Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease

Hawkey, C. J.; Allez, Matthieu; Clark, Miranda; Labopin, Myriam; Lindsay, James O.; Ricart, Elena; Rogler, Gerhard; Rovira, Montserrat; Satsangi, Jack; Danese, Silvio; Russell, Nigel H.; Gribben, John G.; Johnson, Peter; Larghero, Jérôme; Thiéblemont, Catherine; Ardizzone, Sandro; Dierickx, Daan; Ibatici, Adalberto; Littlewood, Timothy; Onida, Francesco; Schanz, Urs; Vermeire, Séverine; Colombel, Jean Fréd́eric; Jouet, J P; Clark, Elizabeth; Saccardi, Riccardo; Tyndall, Alan; Travis, Simon; Farge, Dominique

doi:10.1001/jama.2015.16700

Cited by 155 publications

(160 citation statements)

References 35 publications

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“…14 Few patients in either group met the stringent primary endpoint of clinical remission off all medication for 3 months with no evidence of active ulceration on endoscopic or radiological assessment of the intestine. Patients randomised to conventional therapy after mobilisation were offered HSCT after primary outcome assessment and end of follow-up.…”

Section: Methodsmentioning

confidence: 98%

“…14 Briefly, participants were aged 18 to 50 years with continuing treatment refractory CD not amenable to surgery and impaired quality of life (Inflammatory Bowel Disease Questionnaire (IBDQ), 17 or European Quality of Life Visual analogue scale (EQ-VAS)) 18 …”

Section: Participantsmentioning

confidence: 99%

“…Eligible patients underwent stem cell mobilisation using cyclophosphamide 2gm/m 2 x two days and non-glycosylated Granulocyte Colony Stimulating Factor (G-CSF, filgrastim) 10 μg/kg/day. 14 Patients underwent leukapheresis when the CD34+ count exceeded 20x10 4 /ml to a target of 3-8 x10 6 CD34+ cells/kg body weight and if successful underwent HSCT immediately or after a delay of one year. An intermediate intensity conditioning regimen was used which comprised intravenous cyclophosphamide 50 mg/kg/day x four days and, from day three, rabbit antithymocyte globulin (Genzyme) 2.5 mg/kg/day and methylprednisolone 1 mg/kg/day x three days, with infusion of unselected autologous stem cells (minimum 3x10 6 CD34+ cells/kg) on day seven.…”

Section: Mobilisation and Conditioning Regimenmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 98%

Section: Participantsmentioning

confidence: 99%

Section: Mobilisation and Conditioning Regimenmentioning

confidence: 99%

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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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“…The EBMT paper came out in 2015 [113], presenting a parallel-group randomized clinical trial conducted in 11 European transplant units (Autologous Stem Cell Transplantation International Crohn Disease-ASTIC-trial); the medial follow-up was 1 year. Comparison of immunoablation, with use of the similar CyATG protocol and HCT (n = 23) and control treatment (n = 22), demonstrated no statistically significant in-between group differences in proportions of patients achieving sustained disease remission, with CDAI less than 150 in the last 3 months, or free of active disease.…”

Section: Hct For Crohn's Diseasementioning

confidence: 99%

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

Resnick¹,

Metodiev²,

Lazarova³

2017

Immunotherapy - Myths, Reality, Ideas, Future

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Autoimmune diseases are characterized by recurrent attacks and remissions, but as a rule they progress and eventually cause a severe disability and death. The present chapter contains general characteristics of autoimmune disease pathogenesis, ways to cause immune tolerance by hematopoietic cell transplantation (HCT), clinical aspects of the treatment for established autoimmune diseases with a special attention to multiple sclerosis (MS) and systemic sclerosis (SSc). A profound analysis of authors' point of view and of the available literature has been performed. The promising results allows to consider HCT as a relevant treatment option for a certain autoimmune diseases.

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“…87 A multicenter randomized phase III interventional study, carried out by the European Group for Blood and Marrow Transplantation (EBMT) aimed to test the potential clinical benefits of high-dose immunoablation of early versus delayed (59 weeks) auto-HSCT. 88 All 45 patients of both were mobilized prior to randomization. The early group received immediate HSCT 4 week post-leukapheresis, while the control delay group waited a year for transplantation, but continued conventional therapy.…”

Section: Hematopoietic Stem-cell (Hsc) Therapymentioning

confidence: 99%

Inflammatory Bowel Diseases: Current Therapeutic Approaches and Potential of Using Stem Cells

Srivastava¹

2017

JSRT

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Inflammatory bowel diseases (IBDs) are chronic and progressively deteriorating in nature without many promising curative treatments. Chronic inflammation of not well defined origins is considered to be the root cause of the problem which affects intestinal mucosa with or without transmural involvement. IBDs are divided in two main categories: Crohn's disease (CD) and ulcerative colitis (UC). While there is no long lasting cure for IBDs, current therapies can only reduce the causative inflammatory process with the hope to induce long-term remission. Treatment modalities for the IBDs are still evolving. The increased understanding of the underlying immunopathology has helped identify new targeted treatment options like immunosuppressive antibodies directed against signaling molecules. Use of stem cells, which are capable of modulating the immune system, can offer a long lasting relief to the patients suffering from the disease. The goal for stem cell-based therapy is to achieve long lasting cure, if not a permanent one. To achieve this, it would be desirable to obtain cell types, whether genetically modified or naturally occurring, having a high migratory ability in addition to homing ability into the afflicted parts of intestine. These cells should also have high in vivo survival potential, and then be able to regulate the immune reaction without provoking any response from the host's immune system and repair the injured tissue. Hematopoietic stem cells (HSC) and mesenchymal stromal cells (MSC) therapies are being investigated as a treatment for IBDs. MSC therapy is well tolerated and has minimal established side-effects compared to HSC therapy, which involves ablative chemotherapy. Several clinical studies using MSCs have been initiated and some early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, which can be resolved only by scientifically unveiling the mechanisms of therapeutic action of stem cells. In this review, we summarize current therapies for IBDs and recent advances in the field of stem cell therapy, which offer promise to become the next generation treatment of choice.

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Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease

Abstract: clinicaltrials.gov Identifier: NCT00297193.

Cited by 155 publications

References 35 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

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

Inflammatory Bowel Diseases: Current Therapeutic Approaches and Potential of Using Stem Cells

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