Summary

• Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with tumor necrosis factor (TNF)-blocking agents (initiation of therapy ≤18 years of age), including REMICADE. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents.¹ 
• The malignancies occurred after a median of 30 months (range, 1-84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.¹ 
• Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported REMICADE cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF-blockers or TNF-blockers in combination with these other immunosuppressants.¹ 

POSTMARKETING DATA

On May 8, 2008, Janssen Biotech, Inc (formerly Centocor Ortho Biotech, Inc) received notification from the Food and Drug Administration (FDA) of a potential safety signal in pediatric patients receiving TNF blocking agents. The FDA requested a complete list of all pediatric malignancies, excluding HSTCL, in children, adolescents, and young adult patients ≤22 years of age who had a history of exposure to REMICADE at ≤18 years of age.²

• A search of an internal safety database identified 20 malignancies which met the aforementioned criteria.
• All were equally divided between lymphomas/leukemias and solid tumors. Some of the reported tumor types are those not unexpected in a pediatric population and some are those that have been observed in the setting of immunosuppression.
• A few of the malignancies appear to be unusual occurrences in a pediatric population.

Subsequently, in August 2009, the FDA announced the completion of an analysis of postmarketing data concerning the occurrence of lymphoma and other cancers in children and adolescents treated with TNF blocking agents, including REMICADE.^3,4

• There were 48 pediatric malignancies (32 United States [US] cases and 16 non-US cases) identified over an 8-year period (2001-2008), of which, approximately half of the reported cases were lymphomas (including Hodgkin’s and non-Hodgkin’s lymphoma).
• Of the 48 cases, 31 malignancies were reported in children receiving REMICADE.^3-5

Diak et al

Diak et al (2010)⁵ published the results of the FDA analysis of the Adverse Event Reporting System (AERS).

• The case series included all reports received by the FDA through April 29, 2008 of malignancy in children who had initiated TNF blocker therapy (REMICADE, etanercept, adalimumab) by age 18.
• Of the 48 cases of malignancy in children, 31 malignancies were reported in children following REMICADE use, including 9 cases of HSTCL, 5 cases of non-Hodgkin’s lymphoma, 3 cases of Hodgkin’s lymphoma, and 3 cases of leukemia.
  • Five of the 31 cases were reported in children receiving REMICADE for rheumatic conditions, and 2 cases were reported following in utero exposure to REMICADE.
  • The remaining 24 REMICADE cases were reported in patients with inflammatory bowel disease (IBD), including all of the HSTCL cases.
• The causes of death included HSTCL (9 cases), T-cell lymphoma (1 case), and sepsis after achieving remission of B-cell lymphoma (1 case).
• The majority of patients (88%) also received concomitant immunosuppressive medications such as azathioprine and mercaptopurine.
• Individual causality assessments were not confirmed in the 48 cases of pediatric malignancy due to confounding factors of concomitant drug use, long latency period for malignancy, underlying risk of malignancy in patients with autoimmune disorders, and the lack of details in many of the reports.
• However, reporting rates for US cases of malignancy in children were calculated for all malignancies (66/100,000 patient years), lymphomas including HSTCL (44/100,000 patient years), and lymphomas excluding HSTCL (22/100,000 patient years). REMICADE reporting rates were higher when compared to the background rate of malignancy in the general pediatric population for lymphomas excluding HSTCL (2.4/100,000) and all malignancies (16.8/100,000).
• The reported cases of malignancies through April 29, 2008 in pediatric and young adult patients exposed to REMICADE are summarized in Table: Reported Malignancy Cases with REMICADE in Pediatric and Young Adult Patients Through April 29, 2008.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 9 January 2025.

Summarized in this response are relevant data from prescribing information and FDA postmarketing reports.