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Expert Critique

FROM THE ASCO Reading Room

Bradley W. Anderson, MD Gastroenterology and Hepatology Fellow Mayo Clinic

The following article discusses several studies that frame our current understanding of the relationship between immunosuppressant medications used for the treatment of inflammatory bowel disease (IBD) and lymphoma. While uncommon, the incidence of lymphoproliferative disease including non-Hodgkin lymphoma has previously been shown to be higher amongst patients receiving certain IBD-directed medications, such as thiopurines, compared with non-exposed patients. What has been less clear to date is the lymphoma risk posed by combination therapy (patients receiving both thiopurines and biologic agents) -- a relationship that is difficult to define given several confounding factors. In a recent large cohort study highlighted by this article, hazard ratios reflecting lymphoma risk were defined for several patient groups including unexposed patients, both thiopurine and anti-TNF monotherapy groups, as well as patients on combination therapy. While this study and interpretation of these findings are not without limitations, they do serve to further emphasize the importance of a careful discussion between patient and provider regarding potential medication-associated benefits and risks before selecting a particular IBD treatment option.

Full Critique

The connection between lymphoma, inflammatory bowel disease (IBD), and immunosuppressives has been controversial at least as far back as 1978, when documented Hodgkin's disease as a complication of azathioprine treatment for Crohn's disease (CD). Today the precise connection between lymphoma and immunomodulators remains unclear, with different studies showing varying risk levels.

A 2013 study by reported that ulcerative colitis (UC) patients in a nationwide Veterans Administration cohort of 4,734 patients showed a fourfold increase in lymphoma risk during thiopurine treatment compared with patients not receiving thiopurines. Lymphoma risk increased gradually for successive years of treatment and, fortunately, diminished with discontinuation of the drug.

The incidence rates of lymphoma were 0.60 per 1,000 person-years among patients who had not been treated with thiopurines, 2.31 among those treated with thiopurines, and 0.28 among patients who had discontinued treatment with thiopurines.

In a 2015 meta-analysis of 18 IBD studies, reported that relative to studies from referral centers, population-based studies showed a lower but still significantly increased risk of lymphoma among thiopurine-treated patients. The overall standardized incidence rate was 4.92, ranging from 2.80 in eight population studies to 9.24 in 10 referral studies.

"Population-based data are the most relevant for community-based care because referral-center studies inherently have more severely ill patients," one of the co-authors, Gary R. Lichtenstein, MD, director of the Inflammatory Bowel Disease Center at the University of Pennsylvania in Philadelphia, told 番茄社区.

Especially at risk from thiopurines were men, patients younger than 30, and patients older than 50. "Males were twice as likely to get lymphoma when exposed to azathioprine, and patients under age 30 had the highest relative risk, with a standardized incidence rate of 6.99, rising to about nine-fold in males under age 30," Lichtenstein noted. The highest absolute risk emerged in the 50-and-older age category. "Lymphoma is an age-dependent disease. Over age 50 the relative risk was 4.78, but the absolute risk was highest at one in 354 cases per patient-year."

As for biologics, in a 2014 national Danish study of approximately 56,000 IBD patients, found that exposure to anti-tumor necrosis factor (anti-TNF) therapy was not associated with an increased risk of cancer over a median follow-up of 3.7 years. An increased risk did emerge, however, with longer-term accumulated doses, suggesting that longer follow-up might have found a different outcome.

Most recently, a 2017 study by looked at the risk impact of three treatments -- thiopurines alone, TNF antagonists alone, or both classes of drugs combined -- in a cohort drawn from French national health insurance databases.

Almost 250,000 IBD patients age 18 or older treated from 2009 to 2013 were identified, and of these, 189,289 eligible participants with a median age of 43 (54% women) were followed to the end of 2015.

In that sample, 123,069 were never exposed to either drug class during follow-up, while 50,405 were exposed to thiopurine monotherapy, 30,294 to anti-TNF monotherapy, and 14,229 to combination therapy. By treatment category, the exposure durations were 27, 17, and 8 months, respectively.

Overall, there were 336 lymphoma cases, and 281 of non-Hodgkin's disease:

• 220 cases in unexposed patients, for an incidence rate (IR) per 1,000 person-years of 0.26 (95% CI 0.23-0.29)
• 70 in patients exposed to thiopurine monotherapy, for an IR of 0.54 (95% CI 0.41-0.67)
• 32 in patients exposed to anti-TNF monotherapy, for an IR of 0.41 (95% CI 0.27-0.55), and
• 14 in patients exposed to combination therapy, for an IR of 0.95 (95% CI 0.45-1.45)

Compared with in unexposed patients, the risk of lymphoma was higher among those exposed to either therapy or both therapies in combination. Thiopurine monotherapy had an adjusted hazard ratio (aHR) of 2.60 (95% CI 1.96-3.44, P<0.001), while anti-TNF monotherapy had an aHR of 2.41 (95% CI 1.60-3.64, P<0.001). Combination therapy had the highest aHR – 6.11 (95% CI 3.46-10.8, P<0.001).

The risk was also higher in patients exposed to combination therapy relative to those exposed to thiopurine monotherapy (aHR 2.35, 95% CI 1.31-4.22, P<0.001) or anti-TNF monotherapy (aHR 2.53, 95%CI1.35-4.77, P<0.001).

Lymphoma risk did not differ between adalimumab (Humira) and infliximab (Remicade) -- the absolute risk difference was just 0.04 per 1,000 person-years (aHR 0.95, 95% CI 0.47-1.90, P=0.97).

The researchers cautioned that because combination therapy is often used in severe forms of IBD, the association with elevated lymphoma risk may also reflect the impact of the burden of inflammation rather than treatment alone. The team concluded that the findings could help inform doctor-patient decisions about the benefits and risks of treatment.

Studies such as (Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease) have shown benefits from combination therapy with azathioprine plus anti-TNF. "Combination therapy means higher blood levels of anti-TNF that predict a benefit of therapy," Lichtenstein said, adding that individuals on combination therapy are less likely to develop antibodies against biologics because the immune system is suppressed. "These drugs are foreign proteins, and antibodies to them are a common reason people lose the benefit."

Lichtenstein noted that methotrexate has also recently been shown not to cause lymphoma in IBD patients. In looking at the safety of newer treatments, he said, "patients need to understand that individuals with untreated UC or CD have twice the mortality of the general population, and double the death rate and the severe infectious complication rate when treated with steroids. So you want to limit exposure to steroids yet effectively treat active disease."

For patients at the vulnerable extreme ends of the age scale, it's preferable to try a single agent and avoid combination therapy unless really needed. "Look at disease severity and future prognosis and determine if patients can be treated with a biologic alone rather than combination therapy -- particularly for patients over age 50 and under age 30, especially males," Lichtenstein said. In a recent reanalysis of the SONIC study, CD patients on combination therapy or those achieving high drug levels on monotherapy did about equally well, he noted.

The risk of lymphoma must be kept in perspective, however, Lichtenstein stressed. Lymphoma remains an uncommon cancer compared with colon and lung, and the risk of lymphoma with azathioprine rises only after a full year of exposure and goes down after cessation. "If you use it for 6 to 9 months, the risk does not go up. Furthermore, IBD does not predispose to cancer, and using biologics does not raise the risk of solid-organ cancers."