T-Cell Non-Hodgkin's Lymphomas Reported to the FDA AERS With Tumor Necrosis Factor-Alpha (TNF-α) Inhibitors: Results of the REFURBISH Study

OBJECTIVES: The risk of non-Hodgkin's lymphoma (NHL) with tumor necrosis factor alpha (TNF-alpha) inhibitors is unclear, whether related to concomitant thiopurines usage or due to the underlying inflammatory disease. We sought to review all cases of T-cell NHL reported to the Food and Drug Administration (FDA) in patients receiving TNF-alpha inhibitors for all approved indications and examine the risk of T-cell NHL with TNF-alpha inhibitors in comparison with the use of thiopurines in inflammatory bowel disease (IBD). METHODS: The FDA Adverse Event Reporting System (AERS) was queried for all lymphomas following treatment with the following TNF-alpha inhibitors: infliximab, adalimumab, certolizumab, etanercept, and their trade names. Full reports for T-cell NHL cases were identified using the Freedom of Information Act. In addition, T-cell NHL reported in patients IBD with the use of the thiopurines-azathioprine, 6-mercaptopurine, and their trade names were also collected. A search of MEDLINE was performed for additional T-cell NHL with TNF-alpha inhibitors or thiopurines, not reported to the FDA but available in published literature. The histological subtypes of T-cell NHL reported with TNF-alpha inhibitors were compared with reported subtypes in Surveillance Epidemiology and End Results (SEER) -17 registry. Reported risk of T-cell NHL in IBD with TNF-alpha inhibitors, thiopurines, or concomitant use was calculated using Fisher's exact test using 5-aminosalicylates as control drugs. RESULTS: A total of 3,130,267 reports were downloaded from the FDA AERS (2003-2010). Ninety-one cases of T-cell NHL with TNF-alpha inhibitors were identified in the FDA AERS and nine additional cases were identified on MEDLINE search. A total of 38 patients had rheumatoid arthritis, 36 cases had Crohn's disease, 11 had psoriasis, 9 had ulcerative colitis, and 6 had ankylosing spondylitis. Sixty-eight of the cases (68 %) involved exposure to both a TNF-alpha inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-cell lymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-alpha-inhibitor exposure compared with SEER-17 registry. Nineteen cases of T-cell NHL with thiopurines were identified in the FDA AERS and one additional case on MEDLINE. Reported risk of T-cell NHL was higher with TNF-alpha inhibitor use in combination with thiopurines (95 % confidence interval (CI) 4.98-354.09; P < 0.0001) and thiopurines alone (95 % CI 8.32-945.38; P < 0.0001) but not with TNF-alpha inhibitor use alone (95 % CI 0.13-10.61; P = 1.00). CONCLUSIONS: Risk of T-cell NHL is increased with TNF-alpha inhibitor use in combination with thiopurines but not with TNF-alpha inhibitors alon e. Am J Gastroenterol 2013; 108:99-105; doi:10.1038/ajg.2012.334; published online 2 October 2012