Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis

doi:10.1016/j.ejca.2017.09.019

European Journal of Cancer

Volume 86, November 2017, Pages 248-256

https://doi.org/10.1016/j.ejca.2017.09.019 Get rights and content

Highlights

•
Checkpoint inhibitors can cause immune-related colitis (irColitis).
•
IrColitis can be refractory to immunosuppressive and immunomodulatory therapies.
•
Refractory irColitis is often caused by reactivation of cytomegalovirus (CMV).
•
CMV colitis can resolve after the application of ganciclovir.
•
Different repetitive diagnostic measures are needed to detect CMV colitis.

Abstract

Objectives

Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches.

Methods

Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected.

Results

We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053).

Conclusions

This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.

Section snippets

Background

Recently, monoclonal antibodies directed against different immune checkpoints have revolutionised the therapy of locally advanced and metastatic malignant melanoma and other human malignancies. The anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab as well as the combination of ipilimumab and nivolumab have shown increased progression-free and overall survival in several clinical studies in patients with advanced melanoma [1], [2], [3], [4], [5], [6]. While

Patient cohort

The skin cancer database of the Department of Dermatology of the University Hospital Essen was searched for melanoma patients treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab plus nivolumab between 2006 and 2016. Demographic as well as clinical data were collected for all identified patients. Digital patient records were then searched for the terms ‘diarrhea’ and ‘colitis’. Severity of irColitis was graded according to CTCAE version 4.03 criteria and

Patient cohort

In total, 370 patients were treated with checkpoint inhibitors from 2006 to 2016 at the Department of Dermatology of the University Hospital Essen. As shown in Table 1, 56.5% had received ipilimumab monotherapy, 35.7% PD-1 inhibitor monotherapy (pembrolizumab 22.7%, nivolumab 13%) and 7.8% the combination of ipilimumab and nivolumab. In the patient group with irColitis (n = 41, 11.1% of 370 patients), 73.2% of patients had received ipilimumab, 17.1% had received PD-1 inhibitors and 9.7% the

Discussion

IrColitis is a well-described adverse event of checkpoint inhibition. It can lead to fatal gastrointestinal perforations [9], [10], [11], [12] with deaths in around 1% of the patients treated with 10 mg/kg ipilimumab [13], [14]. Treatment algorithms have been established to standardise the treatment of irColitis. In most cases, irColitis responds to treatment with high-dose steroids with or without additional immune-modulators such as infliximab. Although checkpoint inhibitors recently have

Conflict of interest statement

None declared.

Acknowledgements

The authors would like to thank Marion Schwamborn for her technical support.

References (31)

F.S. Hodi et al.
Improved survival with ipilimumab in patients with metastatic melanoma
N Engl J Med
(2010)
D. Schadendorf et al.
Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma
J Clin Oncol
(2015)
C. Robert et al.
Pembrolizumab versus ipilimumab in advanced melanoma
N Engl J Med
(2015)
C. Robert et al.
Nivolumab in previously untreated melanoma without BRAF mutation
N Engl J Med
(2015)
J.S. Weber et al.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial
Lancet Oncol
(2015)
J. Larkin et al.
Combined nivolumab and ipilimumab or monotherapy in untreated melanoma
N Engl J Med
(2015)
J.S. Weber et al.
Management of immune-related adverse events and kinetics of response with ipilimumab
J Clin Oncol
(2012)
L. Spain et al.
Management of toxicities of immune checkpoint inhibitors
Cancer Treat Rev
(2016)
D. Berman et al.
Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma
Cancer Immun
(2010)
K.E. Beck et al.
Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4
J Clin Oncol
(2006)

K.A. Mitchell et al.

Ipilimumab-induced perforating colitis

J Clin Gastroenterol

(2013)

M. Slingerland et al.

Severe colitis while responding to ipilimumab in metastatic melanoma

Acta Oncol

(2012)

E.D. Kwon et al.

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

Lancet Oncol

(2014)

A.M. Eggermont et al.

Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial

Lancet Oncol

(2015)

M. Rao et al.

Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm

Int J Infect Dis

(2017)

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^☆: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

¹: These authors contributed equally.

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Original ResearchCytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis☆

Highlights

Abstract

Objectives

Methods

Results

Conclusions

Section snippets

Background

Patient cohort

Patient cohort

Discussion

Conflict of interest statement

Acknowledgements

Improved survival with ipilimumab in patients with metastatic melanoma

N Engl J Med

Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma

J Clin Oncol

Pembrolizumab versus ipilimumab in advanced melanoma

N Engl J Med

Nivolumab in previously untreated melanoma without BRAF mutation

N Engl J Med

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial

Lancet Oncol

Combined nivolumab and ipilimumab or monotherapy in untreated melanoma

N Engl J Med

Management of immune-related adverse events and kinetics of response with ipilimumab

J Clin Oncol

Management of toxicities of immune checkpoint inhibitors

Cancer Treat Rev

Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma

Cancer Immun

Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4

J Clin Oncol

Ipilimumab-induced perforating colitis

J Clin Gastroenterol

Severe colitis while responding to ipilimumab in metastatic melanoma

Acta Oncol

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

Lancet Oncol

Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial

Lancet Oncol

Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm

Int J Infect Dis

Original Research
Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis☆