Hepatosplenic T-Cell Lymphoma after Sequential Infliximab, Adalimumab and Natalizumab Therapy for Crohnʼs Disease

Abstract

Purpose: Introduction: Hepatosplenic T cell lymphoma (HSTCL) is characterized by cytotoxic T-cells that infiltrate sinuses of the liver, spleen, and bone marrow. Associated with organ transplant and immune-modifying therapy, about 200 cases of HSTCL have been reported. In 2002, several cases of non-Hodgkin's lymphoma in patients receiving anti-TNFα therapy sparked concern that biologic agents may carry a risk of cancer. We report the first case of a patient with CD diagnosed with HSTCL after receiving natalizumab therapy. Case: This is a 52-year-old man with a 35-year history of CD. Initially treated with sulfasalazine, he developed obstructive symptoms in 1983 requiring ileal and colon resections. In 1989, azathioprine and steroid therapy was started. In 1990, mesalamine therapy replaced azathioprine. He remained off steroids until 1999 when his diarrhea returned and he received three infusions of infliximab followed by budesonide. In 2000, he was diagnosed with polycythemia vera. In 2005, he flared and failed a repeat trial of infliximab, but was successfully switched to adalimumab. In 2008 his diarrhea and rectal discomfort recurred and he was changed to natalizumab monotherapy. At that time, he was noted to have splenomegaly and pancytopenia. A bone marrow biopsy again revealed polycythemia vera. There was a mild response of his Crohn's systems to the second natalizumab infusion, but as he was not sufficiently improved, steroids were restarted, and the natalizumab was discontinued. In 2009, while hospitalized for fever, abdominal pain and diarrhea, an abdominal MRI revealed splenic infarcts. A splenectomy was performed and pathology revealed HSTCL. Discussion: The first case of HSTCL associated with 5-aminosalycilates, steroid and azathioprine therapy was described in 2003. Subsequently, several cases of HSTCL have been reported. Despite the elevated risk of lymphoma with immunomodulator and biologic agents, the recent SONIC trial highlights their efficacy in CD. Natalizumab, an anti-alpha 4 integrin antibody, has been linked to ten cases of progressive multifocal leucoencephalopathy. There have to date been no reported cases of HSTCL associated with natalizumab. We report the first case of a patient with CD treated sequentially with infliximab, adalimumab, and natalizumab, as well as long-term steroids and azathioprine, who developed HSTCL. The likely mechanism is decreased immune surveillance and this case raises the possibility of increased oncogenicity in patients receiving multiple immunosuppressive therapies.