Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial

Abstract

BACKGROUND The randomised controlled ASTIC trial showed no benefit of mobilisation and autologous haematopoietic stem-cell transplantation (HSCT) compared with mobilisation followed by conventional therapy using a stringent primary endpoint (steroid-free clinical remission for 3 months with no endoscopic or radiological evidence of intestinal inflammation) in patients with treatment-refractory Crohn's disease. We now assess HSCT in patients enrolled in the ASTIC trial using endpoints that are traditional for clinical trials in Crohn's disease, and identify factors that predict benefit or harm. METHODS Patients who underwent mobilisation and were randomly assigned to conventional therapy in the ASTIC trial were offered HSCT at 1 year and underwent complete assessment for a further year. We report analyses of the combined cohort of patients who underwent HSCT at any time during the ASTIC trial programme. The primary outcome for this analysis was 3-month steroid-free clinical remission at 1 year after HSCT (Crohn's Disease Activity Index [CDAI] <150). We also examined the degree of endoscopic healing at 1 year. Multivariate analysis was performed to identify factors associated with achieving the primary endpoint by using logistic regression, and factors associated with experiencing a serious adverse event using Poisson regression. Participants were not masked to treatment, but the adjudication panel that reviewed radiology and endoscopy was masked to allocation and visits. All patients who underwent HSCT and had data available at baseline and 1-year follow-up were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00297193. FINDINGS Between June 28, 2007, and Sept 1, 2011, 45 patients were enrolled in the ASTIC trial from 11 European transplant units. 23 patients were randomly assigned to immediate HSCT, and 22 patients were assigned to mobilisation followed by conventional care. After completion of the ASTIC trial, 17 patients from the conventional care group received HSCT. In the combined cohort, data were available for 40 patients at baseline and 38 patients at 1 year after HSCT (one patient died, one withdrew). At 1 year after HSCT, 3-month steroid-free clinical remission was seen in 13 (38%, 95% CI 22-55) of 34 patients with available data for the whole year. Complete endoscopic healting was noted in 19 (50%, 34-66) of 38 patients. On multivariate analyses, factors associated with the primary outcome were short disease duration (odds ratio [OR] 0·64, 95% CI 0·41-0·997 per year; p=0·048) and low baseline CDAI (0·82, 0·74-0·98 per 10 units; p=0·031). 76 serious adverse events occurred in 23 of 40 patients with available data. The most common serious adverse event was infection, most of which were treatment related. Smoking and perianal disease at baseline were independent factors associated with the number of serious adverse events (OR 3·07 [95% CI 1·75-5·38; p=0·0001] for smoking and 3·97 [2·17-7·25; p<0·0001] for perianal disease) on multivariate...

New and Old Therapeutic Options for Luminal Crohn's Disease - An Overview of Current Literature

“…The primary outcomes in ASTIC have been criticized for being too stringent. A further 1 year follow up study, including pooled data from ASTIC, showed clinical benefit in 40 transplant patients [106]. Evidence of efficacy with complete endoscopic healing in 50% of patients, and 47% were assessed as free of disease on endoscopy and radiology imaging at 1 year.…”

“…Of the 23 patients with available data 76 serious adverse events occurred, most commonly treatment related infection. Smoking and per-anal disease were associated with increased serious adverse events [106].…”

Autologe hämatopoetische Stammzelltransplantation bei Autoimmunerkrankungen

“…Dennoch gibt es weiterhin therapierefraktäre Krankheitsverläufe mit hoher Einschränkung der Lebensqualität. Eine randomisierte und kontrollierte Studie zur HSCT liegt vor, konnte aber auf den ersten Blick keine Überlegenheit der HSCT gegenüber der Standardtherapie zeigen [16]. Bei genauerer Betrachtung und insbesondere unter Hinzunahme der Patienten, welche als Rescue-Therapie dann doch noch einer HSCT zugeführt wurden, konnte bei 50 % der Therapierten eine endoskopisch und bioptisch gesicherte komplette Abheilung der Mukosa beobachtet werden [17].…”

Stem cell transplant in inflammatory bowel disease: a promising modality of treatment for a complicated disease course

“…MSCT has been evaluated for the treatment of IBD in two different modalities; intralesional injection to treat fistulas in CD, and intravenous administration to treat luminal CD and UC. Local injection of autologous and allogeneic MSCs have shown positive results in multiple case series and randomized controlled trials compared to placebo in patients with complicated fistulizing disease, not responding to traditional therapies with immunomodulators, anti-TNF alpha agents, and local management, including surgery (23,24). A 12-patient, 6-month, phase 1 trial has shown an 83% rate of complete clinical healing and radiological evidence of response of complicated fistulas in CD patients treated with intrafistulous autologous MSCT (25).…”