The Benefit-to-Risk Balance of Combining Infliximab With Azathioprine Varies With Age: A Markov Model

Abstract

BACKGROUND & AIMS Combination therapy with infliximab and azathioprine has demonstrated benefit over monotherapy for moderate-to-severe Crohn’s Disease. Clinical trials and models have not accounted for age-specific risks associated with these therapies, including the risk of immunosuppression-related cancer and infection. After accounting for these risks, the strategy yielding the greatest benefit may vary with age. METHODS We assessed age-specific risks and benefits of combination therapy compared to infliximab monotherapy using Markov modeling. The base case was a 35 year-old male patient with a 1-year time horizon. We assumed the incidence of lymphoma to be 5.28-fold higher with combination therapy. Secondary analyses accounted for life expectancy, therapy beyond 1 year, and age-specific surgical and infection risks. Quality-adjusted life years (QALYs) were calculated for 25–75-years old individuals. RESULTS Combination therapy was found to be of greater benefit in the base case (0.7522 QALYs for combination therapy vs 0.7426 QALYs for monotherapy). Accounting for life years lost, monotherapy was the best approach if the hazard ratio for lymphoma with combination therapy was >8.1 patients 75 years old. Monotherapy provided greater net benefit to patients 55, 65, or 75 years old if therapy was extended for 9, 7, or 5 years, respectively. For 25 year-old men, monotherapy resulted in fewer deaths but only yielded greater QALYs if the annual incidence of hepatosplenic T-cell lymphoma exceeded 36/100,000 persons. CONCLUSION After accounting for age-specific risks of lymphoma, infection, and surgical complications, benefits of combination therapy outweighed the risks as a short-term and intermediate-term strategy for most patients with moderate-to-severe Crohn’s Disease younger than 65 years. For young male patients, combination therapy yields greater QALYs, but at cost of an increased risk of death from lymphoma.

Cancer Recurrence Following Immune-Suppressive Therapies in Patients With Immune-Mediated Diseases: A Systematic Review and Meta-analysis

“…In contrast, other than cervical cancer, 25 the risk of solid organ cancer development appears unaltered. However, despite the modest increase in risk of malignancy, the absolute risk of incident cancers in individuals with no prior cancer remains very low, providing reassurance regarding the wide spread use of such treatment strategies in the population 26, 27 .…”

Positioning Therapy for Ulcerative Colitis

“…In the absence of contraindications, we recommend starting combination therapy with an anti-TNF and a thiopurine for patients with moderate-to-severe UC, with the recognition of the rare, but uniformly fatal risk, of hepatosplenic T cell lymphoma in young males, which may limit the acceptance of combination therapy by physicians and patients alike. This recommendation may be tempered by the greater risk of serious infection in the elderly populations in whom monotherapy with an anti-TNF drug may be more appropriate [36][37][38][39].…”

Step-Up or Top-Down, Combination with Immunosuppression or Not?

“…Young males with limited disease also cause some additional concern due to the risk of hepatosplenic T-cell lymphoma. Decisions need to be made individually, but for most patients who clinically require a combination therapy, the benefits will probably outweigh the risks [21] .…”

“…The Markov model analysis by Scott et al [21] demonstrated that the addition of an immunosuppressive drug to anti-TNF therapy increases treatment efficacy for infliximab in IBD, outweighing the additive risk. The use of combination therapy appears to add no significant risk for serious complications (e.g.…”