Rare Presentations of T cell and Natural Killer (NK) Cell Lymphomas Associated with Tumor Necrosis Factor Alpha (TNF-α) Inhibition

Abstract

Purpose: Both T cells and NK cells provide surveillance for malignancies. Because TNF-α inhibition leads to impaired NK cell function, cells undergoing malignant transformation may escape detection and proliferate. Cases of T cell lymphomas developing in patients on TNF-α blockers are rarely described. The purpose of this study is to review and describe the clinical features of T cell lymphomas reported to the Food and Drug Administration (FDA) in patients receiving TNF-α blockers. Methods: The FDA 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 infliximab (Remicade, Revellex), adalimumab (Humira, Trudexa), certolizumab (Cimzia), natalizumab (Tysabri) and etanercept (Enbrel). Full reports for all T-cell lymphomas 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- September 2009. Seventy two cases of T cell lymphomas were identified. Twenty four of these were previously reported in literature. Twenty three (32%) were in females. Twenty nine patients were treated for Crohn's disease (40%), 23 had rheumatoid arthritis (32%), 7 had psoriasis (10%), 5 had ulcerative colitis (7%), 4 had other autoimmune disease and the indication was unknown in 4 subjects. Twenty six (36%) of these were hepatosplenic T cell lymphomas (HSTCL), 26 cases (36%) were T cell non-Hodgkin's lymphomas (NHL) and 4 were cutaneous T cell lymphomas. There were 2 cases each of T cell lymphoblastic type lymphoma, intestinal T-cell lymphoma and NK cell lymphoma/leukemia. There was 1 case each of γδ T cell lymphoma/anaplastic large cell lymphoma, hepatosplenic peripheral T cell lymphoma and eight other cases of undefined T cell lymphomas. Average patient age for HSTCl was 35.56(range 12 to 79), for other systemic lymphomas was 53.88 (range 17 to 86) and for cutaneous lymphomas was 52.75 (range 43 to 69), comparable to the age description in literature. The most common TNF-α inhibitors associated with lymphomas were infliximab (30 patients) and etanercept (18 patients). Combined immunomodulator therapy and TNF-α inhibitors were given in 23(89%) of patients with HSTCL and 28(61%) of all others. Mean duration of therapy with anti-TNFα in non-HSTCL was 26.55 months (range 1-81 months). Conclusion: These cases highlight the association between the use of anti-TNFα blockers and T/NK cell lymphomas. Improved epidemiologic analysis should advance our understanding of the relationship of TNF-α inhibition and T cell lymphoma development.