Leonard Calabrese, DO, on Interdisciplinary Management of Immune-Related Adverse Events

The goal of management of immune-related adverse events (irAEs) is to “provide optimum therapy of the irAE with immunotherapy while continuing cancer treatment, ideally to minimize or craft immunosuppression so as not to impair the antitumoral response,” Leonard Calabrese, DO, told the audience at the Interdisciplinary Autoimmune Summit on April 23.

Dr Calabrese is a professor of medicine at the Cleveland Clinic in Cleveland, Ohio, where he also serves as the director of the RJ Fasenmyer Center for Clinical Immunology.

He reviewed the details of immunotherapy and its function in controlling T cell activation. Noting that immunotherapy “is actually a huge umbrella of therapies, but we mostly know the checkpoint inhibitors,” he stated that there is “a tsunami of these therapies coming down the pike” as immunotherapy has proved its effectiveness in treating a variety of cancers.

Whereas only 1% of patients were originally eligible for treatment with immunotherapy, Dr Calabrese said, now more than 40% of patients with cancer are being treated with this therapy.

“Immunotherapy is here to stay,” he stated. “It has given us another avenue of therapy, and when patients respond, responses can be enduring.”

The Achilles’ heel of immunotherapy is the fact that reinvigorating a patient’s immune response in order to treat cancer can in turn create adverse effects, Dr Calabrese said. These irAEs can occur in virtually any organ and often mirror rheumatic diseases such as inflammatory arthritis, skin conditions, inflammatory bowel disease, and more. Grade 1 toxic effects typically require only observation and perhaps some symptomatic therapy.

In Grade 2, he explained, “patients may have pain that limits activity but maybe without inflammation, or a dermatologic condition that is spreading, more than GI cramps. Here, you go into diagnostic mode. Get CRP [C-reactive protein] in arthritis patients. I’d be following the patient with skin reactions to look for signs of more serious conditions such as Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN). With gastric AEs, I may start with symptomatic therapy and perhaps use low-dose steroids.”

Grade 3, Dr Calabrese continued, is when a patient merits hospitalization or intensification of care. “I’ve seen some of the worst cases of polymyalgia and polyarthritis in these patients that I’ve ever seen. It’s very dramatic when we see it. These patients not only warrant escalating care and perhaps admission, but this is when we must be consulting with other clinicians. This is not something that one person in a large medical center can deal with.” At Grade 3, the immunotherapy is typically stopped.

Grade 4 includes patients who have experienced serious irAEs who have not responded to high-dose steroids or have relapsed after dechallenge, he explained.

The most common irAEs are dermatologic, Dr Calabrese said, ranging from maculopapular rush and pruritus to dermatomyositis, vitiligo, and the more severe conditions of SJS and TEN. Gastroenterological AEs, typically seen as colitis, “are among the most common and most feared.” He stated that colitis “requires a vigorous diagnostic approach with CRP, CT scans, and endoscopy. Diarrhea is common in 40%-50% of patients and the incidence of colitis is higher among patients receiving combination immunotherapy. “Colitis is generally self-limiting when treated, but infection must be ruled out.” Treatment may require corticosteroids, but therapies used in inflammatory bowel disease, such biologics and small molecule therapies, may also be helpful.

“Gastros are well-attuned to these points,” Dr Calabrese said. “Where the rubber hits the road is in the interprofessional interaction with the oncologist on issues such as, can these patients be rechallenged, and what are the risks for patients with pre-existing IBD?”

The incidence of inflammatory arthritis as an irAE of immunotherapy is difficult to assess, he stated, but appears to range from 1%-2% of patients up to 4%. Most of these patients have seronegative disease.

“The most distinctive feature of the rheumatic complications of irAEs is that these above all others have the capacity to become chronic diseases,” Dr Calabrese explained. In most other types of irAEs caused by immunotherapy, “once the CPI [checkpoint inhibitor] is stopped the inflammatory base is gone; but 1 out of 4 patients will have persistent arthritis for 2 years or more following CPI therapy. These are the only drugs that I am aware of that can induce an autoimmune state that defies immune dechallenging in such a large percentage of cases.”

He continued, “This is complicated; these patients may relapse with tumors and we need ways of managing them and their arthritis at the same time.”

A very small number of fatal toxic effects from immunotherapy are seen, and these tend to occur early in treatment. Most fatalities are due to myocarditis, which is a very rare complication, Dr Calabrese explained. Combination therapy can cause the very sudden onset of this condition. “We need vigilance, early dechallenge, and aggressive therapy,” in such cases, he said.

A new entity known as Triple-M syndrome —for its 3 presenting conditions of myositis, myasthenia gravis, and myocarditis — has also been seen among immunotherapy patients, Dr Calabrese said. “We’re still trying to understand it. Patients present with full card-carrying myositis and myasthenic syndrome. The first thing to do is to get a troponin. The patient is then whisked to the cath lab, if it’s elevated, to make sure they don’t have coronary syndrome and then treated aggressively for myocarditis. With this vigorous diagnostic approach, we’ve salvaged many of these patients.” Those with Triple-M syndrome are not candidates for rechallenge with immunotherapy, he said.

One interesting point about some irAEs is that they can serve as a biomarker of antitumor response, Dr Calabrese said. They can predict overall response, overall survival, and progression-free survival across different types of cancer and may represent useful biomarkers.

“Yes, if you have an associated immune-related adverse event it is a harbinger—not a guarantee—of more favorable outcome across the board,” he noted. For example, patients treated for melanoma with immunotherapy who develop vitiligo show significantly higher survival rates. However, severe polyarthritis can be a marker of poor response to immunotherapy and may be a marker of tumor progression, Dr Calabrese explained.

When treating irAEs, he stated, “the early targets are still the most exciting.” Anti-tumor necrosis factor (TNF) therapies and those that target interleukin (IL) 6 appear to be among the best choices. Although anecdotal evidence indicates a mixed response to these medications, Dr Calabrese noted that “we know some biologics can be quite safe” and there has been no direct evidence of adverse effects on tumoral response with anti-TNFs. Vedolizumab, a gut-specific anti-integrin, is an option for treating colitis and is less immunosuppressive than other therapies. “Traditional DMARDS [disease-modifying antirheumatic drugs] may blunt response to checkpoint inhibitors,” he added. Janus kinase (JAK) inhibitors have also been used successfully in in life-threatening conditions such as myocarditis.

Essentially, he said, “no targeted therapy is off the table for the treatment of irAEs and I don’t care what that is.”

In 2018, Dr Calabrese wrote in an editorial: “Given these unanswered questions and the complexity of the problems, perhaps our best strategy for now is to expect that the surprises of irAEs from current CPIs will merely prepare us for future surprises.” Experience has shown that was an accurate prediction. To better prepare for those surprises he stressed the need for an interdisciplinary approach and urged major centers to develop interprofessional groups “with interested and invested consultants in all areas so they can share their experience.”

Pre-existing autoimmune disease is not a contraindication for immunotherapy, Dr Calabrese stressed. “The first mission of us as consultants is to get the tumor treated and to save their lives. If we need to treat their irAE, we treat the irAE.”

—Rebecca Mashaw

Calabrese, L. Interdisciplinary management of irAEs and the evolving role of targeted therapies. Presented at: Interdisciplinary Autoimmune Summit. April 23, 2022. Virtual.