Management einer persistierenden Kolitis nach erfolgreicher Immuntherapie eines nicht-kleinzelligen Karzinoms der Lunge

Zusammenfasssung

Immuncheckpoint-Inhibitoren haben als neue Generation von Medikamenten in der Anti-Tumortherapie bemerkenswerte Wirksamkeit gezeigt. Die unspezifische Aktivierung des Immunsystems führt jedoch zu einer Reihe von unerwünschten Nebenwirkungen, sog. immune-related adverse events (irAEs), inklusive des Auftretens von Diarrhoe und Kolitis bei etwa einem Drittel der behandelten Patienten.

Endoskopisch und histologisch gibt es weitreichende Überlappungen der immunvermittelten Kolitis mit der klassischen CED, was eine Unterscheidung erschwert.

Therapeutisch kommen bei Grad-3- (schwere) bis Grad-4-Kolitiden (lebensbedrohlich) neben dem Abbruch der ICI-Therapie hochdosiert Glukokortikoide zum Einsatz. Steroidrefraktäre Fälle (bis 42%) profitieren vom TNF-Hemmer Infliximab. Vedolizumab stellt, analog bei chronisch entzündlichen Darmerkrankungen, die Zweitlinientherapie bei Infliximab-refraktären Fällen dar. Zur Wirksamkeit von Tofacitinib bei therapierefraktären Fällen existieren bislang nur wenige Daten.

Wir beschreiben den Fall und das Therapiemanagement einer schweren und andauernden immunvermittelten Kolitis nach erfolgreicher Immunochemotherapie mit Pembrolizumab bei einem 80-jährigen Mann mit einem metastasierten, nicht kleinzelligen Karzinom der Lunge und vorbestehender Colitis indeterminata (colitis unclassified) sowie weiteren Komorbiditäten.

Abstract

Immune checkpoint inhibitors have shown remarkable efficacy as new-generation drugs in anti-tumor therapy. However, the nonspecific activation of the immune system leads to a number of adverse side effects, so-called immune-related adverse events (irAEs), including the occurrence of diarrhea and colitis in about one third of treated patients.

Endoscopically and histologically, there is significant overlap of immune-mediated colitis with classic IBD, making differentiation difficult.

Therapeutically, high-dose glucocorticoids are used in grade 3 (severe) to grade 4 (life-threatening) colitis, in addition to discontinuation of ICI therapy. Steroid-refractory cases (up to 42%) benefit from the TNF inhibitor infliximab. Vedolizumab, analogous to inflammatory bowel disease, represents second-line therapy for infliximab-refractory cases. Little data exist to date on the efficacy of tofacitinib in refractory cases.

We describe the case and therapeutic management of severe and persistent immune-mediated colitis after successful immunochemotherapy with pembrolizumab in an 80-year-old man with metastatic non-small cell carcinoma of the lung and pre-existing colitis unclassified and other comorbidities.

Schlüsselwörter

Immuncheckpoint Inhibitor - Immune related colitis - Pembrolizumab - Infliximab - Vedolizumab - Tofacitinib - Herpes zoster

Keywords

Immuncheckpoint Inhibitor - Immune related colitis - Pembrolizumab - Infliximab - Vedolizumab - Tofacitinib - Herpes zoster

Publikationsverlauf

Eingereicht: 04. Juni 2021

Angenommen nach Revision: 14. September 2021

Artikel online veröffentlicht:
18. Januar 2022

• Literaturverzeichnis

• 1 Zam W, Ali L. Immune checkpoint inhibitors in the treatment of cancer. Current Clinical Pharmacology 2021;
• 2 Heinzerling L, de Toni E, Schett G. et al. Checkpoint-Inhibitors- the diagnosis and treatment of side effects. Dtsch Arztebl Int 2019; 116: 119-126
• 3 Braun GS, Kirschner M, Rübben A. et al. Nebenwirkungen neuer onkologischer Immuntherapien. Nephrologe 2020;
• 4 Som A, Mandaliya R, Alsaadi D. et al. Immune checkpoint inhibitor-induced colitis: A comprehensive review. World J Clin Cases 2019; 7: 405-418
• 5 Schramm C. Bile Acids, the Microbiome, Immunity, and Liver Tumors. N Engl J Med 2018; 379: 888-890
• 6 Routy B, Le Chatelier E, Derosa L. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359: 91-97
• 7 Haanen JBAG, Carbonnel F, Robert C. et al. ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; (Suppl. 04) iv119-iv142
• 8 Wright AP, Piper MS, Bishu S. et al. Systematic review and case series: flexible sigmoidoscopy identifies most cases of checkpoint inhibitor-induced colitis. Aliment Pharmacol Ther 2019; 49 (12) 1474-1483
• 9 Bergqvist V, Hertervig E, Gedeon P. et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother 2017; 66: 581-592
• 10 Bryant RV, Sandborn WJ, Travis SP. Introducing vedolizumab to clinical practice: who, when, and how?. J Crohns Colitis 2015; 9: 356-366
• 11 Abu-Sbeih H, Ali FS, Alsaadi D. et al. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study. J Immunother Cancer 2018; 6: 142
• 12 Colombel JF, Sands BE, Rutgeerts P. et al. The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut 2017; 66: 839-851
• 13 Abu-Sbeih H, Faleck DM, Ricciuti B. et al. Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease. J Clin Oncol 2020; 38: 576-583
• 14 Johnson DB, Sullivan RJ, Ott PA. et al. Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Oncol 2016; 2: 234-240
• 15 Menzies AM, Johnson DB, Ramanujam S. et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017; 28: 368-376
• 16 Leonardi GC, Gainor JF, Altan M. et al. Safety of Programmed Death-1 Pathway Inhibitors Among Patients With Non-Small-Cell Lung Cancer and Preexisting Autoimmune Disorders. J Clin Oncol 2018; 36: 1905-1912
• 17 Abdel-Wahab N, Shah M, Lopez-Olivo MA. et al. Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review. Ann Intern Med 2018; 168: 121-130
• 18 Sandborn WJ, Su C, Sands BE. et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2017; 376: 1723-1736
• 19 Esfahani K, Hudson M, Batist G. Tofacitinib for Refractory Immune-Related Colitis from PD-1 Therapy. N Engl J Med 2020; 382: 2374-2375
• 20 Bishu S, Melia J, Sharfman W. et al. Efficacy and Outcome of Tofacitinib in Immune checkpoint Inhibitor Colitis. Gastroenterology 2021; 160: 932-934.e3
• 21 Winthrop KL, Melmed GY, Vermeire S. et al. Herpes Zoster Infection in Patients With Ulcerative Colitis Receiving Tofacitinib. Inflamm Bowel Dis 2018; 24: 2258-2265
• 22 Guimaraes P, Quirk D, Furtado RH. et al. Tofacitinib in patients with hospitalized COVID-19-pneumonia. N Engl J Med 2021; 385: 406-415