Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease

Oyama, Yu; Craig, Robert M.; Traynor, Ann E.; Quigley, Kathleen; Statkute, Laisvyde; Halverson, Amy L.; Brush, Mary; Verda, Larissa; Kowalska, Barbara; Krosnjar, Nela; Kletzel, Morris; Whitington, Peter F.; Burt, Richard K.

doi:10.1053/j.gastro.2004.11.051

Cited by 256 publications

(157 citation statements)

References 30 publications

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“…11,30 Therefore, these evidences suggest that SCT could be justified in some patients with IBD, which have already begun to be transplanted in some current trials, 42,43 thus raising the question of whether the cell transplantation or the intense immunosuppression was the critical event for patient recovery. In our study, both therapeutic approaches induced remission of the disease and, although we did not elucidate the exact mechanisms of action of the graft in the treatment of the IBD, we showed that in this model, the infusion of the graft was extremely important to reduce mortality.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease

Godoi

Cardoso

Ferraz

et al. 2010

Bone Marrow Transplant

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Hematopoietic SCT (HSCT) and high-dose chemotherapy are being explored as therapy for various human refractory immune-mediated conditions, including inflammatory bowel diseases (IBD). Nevertheless, the exact immunological mechanisms by which the BM cells (BMCs) or immunosuppression provide remission from these diseases is not yet clear. In this work, we investigated the role of these therapies in the modulation of gut mucosal inflammation in an experimental model of IBD. Colitis was induced in mice by 2,4,6-trinitrobenzenesulfonic acid and after CY was administered (200 mg/kg) alone (CY group) or followed by BMCs infusion (HSCT group). Animals were followed for 60 days. Both HSCT and CY reduced the histopathological features of colitis significantly. Infused cells were localized in the gut, and a marked decrease of CD4 þ leukocytes in the inflammatory infiltrate on days þ 7 and þ 14 and of CD8 þ cells on day þ 7 was found in both treatments allied to impressive reduction of proinflammatory Th1 and Th17 cytokines. Although chemotherapy alone was the best treatment regarding the induction of immunosuppressive molecules, only HSCT resulted in increased survival rates compared with the control group. Our findings indicate that highdose CY followed by HSCT is effective in the modulation of mucosal immunity and in accelerating immune reconstitution after BMT, thus providing valuable tools to support the development and understanding of novel therapeutic strategies for IBD.

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Section: Discussionmentioning

confidence: 99%

Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease

Godoi

Cardoso

Ferraz

et al. 2010

Bone Marrow Transplant

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“…The therapeutic efficacy of autologous HSCT has been previously suggested in studies consisting of small numbers of patients and is now being evaluated in controlled trials in which the study sizes were more substantial and follow-up periods were longer [20][21][22][23][24][25][26][27][28][29][30][31]. The first phase I study [22] included 12 patients with active CD, which were refractory to conventional therapies including anti-TNFa treatment.…”

Section: Hsct and Ibdmentioning

confidence: 99%

“…The first phase I study [22] included 12 patients with active CD, which were refractory to conventional therapies including anti-TNFa treatment. There was an early and sustained clinical remission in 11 of the patients (91.7 %) after a median follow-up of 18.5 months.…”

Section: Hsct and Ibdmentioning

confidence: 99%

Stem cell therapy for inflammatory bowel disease

2015

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Inflammatory bowel disease (IBD) could be curable by ''immune rest'' and correction of the genetic predisposition inherent in allogeneic hematopoietic stem cell transplantation. However, balancing risks against benefits remains challenging. The application of mesenchymal stem cells (MSCs) serving as a site-regulated ''drugstore'' is a recent concept, which suggests the possibility of an alternative treatment for many intractable diseases such as IBD. Depending on the required function of MSC, such as a cell provider, immune moderator, and/or trophic resource, MSC therapy should be optimized to maximize its therapeutic benefit. Therapeutic effects do not always require full engraftment of MSCs. Therefore, optimization of pleiotropic gut trophic factors produced by MSCs, which favoring not only regulating immune responses but also promoting tissue repair, must directly enhance new drug discoveries for treatment of IBD. Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and patients. However, the translational arm of stem cell science remains in a relatively primitive state.Although several clinical studies using MSCs have been initiated, early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, and can be resolved only by scientifically unveiling the mechanisms of therapeutic action. In the present review, the authors outline how such information would facilitate the critical steps in the paradigm shift from basic research on stem cell biology to clinical practice of regenerative medicine for conquering IBD in the near future.

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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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Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease

Cited by 256 publications

References 30 publications

Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease

Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease

Stem cell therapy for inflammatory bowel disease

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

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