Elsevier

The Lancet

Volume 381, Issue 9872, 30 March–5 April 2013, Pages 1116-1124
The Lancet

Articles
Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis

https://doi.org/10.1016/S0140-6736(12)62114-XGet rights and content

Summary

Background

Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group.

Methods

We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m2) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5–6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests.

Findings

Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05).

Interpretation

Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated.

Funding

None.

Introduction

Systemic sclerosis generally affects young women and is a chronic autoimmune disease of unknown cause complicated by a combination of diffuse vasculopathy, immune activation, and tissue fibrosis.1 Standard therapies are unable to reverse disease progression, although several non-randomised trials involving small numbers of patients suggest that autologous haemopoietic stem-cell transplantation (HSCT) can improve skin and stabilise or improve forced vital capacity.2, 3, 4, 5, 6, 7, 8, 9, 10, 11 In the only randomised trial published to date (the American Scleroderma Stem Cell versus Immune Suppression Trial [ASSIST]),2 autologous HSCT improved both skin and forced vital capacity, whereas disease progression was noted in patients treated with the standard therapy of monthly intravenous cyclophosphamide.

Several transplantation trials for systemic sclerosis have been complicated by treatment-related mortality.3, 4, 6, 7, 10, 12 Such mortality was 10% (eight of 79 patients) in the largest reported trial to date, the European Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial.12 For cancer13 and autoimmune diseases including systemic sclerosis,14, 15 published guidelines recommend an echocardiogram to assess cardiac reserve to establish whether a patient can safely tolerate a transplant. However, unlike other diseases for which haemopoietic transplantation is done, the usual disease-related cause of death for systemic sclerosis is cardiac complications arising from pulmonary artery hypertension and primary cardiac or pericardial involvement.16

Therefore, we analysed results from two centres that used the same mobilisation and non-myeloablative HSCT regimen without selection or manipulation of the graft to assess the causes of treatment-related mortality, whether impaired cardiac function affects outcome, and the appropriate screening method before transplantation to prevent enrolment of patients with insufficient cardiac reserve to safely tolerate the procedure.

Section snippets

Study design and patients

We undertook a retrospective analysis of all patients treated with HSCT, either as part of a study or on a compassionate basis, at Northwestern University (Chicago, IL, USA) and the University of São Paulo (Ribeirão Preto, Brazil). Patients were enrolled in institutional review board (IRB)-approved studies and retrospective IRB approval was obtained to report off-study patients. We defined duration of disease as duration from time of diagnosis of systemic sclerosis. Patients were followed up

Results

Between November, 2002, and July, 2011, we included 59 patients at Northwestern University and 31 patients at the University of São Paulo (figure 1). 59 patients were in IRB-approved studies (28 from Northwestern University and 31 from University of São Paulo) and retrospective IRB approval was obtained for 31 patients. Table 1 shows demographic characteristics of 90 patients who were offered autologous HSCT.

Median day of engraftment (absolute neutrophil count >1000 cells per μL) was day 9

Discussion

HSCT was associated with treatment-related mortality in five (6%) of 90 patients in our study, which is about half the rate (eight [10%] of 79 patients) in the European multicentre ASTIS trial.12 Treatment-related mortality in our study was predominantly related to cardiac events (four of five deaths). We attribute the reduced mortality in our study compared with ASTIS to recognition that echocardiogram and resting right heart catheterisation might be insufficient to assess cardiac risk in

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