HOLLYWOOD, FLA. – The benefits of short-term trial immunosuppressive therapy outweigh the risks in inflammatory bowel disease, but certain patient populations require more vigilance than others, Dr. James D. Lewis said at the 2013 Advances in IBD meeting.
"We can probably all agree that thiopurines increase the risk of lymphoma," said Dr. Lewis, of the University of Pennsylvania, Philadelphia, at the conference on inflammatory bowel diseases. "But I’ve gone from ‘probably’ to ‘possibly’ when it comes to using anti-TNF [anti–tumor necrosis factor] therapy. I believe that a short trial of biologics therapy can really inform the risk-benefit balance, moving the conversation from ‘it might make a patient better’ to either it did or it didn’t."
In young males and the elderly, the benefit of combination therapy might not prove worth the risks of the treatment, said Dr. Lewis, "but in the middle ground, I think we have a sweet spot."
Dr. James D. Lewis
Overall, unless ineffective treatment is justifiable for other reasons such as the prevention of antibody formation, it should be discontinued, he said.
Results from the CESAME study, published in 2009, reinforce previously published data, indicating the risk of lymphoma is up to five times higher in IBD patients exposed to thiopurines than in the general population (Lancet 2009;374:1617-25).
"The most important data from CESAME, however, was that patients who discontinued thiopurines had a lymphoma incidence rate that went back to that of the general population," Dr. Lewis said at the meeting, sponsored by the Crohn’s & Colitis Foundation of America.
The link between lymphoma and anti-TNF treatment is harder to establish in IBD patients, because many in this cohort also have been exposed to thiopurines as part of combination therapies, he said.
Combination therapy is possibly associated with a higher risk of lymphoma than thiopurine monotherapy, and it has been shown to lead to a higher incidence rate than biologics monotherapy, said Dr. Lewis.
If you counsel patients that there is a 1 in 2,000 risk of lymphoma per year, he said, but it takes only a quarter of a year to figure out if the drugs are going to work, then the short-term risk is 1.25 per 10,000 that an additional lymphoma would develop because of that 3-month treatment. "And if you stop the treatment, presumably that risk goes away."
The risk-to-benefit ratio would therefore be favorable for most patients who took thiopurines versus those who did not, he said. "The caveat being, the older you get, the more marginal that risk-benefit balance becomes, probably because as you age, your baseline risk for lymphoma is going up."
Regarding the risk of hepatosplenic T-cell lymphoma in patients exposed to immunosuppressive therapy, Dr. Lewis said that when he pooled the risk in person-years from two studies, he "did some back-of-the-envelope calculations and found that in males, the risk might be on the order of 11 in 100,000 person-years of thiopurine exposure."
That means the number needed to harm is about 9,000 patients, which when combined with the possible risk of developing other lymphomas, the number needed to harm is about 6,000 young males for 1 lymphoma death per year, according to Dr. Lewis.
"But I want to caution you that I am almost sure this is an overestimate of the risk, because if this is true, then it means in young males treated with thiopurines who get lymphoma, a third of them would be hepatosplenic lymphomas, and that seems unlikely," he said.
The ultimate magnitude of risk for adding thiopurine therapy for patients, particularly young males, is on par with that of the risk of death from annual use of automobiles, which Dr. Lewis said was approximately 1 in 9,090.
Since "a substantial proportion" of lymphomas associated with immunosuppression are related to the Epstein-Barr virus, according to Dr. Lewis, aside from minimizing unnecessary treatment, which can be hard to define, clinicians might consider discontinuing just thiopurine therapy, or all therapy in the setting of long-term remission. "I’m not endorsing that," he said. "I am saying that is a question for you to consider."
Other considerations include determining the minimum dose of thiopurine or methotrexate necessary to augment the effectiveness of anti-TNF treatment, as well as whether methotrexate is as effective as thiopurines without having an increased lymphoma risk, although only "indirect evidence" currently exists. "It would be nice to see a head-to-head comparison of those," he said.
As for using Epstein-Barr virus serology to help stratify risk, Dr. Lewis said that currently there are no guidelines for it in IBD, and he does not have a set rule to recommend it.