Background/Purpose: High dose immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) have shown efficacy in severe systemic sclerosis (SSc) in phase I and II trials. The ASTIS trial is an international prospective randomized controlled phase III trial comparing safety and efficacy of HSCT versus intravenous (iv) pulse cyclophosphamide (CYC) in early diffuse cutaneous SSc (dcSSc) patients at risk of major organ failure (MOF) or early mortality.

Methods: HSCT comprised mobilization with CYC 2×2 g/m² + G-CSF 10mcg/kg/d, conditioning with CYC 200 mg/kg, rabbit ATG 7.5 mg/kg, followed by reinfusion of CD34+ autologous HSCT. Control patients were treated with 12x monthly iv pulse CYC 750 mg/m². The primary endpoint was event-free survival (EFS), defined as survival until death or development of MOF. Secondary endpoints included changes in modified Rodnan skin score (mRSS), major organ function, SHAQ and toxicity. Treatment effects were analysed on an intention to treat basis and by comparing EFS using the KM survival curves (using log-rank test) and Cox models. In addition, treatment responses in clinical outcome variables such as the mRSS, SHAQ and organ function were compared by analysing the area under the time response curve (AUC) until 2 years of follow-up using the Student’s t-test.

Results: 156 patients were enrolled from March 2001 until October 2009 and randomised to HSCT (n=79) or iv pulse CYC (n=77). Seventy-five patients in each group started treatment. With data cut at 1 May 2012, median follow-up (IR) are 33 (42.0) and 27 (34.0) months in the HSCT and control groups respectively. Fourty-two events occurred: 18 in the HSCT group (16 deaths and 2 irreversible renal failure) and 24 in the control group (deaths only). EFS was time-dependent with a hazard ratio at 84 months of 0.22 (95% CI 0.08-0.58, P= 0.002). Eight deaths in the HSCT group were treatment-related. In the control group, none died from treatment-related causes and most deaths were due to progressive disease. Furthermore, the analysis of AUC showed that the mean absolute changes in mRSS, SHAQ and VC significantly differed in favour of HSCT, while both HSCT and controls experienced a fall in creatinine clearance, greater in the HSCT group (Table 1).

Table 1. Analysis of the area under the time response curve at 2 years follow-up*
	Mean Absolute change		P value
Clinical outcome variable	Transplant (n=67)	Control (n=64)
mRSS	-19.7 (10.2)	-8.7 (12.1)	<0.001
SHAQ	-0.57 (1.14)	-0.2 (0.78)	0.03
VC (% predicted)	4.5 (13.4)	-2.2 (13.7)	0.005
DLCO (% predicted)	-3.88 (10.5)	-3.6 (13.9)	0.8
LVEF (%)	-1.23 (11.9)	-0.75 (10.9)	0.9
Creat.  clearance (ml/min)†	-11.9 (28.6)	-0.95 (22.9)	0.02
* Values are means (standard deviation). † Two patients with renal failure in the transplant arm were excluded from the analysis.

Conclusion: The ASTIS trial is the first international, investigator-initiated, phase 3 HSCT trial in early dcSSc. Despite 10% treatment-related mortality and greater deterioration in renal function, HSCT as compared with iv pulse CYC prolonged event-free and overall survival and resulted in greater improvement of skin score, vital capacity and functional ability, as well as in survival up to 84 months after HSCT.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-dose-immunoablation-and-autologous-hematopoietic-stem-cell-transplantation-versus-monthly-intravenous-pulse-therapy-cyclophosphamide-in-severe-systemic-sclerosis/