Elsevier

The Lancet

Volume 374, Issue 9701, 7–13 November 2009, Pages 1617-1625
The Lancet

Articles
Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

https://doi.org/10.1016/S0140-6736(09)61302-7Get rights and content

Summary

Background

Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study.

Methods

19 486 patients with inflammatory bowel disease, of whom 11 759 (60·3%) had Crohn's disease and 7727 (39·7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29–40).

Findings

At baseline, 5867 (30·1%) of patients were receiving, 2809 (14·4%) had discontinued, and 10 810 (55·5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0·90 per 1000 (95% CI 0·50–1·49) patient-years in those receiving, 0·20/1000 (0·02–0·72) patient-years in those who had discontinued, and 0·26/1000 (0·10–0·57) patient-years in those who had never received thiopurines (p=0·0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5·28 (2·01–13·9, p=0·0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease.

Interpretation

Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders.

Funding

Programme Hospitalier de Recherche Clinique National (AOM05157), 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.

Introduction

Crohn's disease and ulcerative colitis (collectively referred to as inflammatory bowel disease) are chronic inflammatory gastrointestinal disorders of unknown origin. The thiopurine azathioprine and its metabolite, 6-mercaptopurine, are used for their immunosuppressive properties to maintain remission in these disorders.1, 2 They are recommended in various forms of chronic clinically active inflammatory bowel disease, including steroid-dependent forms.3 Organ transplant recipients receiving these drugs as part of their immunosuppressive therapy are at an increased risk of developing lymphoproliferative disorders,4 with a frequent pathogenic association with Epstein-Barr virus.5 No excess risk of lymphoproliferative disorder has been shown in large population-based studies of patients with inflammatory bowel disease,6, 7 but conflicting data have been reported for patients given thiopurines.8, 9, 10 In view of the increasing use of these drugs as maintenance treatment of inflammatory bowel disease, and the availability of alternative maintenance treatments,11, 12, 13 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.

Section snippets

Study design

In this prospective cohort study, the incidence rates of lymphoproliferative disorder were compared in patients treated and not treated with thiopurines during a 3-year follow-up. We also compared reported cases of lymphoproliferative disorder in the cohort with the number of cases expected in the general population with the same age and sex distributions.

Patients with inflammatory bowel disease were recruited to the study from May, 2004, to June, 2005. Follow-up ended on Dec 31, 2007. From

Statistical analysis

We estimated that a minimum of 50 000 person-years of follow-up would be needed for the study to have statistical power of 80% to detect an lymphoproliferative disorder hazard ratio (HR) of at least 3·5 in patients given thiopurines relative to patients not given these drugs, assuming an absolute incidence rate of 20 cases per 100 000 person-years in untreated patients and that 40% of patients with inflammatory bowel disease would be exposed to thiopurines.

Patients were excluded from all

Results

20 775 patients were enrolled in the study. Of these, 19 486 patients (94%) were included in all analyses because they were enrolled by investigators who continued to participate in the study. Follow-up was complete (ie, included a final visit) for 16 459 of these patients (85%), part complete (interim visits but no final visit) for 588 (3%), and non-existent for 2439 (13%). At study entry, 5867 (30%) patients were receiving thiopurines, 2809 (14%) had discontinued thiopurines, and 10 810 (56%)

Discussion

We have shown that risk of lymphoproliferative disorder was five times higher in patients exposed to thiopurines than in those never exposed to these drugs. Old age, male sex, and longer duration of inflammatory bowel disease were also associated with increased risk of incident lymphoproliferative disorder.

Our hypothesis of a constant risk of lymphoproliferative disorder during thiopurine therapy is supported by three considerations. First, in the post-transplant setting the risk of lymphoma is

References (33)

  • JD Lewis et al.

    Azathioprine for maintenance of remission in Crohn's disease: benefits outweigh the risk of lymphoma

    Gastroenterology

    (2000)
  • DC Pearson et al.

    Azathioprine for maintaining remission of Crohn's disease

    Cochrane Database Syst Rev

    (2000)
  • A Timmer et al.

    Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis

    Cochrane Database Syst Rev

    (2007)
  • LJ Kinlen et al.

    Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs

    Br Med J

    (1979)
  • SH Swerdlow et al.

    Post-transplant lymphoproliferative disorders

  • J Askling et al.

    Risk of haematopoietic cancer in patients with inflammatory bowel disease

    Gut

    (2005)
  • Cited by (925)

    • Safety Summary of Pediatric Inflammatory Bowel Disease Therapies

      2023, Gastroenterology Clinics of North America
    View all citing articles on Scopus
    View full text