Abstract
Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4 (CTLA-4), an inhibitory molecule typically expressed on T cells. Blockade of CTLA-4 induces an overall activation of T cells, including an immune-mediated anti-tumour response. Unfortunately, this broad T cell stimulation also causes immune-related adverse events (irAEs), such as dermatitis, colitis, hepatitis and hypophysitis. Ipilimumab is currently available in Belgium as a second line of treatment for patients with advanced melanoma, and is used at a dose of 3 mg/kg of body weight, although higher doses were previously used (up to 10 mg/kg). We performed a retrospective analysis to identify melanoma patients treated with ipilimumab at the Ghent University Hospital between 2010 and 2013. Data on symptoms, stage and timing of ipilimumab, response and adverse events were collected with a special attention to endocrine disturbances, going from a limited involvement of one endocrine axis to development of a hypophysitis. We identified a total of 39 patients with stage III (No. = 7) or stage IV (No. = 32) melanoma, who received a dose of 3 (No. = 31) or 10 (No. = 8) mg/kg. Six patients developed a severe form of irAEs, including one case of colitis (2 %), one case of sarcoidosis (2 %) and 4 cases (10 %) of hypophysitis. Hypophysitis developed between the second and fourth cycle of ipilimumab administration and was independent of the dose used. We describe four cases of involvement of the pituitary gland during treatment with ipilimumab. When managed with vigilant monitoring and high-dose corticosteroids, the acute symptoms resolve, but lifelong hormone substitution therapy can be necessary. Involvement of the pituitary axes is a severe side effect of treatment with ipilimumab with an urgent need for the correct medical intervention.
Similar content being viewed by others
References
Nikolaou V et al. Emerging trends in the epidemiology of melanoma. Br. J. Dermatol. 170(1), 11–19 (2014)
F. Liu et al., A unique gender difference in early onset melanoma implies that in addition to ultraviolet light exposure other causative factors are important. Pigment Cell Melanoma Res. 26(1), 128–135 (2013)
G. Berthod et al., Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J. Clin. Oncol. 30(17), e156–e159 (2012)
S. Andrews et al., Characteristics and management of immunerelated adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma. Cancer Manag. Res. 4, 299–307 (2012)
Fong ZV et al. Comparison of melanoma guidelines in the United States, Canada, Europe, Australia and New Zealand: A critical appraisal and comprehensive review. Br. J. Dermatol. 170(1), 20–30 (2014)
S. Wilgenhof et al., Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor. Anticancer Res. 32(4), 1355–1359 (2012)
J.M. Jeter et al., Ipilimumab pharmacotherapy in patients with metastatic melanoma. Clin. Med. Insights Oncol. 6, 275–286 (2012)
A. Juszczak et al., Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. Eur. J. Endocrinol. 167(1), 1–5 (2012)
J.S. Weber et al., Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30(21), 2691–2697 (2012)
F.S. Hodi et al., Improved survival with ipilimumab in patients with metastatic melanoma. NEJM 363(8), 711–723 (2010)
F. Torino et al., Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist 17(4), 525–535 (2012)
S.M. Corsello et al., Endocrine side effects induced by immune checkpoint inhibitors. J. Clin. Endocrinol. Metab. 98(4), 1361–1375 (2013)
G.Q. Phan et al., Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl. Acad. Sci. U S A 100(14), 8372–8377 (2003)
J.D. Wolchok et al., Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 11(2), 155–164 (2010)
D. Giacomo et al., Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access programme (EAP). J. Clin. Oncol. 31, 9065 (2013)
Chandra et al., Evaluating the safety of anti-CTLA-4 therapy in the elderly with unresectable melanoma. J. Clin. Oncol. 31, 9063 (2013)
P. Boasberg et al., Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. Semin. Oncol. 37(5), 440–449 (2010)
P. Tomasini et al., Ipilimumab: its potential in non-small cell lung cancer. Ther. Adv. Med. Oncol. 4(2), 43–50 (2012)
Z.R. Barnard et al., Hyponatremia associated with ipilimumab-induced hypophysitis. Med. Oncol. 29(1), 374–377 (2012)
K.J. Carpenter et al., Ipilimumab-induced hypophysitis: MR imaging findings. AJNR Am. J. Neuroradiol. 30(9), 1751–1753 (2009)
L. Min et al., Association of ipilimumab therapy for advanced melanoma with secondary adrenal insufficiency: a case series. Endocr. Pract. 18(3), 351–355 (2012)
J.S. Weber et al., Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 119(9), 1675–1682 (2013)
Conflict of interest
The authors have nothing to disclose and indicate no potential conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Marlier, J., Cocquyt, V., Brochez, L. et al. Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports. Endocrine 47, 878–883 (2014). https://doi.org/10.1007/s12020-014-0199-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-014-0199-9