Immune-related colitis is the second most common toxicity associated with checkpoint inhibitors, affecting up to 40% of patients. The ASCO Post interviewed Yinghong Wang, MD, PhD, Director of Medication-Induced Colitis and Enteritis, Director of Fecal Microbiota Transplantation, and Associate Professor in the Department of Gastroenterology, Hepatology, and Nutrition at The University of Texas MD Anderson Cancer Center, Houston.
The ASCO Post asked Dr. Wang to describe her research as well as her approach to managing these challenging patients. She also explores the importance of an endoscopic and histologic evaluation as well as the benefit of the optimal timing and dosing of biologics.
Endoscopic Evaluation and Clinical Outcomes
Although current guidelines provide general recommendations for the evaluation of immune-mediated colitis, you and your colleagues have developed more specific guidelines that begin with endoscopic evaluation. Why, and how?
Current guidelines are general with regard to evaluating this disease entity. The role of endoscopy, histology, and inflammatory markers in the stool, and their impact on outcomes in colitis, has not been well studied, but we’re doing this at MD Anderson. We have found that when patients have “high-risk” features on endoscopic or histologic examination, they tend to have a more refractory disease course and worse outcomes, which influences our decision on treatment.
What are the endoscopic and histologic features of immune-mediated colitis?
We have retrospectively analyzed almost 5,000 patients who received checkpoint inhibitors as monotherapy or in combination. We found immune-mediated colitis was diagnosed in 7% to 25%, depending on treatment. Endoscopy was performed in about half the patients with colitis and revealed a number of features, similar to what we see in Crohn’s disease and ulcerative colitis. Features considered indicative of “high risk” for colitis included deep ulcers ≥ 2 mm, large ulcers ≥ 1 cm, three or more ulcers, and extensive inflammation beyond the splenic flexure proximally.1
Histologic features vary mainly between active inflammation and chronic inflammation. Those seen in active inflammation are cryptitis, crypt abscess, neutrophil infiltration, eosinophil infiltration, and apoptosis, whereas in chronic inflammation, we see crypt architecture distortion, Paneth cell metaplasia, and basal lymphoplasmacytosis. There is a third subtype called microscopic colitis with histologic features of increased lymphocyte infiltration in the epithelium (lymphocytic colitis) and/or collagen band in the subepithelial layer (collagenous colitis).
How does clinical outcome vary according to endoscopic and histologic findings?
In our study, 71 patients had high-risk features, and 111 had no high-risk features on endoscopy; 129 had active inflammation, and 53 did not. We found several significant differences between these cohorts in clinical outcomes.
Patients with high-risk features on endoscopy were more likely to need infliximab or vedolizumab (46% vs 16%; P < .01), require hospitalization (82% vs 67%; P = .03), and be hospitalized longer (mean of 9 vs 6 days; P = .02). Those with active inflammation had significantly more high-grade diarrhea (93% vs 72%; P = .01) and colitis (85% vs 66%; P = .01), more need for intravenous steroids (54% vs 25%; P < .01) and biologics (34% vs 12%; P = .03), more ICU admissions (9% vs 2%; P = .02), and higher recurrence rates (34% vs 12%; P = .01).2
Do patients who have severe diarrhea yet normal endoscopic and histologic findings have different outcomes than those with symptoms and abnormal findings?
We had 28 symptomatic patients with normal endoscopic/histologic features and 154 with abnormal features. Those with abnormal findings had worse outcomes, including significantly more severe diarrhea, need for immunosuppressants and biologics, hospitalizations, and recurrences. This study showed us the importance of endoscopy in the evaluation of immune-related diarrhea/colitis.
Timing of Endoscopy
When in the evaluation should endoscopy be done? How should you perform this test to help patients achieve maximal benefit?
Timing is important. We looked at patients who underwent endoscopy within 7 days of disease onset, vs those in whom it was done more than 7 days after onset. Those with earlier testing had significant reductions in days with symptoms and days of steroid use, as well as a trend for shorter duration of hospitalization.3
If you miss the window of 7 days—as often occurs in real-world practice—don’t worry. If you perform endoscopy within 30 days of the onset of colitis, you can still provide a huge benefit. Testing within 30 days has been associated with significantly less need for and shorter duration of steroids, shorter duration of symptoms, less requirement for ICU admission, and less recurrence. We think the most important benefit from early endoscopy is that you can start infliximab or vedolizumab earlier for severe cases.
Inflammatory Markers
Are there inflammatory markers to predict which patients on checkpoint inhibitors are at high risk for immune-mediated colitis?
We examined the utility of stool lactoferrin for this and found that 70% of -patients with a positive lactoferrin test had abnormal endoscopic findings, and 90% had active histologic inflammation. A simple stool test for lactoferrin is a great tool for screening patients with diarrhea or colitis. This information can help stratify patients who will need endoscopy later.
Clinical Recommendations
Can you put this information together in the form of a recommendation?
Severe immune-mediated colitis can be predicted by high-risk features on endoscopy and active histologic inflammation. Early endoscopic examination and its guidance on the selection of appropriate treatment at appropriate time is associated with a shorter duration of steroid use, shorter duration of symptoms, less hospitalization, and lower risk for recurrence.
Also, a positive fecal lactoferrin test can predict the presence of immune-mediated colitis among patients with diarrhea, so our recommendation is to consider early endoscopy in patients with diarrhea or colitis ≥ grade 2 and a positive stool lactoferrin test in patients with grade 1 symptoms—which can guide your subsequent treatment. You can consider empiric antidiarrheal medications in patients with grade 1 diarrhea/colitis and a negative stool lactoferrin test.
Treatment Type and Timing
What do you consider the best treatment for immune-related colitis?
The guidelines do not give clear recommendations on the type and timing of medical treatment. We conducted a study to assess the clinical outcomes of treatment with infliximab and vedolizumab, looking at dosage and timing. The study included 84 adults receiving checkpoint inhibitors in 2018 with a confirmed diagnosis of immune-related colitis; 50 received infliximab and 34 received vedolizumab, and they could switch to the opposite drug if they failed to respond.3
The recurrence rate was highest among patients receiving infliximab only after steroid use without ever switching to vedolizumab (12 of 50 patients, likely due to less dosing). Recurrence was uncommon in the other groups (most of the patients treated with at least three doses of vedolizumb).
Regarding timing, we used 10 days as a cutoff (the time required at our institution for financial clearance). We found the duration of symptoms to be significantly shorter for patients treated within 10 days of onset (25 vs 50 days). Early treatment was also significantly associated with fewer attempts at steroid tapering, less failed steroid tapering, and fewer hospitalizations.
Duration of Therapy With Biologics
How long do you treat with biologics?
We know that early introduction of infliximab or vedolizumab is important, but how long do we keep the patient on these drugs? We found that three infusions or more was associated with significantly less recurrence of colitis (odds ratio = 0.09, P = .023). If you enable patients to receive a minimum of three doses, they will benefit significantly in the long term.
In addition, endoscopic and histologic remission is also associated with less recurrence. Especially for patients who will resume treatment with checkpoint inhibitors, you can consider adding concurrent colitis treatment as long-term maintenance. Putting this together, we can improve clinical outcomes of immune-mediated colitis with an early introduction of infliximab or vedolizumab, and treatment with at least three doses, with a treating target of endoscopic and histologic remission.
Do you dose-escalate the biologic if patients fail to respond?
Although the occasional patient may require dose escalation, in my experience, if the patient does not respond to low-dose infliximab, he or she won’t respond to high doses either. Also, a lot of patients achieve clinical remission, but on follow-up endoscopy, we see persistent inflammation. If we stop the biologic prematurely, the symptoms recur. This is why endoscopic or histologic remission should serve as a more accurate treating target, not clinical remission.
Management Algorithm
How do these findings fit into the management algorithm at MD Anderson?
There is a difference between current oncologic practice guidelines and our approach. For colitis ≥ grade 2, we offer endoscopy within 7 days of disease onset. We do not wait to start more aggressive immunosuppressive treatment (infliximab or vedolizumab) until the patient has failed to respond to steroids. We introduce infliximab or vedolizumab equally and within 10 days of onset regardless of steroid response.
Also, to minimize disease recurrence, the current guidelines recommend a steroid taper over 4 to 6 weeks, but we start tapering early on and stop within 30 days. It’s been shown that the risk of infection related to steroid use is 50% when you taper over more than 30 days, but 18% if you limit steroids to less than 30 days.
We routinely offer at least three doses of infliximab or vedolizumab and perform follow-up endoscopy to determine the duration of treatment. When patients do not respond after the first two doses, we switch to other biologics or offer fecal microbiota transplant, which we have found to help some patients. Our goal with adequately treating immune-mediated colitis is to enable our patients to resume the appropriate cancer treatment as soon as possible for maximal benefit. ■
DISCLOSURE: Dr. Wang has served as a consultant for Tillotts Pharma AG.
REFERENCES
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, Luo W, et al: Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer 6:95, 2018.
3. 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.
