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Hepatosplenic T Cell Lymphoma Associated With Infliximab Use in Young Patients Treated for Inflammatory Bowel Disease

Mackey, Ann Corken; Green, Lanh; Liang, Li-ching; Dinndorf, Patricia; Avigan, Mark

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Journal of Pediatric Gastroenterology and Nutrition: February 2007 - Volume 44 - Issue 2 - p 265-267
doi: 10.1097/MPG.0b013e31802f6424
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Abstract

The US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) is a spontaneous, voluntary surveillance system that collects reports of adverse events for US marketed medicinal products. Manufacturers holding New Drug Applications or Biologic Licensing Applications must submit adverse events to AERS according to the Code of Federal Regulations. Infliximab is a tumor necrosis factor-α (TNF-α) blocking agent that works by lessening the T cell–mediated effects of an overactive immune system. In 1998 FDA approved infliximab for the treatment of moderately to severely active Crohn disease (CD) in adult patients who have inadequately responded to conventional therapy; it was later approved for the treatment of ulcerative colitis (UC). Up until October 5, 2006, the AERS database has received 8 cases of hepatosplenic T cell lymphoma (HSTCL) associated with infliximab use in young patients receiving treatment for CD (n = 7) and UC (n = 1), including 1 published case (Table 1) (1). Seven cases were reported in the US and 1 case was reported from outside the United States.

T1-19
TABLE 1:
Select demographic data of AERS cases of α/β and γ/δ T cell lymphoma associated with infliximab use from marketing in 1998 to October 6, 2006 (n = 8)

Of the 8 cases of HSTCL, 7 specifically reported hepatosplenomegaly. For 1 case, only a tumor subtype was reported. All 8 patients received concomitant medications known to suppress elements of the immune system (see Table 1). At least 7 patients started infliximab therapy at some point after their other therapies, with overlap of concomitant medications and infliximab (time frame not specified for 1 patient). None of the 8 patients were reported to have additional types of autoimmune diseases. There were 15 cases reported as “T cell lymphoma” in patients using infliximab (all indications, all ages); however, it cannot be determined whether these represented additional cases of HSTCL (subtyping may not have been done or may not have been reported). There were no cases reporting HSTCL associated with other marketed TNF-α blocking agents (eg, etanercept, adalimumab) used for any indication. No cases of HSTCL have been identified in clinical trials. (See below for limitations of data extracted from the AERS database.)

Conventional therapy to treat CD and UC can include the use of azathioprine, mercaptopurine, mesalamine, corticosteroids, and/or methotrexate. A search in AERS and the scientific literature was expanded to identify cases of HSTCL possibly associated with these drugs. The AERS search identified only 1 fatal case of the γ/δ subtype of HSTCL associated with azathioprine use alone (case also published in the literature) (2) and another fatal case of the same associated with mercaptopurine use alone. Both patients were males in their 30s with active CD. Two additional literature cases involved patients who developed HSTCL and died after using azathioprine to treat CD: an 18-y-old man who developed γ/δ subtype (3) and a patient of unspecified age and gender (tumor subtype not specified) (4). No AERS or literature cases associated with mesalamine or methotrexate therapy when used alone to treat CD were identified.

Hepatosplenic T cell lymphoma are rare cancers and comprise only 5% of peripheral T cell lymphomas (a majority of those express the γ/δ T cell receptor gene arrangement and fewer express the α/β T cell receptor). There have been more than 100 cases of this rare lymphoma reported in the literature. Some of these cases involved patients who had received organ transplants. Patients with underlying inflammatory bowel disease are at higher risk for certain cancers such as colorectal cancer. A retrospective cohort study of 17,000 patients with inflammatory bowel disease concluded that there was no increased disease-related risk of lymphoma. The risk for lymphoma in patients with CD who are receiving conventional immunosuppressant therapy remains controversial (1,5).

To collect information on bowel diseases in children, the manufacturer of infliximab is sponsoring a prospective, long-term (20 y) observational registry (The North American Pediatric Inflammatory Bowel Disease Collaborative Registry) of pediatric patients with a confirmed diagnosis of inflammatory bowel disease who are <17 y of age at the time of enrollment. It is planned that approximately 2000 pediatric CD patients treated with infliximab will be enrolled, along with a control group of 2000 pediatric patients with CD given therapies other than infliximab. Approximately 1000 pediatric patients with UC or indeterminate colitis also will be studied. The Registry intends to collect information on all serious adverse events associated with infliximab use.

Because 8 of the more than 100 known HSTCL cases are associated with infliximab use, it appears that patients using this product may be at greater risk for developing this rare lymphoma. It has not been established that infliximab 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). Data from AERS cannot be used to estimate true incidence rates of events because the numerator is underestimated and the denominator can only be estimated. AERS is subject to underreporting because fewer than 10% of adverse events are reported to FDA (6).

In May 2006 FDA approved infliximab for use in pediatric patients 6 y of age and older who have moderately to severely active CD and have had an inadequate response to conventional therapies; a boxed warning for HSTCL was added to the revised product labeling of August 2006. This new approved indication may lead to increased use of infliximab in children and the potential for more cases of HSTCL. Health care practitioners are encouraged to report these rare cases of HSTCL to FDA.

REFERENCES

1. Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol 2005; 40(2):220–222.
2. Navarro JT, Ribera JM, Mate JL, et al. Hepatosplenic T-gamma delta lymphoma in a patient with Crohn's disease treated with azathioprine. Leuk Lymphoma 2003; 44:531–533.
3. Mittal S, Milner BJ, Johnston PW, et al. A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to Fludarabine and Alemtuzumab. Eur J Haematol 2006; 76:531–534.
4. Lemann M, de La Valussiere G, Bouhnik Y, et al. Intravenous cyclosporine for refractory attacks of Crohn's disease (CD): long-term follow-up of patients [abstract]. Gastroenterology 1998; 114(4):A1020.
5. Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia 2000; 14:991–997.
6. Rogers AS, Israel E, Smith CR. Physician knowledge, attitudes, and behavior related to reporting of adverse drug events. Arch Intern Med 1998; 148:1596–1600.
Keywords:

Tumor necrosis factor-α; Immunosuppressive agents; Hepatosplenic T cell lymphoma; Inflammatory bowel disease

© 2007 Lippincott Williams & Wilkins, Inc.