Immunosuppressants probably do not increase the risk of cancer in IBD

In patients with inflammatory bowel disease (IBD) and a history of cancer, immunosuppressive therapies do not appear to increase the risk of cancer, according to an interim analysis of the SAPPHIRE registry.

Although immunosuppressive therapies were associated with numerically higher adjusted hazard ratios for new cancer cases, this association was not considered statistically significant.

“Patients with IBD who already have cancer are typically excluded from clinical trials of new IBD drugs because of fears that their cancer will return. Therefore, data on how much risk of future cancer is associated with taking IBD drugs are limited,” said the study’s lead author, Dr. Steven Itzkowitz, professor of medicine, oncology and medical education at the Icahn School of Medicine at Mount Sinai in New York City.

“Many physicians and patients are hesitant to give potentially very helpful IBD medications to patients with a history of cancer,” added Itzkowitz, who chairs the American Cancer Society’s National Colorectal Cancer Roundtable. “Understanding the risk of taking IBD medications in patients with a history of cancer provides physicians and patients with data to help them make informed decisions about their IBD treatment.”

The study was published online in Clinical gastroenterology and hepatology.

Analysis of the SAPPHIRE registry

The SAPPHIRE registry is a prospective study of the safety of immunosuppression in patients with IBD who had already developed cancer before enrollment. Established in 2016, the registry is affiliated with the New York Crohn’s and Colitis Organization. It follows patients annually to check for the development of malignancy and tracks the original cancer type and IBD medications taken.

In the interim analysis, Itzkowitz and colleagues examined the development of cancers (recurrent or new). The researchers excluded patients who were receiving active cancer treatment (chemotherapy or radiation) or who had more than one cancer before enrollment in the study.

Patients were categorized by drug type, such as tumor necrosis factor inhibitor (anti-TNF), antimetabolite, anti-integrin, anti-interleukin (IL)-12/23, anti-IL-23, Janus kinase inhibitor, or sphingosine-1-phosphate receptor. Those exposed to mesalamine or steroids alone were not considered exposed to the immunosuppressants in question.

Of the 305 patients, 47% were men, 88% were white, and 61% were nonsmokers. The average age at diagnosis of IBD was 32 years, and the average age at diagnosis of cancer was 52 years.

The index cancers included solid organ cancers (46%), dermatologic cancers (32%), gastrointestinal cancers (13%), and hematologic cancers (9%). Of the index cancers with known stage information, 33% were stage I.

During a mean follow-up of 4.8 years, 210 patients (69%) were exposed to immunosuppressive therapy and 36 (17%) of them developed cancer. Of the 95 patients who were not exposed to immunosuppressive therapy, 10 (11%) developed cancer.

Of the 46 new cancer cases, 25 were new onset and 21 were recurrent. The 36 patients who received immunosuppressive therapy and developed cancer during follow-up accounted for 78% of the new onset cancer cases (21 new onset and 15 recurrent).

In an unadjusted analysis, the crude cancer development rate in unexposed patients was 2.58 per 100 person-years versus 4.78 per 100 person-years in patients exposed to immunosuppression (relative risk 1.85).

However, in a proportional hazard model that took into account gender, smoking history, age, stage of the index cancer, and non-melanoma skin cancer, no significant association was found between exposure to immunosuppressive therapies and cancer (adjusted hazard ratio 1.41). Nor was a significant association found between immunosuppression and any of the major drug classes.

“The results did not surprise us, as they seem to confirm the findings from retrospective studies,” Itzkowitz said. “However, we are pleased that the different agents that act on different arms of the immune system appear to be relatively safe in patients with IBD and a history of cancer. However, we must be aware that we need more follow-up and more experience with the newer drugs before we can feel more confident.”

One step forward

Gastroenterologists are increasingly faced with the challenge of deciding on immunosuppressive agents for patients with pre-existing cancer. As more immunosuppressive therapies become available, we are using them earlier in the course of IBD treatment and patients are getting older, said Ashwin Ananthakrishnan, MBBS, associate professor of medicine at Harvard Medical School and a gastroenterologist at Massachusetts General Hospital in Boston.

Ananthakrishnan, who was not involved in this study, has studied the association between immunosuppressive therapies and the risk of cancer recurrence in patients with IBD. He and his colleagues found that neither vedolizumab nor anti-TNF agents were associated with an increased risk of new or recurrent cancer.

“This (the SAPPHIRE interim analysis) was a very important study because it was one of the first prospective studies to look at this question,” he said. “Several studies have looked at this before, but all were retrospective, which increases the potential for bias.”

Itzkowitz and colleagues highlighted many of these retrospective studies and the SAPPHIRE findings in a commentary on the May 2024 American Gastroenterological Association Institute Clinical Practice Update. Although patients with previous cancers may not be at increased risk, patients with active or recent cancer likely are, they wrote. While the authors noted the limited data on IBD therapies in patients with active cancer, they did provide guidance on specific therapies and malignancies. For example, in some cases, thiopurines and anti-TNF agents should be discontinued during cancer treatment and alternative therapies should be considered.

SAPPHIRE researchers plan to continue to follow existing patients and enroll new patients, particularly as new IBD drugs are introduced into clinical practice, Itzkowitz said. The research team is also considering studies that examine patients with IBD who are undergoing active cancer treatment.

Doctors “need more data on the safety of newer drugs and newer mechanisms,” Ananthakrishnan said. “And we especially need to look at outcomes in those who started treatment shortly before cancer diagnosis.”

The study received support from the Crohn’s and Colitis Foundation Clinical Research Alliance and Senior Research Award, the Chemotherapy Foundation, the New York Crohn’s and Colitis Organization, and the Helmsley Charitable Trust. Several authors reported grants, consulting fees, and consultancy work for numerous pharmaceutical companies. Ananthakrishnan reported no relevant disclosures.

Carolyn Crist is a health and medical journalist who covers the latest studies for Medscape Medical News, MDedge, and WebMD.