Among patients with inflammatory bowel disease (IBD), those receiving thiopurine monotherapy, anti–tumor necrosis factor (TNF) monotherapy, or a combination of both may have an increased risk for lymphoma compared with nonusers, a study found.
The researchers say the increased risk is relatively small and should be weighed against the benefit of these drugs for treating IBD.
“Although these differences in the risk of lymphoma were significant in relative terms, their absolute magnitude of less than 1 case per 1000 person-years should be considered against the potential benefit of successful treatment of IBD,” the researchers write.
Rosemary Dray-Spira, MD, PhD, from Agence Nationale de Sécurité du
Médicament et des produits de santé, Saint-Denis Cedex, France, and colleagues report their findings online November 7 in JAMA.
Many clinical trials have suggested that thiopurines and anti-TNF agents have benefit in treating IBD, either alone or in combination. However, studies have also suggested an increased risk for lymphoma associated with thiopurines. The risk with anti-TNF therapy is less clear because many patients taking anti-TNF agents have received thiopurines in the past. So teasing out whether past thiopurine exposure or current anti-TNF therapy increases lymphoma risk poses a challenge.
The researchers conducted a nationwide cohort study using data from French National Health Insurance and hospital discharge databases, which cover all medical prescriptions and hospitalizations for IBD in France since 2006. The study included data from 189,289 adults diagnosed with IBD before December 2013. Patients were followed for a median of 6.7 years and assessed for exposure to thiopurine monotherapy (azathioprine and 6-mercaptopurine), anti-TNF monotherapy (infliximab, adalimumab), a combination of both, or no exposure.
During the study, 336 patients developed lymphoma: 220 cases in unexposed patients (incidence rate [IR] per 1000 person-years, 0.26; 95% confidence interval [CI], 0.23 – 0.29), 70 cases with thiopurine monotherapy (IR, 0.54; 95% CI, 0.41 – 0.67), 32 cases with anti-TNF monotherapy (IR, 0.41; 95% CI, 0.27 – 0.55), and 14 cases with combination therapy (IR, 0.95; 95% CI, 0.45 – 1.45).
In further analyses adjusted for baseline factors and variables associated with IBD diagnosis and treatment, patients exposed to thiopurine monotherapy had more than 2.5 times increased risk for lymphoma compared with unexposed patients (adjusted hazard ratio [aHR], 2.60; 95% CI, 1.96 – 3.44; P < .001). Likewise, the risk for lymphoma was 2.4 times higher with anti-TNF monotherapy (aHR, 2.41; 95% CI, 1.60 – 3.64; P < .001). This risk was more than six times higher with combination therapy (aHR, 6.11; 95% CI, 3.46 – 10.8; P < .001).
Lymphoma risk did not differ between patients receiving thiopurine monotherapy and those receiving anti-TNF monotherapy (aHR, 0.93; 95% CI, 0.60 – 1.44; P = .93).
However, patients receiving combination therapy had about 2.3 times higher lymphoma risk compared with thiopurine monotherapy (aHR, 2.35; 95% CI, 1.31 – 4.22; P < .001) and about 2.5 times higher lymphoma risk compared with anti-TNF monotherapy (aHR, 2.53; 95% CI, 1.35 – 4.77; P < .001), suggesting that increased lymphoma risk with these drugs may be additive, the authors explain.
However, in various sensitivity analyses intended to weed out current from past drug exposures, the results remained unchanged. This suggests that the higher lymphoma risk with combination therapy may be due to the current regimen, rather than past exposure to thiopurines. Likewise, it suggests that current anti-TNF therapy may increase lymphoma risk regardless of past exposure to thiopurines.
Results were consistent regardless of age, sex, IBD type, and Hodgkin vs non-Hodgkin lymphoma.
The authors mentioned several limitations. Combination therapy is often used in severe IBD, so the link between increased lymphoma risk and combination therapy could reflect high levels of inflammation rather than treatment. Also, follow-up for combination therapy was short (8 months), during which time only 14 patients developed lymphoma. So the results carry some certainty and may require longer-term studies for confirmation.
“These findings may inform decisions regarding benefits and risks of treatment,” the researchers conclude.
One or more authors reports consulting, personal fees, nonfinancial support, or being a reviewer for one or more of the following: Imaxio, Enterome, Falk, MSD, Medac, Bristol-Myers Squibb, Janssen, Takeda, Abbvie, FMC HE, Genentech, Otsuka, Vifor, and/or Hospira.
JAMA. Published online November 7, 2017. Abstract
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