Azathioprine and Cancer: An Immune-Drug Risk

Azathioprine is a prescription tablet. Its CAS number is 446-86-6. It is a purine antimetabolite. That means it mimics one of the four building blocks of DNA. The body turns it into 6-mercaptopurine, then into compounds called 6-thioguanine nucleotides. Those get built into DNA in place of the real thing. Fast-dividing immune cells feel that first. That is why the drug quiets the immune system.

Two uses are FDA-approved on the US tablet label. One is preventing rejection after a kidney transplant. The other is treating active rheumatoid arthritis to reduce signs and symptoms. Doctors also prescribe it for other conditions. Those include lupus, autoimmune hepatitis, ulcerative colitis, Crohn's disease and myasthenia gravis. Tablets come in 50 mg, 75 mg and 100 mg strengths.

This page is unusual for a carcinogen page. Nobody meets this drug by accident. It is prescribed on purpose. The cancer risk is real, and it is only half of the ledger.

The label carries a boxed warning, the strongest warning the FDA uses. Its heading is "WARNING - MALIGNANCY." It says that long-term immune suppression with this drug "increases risk of malignancy in humans." It then names two: "post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease."

The warning tells prescribers to know that risk well. It also names the drug's mutagenic potential in both men and women. That means it can damage genes. And it adds a duty: patients must be told.

The National Toxicology Program lists azathioprine at its highest level: "known to be a human carcinogen." That listing rests on studies in people, not on animal data. It first appeared in the Fourth Annual Report on Carcinogens in 1985 and is still there in the Fifteenth.

Two large studies followed patients forward in time. Both looked at kidney transplant recipients, who were treated almost routinely with this drug plus prednisone. Both found higher rates of four cancer groups:

• Non-Hodgkin lymphoma.
• Squamous-cell skin cancer.
• Tumors of the connective tissue, also called mesenchymal tumors.
• Cancer of the liver, bile ducts or gallbladder.

People taking the drug for other reasons had a raised risk of the same cancers, but a lower one. That group covers rheumatoid arthritis, lupus, bowel disease, and some skin and kidney conditions. NTP flags one catch. Rheumatoid arthritis is itself a risk factor for non-Hodgkin lymphoma. So some of the excess belongs to the disease, not the drug.

The animal evidence is weaker, not stronger. Rats fed the drug grew cancer of the ear duct. Mice given it by injection grew lymphoma. IARC judged both sets of studies inconclusive, because of how they were designed and reported. IARC reviewed the drug again in Volume 100A, published in 2012. That volume went back over medicines already called carcinogenic to humans.

The label puts the transplant picture more carefully than a headline would. It says the risk of lymphoma after transplant may be higher with aggressive immune suppression. So it tells doctors to keep therapy at the lowest level that works.

Of everything on that list, skin cancer is the one most within reach. The label is direct about it. Sunlight and ultraviolet light should be limited. Protective clothing helps. So does a sunscreen with a high protection factor.

In practice that means daily habits, not occasional ones: long sleeves, a wide brim, midday shade, and no tanning beds. It also means someone should look at the skin regularly, including places you cannot see. A new scaly patch, a sore that will not heal, or a firm bump that grows deserves an appointment. Our page on preventing skin cancer covers what to look for.

HSTCL is a rare and very aggressive T-cell lymphoma. Post-marketing reports have described it in people treated with azathioprine, and the reported cases have been fatal.

The pattern in those reports is specific. Most occurred in people with Crohn's disease or ulcerative colitis. Most were adolescent and young adult males. Some were on azathioprine alone; others were also taking a TNF-alpha blocker at or before diagnosis. The label adds one more note. The safety and benefit of this drug in Crohn's disease and ulcerative colitis have not been established. It is still widely used that way.

This does not mean a young man with Crohn's disease should never take it. It means the conversation about that specific risk belongs on the table before the first prescription.

Two enzymes clear this drug. TPMT, or thiopurine S-methyltransferase, inactivates it by adding a methyl group. NUDT15 converts the active metabolites into inactive ones. Both genes vary between people, and low activity means the active compound piles up.

The numbers from the label are worth knowing:

• About 0.3 percent of people of European or African ancestry carry two broken copies of TPMT. That is roughly 1 in 300. They have little or no enzyme activity.
• About 10 percent carry one non-working copy and have intermediate activity.
• Three variants, TPMT*2, *3A and *3C, account for about 95 percent of reduced activity.
• NUDT15 deficiency is found in under 1 percent of people of European or African ancestry. Among people of East Asian ancestry, about 2 percent carry two non-working copies and about 21 percent carry one.

People with either gap face severe bone marrow suppression at ordinary doses. It can be life-threatening. They need a different drug, or a much lower dose. Blood count checks are written into the label too. The schedule is weekly for the first month. Then twice a month in months two and three. Then monthly, or more often when doses change.

One drug interaction matters enough to name. Allopurinol blocks one of the two clearance routes. So do other xanthine oxidase inhibitors. Levels then climb, and serious toxicity can follow.

Get help promptly. Fever, a sore throat that will not settle, mouth ulcers, unusual bruising, or bleeding that starts easily can all mean the blood counts have dropped. These are reasons to contact the prescribing team the same day rather than waiting for the next scheduled blood draw.

For kidney transplant, the starting amount is worked out from body weight and begun around the time of surgery. It is usually reduced once the transplant is settled.

For rheumatoid arthritis the starting amount is smaller, again based on weight. It may be raised in small steps from about 6 to 8 weeks onward, at monthly intervals, up to a ceiling the label sets. All of that is prescriber territory, decided with blood tests along the way.

The label also states plainly that the dose should not be pushed to toxic levels to fight threatened rejection, and that leukopenia is not a sign the drug is working.

NCI's summary of transplant risk gives useful context. Transplant recipients face higher rates of many cancers. The four most common are non-Hodgkin lymphoma and cancers of the lung, kidney and liver. Some of these are driven by viruses that a quieted immune system cannot hold down. Epstein-Barr virus and hepatitis B and C are the main ones.

None of this argues for stopping treatment. A rejected kidney and uncontrolled autoimmune disease carry their own mortality. What it argues for is naming the risk out loud, keeping the dose at the lowest level that works, and building sun protection and skin checks into ordinary life. If lymphoma is the risk that worries you most, our page on lymphoma explains what the disease is and how it is found.

• NTP list: azathioprine
• DailyMed: the tablet label
• IARC volume 100A
• NCI: immune suppression