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FDA Drug Safety Communication: Safety Review update on reports of Hepatosplenic T-Cell Lymphoma in adolescents and young adults receiving tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine

For updated information on this issue, please see FDA Drug Safety Communication: UPDATE on Tumor Necrosis Factor (TNF) blockers and risk for pediatric malignancy (11/3/2011)

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary
Table

Safety Announcement

[04-14-2011] The U.S. Food and Drug Administration (FDA) is informing the public that it continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factor (TNF) blockers, as well as with azathioprine, and/or mercaptopurine.

Crohn's disease and ulcerative colitis cause inflammation of the digestive system. Common symptoms are pain in the abdomen, cramps, and diarrhea. Bleeding from the rectum, weight loss, joint pain, skin problems and fever also may occur. Children with the disease may have growth problems, develop intestinal blockage, and experience malnutrition.1

Facts about TNF Blockers, Azathioprine, and Mercaptopurine

  • TNF blockers suppress the immune system by blocking the activity of TNF, a substance in the body that can cause inflammation and lead to immune-system diseases, such as Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. The drugs in this class include Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol) and Simponi (golimumab).
  • Azathioprine (also known as Imuran) and mercaptopurine (known as Purinethol) also suppress the immune system. They are commonly used as part of a combination regimen or used alone to treat Crohn’s disease and ulcerative colitis, although they are not approved for those uses.
  • Azathioprine is approved for the prevention of rejection following renal transplantation and for the reduction of signs and symptoms of rheumatoid arthritis.
  • Mercaptopurine is approved to treat acute lymphatic leukemia.

HSTCL is an aggressive (fast-growing) cancer and is usually fatal. The majority of cases reported were in patients being treated for Crohn’s disease or ulcerative colitis, but also included a patient being treated for psoriasis and two patients being treated for rheumatoid arthritis. FDA is now updating the number of reported cases of HSTCL.

Although most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system, including the TNF blockers, azathioprine, and/or mercaptopurine, there have been cases reported in patients receiving azathioprine or mercaptopurine alone.

FDA believes the risks and benefits of using TNF blockers, azathioprine, and/or mercaptopurine should be carefully weighed when prescribing these drugs to children and young adults, especially for the treatment of Crohn’s disease and ulcerative colitis. Patients should continue to talk to their Healthcare Professionals about the potential risk of HSTCL with use of these medications in order to make the best decision about their medical treatment.

FDA previously communicated about the increased risk of lymphomas and other cancers associated with the use of TNF blockers in children and adolescents in June 2008 and in August 2009 when warnings were added to the TNF blocker labels.

The product labels for Remicade (infliximab) and Humira (adalimumab) have been updated and the product labels for azathioprine and mercaptopurine are being updated to include warnings about HSTCL that have been reported in patients treated with these products.

FDA will continue to communicate any new safety information to the public as it becomes available.


Additional Information for Patients

• Be aware that taking TNF blockers, azathioprine, and/or mercaptopurine may increase the risk of HSTCL.
• Review the Medication Guide that accompanies a prescription for TNF blockers.
• Do not stop taking TNF blockers, azathioprine, and/or mercaptopurine without talking to your healthcare professional.
• Discuss any questions or concerns about these medications with your healthcare professional.
• Report any side effects you experience to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page.

 

Additional Information for Healthcare Professionals
• Discuss with patients and caregivers the increased risk of developing HSTCL, especially in adolescents and young adults, taking into account the risks/benefits of TNF blockers, azathioprine, and/or mercaptopurine, and other immunosuppressive therapies.
• Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.
• Monitor for the emergence of malignancies when a patient has been treated with TNF blockers, azathioprine, and/or mercaptopurine.
• Know that people with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis may be more likely to develop lymphoma than the general U.S. population. Therefore, it may be difficult to measure the added risk of TNF blockers, azathioprine, and/or mercaptopurine.
• Report adverse events involving TNF blockers, azathioprine and/or mercaptopurine to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.

 

Data Summary
FDA is updating the public about the number of reported cases of Hepatosplenic T-cell Lymphoma (HSTCL). From initiation of TNF blocker marketing to December 31, 2010, the following HSTCL cases have been identified in the Adverse Event Reporting System (AERS) database (de-duplicated), the literature, and the HSTCL Cancer Survivors' Network in association with the following agents (mutually exclusive): Infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0), azathioprine (12), and mercaptopurine (3). Of note, in the 20 cases identified with infliximab use, 18 of the patients also were using concomitant mercaptopurine or azathioprine (for the remaining two patients, concomitant drug use was not reported). Of the 5 cases identified with infliximab/adalimumab use, 4 patients were using concomitant mercaptopurine or azathioprine (for the remaining patient, concomitant drug use was not reported). Complete medical histories have not been obtained on some cases to exclude a history of exposure to a potential confounder/co-factor. See Table 1 for the list of cumulative cases associated with selected immunosuppressant use reported as of December 31, 2010.

Due to the potential increased risk for cancers, including HSTCL, the risks and benefits of using TNF blocker products, azathioprine and/or mercaptopurine should be carefully weighed when prescribing these drugs especially in adolescents and young adults.

References

  1. U.S. National Library of Medicine. National Institutes of Health. Crohn's Disease health topic. Available at http://www.nlm.nih.gov/medlineplus/crohnsdisease.html Accessed March 1, 2011.  

 


 

TABLE 1. Cumulative Cases of HSTCL Associated with Selected Immunosuppressant Use† Reported to the Adverse Event Reporting System, the Published Literature, and HSTCL Cancer Survivor's Network as of December 31, 2010

Product Indication for use Sex Patient age in years Duration of use Concomitant agent Outcome
Infliximab§
N=20
CD (17), UC (3) M (17)1, 2, 3, 4
F (3)5
Median =30,
Range=12 to 74
Range: 1 dose to intermittent use for 7-8 years(doses not specified) (19), not stated (1) 18 (azathioprine or mercaptopurine)* Death (17)
Infliximab/ada-limumab§
N=5
CD (4), UC (1), M (5)6, 7, 8 Median=29
Range=21 to 58
Infliximab: Range: 2 doses to 6 years (doses not specified) (5)
Adalimumab
Range: 3 doses to 13 doses (n=5)
4 (azathioprine or mercaptopurine; 1 of the 6 pts also received 3 doses of natalizumab)   Death (4)
Etanercept§
N=1
PS [9] Not stated Not stated Not stated Methotrexate, cyclosporine Not stated
Adalimumab§
N=2
RA F (1), M (1) 61, 70 1 yr, 4.5 months 2 (steroid [1], methotrexate [1]) Death (1)
Certolizumab
N=0
N/A N/A N/A N/A N/A N/A
Golimumab
N=0
N/A N/A N/A N/A N/A N/A
Azathioprine N=12 Hepatitis/UC (1)10
CD (6)11, 12, 13, 14, 15, 20
UC (5) 16, 17, 18
M (8)
F (1)
Unk (3)  
Median=21 Range=15 to 45 (n=10) 4-6 yrs to 17 yrs (12) Steroid (4),
mesalamine (1),
none rpt (7)
Death (10)
Mercapto-purine
N=3
CD (3)19, 20 M (3) Mean=24
Range= 18 to 33 (n=3)
3 to 8 yrs (3) None rpt (3) Death (3)  

  

CD=Crohn's disease, UC=ulcerative colitis, PS=psoriasis, RA=rheumatoid arthritis, N/A= not applicable, Unk=unknown, None rpt= none reported
† Selected immunosuppressants include the following: infliximab, adalimumab, etanercept, certolizumab, golimumab, azathioprine, and mercaptopurine.
§ Cases reported from foreign sources as follows: infliximab (6), infliximab/adalimumab (3), etanercept (1), adalimumab (1), azathioprine (8), and mercaptopurine (1).
* In addition, concomitant steroid use was reported for ten patients.
# Cases are mutually exclusive; based on medication lists provided in case reports, these patients were not receiving immunosuppressant therapy either concomitantly or sequentially.
 

1 Zeidan A, Sham R, Shapiro J, et al. Hepatosplenic T-cell lymphoma in a patient with Crohn's disease who received infliximab therapy. Leuk Lymph 2007: 48(7): 1410-3.
2 Wijeratne R, Teller T, Sekhon H, et al. Hepatosplenic T cell lymphoma following exposure to infliximab in a patient with ulcerative colitis. Inflamm Bowel Dis 2009; 5 (S2): S11.
3 Drini M, Prichard PJ, Brown GJE, et al. Hepatosplenic T-cell lymphoma following infliximab therapy for Crohn's disease. Med J Austral 2008; 189(8): 464-5.
4 Kotlyar D, Blonski W, Porter DL et al. Hepatosplenic T-cell lymphoma (HSTCL) and inflammatory bowel disease (IBD): A rare complication after long-term thiopurine exposure: Case report and systematic review of the literature. Gastroenterology 2009; 36(1): S1133.
5 Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn's disease. J Pediatr Gastroenterol 2005; 40(2): 220-2.
6 Gumbs AA, Zain J, O'Connor OA. Importance of early splenectomy in patients with hepatosplenic T-cell lymphoma and severe thrombocytopenia. Ann Surg Oncol 2009; 16 (7): 2014-7.
7 Bernheim O, Scherl E, Bosworth B, et al. Hepatosplenic T-cell lymphoma after sequential infliximab, adalimumab, and natalizumab therapy for Crohn's Disease. Abstract #P1146 at 74th meeting of the American College of Gastroenterology.
8 Beigel F, Jurgens M, Tiliack C, et al. Hepatosplenic T-cell lymphoma in a patient with Crohn's disease. Nat Rev Gastroenterol Hepatol 2009; 6: 443-6.
9 Grimpen F, Yeung D, Joseph J, et al. Hepatosplenic T cell lymphoma, immunosuppressive agents and biologicals: What are the risks? J Gastroenterol Hepatol 2009; 24: A311.
10 Rosh J. T-cell hepatosplenic lymphoma in an adolescent on azathioprine montherapy for ulcerative colitis and autoimmune hepatitis (abstract). North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NSAPGHAN) 2006 annual meeting.
11 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: 531-3.
12 Mittal C, Milner BJ, Johnston PW, et al. A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to Gludarabine and Alemtuzumab. Eur J Haematol 2006; 76: 531-4.
13 Lemann M, el 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): A 1020.
14 Humphreys MR, Cino M, Quirt I, et al. Long-term survival in two patients with hepatosplenic T cell lymphoma treated with interferon-alpha. Leuk Lymph 2008; IFirst article, pp 1-4.
15 HSTCL Cancer Survivors Network, csn.cancer.org/node/136135, accessed on June 25, 2010 (search identified 2 patients treated for UC and 1 patient treated for CD; note that these cases have not been verified by a health care professional).
16 Keller KM, Magdefrau C, Bohl J, et al. Hepatosplenic T-cell lymphoma in a 15-year-old boy with ulcerative colitis treated with azathioprine for 9 years. J Pediatr Gastroenterol Nutr; 44(6): abstract PG6-12.
17 Vega F, Medeiros LJ, Gaulard P. Hepatosplenic and other γδ T-cell lymphomas. Am J Clin Pathol 2007; 127: 869-80.
18 Moran G, Dillon J, Green J. Crohn's disease, hepatosplenic T-cell lymphoma and no biological therapy: Are we barking up the wrong tree? Inflam Bowel Dis 2008 Dec 9 [Epub ahead of print].
19 Ochenrider MG, Patterson DJ, Aboulafia DM. Hepatosplenic T-cell lymphoma in a young man with Crohn's Disease: Case report and literature review. Clin Lymphoma Myeloma Leuk 20100; 10(2): 144-8.
20 Fowler S, Beyak M, Depew WT, et al. Hepatosplenic T-cell lymphoma in Crohn's disease. Where does the risk lie? Gastroenterology 2010; 138(5): Suppl 1 p. 675.

 

 
 

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