Patients with inflammatory bowel disease who took thiopurines for at least a year had an almost sixfold greater rate of lymphoma than did the general population, researchers reported in the November issue of Clinical Gastroenterology and Hepatology.
But lymphoma risk appeared to return to baseline after patients stopped taking thiopurines, suggesting that immunosuppression – not DNA damage – was the root cause of cancer in these patients, said Dr. David Kotlyar at the National Cancer Institute and his associates (Clin. Gastroenterol. Hepatol. [doi:10.1016/j.cgh.2014.05.015]). The researchers carried out a meta-analysis of 18 cohort studies of IBD that they identified by querying MEDLINE, Embase, the Cochrane databases, and other sources. In all, the studies identified 91 patients with lymphoma that occurred after a median of 18 months of exposure to azathioprine or 6-mercaptopurine (range, 1-109 months), the investigators reported.
In a subanalysis of eight population studies, patients who were currently taking thiopurines had a 5.7-fold greater incidence of lymphoma compared with the general population (95% confidence interval, 3.22-10.1), the researchers said. In contrast, patients who had never used thiopurines or who no longer used the drugs did not have an increased lymphoma risk, they said. In addition, standardized incidence ratios (SIRs) in referral center studies were as high as 9.16 (95% CI, 5.03-17.6), the investigators reported. The IBD seen in referral centers tends to be more severe than that in the population overall, which could explain the discrepancy in SIRs between referral and population studies, they said.
The study also found that men who took thiopurines had a more than threefold greater incidence of lymphoma, compared with the general population (SIR, 3.60; 95% CI, 2.68-4.83), while women had an almost twofold increase in estimated risk (SIR, 1.76; 95% CI, 1.08-2.87). Results of age stratifications varied depending on how the researchers defined age groups, but the absolute risk of lymphoma in men under 30 years of age was substantially higher than expected, they said. However, only two studies included raw data on age, and findings should be interpreted with caution, they added.
“It is important to emphasize that although the relative risks of lymphoma in active users are moderate, there remains a very low absolute risk of lymphoma for any given patient,” said Dr. Kotlyar and his associates. “For patients of all ages and genders, the risk of lymphoma needs to be weighed against the potential benefits of therapy. Further work is needed to understand how this trade-off of potential benefit and harm varies by age, particularly in the era of combination immunosuppression therapy.”
Dr. Kotlyar is funded by the National Institutes of Health. Four of the coauthors reported financial relationships with Pfizer, Centocor, Shire Pharmaceuticals Group, AstraZeneca, GlaxoSmithKline, and many others. The remaining authors reported no conflicts of interest.