Ipilimumab-induced colitis in patients with metastatic melanoma

Felice, Kara M. De; Gupta, Arjun; Rakshit, Sagar; Khanna, Sahil; Kottschade, Lisa A.; Finnes, Heidi D.; Papadakis, Konstantinos A.; Loftus, Edward V.; Raffals, Laura E.; Markovic, Svetomir N.

doi:10.1097/cmr.0000000000000165

Cited by 45 publications

(45 citation statements)

References 15 publications

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“…There is an ongoing debate whether irAEs and/or the severity of irAEs is associated with better cancer-specific outcomes, and whether treatment with immunosuppressive agents potentially counteracts the anti-tumor effect of ICPI therapy. There are several studies supporting these concepts [3, 44–49] but also those refuting them [5, 43, 44, 48, 50–52]. …”

Section: Discussionmentioning

confidence: 99%

Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis

Bergqvist

Hertervig

Gedeon

et al. 2017

Cancer Immunol Immunother

203

156

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Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective activation of the immune system, immune-related adverse events (irAEs) are frequent. Enterocolitis is a common irAE, currently managed with corticosteroids and, if necessary, anti-tumor necrosis factor-α therapy. Such a regimen carries a risk of serious side-effects including infections, and may potentially imply impaired antitumor effects. Vedolizumab is an anti-integrin α4β7 antibody with gut-specific immunosuppressive effects, approved for Crohn’s disease and ulcerative colitis. We report a case series of seven patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016. Clinical, laboratory, endoscopic, and histologic data were analyzed. Patients initially received corticosteroids but were steroid-dependent and/or partially refractory. One patient was administered infliximab but was refractory. The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days. Following vedolizumab therapy, all patients but one experienced steroid-free enterocolitis remission, with normalized fecal calprotectin. This was achieved after a median of 56 days from vedolizumab start, without any vedolizumab-related side-effects noted. The patient in whom vedolizumab was not successful, due to active ulcerative colitis, received vedolizumab prophylactically. This is the first case series to suggest that vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or partially refractory ICPI-induced enterocolitis. A larger prospective study to evaluate vedolizumab in this indication is warranted.

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Section: Discussionmentioning

confidence: 99%

Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis

Bergqvist

Hertervig

Gedeon

et al. 2017

Cancer Immunol Immunother

203

156

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“…CDI alone did not explain his ongoing symptoms, and the temporal relationship with ipilimumab administration, endoscopic findings and improvement with steroids, supported the diagnosis of ipilimumab-associated colitis. It is also important to look for non-colitis related irAEs in these patients, as these may frequently coexist with colitis 6 8. Skin rash and liver dysfunction can occur, and these were ruled out by a careful examination and laboratory testing, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment of grades 1 and 2 diarrhoea in ipilimumab-associated colitis is largely supportive, with fluid and electrolyte replenishment, and antidiarrhoeals 8 9. Patients with persistent grade 2 symptoms or grades 3 and 4 symptoms deserve endoscopic evaluation.…”

Section: Discussionmentioning

confidence: 99%

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Ipilimumab-associated colitis or refractoryClostridium difficileinfection?

Gupta

Khanna²

2015

BMJ Case Reports

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SUMMARYWe present a case of a patient with a diagnostic dilemma who was referred for possible faecal microbiota transplantation (FMT) for refractory diarrhoea secondary to Clostridium difficile infection (CDI). On detailed history, the patient was exposed to ipilimumab concomitantly while being treated for CDI, and was instead diagnosed with diarrhoea secondary to superimposed ipilimumab-associated colitis. Ipilimumab is an anti-CTLA4 monoclonal antibody approved for use in metastatic melanoma and under trial for other indications. Ipilimumab is associated with several immune-related adverse effects, of which diarrhoea and colitis are the most common. While FMT has shown tremendous efficacy in managing recurrent and refractory CDI, it was not offered in this case due to negative C. difficile testing showing a high degree of suspicion for ipilimumab-associated colitis due to recent drug use. Our patient was successfully managed with fluid resuscitation and steroids, and remains symptom free at last follow-up at 9 months. BACKGROUND

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“…1 We agree and recommend that infectious aetiologies (using stool studies such as Clostridium difficile PCR, enteric pathogens PCR or culture, ova and parasite examination or special stains for acid-fast organisms in the appropriate clinical context) should be considered in patients receiving anti-CTLA 4 therapies presenting with diarrhoea and/or colitis. 2,3 Additionally, in the appropriate clinical context, CMV infection should be excluded in these patients prior to initiating immunosuppressive therapy as it may result in worsening of underlying infection. 3 The diagnosis of CMV colitis may be missed if based on only negative plasma PCR results, 4 and stool CMV culture may be false positive or may represent asymptomatic viral shedding.…”

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confidence: 99%