NEW YORK (Reuters Health) – Patients taking azathioprine or 6-mercaptopurine for inflammatory bowel disease (IBD) have more than a five-times higher risk of developing a lymphoproliferative disorder compared to IBD patients not receiving thiopurines, researchers from France reported Monday in The Lancet.

“The frank excess risk” of malignant lymphomas is due to a lack of control of chronic viral infection, particularly with Epstein-Barr virus (EBV) infection, Dr. Laurent Beaugerie from Hôpital Saint-Antoine, Paris, France noted in an email to Reuters Health.

But, Dr. Beaugerie and colleagues note in their report, “the absolute cumulative risk of lymphoproliferative disorder in young patients receiving a 10-year course of thiopurines remains low (< 1%)." “In this setting, thiopurines remain an excellent maintenance treatment for IBD patients with chronic active disease, with very favorable benefit-risk ratio,” Dr. Beaugerie noted. In elderly patients, however, “Considering the very prolonged periods of treatment or initiation of treatment in elderly patients, we need to perform specific benefit-risk studies, matching thiopurines with alternative maintenance treatments (anti-TNF),” the researcher said. The findings are based on a prospective observational study of 19,486 patients with IBD, of whom 11,759 (60.3%) had Crohn’s disease and 7,727 (39.7%) had ulcerative colitis or unclassified IBD. At baseline, 30.1% of patients were receiving thiopurines, 14.4% had discontinued thiopurines, and 55.5% had never received them. Over a median of 35 months, 22 new cases of non-Hodgkin’s lymphoproliferative disorder and 1 new case of Hodgkin’s lymphoma were diagnosed. Of the 23 patients with new-onset lymphoproliferative disease, 15 were taking thiopurines when their symptoms began, 2 had stopped taking them, and 6 had never received them. Twelve of the 15 who were currently receiving thiopurines had B-cell disorders similar to post-transplant lymphoproliferative disorder. This finding, and the fact that most cases were associated with EBV virus, suggests “a major role of immunosuppression in both settings,” the authors note. Incidence rates of lymphoproliferative disorder per 1000 patient-years were 0.90 in those receiving thiopurines, 0.20 in those who had discontinued thiopurine therapy, and 0.26 in never-users (p = 0.0054). The adjusted hazard ratio for lymphoproliferative disease in thiopurine users compared to never users was 5.28. The authors of a commentary say, “This study is highly relevant: in our experience 30-50% of patients with IBD are treated with (thiopurines) at some point in the course of their disease.” “Although we recognize the slightly increased risk of lymphoma, these agents will probably remain one of the cornerstones of treatment,” Drs. Geert D’Haens and Paul Rutgeerts of University Hospital Gasthuisberg, Leuven, Belgium add. Nonetheless, they urge physicians to “be cautious when prolonged combined and deep immunosuppression is needed to achieve disease control.” Reference:
Lancet 2009.