2014). Public sumary document: Alemtuzumab, solution for infusion, 10 mg/ ml, Lemtrada - July 2014, PBS, Canberra Available from: Stem cell therapy for non-haematological (autoimmune) indications: March

106 Search Strategy Search criteria to be used (MeSH terms) Search terms for multiple sclerosis Search terms for systemic sclerosis Search terms for systemic lupus erythematosus MeSH multiple sclerosis stem cell MeSH Scleroderma, Systemic Stem cells MeSH Stem cell Lupus nephritis Systemic lupus erythematosus Text words multiple sclerosis[keyword] stem cell[keyword] Limits Human, English, 2009 to current Text words systemic scleroderma systemic sclerosis stem cell* Limits English, Human, last 10 years Text words Stem cel* Stem cell Lupus Nephritis Systemic lupus erythematosus Limits English HTA sites Centre for Reviews and Dissemination, University of York Number of studies included All evidence included for assessment in this New and Emerging Health Technology Report has been assessed according to the revised NHMRC levels of evidence. A document summarising these levels may be accessed via the HealthPACT web site. Total number of studies, 19 (MS); 10 (SSc); 12 (SLE) studies. Total number of Level II, 0 (MS); 3 (SSc); 0 (SLE) studies. Total number of Level III-2, 0 (MS); 0 (SSc); 2 (SLE) studies. Total number of Level IV, 19 (MS); 7 (SSc); 10 (SLE) studies. Stem cell therapy for non-haematological (autoimmune) indications: March

107 Appendices Appendix A Estimation of the number of patients with relapsing remitting multiple sclerosis failing interferon beta and alemtuzumab, or alemtuzumab only Patient failed alemtuzumab only Percenta ge Number of patients Incidence of all subtypes of MS (per annum) 1000 Percentage of patients diagnosed with RRMS 85% 850 MS Australia Percentage of patients relapsed following alemtuzumab only 22% 187 Reference CAMMS223, treatment naïve (3-year results) 132 Failed interferon beta-1a and then failed alemtuzumab Incidence of all subtypes of MS (per annum) 1000 Percentage of patients diagnosed with RRMS 85% 850 MS Australia Proportion of relapsed patients following interferon CAMMS223, treatment naïve (3-year 42% 357 beta-1a results) 132 Proportion of relapsed patients following CARE MS-II, treatment experienced (2-year 35% 125 Alemtuzumab results) 132 Stem cell therapy for non-haematological (autoimmune) indications: March

108 Appendix B Profiles of all included studies for HSCT and MSCT for multiple sclerosis Study Type of study Location N Type of MS Mean age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Median baseline EDSS Baseline inflammatory activity Haemopoietic stem cell transplantation Nash et al (2014) 80 Multi-centre, single-arm, phase II clinical trial USA 25 RRMS 37.3 (SD=7.7) (range 27-53) 8:17 Mean 5.7 (SD=3.7) NR Median 4.5 (3.0 to 5.5) NR Burman et al (2014) 81 Retrospective, multi-centre ( ) Sweden 48 RRMS: 40 SPMS: 5 PPMS: 2 PRMS: 1 31 (range 9-52) 22: months (range 4-300); RRMS: 66 months (4-192) NR Median 6.5 (range ) (n=62) AAR: 4.1 (range 0-12) AAR (RRMS): 4.8 (range 0-12) MRI activity: 25/41 (61%) IgG index in CSF: 0.81 (±0.24) (n=26) Muraro et al (2013) 82 Retrospective, cohort study, ( ) International 281 RRMS: 46 SPMS: 186 PPMS: 32 PRMS: (range 14-65) 117:164 NR Reported to CIBMTR or EBMT, record of baseline EDSS score, subtype of MS, treatment protocol and 1 follow-up post-hsct Median 6.5 (range ) NR Pasquini et al (2012) 83 Review of patient database North America and South America Identified 160: Included 143; RRMS: 8 SPMS: 62 PPMS: 23 PRMS: 0 NR: 50 Median 38 (all autoimmune diseases) 143:196 (all autoimmune diseases) 35 months Cases reported to CIBMTR, the Seattle Consortium, and 2 Brazilian centres (53 centres) Median 6.5 (range, ) (n=62) NR Shevchenko et al (2012) 84 Phase II trial Russia 95 RRMS: 42 SPMS: 35 PPMS: 15 PRMS: :59 NR aged years; McDonald criteria clinically definite MS; EDSS ; normal mental status; no severe concomitant diseases Median 3.5 NR Stem cell therapy for non-haematological (autoimmune) indications: March

109 Study Type of study Location N Type of MS Mean age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Median baseline EDSS Baseline inflammatory activity Mancardi et al (2012) 85 Prospective and retrospective multicentre study (EBMT registry) Italy 74 a RRMS: 33 SPMS: 41 PPMS: 0 PRMS: (range, 16-53) 11.2 years (range1-28) Severe clinical course in past 12 months (deterioration of 1 point on EDSS median: 6.5 (range 3.5-9); mean: 6.3 (range 3.5-9) Mean relapse: 1.8 (range, 0-8); RRMS: 2.8 (range, 0-8); SPMS: 1.1 (range, 0-4) MRI activity: 32/45 Mean 4.4 lesions (range 0-28) n=45 Bowen et al (2012) 86 [Nash et al 2003] Multicentre study, USA 26 RRMS: 1 SPMS: 17 PPMS: 8 Median 41 years (range, 27-60) 14:12 Median 84 months (range ) Clinically definite or labsupported definite MS (Poser criteria); worsening EDSS of 1 point over previous year; EDSS median 7.0 (range ) MRI activity: 7/26 (27%) CSF: 12/20 (60%) Chen et al (2012) 89 Xu et al (2011) 90 Retrospective, China 25 RRMS: 3 SPMS: 19 PPMS: 1 PRMS: 2 Case series China 36 CMS: 15 OMSM: 21 median 37.3 years (range 15 64) CMS: 35.7±7.8 OMSM: 34.5±9.1 6:19 median 48 months (range 7 147) CMS: 7:8 OMSM: 2:19 CMS: 59.9±51.1 OMSM: 81.3±75.5 clinically definite MS (Poser criteria) Secondary progressive MS according to McDonald criteria median 8.0 (range ) CMS: 6.8±1.1 OMSM: 6.5±1.3 MRI activity: 14/25 (56.0%) LESCL lesions: CMS: 6/15 (40%); OMSM: 17/21 (81%) Fassas et al (2011) 91 [Fassas et al 1997)] 92 Phase I/II, single centre, Greece 35 RRMS: 1 SPMS: 19 PPMS: 11 RPMS: 3 ARPMS: 1 Median 40 years (19 54) 16:19 median 7 years (1 18) Aged < 55, followed-up for at least 2 years; clinically definite MS (Poser criteria) median 6 ( ) MRI activity: 12/30 (40%) Farge et al (2010) 19 Observational study, Worldwide (27 countries) 345 (900 autoimmune diseases) NR 35 years (14-65) 135: months ( ) Cases reported to the EBMT registry NR NR Stem cell therapy for non-haematological (autoimmune) indications: March

110 Study Type of study Location N Type of MS Mean age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Median baseline EDSS Baseline inflammatory activity Hamerschlak et al (2010) 93 Prospective multicentre trial (two conditioning regimens), Brazil : 21/ : 20/41 All: RRMS: 4 SPMS: 33 PPMS: 4 BEAM/ATG: RRMS: 1 SPMS: 18 PPMS: 2 CY/ATG: RRMS: 3 SPMS: 15 PPMS: 2 All: mean 42 years (range 27 53) BEAM/ATG: median 42 years (29 52) CY/ATG: median 41 years (27 53) All: 17:24 BEAM/ATG: 10:11 CY/ATG: 7:13 All: NR median BEAM/ATG: 8 years (2 22) median CY/ATG: 7 years (3 14) Clinically definite MS (Poser s criteria); aged years old; evaluated by MRI; Type of MS (RRMS, PPMS, SPMS, PRMS). All: NR median BEAM/ ATG: 6.5 (5 7) median CY/ATG: 6.5 (4.5 7) MRI activity (all): 8/41 (20%) MRI activity (BEAM/ATG): 7/21 (33%) MRI activity (CY/ATG): 1/20 (5%) Guimaraes et al (2010) 94 Descriptive study with longitudinal cross-section, RRMS: 7 SPMS: 22 PPMS: 5 NR 16:18 NR Diagnosis of MS; age >18 years; patient at BMTU; presenting medical and psychological conditions NR NR Krasulova et al (2010) 95 Open label single-centre experience Czech Republic 26 RRMS: 11 SPMS: 15 median 33 years (range 19-44) 11:15 median 7 years (2-19) progressive phase (SPMS): median 3 years (range 2-6) NR median 6.0 ( ) AAR (RRMS): median 2 (range 1-5) Relapse rate: median 2 (range 1-5) Burt et al (2009) 96 Phase I/II study, USA 21 RRMS:21 median 33 years (range years) median 5 years (range years) Aged years, met McDonald criteria; met Poser criteria clinically definite MS; treatment failure ( 6 months) interferon beta; EDSS months after last acute MS attack; normal renal, cardiac, pulmonary, and median 3.1 points (range points) Relapses 12 months prior: 100% (50 relapses) Stem cell therapy for non-haematological (autoimmune) indications: March

111 Study Type of study Location N Type of MS Mean age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Median baseline EDSS Baseline inflammatory activity hepatic function; no history of previous/active malignancy (except localised cutaneous basal / squamous cell carcinoma / carcinoma in situ of the cervix). Mesenchymal stem cell therapy Connick et al (2012) 101 Open-label phase IIA proof-ofconcept study, UK 10 SPMS: 10 All had optic nerve involvement Mean 48.8 years (SD=4.1) (range, 40 53) 7:3 Mean 14.4 years (SD=7.9) (range, 5 26) aged years; clinically definite MS (Poser criteria); EDSS , clinical optic nerve involvement, abnormal visual evoked potentials from eye/s consistent with demyelination, a retinal nerve fibre layer thickness of at least 45 μm in one eye, a T2 lesion on MRI of the optic nerve. Exclusion: bleeding disorder, interferon beta or glatiramer acetate within 6 months, or previous other disease modifying therapies at any point. Mean 6.1 (SD=0.3) (range, ) Clinical relapse in pretreatment phase (n=2) Bonab et al (2012) 102 Open-label phase II study, Iran 25 SPMS: 23 PRMS: 2 Mean 34.7 years (±7) 6:19 Clinically definite MS (Poser and revised McDonald criteria; SPMS or PRMS; suboptimal response to conventional MS treatments; aged years, EDSS 3.5 7, increase EDSS >1 or evidence of inflammatory disease activity ( 2 relapses past year PRMS, or 1 Gd enhanced lesion SPMS); disease duration 2 Mean 6.1±0.6 Median 6 (3.5-7) Stem cell therapy for non-haematological (autoimmune) indications: March

112 Study Type of study Location N Type of MS Mean age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Median baseline EDSS Baseline inflammatory activity and 15 years. Exclusion: haemodynamic/ homeostasis disorder; chronic disease other than MS; Serum creatinine 1.7 mg/dl, increased liver enzymes 3 folds of normal range, or white blood cell count 3000 /MicL, history of cytotoxic treatments 2 months prior. Yamout et al (2010) 103 Karussis et al (2010) 104 Phase I trial Lebanon 10 SPMS: 9 RRMS: 1 Phase I/II open trial MS: 15 ALS: 19 Mean 43 years Median 44 MS Mean 35.3 years (SD=8.6) years; ALS mean 53.0 years (SD=11.2) years 4:6 Mean 20 years 7:8 (MS) 10:9 (ALS) MS mean 10.7 (2.9) (range, 5 15) years; ALS mean 34.3 (20.6) (range, 6 84) months Definite MS (revised McDonald criteria), aged years, failure of standard medical therapy, EDSS of 4.0 to 7.5. Exclusion: clinical relapse within 30 days; bone marrow disease, glaucoma or other condition (retinal nerve fibre) MS: clinically definite MS (Poser criteria), aged years, not pregnant; disease duration > 5 years, failure to respond to medical therapy. Exclusion: cytotoxic medications 3 months prior; cardiac, renal, or hepatic failure or other; active infection; severe cognitive MS: Mean 6.7 (SD=1.0) (range, ) decline Abbreviations: AAR: annualised relapse rate; ADs: autoimmune diseases; ALS: amyotrophic lateral sclerosis; BEAM/ATG: BEAM/anti-thymocyte globulin; BMTU: bone marrow transplant unit; CIBMTR: center for international blood and marrow transplant research; CMS: conventional multiple sclerosis; CY/ATG: cyclophosphamide/anti-thymocyte globulin; EBMT: European group for blood and marrow transplantation; LESCL: longitudinally extensive spinal cord lesions; MS: multiple sclerosis; RRMS: relapse-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; OSMS: opticospinal multiple sclerosis; PPMS: primary progressive multiple sclerosis; PRMS: progressive-relapsing multiple sclerosis; MRI: magnetic resonance imaging; NR: Not recorded; SD: standard deviation; a 21 out of 74 patients were enrolled in a pilot prospective multi-centre trial by Saccardi et al. (2005). Stem cell therapy for non-haematological (autoimmune) indications: March

113 Appendix C Cochrane risk of bias assessment of the direct randomised trials of HSCT for systemic sclerosis Burt et al. (2011) 108 van Laar et al. (2014) SELECTION BIAS Random sequence generation -biased allocation to interventions due to inadequate randomisation Low Low Allocation concealment biased allocation to interventions due to inadequate concealment of allocations prior to assignment 2. PERFORMANCE BIAS Blinding of participants and personnel performance bias due to knowledge of the allocated interventions by participants and personnel during the study 3. DETECTION BIAS Blinding of outcome assessment detection bias due to knowledge of the allocated interventions by outcome assessors Low High unable to blind due to procedure High Low High unable to blind due to procedure High 4. ATTRITION BIAS Incomplete outcome data attrition bias due to amount, nature or handling or incomplete outcome data. Low Low 5. REPORTING BIAS 5.1 Selective reporting reporting bias due to selective outcome reporting Low Low 6. OTHER BIAS 6.1 Bias due to problems not covered above High Low Brief description and reason: Study was stopped early due to benefit before the planned 60 patients were recruited, given that performance and detection bias were high due to inability to blind, this may bias results towards treatment arm Stem cell therapy for non-haematological (autoimmune) indications: March

114 Appendix D Profiles of included observational studies for systemic sclerosis Study Type of study Location N Median age (years) Gender (Female %) Mean disease duration prior to HSCT (months) Inclusion criteria mrss FVC Burt et al (2013) 15 Retrospective Observational USA and Brazil (16-71) 73 (81%) 25 (2-156) All patients treated with HSCT at two centres, either as part of a study or on a compassionate basis 24 (3-47) 67% (31-103) Moore et al (2012) 109 Observational pilot Australia (23-46) 8 (80%) 16 (10-35) Rapidly progressive inflammatory diffuse scleroderma Less than three years since diagnosis 25 (15-40) 83% (68-118) lung and/or heart involvement not stabilised on monthly i.v. cyclophosphamide Henes et al (2012) 14 Observational Germany (19-65) 18 (69%) 27 (12-204) Failure of cyclophosphamide Rapidly progressive diffuse disease with a poor prognosis 18 (2-32) NR Farge et al (2010) 19 Observational Europe multicentre (8-69) 123 (71%) 30 (3-256) All consecutive patients reported to the European Bone and Marrow Transplantation Registry from 1996 to December 2007 NR NR Vonk et al (2008) 110 Observational Netherlands and France (16-65) 19 (73%) 24 ( ) rapidly progressing disease 2 years disease >2 years with major organ involvement (lung, digestive or kidney) 32 (9-51) 8 (31%) <70% predicted Nash et al (2007) 111 Observational USA multicentre (23-61) 26 (76%) NR diffuse scleroderma < 4years aged <65 30 (3-48) 71 (27-103) progressive pulmonary disease mortality risk 50% at 5 years with conventional treatment Stem cell therapy for non-haematological (autoimmune) indications: March

115 Appendix E Profiles of included studies for systemic lupus erythematosus Study Type of study Location N Age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Baseline SLEDAI Alchi et al (2012) 115 Retrospective survey EBMT 28 Mean 29 (range 16-48) 3:25 52 months (range 9-396) NR NR Song et al (2011) 17 Non-randomised experimental trial China 17 Median 23 months (range 16-38) 20 Median 28 months (range14-62) 3:12 Median 33.6 months (range 6-108) 1:19 Median 11 months (range 1-49) - Transfusion dependent autoimmune cytopenias, severe pericarditis (symptomatic pericardial effusions causing shortness of breath, haemodynamic compromise, or chronic and disabling pain despite narcotic use). - Involvement of the lung (vasculitis, pneumonitis, alveolar haemorrhage), - Involvement of the central nervous system (cerebritis or transverse myelitis), - World Health Organization class III or IV glomerulonephritis NR NR Su et al (2013) 116 Case series study China 5 Mean 10.4(range 6-14) 3:2 26 months (range 5-90) at least one of these criteria: (1) the use of conventional drugs to treat the disease was futile; (2) the disease is progressive or recurs frequently, which renders a poor prognosis; (3) important organs are involved, resulting in a lifethreatening condition; and (4) patients may be intolerant to the toxic drugs and consequent side effects 24 (range 15-38) Meng et al (2011) 16 Comparative study China ±0.8 0:11 NR 20± ±2.5 0:39 NR 21±3 Farge et al Observational study EBMT (range 58 months (range 2- NR NR Stem cell therapy for non-haematological (autoimmune) indications: March

116 Study Type of study Location N Age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Baseline SLEDAI (2010) ) 396) Alexander et al (2009) 117 Wang et al (2014) 20 Wang et al (2013) Phase I/II clinical trial Germany Nephritis (n=7) Phase I/II interventional clinical trial (range 19-48) China 40 Mean Follow up study China Severe and refractory (range 16-54) 31.5 (range 12 56) 2:5 Persistently active disease with poor prognosis and inadequate response to standard protocols Adequate function of all major organs in order to tolerate conditioning and transplantation. 2: months (range ) The eligibility criteria included treatment-refractory and active disease, as well as a SLEDAI score of more than 8 or at least one BILAG grade A or at least two BILAG grade B manifestations (range 19-30) Mean (range 4-34) 7: (2-264) Progressive and active disease with SLEDAI score of 8 NR Liang et al (2010) 124 Sun et al (2010) 122 Unblended clinical trial China 15 Mean (range 12-44) Single-arm trial China 16 Mean (range 17-55) 1:14 Mean months (range ) Mean months (range 2-168) One of the following features: (1) progressive and active disease with a SLEDAI score 8, despite continuous treatment with intravenous pulse CY with a total dosage of mg every month for at least 6 months or oral MMF mg/day for at least 3 months and continued daily dosage of more than 20 mg of prednisone or its equivalent; (2) refractory immune-mediated thrombocytopoenia; (3) refractory LN Progressive and active disease, with a SLEDAI score of 8, lack of response to treatment with monthly intravenous pulse CY (500 1,000 mg/m2) for 6 months or lack of response to treatment with oral MMF (2,000 mg/day) for 3 months, and continued daily doses of >20 mg of prednisone or its equivalent. Patients were also included if they had refractory immune-mediated transfusion-dependent thrombocytopenia or refractory lupus nephritis, regardless of whether they met the eligibility criteria described above. Mean 12.8 (range 8-20) Mean (range 9-27) Li et al (2013) 121 Phase I/II interventional clinical trial China 35 Mean (range 16-62) 1:34 Mean months (range 6-251) The eligibility criteria included: (1) and (2) and (3) or (4): (1) progressive and active disease with a SLEDAI score 8; (2) refractory cytopenia (3) unresponsive to treatment with monthly i.v. pulse CY 500~1000 mg/m2 for at least 6 months, or oral MMF 2 gm/day, azathioprine 200 mg/day, leflunomide 20 mg/day alone or in combination at least 3 months; (4) continued daily dosage of 420mg of prednisone Mean 12.6 (range 4-34) Stem cell therapy for non-haematological (autoimmune) indications: March

117 Study Type of study Location N Age (years) Male: Female Mean disease duration prior to HSCT Inclusion criteria Baseline SLEDAI or its equivalent for maintenance treatment Wang et al Phase I/II China Single Mean 5:25 Mean Progressive and active disease, with a SLEDAI score of 8, NR (2012) 120 interventional clinical lack of response to treatment with monthly intravenous trial (range 62 (range 7-232) pulse CY (500 1,000 mg/m2) for 6 months or lack of 12-47) response to treatment with oral MMF (2,000 mg/day) for 3 Double Mean 2:26 Mean months, and continued daily doses of >20 mg of prednisone or its equivalent. Patients were also included if they had (range 92 (12-264) refractory immune-mediated transfusion-dependent 16-54) thrombocytopenia or refractory lupus nephritis, regardless of whether they met the eligibility criteria described above. Abbreviations: SLEDAI: systemic lupus erythematosus disease activity index; BILAG: British Isles Lupus Assessment Group; CY: cyclophosphamide; EBMT: European group for blood and marrow transplantation; MMF: mycophenolate; mg: milligram; HSCT: Haemopoietic stem cell transplantations. Stem cell therapy for non-haematological (autoimmune) indications: March

118 Appendix F MS Australia statement on Autologous Hematopoietic Stem Cell Transplant (HSCT) treatment. 27 February 2014 Last night MS Australia featured in a Channel 7 report on Autologous Hematopoietic Stem Cell Transplant (HSCT) treatment. You can view the story here: To clarify MS Australia s position on HSCT please see this statement from MSA CEO Debra Cerasa: Multiple Sclerosis is a debilitating condition, particularly for people with less common, more progressive forms of the disease. Currently, there are no treatments available that treat progressive MS, which is why we understand people facing this diagnosis will wish to explore every possible avenue in order to experience some relief. Autologous Hematopoietic Stem Cell Transplant (HSCT) treatment is one such treatment that people in Australia and internationally have undertaken in order to address their symptoms. The current issue with this treatment however is it is still in its very early stages. It is an intrusive procedure with many high-risk steps and includes high doses of chemotherapy which can knock people around considerably. Currently, there is not significant evidence to determine if the treatment is safe, or that identifies which people actually benefit from this treatment - as results are varied. The pleasing thing is large scale international studies are underway and there is one clinical trial currently running in Sydney that will help discover more information about HSCT. Our colleagues at MS Research Australia are also compiling a registry of people undertaking HSCT treatment in Australia so that we can map their experience with the treatment. To date this registry shows less than 40 people with MS have received bone marrow transplants to treat active, highly aggressive cases of MS. The procedure has been carried out at a number of sites, including sites in Perth and Sydney. Internationally, only a few hundred patients have been treated this way. However the outcomes have still been mixed. There are some who have undertaken the treatment who have seen no benefit. Stem cell therapy for non-haematological (autoimmune) indications: March

119 As a high-risk, unproven treatment, stem cell therapy is currently only considered by some doctors and hospitals on a case-by-case basis for those who have an early, aggressive form of MS that is resistant to all other treatments. To be absolutely clear MS Australia does not oppose the treatment. If people with aggressive forms of MS wish to pursue this treatment we recommend that they seek out as much information on the risks and potential benefits of the treatment as they relate to their circumstances and do so in conjunction with their neurologist. At the same time through the MS Research Australia HSCT Registry we will continue to contribute to the growing body of work underway to find out more about the treatment and determine more accurate criteria to identify which patients are more likely to benefit from the treatment and what the most appropriate treatment guidelines are. Stem cell therapy for non-haematological (autoimmune) indications: March

120 Appendix G MS Australia s statement on stem cells There is a great deal of scientific and media interest in stem cells as a possible treatment for MS. Some scientific reports do reveal encouraging clinical findings, but a lot of work still needs to be done to prove their effectiveness and safety for people with MS. MS Australia does not oppose stem cell treatment. Instead we want people to know all the facts, to fully understand the risks and the side effects as well as the potential benefits, and to most importantly discuss this with their neurologist to ultimately decide whether they are a suitable candidate for the treatment. If you have any questions or recommendations for future content please contact us with your suggestions at [email protected]. What are stem cells? Stem cells are cells which are able to differentiate into other types of cells and are capable of self-renewal or multiplying to produce greater numbers. Stem cell treatments are any therapies which target or use stem cells usually to replace or repair damage. What is stem-cell treatment? Stem cell therapy is any treatment that uses or targets stem cells. This is usually to help replace or repair damaged cells or tissues, but can also be used to prevent damage from happening in the first place. Stem cell therapy might either involve transplanting stem cells or giving drugs that target stem cells already in the body. Stem cell treatments currently in use for MS use autologous haematopoietic stem cells (HSCs) adult stem cells from the blood or bone marrow which are taken from the patient s own blood or bone marrow. The aim of HSC transplant is to re-boot the immune system. This is an aggressive and high-risk treatment which involves a number of steps, including: 1. Collecting or harvesting the HSCs from the bone marrow or blood of the patient 2. Purifying and concentrating the HSCs in the laboratory 3. Freezing or cryopreserving the cells in the laboratory until they are required 4. Administering chemotherapy to destroy the patient s immune system (conditioning) 5. Returning the thawed HSCs to the patient by infusion What is the clinical experience in Australia? In Australia, less than 40 people with MS have received bone marrow transplants to treat active, highly aggressive cases of MS. The procedure has been carried out successfully at a number of sites, including the Sir Charles Gairdner Hospital in Perth and St Vincent s Hospital in Sydney. Internationally, hundreds of patients have been treated this way. Stem cell therapy for non-haematological (autoimmune) indications: March

121 The outcomes have been mixed and the treatment is still considered experimental by the international research community. As a high-risk, unproven treatment, stem cell therapy is currently only considered by some doctors and hospitals on a case-by-case basis for those who have an early, aggressive form of relapsing MS that is resistant to all other treatments. It is not a treatment for everybody living with MS. However there is hope and a world-wide commitment to learn more about how the treatment could apply to people with MS. Research is underway to understand HSCT, how it impacts people with MS, and which people with MS could benefit from the treatment. This includes large scale trials in Europe, the US and Canada as well as a smaller scale trial at St Vincent s Hospital in Sydney. Stem cell therapy for non-haematological (autoimmune) indications: March

122 Appendix H NHMRC warns of the risks associated with unproven stem cell therapies in Australia and overseas Summary media release information Date: 19 December 2013 Type: Media Release Contact for further information: NHMRC Media Team: The National Health and Medical Research Council has warned that unproven stem cell treatments available in Australia and overseas could pose risks to the health and well-being of patients. Today, NHMRC released Stem Cell Treatments a Quick Guide for Medical Practitioners and the patient-targeted document Stem Cell Treatments Frequently Asked Questions. These documents inform medical practitioners and their patients about the stem cell treatments that are available, and the risks associated with unproven treatments. The science of stem cells offers great potential for treating a number of conditions, however in many cases further research is required to demonstrate safety and effectiveness. Currently, the only stem cell treatment for which safety and efficacy has been scientifically established is haematopoietic (blood) stem cell transplantation for the treatment of certain blood and immune system disorders. An increasing number of people are travelling overseas for stem cell treatments which are unproven, often referred to as stem cell tourism. Unproven treatments using a mixture of the patient s own (autologous) cells are also being offered by private clinics in Australia. A new medical treatment should be tested through clinical trials to show that it is safe and effective before it is made available to the public, NHMRC CEO Professor Warwick Anderson said. Patients should investigate the option of participating in a registered clinical trial if they are interested in undergoing new stem cell treatments, rather than pursuing unproven treatments. Unproven stem cell treatments can result in serious health complications such as infection, allergic reaction or immune system rejection and in some cases, the development of cancer. In addition to the health and safety risks, these treatments often involve significant financial costs. Undergoing unproven treatments may also interfere with or delay a patient accessing proven and potentially beneficial therapies or treatment plans. Stem cell therapy for non-haematological (autoimmune) indications: March

123 NHMRC encourages patients considering stem cell treatments to seek additional information from a trustworthy source other than the treatment provider and speak to their general or specialist medical practitioners. "Medical practitioners should ensure their patient has a thorough understanding of the potential risks associated with undergoing these treatments, NHMRC CEO Professor Warwick Anderson said. Our resources provide information to support practitioners and patients in their discussions about stem cell treatments, and ultimately to assist people to make informed choices about their medical care. Stem cell therapy for non-haematological (autoimmune) indications: March