Common Immune-Related Adverse Events: Spotlight on Gastrointestinal and Hepatic Toxicities
At the inaugural MD Anderson Clinical Education Symposium on Immunotherapy Organ Toxicity Management (IOTOX), a panel of experts discussed common immune-related adverse events associated with immune checkpoint inhibitor therapy, including gastrointestinal (GI), hepatic, dermatologic, pulmonary, and endocrine immune-related adverse events. Yinghong (Mimi) Wang, MD, PhD, and Hao Chi (Joseph) Zhang, MD, discussed GI and liver toxicities, respectively, and armed oncologists with knowledge to diagnose, treat, and avoid recurrence of these toxicities in clinical practice.
Yinghong (Mimi) Wang, MD, PhD
Hao Chi (Joseph) Zhang, MD
Gastrointestinal Immune-Related Adverse Events: Focus on Colitis
A wide range of GI toxicities are associated with immune checkpoint inhibitors, according to Dr. Wang, Associate Professor of Gastroenterology, Hepatology, and Nutrition at MD Anderson. Within the GI lumen, mucositis, esophagitis, gastroenteritis, and colitis can occur because of immunotherapy, whereas extraluminal involvement includes cholecystitis, appendicitis, and diverticulitis. Dr. Wang focused solely on colitis in her presentation, as the most extensive studies in the literature direct attention to this GI immune-related adverse event.
Clinical presentation of immunotherapy-related colitis includes diarrhea and colitis-related symptoms. Using the Common Terminology Criteria for Adverse Events grading system, diarrhea is graded based on the frequency of bowel movements above baseline, whereas colitis-related symptoms include abdominal pain, blood and mucus in the stool, and fever. The time of onset of immunotherapy-related colitis ranges from the first dose of treatment up to 1 year after the last dose, but most occur within 2 to 3 months after exposure to immune checkpoint inhibitors.
Endoscopic presentation of colitis varies widely.1 Severe inflammation is associated with large, deep ulcers throughout the colon; moderate inflammation shows diffuse erythema, inflammatory exudate, and superficial ulcerations. “Mild inflammation is associated with patchy erythema, aphtha, edema, or even normal-looking mucosa and is frequently associated with histologic inflammation,” Dr. Wang noted.
Stool biomarkers (lactoferrin and calprotectin) can be used in the process of colitis evaluation and as surrogate markers for disease monitoring and treatment of colitis.2 Lactoferrin has a sensitivity of 70% in predicting endoscopic inflammation and a sensitivity of 90% in predicting histologic inflammation.
“The other fecal biomarker, calprotectin, is measured quantitatively,” she explained. “There is a strong association between calprotectin level and endoscopic severity of immunotherapy-related colitis. A higher level of calprotectin is associated with severe colitis presenting with significant ulcerations on endoscopy.”
According to Dr. Wang, GI toxicity is associated with better overall survival in patients receiving immunotherapy.3 “Interestingly, patients who develop GI toxicities have significantly better overall survival on long-term follow up,” she said. “We’re referring to a 50% survival rate, compared with just 15% in patients who do not have GI toxicities. Even among patients who had GI toxicity that was mild enough not to require medical treatments, their survival benefit is still significant.”
Therefore, the treatment goal in these patients is to control the GI toxicity and resume effective cancer treatment as soon as possible, and for as long as needed, she added.
Concerning the timing of endoscopy in the evaluation of immunotherapy-related colitis, earlier is better. “If a patient undergoes endoscopy within 30 days of the disease course, that provides the benefit of lower requirement for IV corticosteroid, lower duration of steroid exposure, and also less colitis recurrence (from 50% to about 22%),” she said. “We see a similar benefit if we’re able to offer endoscopy within 7 days.”2
According to Dr. Wang, the factor that most significantly affects outcomes in these patients is early introduction of selective immunosuppressive therapy, which hinges on early endoscopy to assess the severity of colitis. Endoscopic remission could decrease the recurrence of colitis; therefore, endoscopic remission could serve as a better treatment target than clinical remission.4
“However, in real-world practice, it may not be feasible to frequently repeat colonoscopy or endoscopy for certain patients, especially those with significant comorbidities,” she said. “Therefore, fecal calprotectin can be a good noninvasive surrogate marker to predict colitis remission and to guide treatment duration.”
Infliximab and vedolizumab are the two most frequently used biologic agents for treating immunotherapy-related colitis. Patients on these drugs have similar severity of diarrhea and colitis, but patients on vedolizumab have less steroid exposure, fewer hospital stays, and fewer steroid-tapering attempts. Clinical remission in patients on these drugs is equivalent, but recurrence is significantly lower in patients given vedolizumab (14% vs 29%).5
On resumption of immune checckpoint inhibitors, recurrence of colitis is lower with anti–PD-1/L1 rather than anti–CTLA-4.6 In patients who require long-term immune checkpoint inhibitors after colitis, concurrent selective immunosuppressive therapy with infliximab or vedolizumab may successfully reduce colitis recurrence, according to Dr. Wang.7,8
Finally, new research shows that fecal transplant may be considered an alternative strategy for immunotherapy-related colitis—as compassionate or front-line treatment—with an efficacy of 75% to 83%.9
Evolving Landscape in Hepatobiliary Immune-Related Adverse Events
Dr. Zhang, Assistant Professor of Gastroenterology, Hepatology, and Nutrition at MD Anderson Cancer Center, discussed the latest understanding and practices regarding immune-mediated hepatobiliary toxicities. These findings in the literature pertain to cholestatic biochemical labs, the role of liver biopsy, optimizing the use of steroids, and potential efficacy of tocilizumab in treating this toxicity.
“Our management of this toxicity is still evolving based on emerging published clinical experience,” he noted. “The understanding of hepatobiliary immune-related adverse events is still in its infancy.”
ABOUT THE IOTOX SYMPOSIUM
The inaugural Immunotherapy Organ Toxicity (IOTOX) Education Symposium took place at The University of Texas MD Anderson Cancer Center in Houston on December 3, 2022. This new symposium provided a comprehensive review of more than 10 organ systems and associated toxicities related to immunotherapy. The event was joined by 5 external guest speakers who are nationally recognized as IO toxicity guideline authors, as well as more than 30 MD Anderson speakers and session moderators, all of whom have a great deal of knowledge and experience with patients experiencing these toxicities. It brought the worldwide oncologic community together to exchange knowledge on IO toxicity and promoted future collaborations among and between academic centers to further improve patient care and outcomes.
While the current practice paradigm allows for "pushing through" treatment with immune checkpoint inhibitors for grade 1 toxicity, Dr. Zhang suggests, "For more severe toxicities, documented literature compels us to make synchronized efforts to redefine and refine the paradigms as well as to address areas of urgent unmet need,” he added.
Immune checkpoint inhibition is not actually a direct hepatotoxin but instead exerts an inflammatory effect through a T-cell-mediated process in the liver. And, as with all drug-induced liver injury, immune-mediated hepatobiliary toxicity is a diagnosis of exclusion. Overall, immune-mediated hepatobiliary toxicity has an incidence of up to 30%, with 1 in 10 patients experiencing grade 3 to 4 immune-mediated hepatobiliary toxicity with combination immune checkpoint inhibitors—more than double the incidence from the sum of two monotherapies, Dr. Zhang explained. Onset can occur anytime within the first year after the last exposure to immune checkpoint inhibitors, but for most patients, it occurs 5 to 13 weeks from the start of treatment.
When initially approaching a diagnosis, it’s important to make the distinction between liver enzymes and liver function tests. “They are not the same,” stated Dr. Zhang. “Liver enzymes should include alkaline phosphatase and GGT [gamma-glutamyl transferase]. What drives urgency and acuity of care should be abnormal liver synthetic function and signs of acute liver failure.”
The R-factor is determined by proportioning the ratio of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values, which are measured in the patient, to the upper limit of normal (ULN). The R-factor is used to define the pattern of liver injury. If the R-factor is at least 5, it can be said that hepatocellular damage has occurred. In terms of initial diagnostic tests, first and foremost, viral infectious hepatitis must be ruled out, and imaging should be tailored to the clinical scenario. “Patients with cholestasis may warrant MRI with magnetic resonance cholangiopancreatography, rather than just an ultrasound,” he advised.
Liver biopsy is—in most cases—needed to make a diagnosis, akin to the diagnostic approach for idiopathic autoimmune hepatitis. “This is because you’re about to subject these patients to significant immunosuppression, and 1 in 10 suspected cases of immune-mediated hepatobiliary toxicity is actually disproven by liver biopsy,” he said.
According to Dr. Zhang, cholangiopathic phenotypes are important to recognize because these patients don’t do well with steroids in the first place. Cholangiopathy is attributed to poor steroid responsiveness; even if these patients do respond initially, they may relapse.
As for acute liver failure in immune-mediated hepatobiliary toxicity, it is rarely described, with only a handful of case reports available. In terms of management, not all patients with grade 2 to 4 immune-mediated hepatobiliary toxicities require steroids,” Dr. Zhang said. However, immune-mediated hepatobiliary toxicity is an immune-mediated process, so some patients will require steroids. Identifying those patients requires observing trends in liver enzymes for a week-long “grace period.”
Dr. Zhang continued: “We estimate that one-third to one-half of patients don’t need steroids. Of those who do, expect one-third to be steroid-responsive, and almost one-third to be steroid-refractory.”
Steroid treatment options include prednisone or budesonide (with IV methylprednisone used in specific hospitalized patients). Dr. Zhang prompted reflection upon standard induction treatment options for idiopathic autoimmune hepatitis, which include prednisone at 60 mg/d, prednisone at 30 mg/d plus azathioprine at 50 to 100 mg/d, or budesonide at 9 mg/d with or without azathioprine at 50 to 100 mg/d. “This should be the reference prototype yet has not been reflected in the various guidance iterations,” he said.
Documented literature shows no benefit beyond 60 mg of corticosteroids. “If you commit to induction steroids, you must keep the dose until the ALT [alanine aminotransferase] level is almost normal before tapering across 4 to 6 weeks, as premature tapering can cause rebound and prolonged steroid use,” Dr. Zhang explained. “Don’t be afraid of rebound, as that’s your first signal of steroid dependence and your clue that you need to escalate sooner.” Steroid response might be considered adequate if the ALT level drops below 35% of the initial value after seven days.
Budesonide has less systemic absorption and 90% first-pass metabolism in the liver; thus, it leads to fewer steroid-related side effects and is a favorable choice in patients with comorbidities or impending surgeries.12 However, it should be avoided in patients with cirrhosis or frank liver dysfunction.
Dr. Zhang noted that adjunctive medicines can be used, including ursodiol, mycophenolate mofetil, azathioprine, and tacrolimus, but no head-to-head or controlled trials have been conducted on any of these agents.
An area of urgent unmet need centers on patients who don’t respond to steroids; in these challenging scenarios, tocilizumab has demonstrated great promise.10,11 “My group has treated 22 patients over the last 2 years. Our case series last year revealed benefit of tocilizumab for three populations: steroid-refractory, steroid-dependent, or with recurrent immune-mediated hepatobiliary toxicities.”
Tocilizumab intersects with interleukin-6 liver biology and may help patients achieve steroid-free biochemical remission. However, it may not overcome the sequelae of severe cholangiopathy if the diagnosis is delayed. “One or two doses does the trick. So, we should focus efforts on cytokine-based, steroid-sparing biologic therapies in this field,” he added. “Our vision is that one day, tocilizumab could be considered as a front-line agent with or without steroids and could reduce or eliminate the need for steroid use altogether.”
Finally, Dr. Zhang noted that rechallenging patients with immune checkpoint inhibitors after recovery from grade 3 or 4 immune-mediated hepatobiliary toxicity is safe for the vast majority. “The literature shows that two-thirds to three-fourths of patients do not experience recurrence of immune-mediated hepatobiliary toxicities, which really challenges the current guidelines,” he pointed out. “The blanket statement that immune checkpoint inhibition should be permanently discontinued for this population must be reconsidered. The difficulty lies in the fact that we don’t know how to predict who will develop recurrent immune-mediated hepatobiliary toxicities again.”
DISCLOSURE: Dr. Wang is a consultant with Sorriso Pharmaceuticals, Mabquest, Sanarentero, AzurRx, and Illya Pharma and has received research grant funding from Gateway, Adopt a Scientist, Moonshot, Health and Environmental Sciences Institute, and Sabin Fellowship. Dr. Zhang reported no conflicts of interest.
1. Wang Y, Abu-Sbeih H, Mao E, et al: Endoscopic and histologic features of immune checkpoint inhibitor–related colitis. Inflamm Bowel Dis 24:1695-1705, 2018.
2. Abu-Sbeih H Ali FS, Wang L, et al: Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor–induced colitis. J Immunother Cancer 6:95, 2018.
3. Wang Y, Abu-Sbeih H, Mao E, et al: Immune-checkpoint inhibitor–induced diarrhea and colitis in patients with advanced malignancies: Retrospective review at MD Anderson. J Immunother Cancer 6:37, 2018.
4. Abu-Sbeih H, Ali FS, Wang X, et al: Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor–induced colitis. J Immunother Cancer 7:93, 2019.
5. Zou F, Faleck D, Thomas A, et al: Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: A two-center observational study. J Immunother Cancer 9:e003277, 2021.
6. Abu-Sbeih H, Ali FS, Naqash AR, et al: Resumption of immune checkpoint inhibitor therapy after immune-mediated colitis. J Clin Oncol 37:2738-2745, 2019.
7. Zou F, Faleck DM, Thomas AS, et al: Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in cancer patients. Gastroenterology 160(6 suppl):S-711, 2021.
8. Badran YR, Zou F, Durbin S, et al: Concurrent immune checkpoint inhibition and selective immunosuppressive therapy in patients with immune-related enterocolitis. Gastroenterology 162(7 suppl):S-79, 2022.
9. Thomas AS, Halsey T, Jiang ZD, et al: Microbiome alteration via fecal microbiota transplantation is effective for immune checkpoint inhibitor–induced colitis refractory to immunosuppressive therapy. Am J Gastroenterol 116:S68-S69, 2022.
10. Zhang HC, Miller ED, Wang L: Tocilizumab as an effective steroid-sparing agent for the treatment of recurrent and steroid-dependent immune checkpoint inhibitor–mediated hepatotoxicity: A case study and insight into pathophysiology. Am J Gastroenterol 117:e1896-e1897, 2022.
11. Zhang H, Miller E, Wang L, et al: Early use of tocilizumab as an effective steroid-sparing strategy for the treatment of immune checkpoint inhibitor–mediated cholangiopathy: Building foundations for personalized management. 2022 American College of Gastroenterology Annual Meeting. Abstract A0541. Presented October 23, 2022.
12. Zhang HC, Wang L, Wang Y, et al: Budesonide as an alternative steroid agent, in combination with adjunctive agents, for the treatment of immune checkpoint inhibitor-mediated cholangiohepatitis: A case study. Am J Gastroenterol 116:S1139, 2021.