Hepatosplenic T Cell Lymphoma Associated with Infliximab Use in Young Patients Treated for Inflammatory Bowel Disease: Update

Abstract

In February 2007, the Food and Drug Administration (FDA) reported eight cases of hepatosplenic T cell lymphoma (HSTCL) associated with infliximab use in young patients treated for inflammatory bowel disease (IBD) that were received by our Adverse Event Reporting System (AERS) database (1). Although our initial report described cases of HSTCL associated with infliximab use, cases have since been reported with another member of the TNF blocker class as well. This publication serves as an update of cumulative HSTCL cases associated with immunosuppressant use since our previous publication (1). As a class, the FDA-approved TNF blockers currently include the biological agents infliximab, adalimumab, etanercept, and certolizumab. These agents block the biological effects of TNF-α including induction of proinflammatory cytokines as well as leukocyte chemotaxis and activation. From time of marketing in 1998 through June 30, 2008, FDA's AERS database has received a total of 15 cases of HSTCL in patients with IBD treated with TNF blocker therapy: 13 cases were associated with infliximab use and 2 cases were associated with infliximab use followed by adalimumab use; all patients were receiving concomitant immunosuppressants (Table 1). These numbers are cumulative and include the cases reported in our previous publication (the first eight cases in Table 1 [note that cases 4 and 11 also were reported in the literature]) (2,3).TABLE 1: Select clinical and demographic data of AERS cases of alpha/beta and gamma/delta T cell lymphoma associated with infliximab use or infliximab/adalimumab use from marketing in 1998 to June 30, 2008† (n = 15)In addition to patients with IBD, AERS has received 1 case of fatal γδ HSTCL in a 61-year-old female who received adalimumab for 1 year, concomitantly with steroids only, to treat rheumatoid arthritis; she had received approximately 1 year of methotrexate therapy 3 years before the diagnosis of HSTCL. There have been no other cases of HSTCL associated with adalimumab use to treat any indication reported to AERS or published in the scientific literature. There have been no cases of HSTCL associated with infiximab use to treat any condition other than IBD reported to AERS or the scientific literature. As for other TNF-blocking agents (ie, etanercept or certolizumab), no cases of HSTCL for any indication have been reported to AERS or the scientific literature (note that etanercept is not indicated for treatment of IBD and certolizumab was approved by the FDA in April 2008). Smaller numbers of HSTCL cases have been reported in association with other immunomodulating agents (without TNF blockers) used to treat IBD: 7 cases are associated with azathioprine use and 3 cases are associated with mercaptopurine use. Seven cases associated with azathioprine use have been published; many of these reports provided little specific clinical and/or demographic data (4–10). Of the 7 cases, all developed HSTCL (5 reported γδ subtype, 2 did not report a subtype) associated with azathioprine use to treat Crohn disease (CD; n = 4), ulcerative colitis (UC; n = 2), or UC/hepatitis (n = 1) for a duration of 4 to 17 years (mean 7.5 years). Two of these patients were receiving steroids concomitantly; no concomitant immunosuppressants were reported for the other 5 patients. Three patients were male, 1 patient was female, and sex was not specified for 3 patients; the mean age was 22 years (n = 5). Five of the 7 cases were fatal. AERS has received 2 fatal cases of γδ HSTCL in male patients (younger than 18 and 33) using mercaptopurine to treat CD for a duration of 3 to 5 years; an additional case in the literature identified a patient of unknown age and sex who developed HSTCL after using mercaptopurine for an unknown duration to treat CD (little information provided) (11). No AERS or literature cases associated with mesalamine or methotrexate therapy when used alone to treat IBD were identified. As discussed in our previous publication, HSTCL is a rarely occurring tumor (2); to date, there have been fewer than 200 cumulative cases of this lymphoma reported in the literature. In turn, the pediatric IBD population is estimated to be 100,000 children (younger than 18 years of age) affected in the United States; the number of patients with severe IBD would be smaller (12). Because 15 of the fewer than 200 known HSTCL cases are associated with infliximab use (and rarely adalimumab use), it appears that young patients using these products may be at greater risk for developing this lymphoma. It has not been established that infliximab or adalamimub had an exclusive or primary role in the pathogenesis of each reported case of HSTCL. These cases could be causally related to a number of factors (eg, underlying disease, exposure to concomitant immunosuppressant medications). Health care practitioners are encouraged to report cases of HSTCL to FDA (http://www.fda.gov/medwatch).