Reactivaion of immune-related colitis during targeted therapy in a patient with metastatic cutaneous melanoma

Background. The development of unique immune-related adverse events (irAEs) is a known hallmark of immunotherapy. Generally, such complications occur during the first 3–6 months of immunotherapy, however, the experience with immune checkpoint inhibitors (ICIs) shows that irAEs can also occur after completion of ICI therapy, as well as during other anticancer treatment regimens. Description of the clinical case. We present a clinical case of a patient with metastatic cutaneous melanoma, who had recurrent events of grade 2 immune-mediated diarrhea during the 2^ndline of therapy. After completion of the course of immunosuppressive therapy with systemic glucocorticoids, irAE resumed, and mesalazine and budesonide (local steroid) with subsequent dose reduction were prescribed. Maintenance anti-inflammatory therapy and re-induction of targeted therapy with BRAF- and MEK-inhibitors due to the progression of the disease resulted in the reactivation of immune-mediated colitis. The complication was successfully managed by increasing dose of local steroid to full dose. Anticancer therapy was continued at the same regime without recurrent episodes of irAEs. Conclusion. When changing the anticancer treatment regimen, the recurrence of irAEs dictates careful monitoring of toxicity and the importance of timely selection of the optimal treatment algorithm to improve the quality and longevity of cancer patients.

1. Kennedy L.B., Salama A.K.S. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020; 70(2): 86–104. doi: 10.3322/caac.21596.

2. Martins F., Sofiya L., Sykiotis G.P., Lamine F., Maillard M., Fraga M., Shabafrouz K., Ribi C., Cairoli A., Guex-Crosier Y., Kuntzer T., Michielin O., Peters S., Coukos G., Spertini F., Thompson J.A., Obeid M. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019; 16(9): 563–80. doi: 10.1038/s41571-019-0218-0.

3. Gupta A., De Felice K.M., Loftus E.V. Jr, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015; 42(4): 406–17. doi: 10.1111/apt.13281.

4. Wang D.Y., Salem J.E., Cohen J.V., Chandra S., Menzer C., Ye F., Zhao S., Das S., Beckermann K.E., Ha L., Rathmell W.K., Ancell K.K., Balko J.M., Bowman C., Davis E.J., Chism D.D., Horn L., Long G.V., Carlino M.S., Lebrun-Vignes B., Eroglu Z., Hassel J.C., Menzies A.M., Sosman J.A., Sullivan R.J., Moslehi J.J., Johnson D.B. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 2018; 4(12): 1721–8. doi: 10.1001/jamaoncol.2018.3923. Erratum in: JAMA Oncol. 2018; 4(12): 1792.

5. Cramer P., Bresalier R.S. Gastrointestinal and Hepatic Complications of Immune Checkpoint Inhibitors. Curr Gastroenterol Rep. 2017; 19(1): 3. doi: 10.1007/s11894-017-0540-6.

6. Protsenko S.A., Antimonik N.Yu., Bershtein L.M., Zhukova N.V., Novik A.V., Nosov D.A., Petenko N.N., Semenova A.I., Chubenko V.A., Kharkevich G.Yu., Yudin D.I. Practical Guidelines for the Management of Immune-Mediated Adverse Events. Malignant tumours. Russian Society of Clinical Oncology. 2020; 10(3s2): 168–99. (in Russian). doi: 10.18027/2224-5057-2020-10-3s2-50.

7. National Comprehensive Cancer Network, Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Management of ImmunotherapyRelated Toxicities, Version 1.2022. URL: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf [cited 2022 Mar 30].

8. Keane J., Gershon S., Wise R.P., Mirabile-Levens E., Kasznica J., Schwieterman W.D., Siegel J.N., Braun M.M. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001; 345(15): 1098–104. doi: 10.1056/NEJMoa011110.

9. Ng S.C., Hilmi I.N., Blake A., Bhayat F., Adsul S., Khan Q.R., Wu D.C. Low Frequency of Opportunistic Infections in Patients Receiving Vedolizumab in Clinical Trials and Post-Marketing Setting. Inflamm Bowel Dis. 2018; 24(11): 2431–41. doi: 10.1093/ibd/izy153.

10. Marthey L., Mateus C., Mussini C., Nachury M., Nancey S., Grange F., Zallot C., Peyrin-Biroulet L., Rahier J.F., Bourdier de Beauregard M., Mortier L., Coutzac C., Soularue E., Lanoy E., Kapel N., Planchard D., Chaput N., Robert C., Carbonnel F. Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease. J Crohns Colitis. 2016; 10(4): 395–401. doi: 10.1093/ecco-jcc/jjv227.

11. Owen C.N., Bai X., Quah T., Lo S.N., Allayous C., Callaghan S., Martínez-Vila C., Wallace R., Bhave P., Reijers I.L.M., Thompson N., Vanella V., Gerard C.L., Aspeslagh S., Labianca A., Khattak A., Mandala M., Xu W., Neyns B., Michielin O., Blank C.U., Welsh S.J., Haydon A., Sandhu S., Mangana J., McQuade J.L., Ascierto P.A., Zimmer L., Johnson D.B., Arance A., Lorigan P., Lebbé C., Carlino M.S., Sullivan R.J., Long G.V., Menzies A.M. Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma. Ann Oncol. 2021; 32(7): 917–25. doi: 10.1016/j.annonc.2021.03.204.

12. Couey M.A., Bell R.B., Patel A.A., Romba M.C., Crittenden M.R., Curti B.D., Urba W.J., Leidner R.S. Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance. J Immunother Cancer. 2019; 7(1): 165. doi: 10.1186/s40425-019-0645-6.

13. Sarofim M., Winn R. Rare case of delayed onset colitis due to immunotherapy for malignant melanoma. ANZ J Surg. 2019; 89(10): 472–3. doi: 10.1111/ans.14768.