Hepatosplenic T-cell Lymphoma (HSTCL) in Patients Receiving Tumor Necrosis Factor Alpha (TNF-α) Inhibitors: A Review of Cases Reported to the Food and Drug Administration (FDA)

Abstract

Purpose: Hepatosplenic T cell lymphoma (HSTCL) is a rare but lethal lymphoma. The Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial has demonstrated the benefit of combining infliximab with an immunomodulator in moderate-to-severe Crohn's disease. Unfortunately, combined immunosuppresion is also a reported risk factor for the development of HSTCL, generally in pediatric male patients with inflammatory bowel disease (IBD). The purpose of the study is to review all cases of HSTCL reported to the FDA in patients receiving TNF-α blockers. Methods: The FDA adverse event reporting system (AERS) database is available for public access. Individual reports were downloaded as ASCII files and analyzed using a database created with the Access program (Microsoft Corp., Redmond, WA). The database was queried for lymphomas reported with the following biological agents: infliximab, (Remicade, Revellex), adalimumab, (Humira, Trudexa), certolizumab, (Cimzia), natalizumab (Tysabri) and etanercept (Enbrel). Full reports for all T-cell lymphomas including HSTCL were obtained from the FDA using the Freedom of Information Act. Results: A total of 2,097,223 files were downloaded from the FDA AERS system for the years 2004-2009. Twenty six cases of HSTCL (8 not previously described) were identified. Twenty three (89%) were in patients with IBD (3 in Ulcerative colitis) and three cases occurred in rheumatoid arthritis patients. Five cases (19%) were females. Seven cases (27%) occurred in patients > 50 yrs of age and 4 cases (15%) were seen in patients >65 yrs of age. Twenty three cases (89%) occurred in patients receiving a TNFα blocker and a second immunomodulator, including azathioprine (12 cases), 6-Mercaptopurine (9 cases) and methotrexate (1 case) and azathioprine with past use of methotrexate and leflunomide in 1 case. Twenty patients received infliximab, 3 received infliximab followed by adalimumab, 1 received infliximab followed by adalimumab then natalizumab and 2 received adalimumab. Seventeen cases were gammadelta tumor subtype, 5 were alpha-beta and 3 were unknown. One case showed trisomy 13 on chromosomal analysis, not typical of HSTCL. Twenty one (81%) patients were reported to have expired despite treatment. Conclusion: HSTCL is most common in pediatric males with IBD. However, adults, senior citizens, women and patients with rheumatoid arthritis receiving TNF-α blocking agents and immunomodulators are also at risk. Improved disease outcomes using combination therapy described in the SONIC trial should be tempered by reports of additional patient groups developing HCTCL.