Elsevier

The Lancet

Volume 378, Issue 9790, 6–12 August 2011, Pages 498-506
The Lancet

Articles
Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial

https://doi.org/10.1016/S0140-6736(11)60982-3Get rights and content

Summary

Background

Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide.

Methods

In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m2 intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with ClinicalTrials.gov, number NCT00278525.

Findings

Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04–∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted.

Interpretation

Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed.

Funding

None

Introduction

Systemic sclerosis is a chronic disease that starts as a diffuse vasculopathy, followed by immune activation and subsequent tissue fibrosis.1 Haemopoietic stem-cell transplantation (HSCT) is a potential treatment for systemic sclerosis2, 3, 4, 5, 6, 7, 8 and relies on early intervention during immune activation. However, there have been no randomised trials published about outcomes of such transplantation for autoimmune diseases in general or systemic sclerosis in particular. Previous studies of HSCT for systemic sclerosis showed significant improvements in skin flexibility, as measured by modified Rodnan skin score (mRSS),9 and two small non-randomised studies suggested that HSCT improves lung function.10, 11 However, positive efficacy outcomes were tempered by initial reports of high treatment-related mortality, albeit which diminished with increased experience, and absence of a randomised control group.12 In our phase 2 American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST), we aimed to assess safety and efficacy of autologous non-myeloablative HSCT compared with a control group who received one dose of intravenous cyclophosphamide every month for 6 months.

Section snippets

Study design and patients

In our randomised phase 2 trial, we screened consecutive patients at Northwestern Memorial Hospital (Chicago, IL, USA). Patients were eligible if they were aged younger than 60 years and had diffuse systemic sclerosis (defined as cutaneous involvement proximal to the elbow or knee with an mRSS of more than 14), and internal-organ involvement, which was defined as at least one of the following features: diffusing capacity of carbon monoxide (DLCO) of less than 80% or decline in forced vital

Results

We enrolled 19 patients between Jan 18, 2006, and Nov 10, 2009 (table 1, figure 2). No deaths occurred in either treatment group during follow-up. For patients treated with HSCT, engraftment of white blood cells (absolute neutrophil count >500 cells per μL) occurred at a mean of 10 days (SD 1·4) and platelets (transfusion independent >20 000 cells per μL) occurred at a mean of 11 days (2·4). Patients received a mean of 5·3 units (5·5) of single donor platelet transfusion and 4·4 units (2·3) of

Discussion

In our study, non-myeloablative HSCT significantly improved forced vital capacity, decreased diseased-lung volume, and showed that systemic sclerosis interstitial lung disease might be at least partially reversed with continued improvement in lung function for at least 2 years after transplantation. The improvement that we noted in lung function after HSCT was associated with improved high-resolution chest CT, skin score, and quality of life. Non-myeloablative autologous HSCT is the first

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