Autologous haematopoietic stem cell transplantation (aHSCT) for severe resistant autoimmune and inflammatory diseases – a guide for the generalist

Key points

• Autologous HSCT has the potential to induce sustained clinical remissions in otherwise resistant or poor prognosis autoimmune diseases enabling reduction and even long-term withdrawal of immunosuppressive and biological therapies

• Although a wide range of autoimmune diseases have been treated, the evidence base is greatest in relapsing remitting MS, diffuse systemic sclerosis and Crohn's disease

• Autologous HSCT requires close collaboration between experienced transplant haematologists and relevant disease specialists in patient selection, management and follow-up. Early referral of patients is essential to optimise clinical outcomes and minimise risks

• Autologous HSCT may lead to ‘rebooting’ of the immune system through regeneration and rediversification of the T and B-cell repertoire and increased regulatory T-cell activity

• There may be health economic benefits to a one-off intensive treatment over long-term administration of biological and immunosuppressive therapy

Multiple sclerosis

Current disease modifying therapies (DMTs) reduce relapse rates in patients with relapsing remitting MS (RRMS) but their impact on disability is limited. DMTs for progressive MS are scarcely effective and early intervention at the inflammatory RRMS phase of this illness is therefore key to preventing long-term disability.^9–11

Autologous haematopoietic stem cell transplantation has been used in the treatment of MS since 1995. Initially, patients with advanced progressive disease were treated with limited benefit.^9–11 A small phase II randomised controlled trial (RCT) confirmed reduced magnetic resonance imaging (MRI) disease activity with aHSCT,¹² which strongly supported further phase III studies with primary clinical endpoints. There is now increasing evidence that its early use in patients with highly active RRMS results in significant reduction in clinical and MRI disease activity as well as improving patients’ disability to a significantly greater degree compared with currently available DMTs.^9–11 The recent results of the MIST study (ClinicalTrials.gov identifier: NCT00273364), which compared the effectiveness of aHSCT against standard DMTs, suggests that aHSCT can be safely administered and is significantly more effective.¹³ However, alemtuzumab, one of the most effective DMTs, was not included in the control arm. An RCT of aHSCT with alemtuzumab would resolve the question of relative efficacy.

Outside of clinical trials, current consensus supports the use of aHSCT in patients with RRMS who are young (<45 years old), able to ambulate independently, have illness duration of <10 years, and at least two clinical relapses in the previous year despite the use of DMTs with MRI evidence of concurrent disease activity. Patients with higher degrees of disability, or occasionally progressive disease course, can be considered if there is clear evidence of significant clinical and MRI disease activity although the benefit in these patients is more limited. Potential patients should be discussed with, and treated in, specialised centres with an interest in aHSCT for MS.

Rheumatological diseases

SSc is a multisystem autoimmune connective tissue disease; rapidly progressive diffuse cutaneous SSc (dcSSc) has a 5-year mortality up to 30%. Vasculopathy, excessive collagen deposition, inflammation in the skin and internal organs (lung, gastrointestinal, cardiovascular and renal) result in fibrosis and organ failure, with death most commonly a consequence of pulmonary arterial hypertension or interstitial lung disease. Effective drug therapy for SSc is lacking; disease-modifying antirheumatic drugs (DMARDs) and biologics have failed to show lasting benefit; cyclophosphamide over 12 months has shown short-term benefit compared with placebo.^4,8,14–16

Three RCTs in SSc comparing aHSCT to cyclophosphamide have been reported: ASSIST,¹⁴ ASTIS¹⁵ and SCOT¹⁶ (Table 2). All studies compared aHSCT to monthly pulsed intravenous cyclophosphamide. ASSIST randomised patients to aHSCT or cyclophosphamide for 6 months and 19 patients were followed for 2 years. There was a significant improvement in respiratory and cutaneous disease in the aHSCT group with no transplant related mortality (TRM) reported. ASTIS compared aHSCT to cyclophosphamide for 12 months in 156 patients with early dcSSc and a median follow-up of 5.8 years. The primary endpoint was event-free survival (time from randomisation until the death or persistent major organ failure). In the aHSCT arm there were 22 events including 19 deaths (TRM 10%) predominantly attributed to SSc-related cardiac dysfunction. Long-term event-free and overall survival rates were higher with aHSCT. SCOT randomised 75 patients with severe SSc to aHSCT versus cyclophosphamide for 12 months, followed up for 4.5 years. The primary endpoint was a global rank composite score (GRCS) based on a hierarchy of disease features. AHSCT resulted in significantly better clinical outcomes compared with cyclophosphamide, with fewer events of conditioning-associated cardiac toxicity and TRM was reduced compared with ASTIS.

Improvements in disease control and long-term survival make aHSCT in selected patients with SSc increasingly attractive. Given that pre-existing pulmonary vascular and cardiac involvement are major contributors to TRM risk, an extensive cardiothoracic evaluation is mandatory for appropriate patient selection.⁵

AHSCT has also been used successfully in the treatment of other severe autoimmune connective tissue diseases including systemic lupus erythematosus (SLE),¹⁷ rheumatoid and other inflammatory arthritides, dermato- and polymyositis and systemic vasculitis.^3,4 However, in contrast to SSc, the success of standard immunomodulatory treatments and newer biological therapies in the management of these diseases has been such that in practice aHSCT is only considered for those individuals with severe recalcitrant disease.

Crohn's disease

Despite advances in conventional and biological therapies, a substantial minority of CD patients experience treatment refractory disease that results in a marked reduction in quality of life, leaving such individuals with limited therapeutic options. Surgical resection may not be feasible or may be declined by the patient if it will result in a permanent stoma.⁶

Initial case series and single-centre cohort studies suggested that aHSCT could induce sustained clinical benefit. To date there has only been one randomised controlled trial to assess the value of aHSCT in refractory CD, the ASTIC trial¹⁸ (see Table 3). ASTIC was a negative trial partly due to a very ambitious primary endpoint, and partly as the control arm also delivered a significant dose of cyclophosphamide for stem cell mobilisation resulting in transient reduction in clinical disease activity. Patients randomised to the control group in ASTIC could undergo aHSCT after the primary endpoint had been assessed and underwent the same schedule of assessments over the subsequent year. When analysed as the combined cohort of all 40 patients that underwent aHSCT, there were significant improvements in clinical disease activity, quality of life and endoscopic disease activity after one year; 50% of this group had complete mucosal healing, an important endpoint in CD and associated with improved long-term outcomes.¹⁹

Long-term outcomes after aHSCT are also reported in single-centre and registry cohorts. Significantly, the majority of patients who relapsed after aHSCT subsequently responded to reintroduction of anti-TNF therapy.^6,20

Further research is required to assess the place of aHSCT in the management of patients with treatment refractory and poor prognosis CD. ASTIClite is an NIHR-funded randomised controlled trial that will assess the benefit and risks of a low intensity mobilisation and conditioning HSCT regimen compared to the best currently available medical care in patients with significant CD refractory to at least two classes of biologic therapy. The primary endpoint will be mucosal healing, and patients who are randomised to HSCT but have disease recurrence at 6 months will restart anti-TNF therapy.²¹

Other diseases

A variety of other autoimmune diseases have been treated with aHSCT and are summarised in Table 2. In these rarer disease indications, it has been challenging to conduct large-scale clinical trials, at least of the randomised type, and this is where the transplant registries have been especially useful. Outcomes of HSCT in these indications can be accessed via recent reviews of the field.^3,4

Mechanisms of action

In the early stages the administration of high doses of cytotoxic therapy has a profound anti-inflammatory effect (see Fig 1, under ‘aHSCT ablation’). Subsequently, post-transplant immune reconstitution studies have supported re-diversification of T-cell repertoire, with quantitative and qualitative changes in T-regulatory cell numbers (see Fig 1, under ‘aHSCT reconstitution’). Other immune compartments, such as naive B cells and NK cells may also be regenerated. Effects on the adaptive immune system persist well beyond the transplant period and the lymphocyte repopulation phase, supporting the notion of an immune reset or reboot. In addition to providing insights on immune reconstitution, concurrent scientific studies conducted while destroying and rebuilding dysfunctional immune systems may also provide useful insights into the aetiology and pathogenesis of autoimmune diseases.^7,11,21

• Download figure
• Open in new tab
• Download powerpoint

Fig 1.

Potential mechanisms of action of aHSCT in autoimmune diseases. In individuals with genetic susceptibility towards autoimmune disease, exposure to multiple environmental factors such as viral infection and toxic or metabolic damage (top), may induce autoimmune disease through aberrant antigen (Ag) mediated activation of T cells (centre). In aHSCT the cytotoxic chemotherapy ablates the lymphoid system including T lymphocyte immunity (as depicted). The leukocyte depletion enables an immune reconstitution that restores the predominance of anti-inflammatory regulating factors (bottom left) over inflammatory effectors (bottom right). These mechanisms may explain induction of long-lasting suppression of some autoimmune diseases by aHSCT.

Conflicts of interest

JAS declares honoraria from Sanofi and Jazz. PAM declares travel support and speaker honoraria from Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono and Sanofi Aventis. AL declares advisory board membership, speaker fees or consultancy for MSD, Abbvie, Janssen, Takeda, Medtronic, Vifor Pharma and Shield Therapeutics. There are no other declarations.