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T-Cell Non-Hodgkin’s Lymphomas Reported to the FDA AERS With Tumor Necrosis Factor-Alpha (TNF-α) Inhibitors: Results of the REFURBISH Study
Parakkal Deepak, MD1, Humberto Sifuentes, MD2, Muhammed Sherid, MD3, Derrick Stobaugh, BA, BS4, Yama Sadozai, BS1 and Eli Daniel Ehrenpreis, MD, AGAF4,5 OBJECTIVES:

The risk of non-Hodgkin’slymphoma (NHL) with tumor necrosis factor alpha (TNF-α) 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-α inhibitors for all approved indications and examine the risk of T-cell NHL with TNF-α inhibitors incomparison with the use of thiopurines in inflammatory bowel disease (IBD). The FDA Adverse Event Reporting System (AERS) was queried for all lymphomas following treatment with the following TNF-α 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 inpatients 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-α inhibitors or thiopurines, not reported to the FDA but available in published literature. The histological subtypes of T-cell NHL reported with TNF-α inhibitors were compared with reported subtypes in SurveillanceEpidemiology and End Results (SEER) -17 registry. Reported risk of T-cell NHL in IBD with TNF-α inhibitors, thiopurines, or concomitant use was calculated using Fisher’s exact test using 5-aminosalicylates as control drugs. A total of 3,130,267 reports were downloaded from the FDA AERS (2003–2010). Ninety-one cases of T-cell NHL with TNF-α inhibitors were identified in the FDA AERS and nineadditional 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-α inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-celllymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-α-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-α inhibitor use in combination withthiopurines (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-α inhibitor use alone (95% CI 0.13–10.61; P = 1.00). TNF-α inhibitors alone.

METHODS:

RESULTS:

CONCLUSIONS: Risk of T-cell NHL is increased with TNF-α inhibitor use in combination with thiopurines but not with
Am J Gastroenterol 2013; 108:99–105;doi:10.1038/ajg.2012.334; published online 2 October 2012

1 Department of Gastroenterology, NorthShore University Health System, Evanston, Illinois, USA; 2Department of Gastroenterology and Hepatology, Georgia Health Sciences University, Augusta, Georgia, USA; 3Aspirus Wausau Hospital Hospitalists, Wausau, Wisconsin, USA; 4Center for the Study of Complex Diseases, Research Institute, NorthShore UniversityHealthSystem, Evanston, Illinois, USA; 5Highland Park Hospital, NorthShore University Health System, Highland Park, Illinois, USA. Correspondence: Eli Daniel Ehrenpreis, MD, AGAF, Highland Park Hospital, NorthShore University Health System, 777 Park Avenue West, Highland Park, Illinois 60035, USA. E-mail: ehrenpreis@gipharm.net Previous presentation of data: Findings presented in part at the...