Crohn disease: remissions but no cure

In this issue of Blood, Burt and colleagues demonstrate that patients with severe refractory Crohn disease achieved clinically meaningful improvement and substantially reduced their requirements for immunosuppressive therapy after high-dose cyclophosphamide and antithymocyte globulin followed by autologous HCT. Clinical relapse-free survival was 96% at 1 year, 63% at 3 years, and 36% at 5 years.¹ 

Crohn disease (CD) is an immune-mediated, chronic disease of the gastrointestinal tract that causes significant debility from diarrhea, weight loss, strictures, fistulas, abscesses, and short bowel syndrome. Patients with mild-to-moderate symptoms are treated with mesalamine, a topical glucocorticoid or prednisone. For patients whose symptoms cannot be controlled, the best available approaches include surgical resection (particularly for obstruction, abscess, and fistula formation) and combination therapy with infliximab and azathioprine.²  However, 1 year after infliximab/azathioprine therapy, more than 50% of patients with refractory moderate-to-severe disease at baseline were treatment failures, requiring additional glucocorticoid therapy. After the initial reports of the promising results of intensive immunosuppression followed by autologous hematopoietic cell transplantation (HCT) for CD, the hope was that this approach might result in sustained remissions for a substantial proportion of the patients.^3,4  It was recognized, however, that the genetic predisposition for CD was unlikely to be altered by intense immunosuppression followed by autologous HCT so that there was a risk the relapse rate would be high.

Burt et al now report on a larger number of CD patients (n = 24), with 5-year follow-up for 18 of the 24. The high rate of clinical responses seen initially was again observed in the additional patients. However, with the longer follow-up, a high rate of relapse has in fact been observed. Fourteen of 19 patients (73%) with follow-up of at least 4 years were restarted on therapy. There did not appear to be a time after which patients were not at risk of relapse, so it would be expected that patients will continue to relapse beyond the 5-year follow-up. Re-regulation of the immune response to self-antigens may have been induced to account for the prolonged clinical remissions in some patients, but this was insufficient to maintain remission indefinitely. Regarding the stability of the initial clinical responses, the investigators should be commended for the long-term follow-up because this is recognized as a significant challenge: most clinical trials of CD do not provide patient follow-up beyond 1-2 years.

Is intense immunosuppression followed by autologous HCT a potentially useful therapy for severe CD not responding to first-line or second-line therapy if there is a high risk of relapse? The first hurdle to acceptance of this approach was evidence that autologous HCT could be done safely. In the Burt paper, no treatment-related mortality was observed and complications did not appear greater than what would be observed after autologous HCT for hematologic malignancies. Moreover, as noted by the authors, population-based studies of patients with refractory CD show an increased mortality risk across time with standard treatments, a risk that may be higher now than in the past because of more intense immune suppression from biologic agents, resulting in fatal infections.⁵  The second hurdle was demonstrating substantial efficacy. The majority of patients were in remission for 2 or more years and up to one-fourth of the patients had a sustained remission at 5 years. As the cohort reported by Burt et al is similar to the demographics (young adults) and CD severity of patients randomized to receive infliximab and azathioprine,²  one could reasonably argue that intense immunosuppression followed by autologous HCT is superior to the best available medical care at 1 year (96% vs ∼ 50% of patients in glucocorticoid-free remission).

Limitations of the current study were its small sample size and the lack of objective data on mucosal ulceration and healing after HCT. The latter limitation may have resulted in an overestimate of their clinical success rate. It has also been hypothesized that CD might be less aggressive or more responsive to therapy after intense immunosuppression even if a relapse occurs. Based on the study by Burt et al, this new treatment modality would appear to be a potentially valuable new approach for managing those difficult CD cases who have failed previous treatments even if there is a high relapse rate. For patients with severe disease and a miserable quality of life, the benefits could outweigh the risks and cost of the procedure, considering the alternatives.⁶  The relative merits of intense immunosuppression followed by autologous HCT for refractory CD will be determined by a randomized clinical trial of immediate autologous HCT versus best-available medical therapy, followed by HCT delayed by 1 year (a trial that is currently accruing patients in Europe).⁷ 

If there is a high CD relapse rate after autologous HCT, are there preventive measures that would prevent relapses? The CD literature does not offer much hope in this regard, as clinical trials have not identified agents that are safe and that alter the natural history of CD.^8,9  A more intensive immunosuppressive conditioning regimen might reduce the relapse risk but would likely increase the risk of the procedure. This important article, however, supports the notion that adaptive immunity is key to CD pathogenesis. Replacing the adaptive immune system with autologous cells has resulted in CD recurrence if given enough time as now reported. Similar but durable results could theoretically be achieved if the transplanted immune cells were genetically devoid of CD-risk polymorphisms. This experiment has been done, and prolonged remissions of CD have been observed in CD patients after allogeneic HCT for a concomitant hematologic malignancy.¹⁰  The risk of transplantation-related mortality after myeloablative allogeneic HCT has decreased by 50% over the past decade,¹¹  such that allogeneic HCT might now be considered as an experimental approach for refractory CD. Allografts, however, carry risks of morbidity caused by acute and chronic graft-versus-host disease that do not exist after autologous HCT. The study by Burt et al provides the basis for future strategies using HCT to achieve a cure for CD.