T-Cell Lymphomas in the Era of Tumor Necrosis Factor Alpha (TNF-α) Inhibition: A Review of the Food and Drug Administration Adverse Event Reporting System (FDA AERS): Results of the REFURBISH study: ACG Lawlor Resident Award

Abstract

Purpose: Immunomodulators and tumor necrosis factor alpha inhibitors (TNF-α inhibitors) are shown to increase the risk of lymphoma. We sought to clarify risk for T cell lymphomas with these drugs as single agents and in combination by reviewing cases reported to the FDA AERS and performing a Medline search. Methods: Individual reports from the FDA AERS were downloaded as ASCII files and analyzed with an Access database (Microsoft Corp., Redmond, WA). The database was queried for lymphomas reported with infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia), etanercept (Enbrel), azathioprine and 6-mercaptopurine. Complete reports for all cases were obtained from the FDA using the Freedom of Information Act. Prescription sales data was accessed from SDI Health LLC (Plymouth, Pa). A MEDLINE search was performed to check for reports of T-cell lymphoma with these drugs. Results: 3,183,922 files were downloaded from the AERS system for the years 2000-2010. 120 cases of T-cell lymphoma were identified. 31 of these were previously reported in literature. 7 additional cases were found on MEDLINE. 48 patients were treated for Crohn's disease (37.8%), 38 had rheumatoid arthritis (29.9%), 14 had ulcerative colitis (11%), 11 had psoriasis (8.7%) and 16 had other or unknown indications. 79 cases (62.2%) were in males. There were 46 cases (36.2%) of hepatosplenic T-cell lymphoma (HSTCL), 28 (22.1%) T-cell non-Hodgkin's lymphomas (NHL) and 19 (15.8%) cutaneous T-cell lymphomas. The median age for HSTCL was 26 years (range 12-79), 58 years for T-cell NHL (range 20-81) and 64.5 years for cutaneous T lymphoma (range 39-83). 65 cases (51.2%) were reported with combination of TNFα inhibitors and immunomodulators, 39 with TNFα inhibitors alone and 23 with immunomodulators alone. The time to lymphoma diagnosis from the first dose of TNFα inhibitors for patients on combination therapy was 2.5 years and 2.35 years for TNFα inhibitors alone (p=0.26). There was no statistical difference in duration of drug exposure for T-cell lymphomas with immunomodulators alone compared to combination therapy (6 years versus 4.2 years, p=0.08). Estimated risk of T-cell lymphomas with infliximab was 1 in 16,912 prescriptions, 1 in 29,904 with certolizumab, 1 in 219,518 with adalimumab and 1 in 334,300 with etanercept. Conclusion: TNFα inhibitors and immunomodulators are associated with the development of T-cell lymphomas. Although rare, awareness of these entities is relevant for prescribing clinicians.