Abstract
Objective
Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4, that has been shown to significantly improve survival in patients with metastatic melanoma. Blocking cytotoxic T-lymphocyte antigen-4 elicits T cell activation, proliferation and anti-tumor response, but can also trigger immune-related adverse events. Among immune-related endocrinopathies, hypophysitis represents the most frequent, with an incidence up to 17% in patients treated with ipilimumab.
Design and methods
We report nine cases of ipilimumab-induced hypophysitis in a cohort of 273 patients treated with ipilimumab between 2006 and 2015, as part of clinical trials or after its marketing. Thyroid function tests were scheduled at screening and during follow up (every 21 days) in all patients. Cortisol, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, and estradiol (for females) or testosterone (for males), prolactin, growth hormone, insulin-like growth factor 1 were measured only in case of clinical suspicion.
Results
The incidence of hypophysitis was 3.3%. The most frequent pituitary failure was adrenocorticotropic hormone and thyroid stimulating hormone secretion with a complete recovery of thyroid stimulating hormone, but not of adrenocorticotropic hormone during follow up. All patients had negative pituitary antibodies. The main symptoms at diagnosis were fatigue and headache.
Conclusion
Clinicians should be aware about the risk of hypophysitis during treatment with immune check-point inhibitors and the necessity of investigating pituitary function during therapy. Pituitary magnetic resonance imaging does not seem pivotal for a definite diagnosis if not performed at the onset of disease.
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References
F.S. Hodi, S.J. O'Day, D.F. McDermott, R.W. Weber, J.A. Sosman, J.B. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, J.C. Hassel, W. Akerley, A.J. van den Eertwegh, J. Lutzky, P. Lorigan, J.M. Vaubel, G.P. Linette, D. Hogg, C.H. Ottensmeier, C. Lebbé, C. Peschel, I. Quirt, J.I. Clark, J.D. Wolchok, J.S. Weber, J. Tian, M.J. Yellin, G.M. Nichol, A. Hoos, W.J. Urba, Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010)
S.M. Corsello, A. Barnabei, P. Marchetti, L. De Vecchis, R. Salvatori, F. Torino, Endocrine side effects induced by immune checkpoint inhibitors. J. Clin. Endocrinol. Metab. 98, 1361–1375 (2013)
A.T. Faje, R. Sullivan, D. Lawrence, N.A. Tritos, R. Fadden, A. Klibanski, L. Nachtigall, Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J. Clin. Endocrinol. Metab. 99, 4078–4085 (2014)
M. Ryder, M. Callahan, M.A. Postow, J. Wolchok, J.A. Fagin, Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr. Relat. Cancer. 21, 371–381 (2014)
L. Min, F.S. Hodi, A. Giobbie-Hurder, P.A. Ott, J.J. Luke, H. Donahue, M. Davis, R.S. Carroll, U.B. Kaiser, Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. Clin. Cancer Res. 21, 749–755 (2015)
F. Albarel, C. Gaudy, F. Castinetti, T. Carré, I. Morange, B. Conte-Devolx, J.J. Grob, T. Brue, Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur. J. Endocrinol. 172, 195–204 (2015)
A.M. Di Giacomo, M. Biagioli, M. Maio, The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin. Oncol. 37, 499–507 (2010)
S. Iwama, A. De Remigis, M.K. Callahan, S.F. Slovin, J.D. Wolchok, P. Caturegli, Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl. Med. 6, 230ra45 (2014)
A.V. Maker, J.C. Yang, R.M. Sherry, S.L. Topalian, U.S. Kammula, R.E. Royal, M. Hughes, M.J. Yellin, L.R. Haworth, C. Levy, T. Allen, S.A. Mavroukakis, P. Attia, S.A. Rosenberg, Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J. Immunother. 29, 455–463 (2006)
A. Faje, Immunotherapy and hypophysitis: clinical presentation, treatment, and biological insights. Pituitary 19, 82–92 (2016)
P. Caturegli, G. Di Dalmazi, M. Lombardi, F. Grosso, H.B. Larman, T. Larman, G. Taverna, M. Cosottini, I. Lupi, Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am. J. Pathol. 186, 3225–3235 (2016)
A. Ricciuti, A. De Remigis, M.A. Landek-Salgado, L. De Vincentiis, F. Guaraldi, I. Lupi, S. Iwama, G.S. Wand, R. Salvatori, P. Caturegli, Detection of pituitary antibodies by immunofluorescence: approach and results in patients with pituitary diseases. J. Clin. Endocrinol. Metab. 99, 1758–1766 (2014)
Acknowledgements
Michele Maio has received research grants and has taken part to advisory boards by Bristol-Myers-Squibb.
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This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Brilli, L., Danielli, R., Ciuoli, C. et al. Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab. Endocrine 58, 535–541 (2017). https://doi.org/10.1007/s12020-017-1289-2
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DOI: https://doi.org/10.1007/s12020-017-1289-2