Colitis After Cancer Immunotherapy: Considerations for a Prevalent Immune-Related Adverse Event
HUGHES-DOCTOROFMEDICINETHESIS-2019.pdf (1.121Mb)(embargoed until: 2021-05-01)
Hughes, Michael Sang
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CitationHughes, Michael Sang. 2019. Colitis After Cancer Immunotherapy: Considerations for a Prevalent Immune-Related Adverse Event. Doctoral dissertation, Harvard Medical School.
AbstractBackground: Immune checkpoint inhibitors (CPIs) have revolutionized oncologic therapy but can lead to immune-related adverse events (irAEs). Corticosteroids are first-line treatment with escalation to biologic immunosuppression in refractory cases. CPI-related gastroenterocolitis (GEC) affects 20-50% of patients receiving CPIs and carries significant morbidity and mortality. The severe form of disease is not well-described. In addition, patients with a histopathologically defined subset of CPI-related GEC, which we term CPI-related microscopic colitis (MC), may benefit from first-line budesonide administration. We present the retrospective clinical characterization of CPI-related GEC requiring admission at a single institution (inpatient GEC cohort) and a retrospective preliminary evaluation of a pilot cohort of CPI-related MC treated with budesonide (MC cohort).
Methods: For the inpatient GEC cohort, clinical, laboratory, radiographic, and endoscopic data were extracted from charts of all melanoma patients ≥18 years of age admitted to one institution for CPI-related GEC, from 2/05/2011 to 12/13/2016. Patients were followed until 12/31/2017 for further admissions. Survival, outcomes, and pharmaceutical-use analyses were performed.
For the MC cohort, clinical, laboratory, and endoscopic data were extracted from charts of all patients ≥18 years of age with prior CPI exposure and prior flexible sigmoidoscopy performed from 3/1/2017 to 12/31/18 for evaluation of possible colitis. CPI-related MC was defined as clinical and histopathologic evidence of colitis without endoscopic evidence of inflammation (Mayo Endoscopic Score 0). Diagnoses were confirmed by two reviewers, one with expertise in CPI complications. Survival and outcomes analyses were performed.
Results: Median time-to-admission from initial CPI exposure for the overall cohort was 73.5 days. Median length of stay was 4.5 days. 50.0% required second-line immunosuppression. Readmission for recrudescence occurred in 33.3%. Common Terminology Criteria for Adverse Events (CTCAE) grade was not significantly associated with outcomes. Hypoalbuminemia (p=0.005), relative lymphopenia (p=0.027), and decreased lactate dehydrogenase (p=0.026) were associated with second-line immunosuppression. There was no difference in PFS or OS (p=0.367, 0.400) for second-line immunosuppression. Subgroup analysis showed that early corticosteroid administration (p=0.045) was associated with decreased PFS.
There was no significant difference in average age or sex distribution between patients with MC and patients with non-MC GEC. Exposure to potential MC triggers tended to occur more often in the MC than non-MC cohort. Symptoms tended to start a median of 84 days later in the MC cohort, with borderline significance (p=0.064). Budesonide administration tended to result in faster symptom resolution (p=0.070). 10/12 (83.3%) patients with MC received additional cycles of immunotherapy after budesonide. Univariate Cox regressions showed that budesonide administration was significantly protective against treatment failure (HR 0.33, 95% CI 0.14-0.81) and borderline protective against progressive disease (HR 0.27, 95% CI 0.04-0.91).
Conclusions: Severe CPI-related GEC typically manifests within 3 months of immunotherapy exposure. Rates of second-line immunosuppression and readmission for recrudescence were high. CTCAE grade did not capture heterogeneous degree of severity in our cohort. Second-line immunosuppression was not associated with poorer oncologic outcomes; however, early corticosteroid exposure was associated with decreased PFS.
CPI-related MC, defined as clinical and histopathologic evidence of colitis with Mayo Endoscopic Score 0, is a clinical subset of CPI-related GEC that tends to present later in the course of immunotherapy. Budesonide is an effective treatment for CPI-related MC that controls symptoms and prolongs time on immunotherapy.
Further prospective investigation is warranted in both cohorts.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42069192