Original Article

Bone Marrow Transplantation (2010) 45, 1014–1021; doi:10.1038/bmt.2009.305; published online 26 October 2009

Multiple Sclerosis

Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis

P Tappenden1, R Saccardi2, C Confavreux3, B Sharrack4, P A Muraro5, G L Mancardi6, T Kozak7, D Farge-Bancel8, J Madan1, R Rafia1, R Akehurst1 and J Snowden9

  1. 1Health Economics and Decision Science (HEDS), School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
  2. 2Bone Marrow Transplant Unit, UO Ematologia, Policlinico Careggi, Florence, Italy
  3. 3Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Service de Neurologie A and EDMUS Coordinating Center, Lyon, France
  4. 4Department of Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
  5. 5Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College, London, UK
  6. 6Department of Neurosciences, Ophtalmology and Genetics, University of Genova, Genova, Italy
  7. 7Charles University Prague, Clinical Haematology, Prague, Czech Republic
  8. 8Hôpital Saint-Louis, Service de Médecine Interne et Pathologie Vasculaire, Paris, France
  9. 9Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

Correspondence: P Tappenden, School of Health and Related Research (ScHARR), University of Sheffield, Regent Court, 30 Regent Street, Sheffield, England S1 4DA, UK. E-mail: p.tappenden@sheffield.ac.uk

Received 11 June 2009; Revised 16 September 2009; Accepted 20 September 2009; Published online 26 October 2009.

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Abstract

Treatment options for secondary progressive multiple sclerosis (SPMS) are limited. Mitoxantrone is routinely used to stabilize disease progression; however, evolving evidence suggests clinical benefit from intensive treatment with autologous haematopoietic stem cell transplantation (HSCT). Given differences in cost and outcomes, preliminary cost-effectiveness studies are warranted if this approach is to be developed for more widespread application in SPMS. We developed a decision-analytic Markov model to explore the potential cost-effectiveness of autologous HSCT versus mitoxantrone in SPMS, using patient-level data from registry sources. The model evaluates the lifetime costs and health outcomes associated with disability progression and relapse. Sensitivity analyses were undertaken to examine the uncertainty surrounding cost-effectiveness outcomes. In the absence of randomised controlled trial (RCT) evidence, conditions for comparative analysis were not ideal. Under optimistic assumptions, HSCT is estimated to cost below £3000 per quality adjusted life year gained. However, when a strict 6-month sustained progression rule is adopted, HSCT may be less effective and more expensive than mitoxantrone. The model results were sensitive to reducing procedural costs and HSCT-related mortality. We conclude that HSCT could potentially achieve an acceptable level of cost-effectiveness. However, caution should be exercised as large, high-quality RCTs comparing HSCT versus mitoxantrone are necessary to validate these findings.

Keywords:

haematopoietic stem cell transplantation; mitoxantrone; multiple sclerosis; costs and cost analysis; economics

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Introduction

Multiple sclerosis (MS) is a chronic immune mediated disease of the central nervous system that affects ~0.1% of Caucasians of north and central European ancestry.1 Early underlying pathogenic mechanisms include inflammation, demyelination and axonal loss, whereas chronic axonal degeneration predominates at a later stage. MS is characterized by a variety of symptoms including visual impairment, limb weakness, sensory disturbance, balance and postural problems, sphincter dysfunction, cognitive impairments, pain and fatigue.2 Most patients become disabled as the disease progresses with ~50% requiring walking aids or the use of wheelchairs within 15 years of onset.3 The disease has a considerable impact on a patient's quality of life, and the costs of managing the disease can be substantial, particularly in the later stages of disease progression.4, 5, 6 Disease progression is most commonly measured using the Expanded Disability Status Scale (EDSS), a 20-point ordinal scale ranging from 0 (normal neurological assessment) to 10 (death due to MS).7 In the majority of patients, the illness runs an initial relapsing remitting (RRMS) course characterized by episodes of acute neurological dysfunction followed by full or partial recovery, usually culminating in a secondary progressive (SPMS) course during which disability progresses gradually with or without occasional relapses, minor remissions and plateaus. It has been estimated that ~50% of patients with RRMS develop SPMS within the first 15–20 years of their disease,8 although more recent longitudinal data suggest that time to conversion may be considerably longer.9

In recent years, much attention has been focussed on the clinical effectiveness and cost-effectiveness of disease-modifying therapies for RRMS, most notably interferon-β, glatiramer acetate and natalizumab.10 However, treatment options for SPMS are more limited, the evidence base supporting their use is less well developed, and consequently, potentially efficacious therapies are more likely to be used off licence. One of the more common treatment options for SPMS is mitoxantrone, a type II topoisomerase inhibitor with antineoplastic and immuno-suppressive effects. Evidence from randomised controlled trials (RCTs) suggests that mitoxantrone may delay progression in SPMS.11 However, the drug is dose limited, carrying a maximum cumulative lifetime dose of 120mg.12 In Europe, mitoxantrone is typically administered at a dose of 20mg monthly for a maximum period of 6 months; however, the drug has been trialled using a dose of 12mg/m2 every 3 months for up to 2 years.11

For over a decade now, autologous haematopoietic system cell transplantation (HSCT) has been studied as a potential means of delivering intensive immune suppression in patients with severe autoimmune and inflammatory diseases.13, 14 Given the limited effective treatment options, SPMS has been one of the main disease category candidates for this treatment approach. To date, over 300 MS patients have been registered in the European Group for Blood and Marrow Transplantation (EBMT) database. Single-arm studies have provided support for the benefit of autologous HSCT as a potent modifier of disease activity, reflected by stabilisation of disease and reduction of magnetic resonance imaging activity. A randomised trial (ASTIMS) is ongoing, which will add further data on the radiological and clinical activity of autologous HSCT compared with mitoxantrone.15 However, this is a Phase II trial, which has only a limited capacity to provide robust evidence of the relative clinical benefit of autologous HSCT over mitoxantrone.

Given the high initial costs of HSCT, there remain important questions concerning whether this treatment is expected to represent value for money in comparison to mitoxantrone and other less intensive treatments. This examines the potential cost-effectiveness of autologous HSCT versus mitoxantrone in the treatment of patients with SPMS. As such, this study represents the first economic analysis of autologous HSCT for MS.

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Materials and methods

Model scope

We developed a decision-analytic Markov model to evaluate the incremental cost-effectiveness of autologous HSCT versus current standard therapy (mitoxantrone) in SPMS based on an indirect comparison between two registry datasets. Other aggressive relapsing/remitting forms of MS in which HSCT may have clinical benefit are not represented within the economic analysis. The primary economic outcome is the incremental cost per quality adjusted life year (QALY) gained. This describes the additional cost required to produce an extra year of life in a notional state of ‘perfect health’.16 The analysis was undertaken from the perspective of the UK NHS and Personal Social Services. It is good practice in health economic evaluation to place greater weight on those events that occur in the present than those that occur in the future; in line with current methodological recommendations, costs and health outcomes were discounted at a rate of 3.5%.17 In the base case analysis, the model evaluates differences in costs and health outcomes over a lifetime horizon.

Model structure

The model is comprised of 10 mutually exclusive health states. These states represent whole EDSS points from EDSS 1.0 through EDSS 9.5; an additional absorbing state is used to describe death due to MS (EDSS 10) together with death due to other causes. The model assumes a cycle length of 1-year in duration. During any given model cycle, patients may remain in their current EDSS state, progress to a more advanced EDSS state, regress to a better EDSS state, or die due to MS or other causes. The model assumes that patients may experience one or more relapses during any model cycle; the probability of experiencing relapse is assumed to be dependent on the current EDSS score of the patient. Progression is determined by a transition matrix, which describes the probability of moving from each state to any other health state in the model during each cycle. Each EDSS state is associated with a specific level of health-related quality of life (HRQoL) and cost associated with disease management. Altering the natural history of the disease through delaying disease progression results in a different trajectory through the model health states and generates different profiles of costs and QALYs gained for each treatment option. A simple schematic of the model structure is shown in Figure 1.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Simplified Markov model structure.

Full figure and legend (66K)

Modelling baseline disease progression

Given the absence of RCT evidence concerning the efficacy of autologous HSCT versus mitoxantrone (or indeed any other therapy) within this patient population, it was necessary to construct an indirect comparison based on patient records contained within two MS registries: the Lyon Clinique de Neurologie MS Registry18 and the EBMT MS registry.19 To allow for the fairest possible comparison between the two treatment groups, we attempted to match similar patients across the databases to adjust for known heterogeneities. Baseline disease progression rates for patients receiving mitoxantrone were derived from an analysis of patient-level clinical outcomes data from a subset of patients receiving mitoxantrone included in the Lyon Clinique de Neurologie Registry.18 The Lyon Clinique de Neurologie is a single centre for diagnosis confirmation, follow-up and treatment of MS patients for Lyon city and the Rhones Alpes Region. Between 1992 and 2007, 257 patients followed up within this registry received at least one dose of mitoxantrone (105 males and 152 females). The mean age at the start of the treatment was 39 years (range, 14–64 years). At baseline, 61 patients had primary progressive MS, 52 patients had RRMS and 144 patients had SPMS. Mean duration of follow-up among these patients was 4.3±3.2 years (range, 0–14.9 years). Within this registry, disability was assessed using the EDMUS Grading Scale,20 which is derived from the Kurtzke's Disability Status Scale.21 EDSS and EDMUS Grading Scale scores were assumed transposable based on their close correlation and the linear association observed between the two scales.22

A subset of patients followed up within the Lyon Clinique de Neurologie MS Registry was selected to match those patients included in the EBMT registry. Patients receiving mitoxantrone were thus included in the health economic analysis if they had a baseline EDSS score greater than or equal to3 and <8, and if they had SPMS at the start of treatment. Patients were excluded if they had only one EDSS observation over the entire follow-up period, or if EDSS outcomes were not available within 30 days after the start of the mitoxantrone treatment. EDSS outcomes were available for 118 SPMS patients receiving mitoxantrone. The characteristics of the mitoxantrone patient group are presented in Table 1. Each patient underwent between 2 and 42 EDSS evaluations over the entire follow-up period. As observations were not recorded at routine intervals, maximum likelihood estimation techniques were used to derive the probability that a patient transits from one EDSS state to any other EDSS state during any time interval. To allow for multiple transitions within an annual model cycle (for example progression from EDSS 3.0 to EDSS 6.0), the maximum likelihood estimation model was developed using weekly transition probabilities. The resulting transition matrix provides an analytic solution to the set of transition rates, which provide the best fit to the empirical EDSS progression data for the mitoxantrone group over their entire follow-up period. This maximum likelihood estimation model assumes that transitions between EDSS states may be progressive or regressive; that is, disability in individual patients may worsen or improve over time. Weekly probabilities were converted into annual probabilities using simple matrix multiplication.


Modelling the relative effectiveness of autologous HSCT versus mitoxantrone—sources of data, assumptions and caveats

The relative effectiveness of HSCT versus mitoxantrone was modelled based on the relative hazard ratio for progression between EDSS outcomes for the 118 mitoxantrone patients18 and the 47 HSCT patients.23 Kaplan–Meier PFS curves were constructed using individual patient-level data from both registries. Characteristics of selected patients were generally similar between both registries (see Table 1). A parametric Weibull survival model was fitted to the Lyon mitoxantrone group data using standard regression techniques. The implied relative hazard ratio for PFS, which describes the relative progression-free survival benefit for autologous HSCT versus mitoxantrone, was estimated using simple least squares regression assuming proportional hazards between the two treatment groups.

Importantly, the Lyon and EBMT registries are subject to differences in terms of the frequency of clinical visits for EDSS assessment and the methods of recording disease progression (EDMUS versus EDSS). Within the EBMT registry, patients underwent regular EDSS assessments typically at 6-monthly intervals. Conversely, within the sample of patients from the Lyon database, clinical visits were highly opportunistic, with the interval between consecutive clinical visits ranging from 1 day to 2840 days. Consequently, the application of a strict 6-month sustained progression rule to the Lyon data is likely to bias against HSCT. Further, the Lyon dataset suggests some evidence of concurrent relapse and/or progressive disease at the point at which patients started mitoxantrone treatment. As a result, the stability of the EDSS score for many patients starting mitoxantrone treatment may be questionable. It should also be noted that although we attempted to match similar patients across the two databases, there may also be differences in terms of the indications for commencing treatment with mitoxantrone treatment and HSCT. In combination, these factors make it extremely difficult to provide a reliable assessment of relative differences in sustained disease progression between the two treatment groups given current evidence.

To address this issue, the economic analysis focussed on three different interpretations of the Lyon progression data. The first is a strict application of a 6-month sustained progression rule; this is likely to overestimate the effectiveness of mitoxantrone in patients who underwent clinical visits within short intervals. The second approach uses a sustained progression confirmation rule applied to the next clinical EDSS assessment rather than at 6 months. The third approach allows for uncertainty in the baseline EDSS score of the Lyon patients; within this analysis, disease progression is defined as any sustained increase in EDSS irrespective of the EDSS score at baseline. It is possible that the latter two analyses will bias in favour of HSCT over mitoxantrone, although the extent of this is unclear. The resulting indirect comparison scenarios are presented in Figure 2. It should be noted that the time zero benchmark relates to the point of starting mitoxantrone treatment within the Lyon sample, and the time of transplantation within the EBMT registry.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Progression-free survival results from indirect comparisons of HSCT versus mitoxantrone.

Full figure and legend (72K)

Incidence of MS relapse

The model assumes that the annual probability that a patient will experience a relapse is dependent on their current EDSS state. The number of relapses experienced within each EDSS state was derived from the Lyon dataset, based on all observations since the patient commenced mitoxantrone treatment, together with the time spent in each state. The number of observed relapses in each state was divided by the observed number of years spent in each state to generate the EDSS-specific probability of relapse. Given the limitations in evidence for HSCT, the model assumes that transplantation does not have a direct effect on reducing MS relapse; however, the impact of delaying EDSS progression through autologous HSCT leads to an indirect reduction in the number of relapses experienced for HSCT patients. Limited case series have reported a dramatic reduction in relapse in patients with SPMS following HSCT;24 however, there is currently no controlled evidence to show the magnitude of this potential benefit. This assumption may therefore underestimate the benefit of HSCT in reducing MS relapse.

Transplant-related mortality

The baseline model assumes that autologous HSCT is associated with a transplant-related mortality rate of 5.3% based on years 1995–2000.25 This represents an unfavourable assumption against HSCT; increased experience and better patient selection led to a substantially lower transplant-related mortality rate of 1.3% for the period 2001–2007.19 The transplant-related mortality rate is applied only in the first year of the model simulation.

Health-related quality of life

The model assumes that each health state is associated with a unique level of HRQoL, measured using a single index scale whereby 1 represents a notional state of ‘perfect health’ and 0 represents a state equal to ‘dead’.16 The time spent in each EDSS state is weighted by its respective HRQoL level to generate an estimate of the number of QALYs gained in each treatment group over. The model assumes that HRQoL experienced by patients with SPMS decreases as they progress along the EDSS, hence later EDSS states are associated with lower HRQoL scores. HRQoL scores were drawn from a previously published multivariate linear regression analysis of 2048 patients.26 The model assumes a reference value of 0.87, which represents the health utility score for a female patient with no recent relapse, EDSS 0, with RRMS. Additional covariates (EDSS score, MS disease-type classification, sex) to the simple additive regression equation are used to generate utility scores for each health state. A further covariate describing the impact of relapse on health utility was applied to the expected probability of relapse within each EDSS health state.

Costs included in the health economic model

The model includes two groups of cost components: intervention costs (treatment costs for mitoxantrone and autologous HSCT together with any related adverse events) and other costs associated with the management of MS unrelated to the interventions under evaluation.

Treatment costs

The model assumes that all costs associated with treatment and related adverse events are incurred during the first year of the simulation. For the mitoxantrone treatment group, the model assumes that patients receive 20mg mitoxantrone plus 1g methylprednisolone monthly; this is consistent with the treatment schedule used within the Lyon registry.20 The model assumes that patients receive a maximum of six doses of this regimen, each of which requires a daycase attendance. The model assumes that 5.93% patients withdraw prematurely from the mitoxantrone treatment course due to a lack of efficacy or intolerance to treatment, based on the experience of the subgroup of 118 patients included from the Lyon Registry.18 As data were not available concerning the point at which patients withdraw from mitoxantrone treatment, the model assumes that these patients drop out half-way through the treatment course, thus incurring only half of the cost of a full treatment course. In addition, patients receiving mitoxantrone are assumed to receive a magnetic resonance imaging scan, an electrocardiogram and an echocardiogram at the beginning and end of the treatment course. It should be noted that mitoxantrone is associated with adverse events, in particular nausea, vomiting and neutropenia.11, 12 The model assumes that patients experiencing nausea/vomiting will be treated with a 7-day course of domperidone, whereas patients experiencing neutropenia will require an additional daycase attendance. Evidence concerning the probability of experiencing adverse events was not available within the Lyon dataset; hence, this was drawn from a large RCT of mitoxantrone in MS reported by Hartung et al.11 Other rare adverse events, such as mitoxantrone-induced leukaemia were excluded from the model analysis. All hospital resources were valued using 2006–7 NHS Reference Costs,27 whereas drug acquisition costs were sourced from the British National Formulary (BNF 55).28

National tariff costs for autologous HSCT were not available and the true cost of the procedure is likely to vary by geographical location. For the purpose of the model analysis, the per-patient cost of the autologous HSCT procedure in MS was assumed to be £30000, based on the current tariff for the Sheffield Teaching Hospitals NHS Foundation Trust, as a typical UK costing. Approximately £24 000 of this tariff covers routine costs for the autologous harvest and transplant procedure (for the mainstream indication of relapsed lymphoma in which the BEAM regimen is routinely used), The remaining £6000 is included for additional baseline assessments, supplementary treatments with anti-thymocyte globulin and methylprednisolone, along with additional inpatient attendances, nine weekly CMV tests and treatment of CMV reactivation, where required. These further costs are included to create costs of the entire autologous transplant procedure for patients with SPMS according to previously published protocols.15

Disease management costs

There is evidence to suggest that the costs of MS care increase dramatically with increasing EDSS disability and impairment.4, 5 Disease management costs associated with each model health state were derived from recent submission to the National Institute for Health and Clinical Excellence on the clinical and cost-effectiveness of natalizumab for the management of rapidly evolving MS.29 This analysis reported the results of a seemingly unrelated regression model. The costs associated with each EDSS score in SPMS were derived directly from the report; the expected cost of relapse was incorporated into the EDSS-specific cost based on the expected probability of relapse for each EDSS state. All costs were reported from the perspective of the NHS and Personal Social Services; indirect costs such as lost productivity and out-of-pocket expenses were excluded from the analysis.

Handling uncertainty

In the absence of direct RCT evidence comparing autologous HSCT versus mitoxantrone within this patient group, a comprehensive probabilistic analysis of parameter uncertainty is unlikely to be of value for policymakers. Although the use of a modelling framework is useful in examining the potential cost-effectiveness of autologous HSCT, the use of an indirect comparison does not fully reconcile issues concerning the relative clinical benefit of autologous HSCT compared with mitoxantrone. A key assumption within previous MS models concerns the duration over which the additional PFS benefit is applied.30, 31 To elucidate this issue, sensitivity analyses were conducted over three treatment duration scenarios:

  • Effectiveness duration scenario 1 (optimistic): This scenario assumes that the additional PFS benefit for HSCT is sustained indefinitely; in statistical terms, this represents an assumption of proportional hazards between the treatment groups. Within this scenario, the relative hazard ratio for PFS is applied for the remaining lifetime of the entire patient group.
  • Effectiveness duration scenario 2 (pessimistic): This scenario assumes that the additional PFS benefit for HSCT is sustained for a duration of 5 years. Beyond this point, the relative hazard ratio is assumed to be 1.0.
  • Effectiveness duration scenario 3 (middle ground): This scenario assumes that the additional PFS benefit for HSCT is sustained for 10 years. Beyond this point, the relative hazard ratio is assumed to be 1.0.

In addition, simple sensitivity analysis was undertaken to explore the expected impact of varying individual model parameters on the incremental cost-effectiveness of autologous HSCT. This included varying assumptions concerning the HSCT transplant-related mortality rate, the relative PFS hazard ratio between HSCT and mitoxantrone, the tariff cost of HSCT, the costs of managing MS, and the discount rate.

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Results

The central estimates of cost-effectiveness for autologous HSCT versus mitoxantrone across the three scenarios are presented in Table 2. The base case results over the three scenarios suggest that autologous HSCT has the potential to provide health gains at a cost which is currently considered acceptable to UK policymakers.17 However, the results suggest that the uncertainty surrounding the interpretation of the clinical evidence has the capacity to dramatically influence cost-effectiveness outcomes. In the most optimistic scenario (scenario 3), the cost-effectiveness of autologous HSCT is expected to be around £2800 per additional QALY gained. However, within the pessimistic scenario, HSCT is expected to be dominated by mitoxantrone (that is it is less effective and more expensive). When confirmation of disease progression is applied at consecutive visits, the cost-effectiveness ratio is estimated to be around £74 000 per QALY gained; under this scenario, HSCT is unlikely to be considered value for money for the NHS.


The sensitivity analysis suggests that observed improvements in transplant-related mortality may markedly improve the cost-effectiveness of autologous HSCT; this is especially true for scenario 2 whereby the cost-effectiveness ratio for HSCT begins to approach a level considered acceptable by policymakers. The model is relatively insensitive to disease management costs; however, the cost of transplantation itself may have a considerable impact on its resulting cost-effectiveness (Table 3).


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Discussion

MS represents a considerable challenge for health resources; the costs to the individual and to society are high, not only in long-term treatments but also in terms of work disability. Current pharmacological treatments include immunomodulating agents such as interferon-β, natalizumab, copaxone, pulsed intravenous steroids, cyclophosphamide and mitoxantrone. There is a need for ongoing administration of many of these agents, which in turn is associated with considerable ongoing cost. None of these treatments successfully control progressive disease or long-term disability, and therefore new approaches whereby a single one-off treatment may result in sustained remissions, such as autologous HSCT, are particularly attractive.

The initial costs of autologous HSCT are extremely high, and for any new treatment to be applied widely in a resource constrained health service, such as the National Health Service in the UK, and many European health services, it is necessary to demonstrate value for money in the context of other competing priorities. The aim of this study was to establish, based on the best current data, whether this autologous HSCT has a realistic prospect of cost-effectiveness in term of benefits gained over less expensive ‘standard’ treatment approaches, in particular, mitoxantrone, which is now widely used as a means of reducing progression of disability in SPMS.

Autologous HSCT is a relatively new approach, and the evidence for its clinical effectiveness is limited to the last decade. Although supportive data in animal models has been available for many years, it was not until 1997 that the first experience of high-dose chemotherapy and autologous HSCT in MS in the clinical setting was published. Since then, the number of patients and published studies have grown steadily and currently ~300 patients have been treated in Europe and a further 200 in North America.19 A number of retrospective analyses have been performed using the relatively large number of patients, and the European database formed the basis for the modelling of the transplant arm in this study.14 Almost in parallel, regulatory approval of mitoxantrone for treating SPMS has resulted in its widespread use in clinical practice. Currently, however, there is no published prospective comparative evidence of clinical efficacy for autologous HSCT versus pharmacological therapies. In this study, we therefore used the highest quality data presently available, that is in the EBMT and Lyon databases to model cost and quality of life estimates for autologous HSCT and mitoxantrone, respectively, in a case–control manner.

Given the substantial gaps in the current evidence base, the model analysis should be interpreted in the light of the evidence used to populate it. Although the model analysis should be considered exploratory rather than definitive, the use of such an explicit approach is valuable in terms of bringing the current available evidence to bear on the decision problem, but also in terms of structuring the problem itself. Despite this, modelling cannot be considered a substitute for good quality clinical trial evidence. Using this approach, we were able to draw out key uncertainties in the evidence base, which may influence the cost-effectiveness of HSCT: principally the relative hazard ratio of HSCT versus mitoxantrone and the duration over which this hazard ratio is applicable. The sensitivity analysis also highlights the importance of minimising transplant-related mortality. In recent years, treatment-related mortality has decreased to around 1.3%, which is likely to reflect both increased clinical experience together with better patient selection criteria.19 Although HSCT has the potential to represent a cost-effective use of health-care resources, this cannot be fully established given the current available clinical evidence base.

The principal source of uncertainty within this analysis relates to the absence of direct RCT evidence in this field. Although registry data were available through which to construct an indirect comparison, there are important differences between these datasets, which lead to significant difficulties in their comparative interpretation. The cost-effectiveness of HSCT is largely hinged on the interpretation of the EBMT and Lyon datasets, both in terms of the relative effectiveness of HSCT and the duration over which such effects may be observed. Thus, in conclusion, although the model suggests that HSCT has the potential to achieve a level of cost-effectiveness that is acceptable to policy-makers and health-care purchasers, caution should be exercised as large, high-quality RCT comparing HSCT versus mitoxantrone in terms of clinical endpoints are necessary to validate these findings. This study has focussed specifically on the potential cost-effectiveness of autologous HSCT in the management of SPMS. However, the clinical utility of HSCT may extend beyond SPMS. Further analyses are required to examine the economic value of HSCT for the treatment of rapidly progressing, relapsing-remitting and aggressive forms of MS.

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Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

This study was undertaken without commercial or research funding.

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