Autologous stem cell transplantation in severe treatment-resistant Crohn's disease: long-term follow-up of UK patients treated on compassionate basis

Snowden, John A.; Ansari, Azhar; Sachchithanantham, Sajitha; Jackson, Graham; Thompson, NP; Lobo, Alan; Sanderson, Jeremy; Kazmi, Majid

doi:10.1093/qjmed/hcu095

Cited by 28 publications

(29 citation statements)

References 21 publications

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“…6 There has been considerable interest in case reports that autologous haematopoietic stem cell transplantation (HSCT) can induce sustained disease remission in such patients. [7][8][9][10][11][12][13] The ASTIC trial compared outcome at one year in 23 patients with refractory CD after autologous HSCT to 22 undergoing stem cell mobilisation alone. 14 This was a negative trial and few patients in either arm achieved the ambitious primary endpoint of clinical remission off therapy for 3 months with no endoscopic or radiological evidence of intestinal inflammation.…”

Section: Introductionmentioning

confidence: 99%

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

Lindsay

Allez

Clark

et al. 2017

The Lancet Gastroenterology & Hepatology

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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...

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Section: Introductionmentioning

confidence: 99%

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

Lindsay

Allez

Clark

et al. 2017

The Lancet Gastroenterology & Hepatology

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“…Through a Phase I/II study of 12 patients, Hasselblach et al also demonstrated that HSCT can induce remission in refractory Crohn disease; however 78% relapsed after a mean of 10 months. Similarly Snowden et al conducted a retrospective evaluation on six patients with severe treatment resistant Crohn disease demonstrating 83% obtaining remission at 3 months and again median time to next treatment being 10 months. In both studies there was a pattern of patients coming off total parenteral nutrition and reducing the need for surgery despite recurrence of disease.…”

Section: Introductionmentioning

confidence: 99%

The role of autologous haemopoietic stem cell transplantation in the treatment of autoimmune disorders

Rebeiro

Moore

2016

Internal Medicine Journal

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Autologous haemopoietic stem cell transplantation (HSCT) has been used for over 30 years for malignant haematological diseases, such as myeloma and lymphoma, with considerable success. More recently this procedure has been adopted as a form of high dose immunosuppression in selected patients with autoimmune diseases that are resistant to conventional therapies. Animal models have previously outlined the rationale and validity of HSCT in patients with these non-malignant, but in many cases, life-threatening conditions. Recent data have that deletion of putative autoreactive immune clones with reconstitution of a thymic driven, tolerant immune system occurs in HSCT for auto-immune patients. Two randomised control trials have confirmed that HSCT is superior to monthly cyclophosphamide in systemic sclerosis with a highly significant disease free and overall survival benefit demonstrated in the Autologous Stem cell Transplantation International Scleroderma trial. Over 2000 patients worldwide with autoimmune conditions have been treated with HSCT - the commonest indications being multiple sclerosis (MS) and systemic sclerosis. Encouraging relapse free survival of 70-80% at 4 years, in heavily pre-treated MS patients, has been demonstrated in Phase II trials. A Phase III trial in MS patients who have failed interferon is currently accruing patients. Future challenges include improvements in safety of HSCT, particularly in cardiac assessment of systemic sclerosis patients, cost-benefit analyses of HSCT compared to standard therapy and establishment of centres of excellence to continue to enhance the safety and benefit of this exciting new therapy.

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“…To date, a total of 138 cases have been described (Table ) who were rescued from an invalidating condition by this therapeutic strategy despite the withdrawal of drugs in most of them . However, the lack of objective data on mucosal healing in several cases may have resulted in an overestimation of the success rate.…”

Section: Cellular Therapies In Inflammatory Bowel Diseasementioning

confidence: 99%

“…Altogether, these studies highlight that the benefit for refractory patients treated with autologous HSC transplantation is only slightly superior to the best available medical care at 1 year, thus their exposure to increased toxicity and mortality risk seems unacceptable . Finally, the rate of clinical relapse‐free survival, defined as the percentage of patients who do not need to restart medical therapy, decreases progressively over time . In this regard, a still unsolved matter regards whether the reappearance of symptoms should be considered a relapse due to residual pathogenic T cells or a new‐onset of the same disease due to the strong influence of environmental factors in converting genotypic predisposition into frank disease.…”

Section: Cellular Therapies In Inflammatory Bowel Diseasementioning

confidence: 99%

Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases

2016

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Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. STEM CELLS 2016;34:1474-1486 SIGNIFICANCE STATEMENTThe advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward in the treatment and, possibly, the cure of chronic inflammatory conditions, including immune-mediated enteropathies. By virtue of the ability to favor tissue regeneration and expansion of T cells with regulatory function, mesenchymal stem cells seem the best candidate. Moreover, the lack of immunogenicity makes them perfectly suitable in these nonlifethreatening conditions as their infusion may be performed across histocompatibility locus antigen barriers without the immunoablative regimen. However, further investigations are needed to discover the underlying mechanisms of action of these novel therapeutic strategies.

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Autologous stem cell transplantation in severe treatment-resistant Crohn's disease: long-term follow-up of UK patients treated on compassionate basis

Cited by 28 publications

References 21 publications

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

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

The role of autologous haemopoietic stem cell transplantation in the treatment of autoimmune disorders

Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases

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