Autologous Hematopoietic Stem Cell Transplantation in Autoimmune Diseases

Claudio Annaloro; Francesco Onida; Giorgio Lambertenghi Deliliers


Expert Rev Hematol. 2009;2(6):699-715. 

In This Article

Crohn's Disease

Crohn's disease is a chronic inflammatory bowel disease potentially involving any site of the digestive tract and leading to multiple local and extra-intestinal complication. CD is currently classified as an immune-mediated disease, but it cannot be considered a true AD.[111–113] Although its pathogenesis is largely obscure, multiple predisposing factors have been recognized, including genetic predisposition, altered immune response, environmental factors and, possibly, HSC dysfunction resulting in a dysfunctional immune response.[111,113] This last assumption has been somewhat reinforced by the development of CD in a neoplastic patient receiving allogeneic HSCT from a CD-affected sibling donor.[113]

Treatment relies on anti-inflammatory, immunosuppressive and immunomodulating agents. Recent anti-TNF monoclonal antibodies have increased the rate and quality of response in patients with advanced disease. CD commonly exhibits a relapsing–remitting course, but a subset of patients emerge refractory even to the newer drugs, including anti-TNF monoclonal antibodies. Although life expectancy is not expected to be reduced in the general CD population, at least in the first decade, it has been shown that refractory patients build up a group with reduced life expectancy, making autografting a possibly cost-effective strategy.[114] In this regard, it should be also emphasized that QoL in patients with refractory CD might be heavily reduced even in the early phases of the disease.[115]

The history of autologous HSCT in CD is rather recent. Reports of even striking improvement of CD after autografting for concomitant malignant disease[111,116] enabled some group to treat single or small groups of patients with advanced and refractory disease.[30,117] In the same years, single cases of significant clinical improvements following stem cell mobilization with high-dose-CTX (4 g/m2) were reported, raising the question as to whether this procedure of mobilization by itself may be of benefit to patients with CD. Moreover, Crohn's Disease Activity Index (CDAI) offered an instrument to determine disease activity, indication to autologous HSCT and response to therapy.[64]

The first rather large monocentric series was published by Oyama who reported a high rate of response, including complete remission, and durable response in patients receiving positively selected CD34 stem cells after HD-CTX conditioning.[118] The experience acquired some consent among gastroenterologists.[119] In 2007, our group reported the results obtained in an initial series of four CD patients with high CDAI and refractory to various line of therapy, including infliximab. After a CTX/ATG conditioning regimen, the patients received unselected HSC. A long-term endoscopic remission, without maintenance therapy, was achieved in two of these four patients[112] and in two out of three subsequent additional patients [Cassinotti A, Unpublished Data]. These experiences showed that endoscopy and CDAI-proven complete response (CR) is therefore a target that can be achieved in the majority of patients undergoing autologous HSCT for CD; so far, relapse has been relatively uncommon.[113,120]

Altogether, the results from these studies suggest that autotransplant may be effective in patients with refractory CD; yet, it cannot be concluded whether this treatment is better than any best clinical care.

To answer this question and others concerning this treatment strategy, the EBMT Phase III Autologous Stem cell Transplantation International Crohn's disease (ASTIC) trial is currently ongoing, comparing direct versus delayed (1-year post-mobilization) autologous HSCT. The primary objective of this study is to evaluate the potential clinical benefit of HSC mobilization followed by high-dose immunoablation and autologous stem cell transplantation versus HSC mobilization only followed by best clinical practice in patients with CD; the primary end point will be the proportion of patients in sustained disease remission at 1 year.

It can be speculated that autologous HSCT in CD may exert multiple beneficial effects, ranging from the immune 'resetting' to a correction of a possible stem cell disorder, and of some form of intestinal dysmicrobism.[112,113] Our data suggest that encouraging results can be obtained even with unselected HSC, thus further reducing the risks of HSCT.[112] On the other hand, newer anti-TNF agents bear the potential of inducing a response also in infliximab-resistant patients, and can somewhat discourage the referral to autologous HSCT. An open question could be whether such newer drugs should be considered as competitors of HSCT in clinical trials or patients should be referred to HSCT only after failure of even these last approaches.


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