What is the percentage of patients at risk of developing lymphoma when taking Azathioprine (Immunosuppressive medication)?

From the Guidelines

The risk of lymphoma in patients taking azathioprine is estimated to be approximately one case per 1000 patient years of azathioprine treatment. This translates to a roughly 0.1% annual risk. The cumulative risk increases with longer duration of therapy. This increased risk is attributed to azathioprine's immunosuppressive effects, which can impair immune surveillance of malignant cells and potentially allow Epstein-Barr virus-driven lymphoproliferation 1. The risk appears higher in certain patient populations, such as those with rheumatoid arthritis. Patients should be monitored for symptoms such as unexplained fever, night sweats, unintentional weight loss, or enlarged lymph nodes. Despite this increased risk, for most patients with autoimmune conditions requiring immunosuppression, the benefits of azathioprine therapy typically outweigh the relatively small absolute risk of lymphoma development. Some key points to consider when evaluating the risk of lymphoma in patients taking azathioprine include:

• The risk of lymphoma is higher in certain patient populations, such as those with rheumatoid arthritis 1
• The cumulative risk increases with longer duration of therapy
• Patients should be monitored for symptoms of lymphoma, such as unexplained fever, night sweats, unintentional weight loss, or enlarged lymph nodes
• The benefits of azathioprine therapy typically outweigh the relatively small absolute risk of lymphoma development for most patients with autoimmune conditions requiring immunosuppression. It is essential to weigh the potential risks and benefits of azathioprine therapy for each individual patient, considering factors such as the severity of their condition, the potential for alternative treatments, and their overall health status 1.

From the FDA Drug Label

The relative incidences in clinical studies are summarized below: ToxicityRenal HomograftRheumatoid Arthritis Lekopenia (any degree)>50%28% <2500 cell/mm 316%5.3% Infections20%<1% Neoplasia* Lymphoma0. 5% Others2. 8%

The percentage of patients at risk of lymphoma with azathioprine is 0.5% in renal homograft recipients, as stated in the drug label 2.

• The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population.
• In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine was 1.8 cases per 1000 patient-years of follow-up.

From the Research

Lymphoma Risk with Azathioprine

• The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with azathioprine has been studied in several research papers 3, 4, 5, 6.
• A meta-analysis published in 2005 found that the pooled relative risk of lymphoma associated with azathioprine or 6-mercaptopurine therapy was 4.18 (95% confidence interval 2.07-7.51) 3.
• Another study published in 2001 estimated that the risk of lymphoma in IBD patients treated with azathioprine or 6-mercaptopurine was around fivefold compared to no immunosuppressive use, and tenfold compared to the general population 4.
• A historical cohort study published in 2013 found that azathioprine use was associated with an increased risk of overall cancer, including lymphoid tissue cancer and urinary tract cancer, in patients with IBD 5.
• A meta-analysis published in 2015 estimated that the relative risk of lymphoma in patients with IBD exposed to thiopurines was 4.92 (95% confidence interval 3.10-7.78), with a higher risk observed in current users and men 6.
• However, it's worth noting that the study published in 2025 7 does not provide direct evidence on the risk of lymphoma with azathioprine, as it discusses the association between mycophenolate mofetil and primary cerebral lymphoma in a patient with autoimmune hepatitis.

Percentage of Patients at Risk

• The exact percentage of patients at risk of lymphoma with azathioprine is not explicitly stated in the studies, but the relative risks and standardized incidence ratios provided can be used to estimate the increased risk.
• For example, the study published in 2005 found that the pooled relative risk of lymphoma was 4.18, which means that the risk of lymphoma was approximately 4.18 times higher in patients treated with azathioprine or 6-mercaptopurine compared to the general population 3.
• The study published in 2015 found that the absolute risk of lymphoma was highest in patients over 50 years old, with an estimated 1:354 cases per patient-year 6.