Thiopurine Treatment of Inflammatory Bowel Disease Linked to Risk for Lymphoproliferative Disorders

Laurie Barclay, MD

October 27, 2009

October 27, 2009 — Thiopurine treatment of inflammatory bowel disease is linked to a risk for lymphoproliferative disorders, according to the results of a prospective observational cohort study reported online in the October 19 issue of The Lancet.

"Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial," write Laurent Beaugerie, MD, from Hôpital Saint-Antoine in Paris, France, and colleagues. "In view of the increasing use of these drugs as maintenance treatment of inflammatory bowel disease, and the availability of alternative maintenance treatments, settlement of this issue by means of prospective studies is important. We therefore initiated a nationwide prospective observational cohort, called CESAME (Cancers Et Surrisque Associé aux Maladies inflammatoires intestinales En France), which was designed mainly to assess the possible excess risk of lymphoproliferative disorder in patients with inflammatory bowel disease receiving thiopurines."

In this French cohort study, 680 gastroenterologists enrolled 19,486 patients with inflammatory bowel disease, including 11,759 (60.3%) with Crohn's disease and 7727 (39.7%) with ulcerative colitis or unclassified inflammatory bowel disease. During follow-up (median, 35 months; interquartile ratio, 29 - 40 months), the enrolling physicians provided details of immunosuppressive treatment, cancer diagnoses, and deaths. The investigators determined the risk for lymphoproliferative disorder in association with use of thiopurine treatment.

At enrollment, 5867 (30.1%) of patients were being treated with thiopurines, 2809 (14.4%) had discontinued thiopurine therapy, and 10,810 (55.5%) had never been treated with thiopurines. During follow-up, there were 23 incident cases of lymphoproliferative disorder, including 1 of Hodgkin's lymphoma and 22 of non-Hodgkin's lymphoproliferative disorder.

In patients being treated with thiopurines, the incidence rate of lymphoproliferative disorder was 0.90 per 1000 patient-years (95% confidence interval [CI], 0.50 - 1.49) vs 0.20 per 1000 patient-years (95% CI, 0.02 - 0.72) in those who had discontinued thiopurine therapy and 0.26 per 1000 patient-years (95% CI, 0.10 - 0.57) in those who had never had exposure to thiopurines (P = .0054). For patients receiving thiopurines vs those who had never been treated with thiopurines, the multivariate-adjusted hazard ratio for lymphoproliferative disorder was 5.28 (95% CI, 2.01 - 13.9; P = .0007).

"Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders," the study authors write. "Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease."

Other factors associated with an increased risk for lymphoproliferative disorders were old age, male sex, and longer duration of inflammatory bowel disease.

Limitations of this study include the possibility that patients with uncontrolled inflammation are overrepresented in the group receiving thiopurines, and lack of data on whether the risk for lymphoproliferative disorder is also increased in patients receiving immunosuppressants other than thiopurines.

"Extrapolating our results, the absolute cumulative risk of lymphoproliferative disorder in young patients receiving a 10-year course of thiopurines remains low (<1%) and does not undermine the positive risk-benefit ratio of these drugs," the study authors conclude. "For elderly patients and unlimited treatment periods, the question should be addressed in dedicated studies."

In an accompanying comment, Geert D'Haens, MD, and Paul Rutgeerts, MD, from University Hospital Gasthuisberg in Leuven, Belgium, describe the risks and benefits of various monotherapies and combination therapies for inflammatory bowel disease.

"Although we recognise the slightly increased risk of lymphoma, these agents will probably remain one of the cornerstones of treatment," Drs. D'Haens and Rutgeerts write. "Nonetheless, physicians should be cautious when prolonged combined and deep immunosuppression is needed to achieve disease control."

Programme Hospitalier de Recherche Clinique National, Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie supported this study.

Some of the study authors have disclosed various financial relationships with UCB Pharma, Sanofi-Aventis, Abbott, Ferring Pharmaceuticals, ActoGeniX NV, AstraZeneca, Berlex, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix SL, Chemocentryx, Centocor, Cosmo Technologies, Danone France, Elan Pharmaceuticals, Genentech, Giuliani SPA, Given Imaging, GlaxoSmithKline, Millenium Pharmaceuticals, Neovacs SA, Ocera Therapeutics, Otsuka American Pharmaceuticals, PDL Biopharma, Pfizer, RiboVax Biotech, Schering-Plough Corp, Shire Pharmaceuticals, Synta Pharmaceutical Corp, Teva Pharmaceuticals, Therakos, Wyeth Pharmaceuticals, Falk Pharma, Intestinal Biotech Development, Ipsen-Beaufour France, Bayer-Schering, Eli Lilly, and/or Servier.

Drs. D'Haens and Rutgeerts have disclosed no relevant financial relationships.

Lancet. Published online October 19, 2009. Abstract

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