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MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe

Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been sho...

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Autores principales: Seejore, Khyatisha, Giannoudi, Marilena, Osborn, Djoah, Lynch, Julie Marie, Dunwoodie, Elaine, Hook, Jane, Marples, Maria, Murray, Robert Douglas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208295/
http://dx.doi.org/10.1210/jendso/bvaa046.1486
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author Seejore, Khyatisha
Giannoudi, Marilena
Osborn, Djoah
Lynch, Julie Marie
Dunwoodie, Elaine
Hook, Jane
Marples, Maria
Murray, Robert Douglas
author_facet Seejore, Khyatisha
Giannoudi, Marilena
Osborn, Djoah
Lynch, Julie Marie
Dunwoodie, Elaine
Hook, Jane
Marples, Maria
Murray, Robert Douglas
author_sort Seejore, Khyatisha
collection PubMed
description Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been shown to significantly improve survival in patients with metastatic melanoma. Immune-related adverse events (irAEs) occur in some patients with increased T-cell activation, of which ipilimumab-related hypophysitis (IH) is an important endocrine complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients. Patients and Methods We retrospectively evaluated consecutive adult patients with melanoma treated between December 2010 and August 2019 at a tertiary cancer centre. All patients received ipilimumab (3mg/kg) monotherapy or in combination with PD-1 (programmed cell death protein 1) inhibitors (nivolumab or pembrolizumab). Symptoms, pituitary hormone assessment, pituitary imaging and patient survival were assessed. Results Of 189 patients, 23 patients (12.2%, 13 male; age 59.2±11.8 years) presented with hypophysitis, two having received ipilimumab monotherapy. The median onset was at 17.3 weeks (range: 6.7-160 weeks) after treatment start, occurring in 57% after the fourth infusion (n=13). Five patients developed late-onset IH (range: 30.1-160 weeks) whilst on treatment with PD-1 inhibitors. Three of the patients developing hypophysitis (13%) received only a single ipilimumab infusion. Additional irAEs were diagnosed in 16 patients (70%) with IH, including six cases of destructive thyroiditis and one of autoimmune diabetes. The main presenting symptom of IH was lethargy (n=18, 78%) followed by headache (n=8, 35%). Corticotroph deficiency with cortisol levels <83 nmol/l (<3μg/dL) at presentation were observed in all patients. At diagnosis, a drop in cortisol level of >70% over a median time of 22 days (range: 3-39 days) was evident in 87% patients. A fall in fT4 level of at least 20% from baseline was observed in ten patients (59%, 10/17 – after excluding patients with thyroiditis) at a median of 4 weeks (range: 0-8 weeks) prior to the diagnosis of IH. Gonadotroph deficiency was detected in three male patients. At the end of follow-up (median 14.3 months, range: 1-61.5 months after IH diagnosis), corticotroph deficiency was persistent in all patients; seven of ten patients recovered thyrotroph function and gonadotroph deficit resolved in one patient. Three patients with hypophysitis died within the first year of immunotherapy. Conclusion The incidence of IH was 12.2%, predominantly occurring after the fourth infusion. IH is characterised by acute severe drop in cortisol levels to less than 3μg/dL. A falling fT4 may herald development of ACTH deficiency.
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spelling pubmed-72082952020-05-13 MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe Seejore, Khyatisha Giannoudi, Marilena Osborn, Djoah Lynch, Julie Marie Dunwoodie, Elaine Hook, Jane Marples, Maria Murray, Robert Douglas J Endocr Soc Neuroendocrinology and Pituitary Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been shown to significantly improve survival in patients with metastatic melanoma. Immune-related adverse events (irAEs) occur in some patients with increased T-cell activation, of which ipilimumab-related hypophysitis (IH) is an important endocrine complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients. Patients and Methods We retrospectively evaluated consecutive adult patients with melanoma treated between December 2010 and August 2019 at a tertiary cancer centre. All patients received ipilimumab (3mg/kg) monotherapy or in combination with PD-1 (programmed cell death protein 1) inhibitors (nivolumab or pembrolizumab). Symptoms, pituitary hormone assessment, pituitary imaging and patient survival were assessed. Results Of 189 patients, 23 patients (12.2%, 13 male; age 59.2±11.8 years) presented with hypophysitis, two having received ipilimumab monotherapy. The median onset was at 17.3 weeks (range: 6.7-160 weeks) after treatment start, occurring in 57% after the fourth infusion (n=13). Five patients developed late-onset IH (range: 30.1-160 weeks) whilst on treatment with PD-1 inhibitors. Three of the patients developing hypophysitis (13%) received only a single ipilimumab infusion. Additional irAEs were diagnosed in 16 patients (70%) with IH, including six cases of destructive thyroiditis and one of autoimmune diabetes. The main presenting symptom of IH was lethargy (n=18, 78%) followed by headache (n=8, 35%). Corticotroph deficiency with cortisol levels <83 nmol/l (<3μg/dL) at presentation were observed in all patients. At diagnosis, a drop in cortisol level of >70% over a median time of 22 days (range: 3-39 days) was evident in 87% patients. A fall in fT4 level of at least 20% from baseline was observed in ten patients (59%, 10/17 – after excluding patients with thyroiditis) at a median of 4 weeks (range: 0-8 weeks) prior to the diagnosis of IH. Gonadotroph deficiency was detected in three male patients. At the end of follow-up (median 14.3 months, range: 1-61.5 months after IH diagnosis), corticotroph deficiency was persistent in all patients; seven of ten patients recovered thyrotroph function and gonadotroph deficit resolved in one patient. Three patients with hypophysitis died within the first year of immunotherapy. Conclusion The incidence of IH was 12.2%, predominantly occurring after the fourth infusion. IH is characterised by acute severe drop in cortisol levels to less than 3μg/dL. A falling fT4 may herald development of ACTH deficiency. Oxford University Press 2020-05-08 /pmc/articles/PMC7208295/ http://dx.doi.org/10.1210/jendso/bvaa046.1486 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Neuroendocrinology and Pituitary
Seejore, Khyatisha
Giannoudi, Marilena
Osborn, Djoah
Lynch, Julie Marie
Dunwoodie, Elaine
Hook, Jane
Marples, Maria
Murray, Robert Douglas
MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe
title MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe
title_full MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe
title_fullStr MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe
title_full_unstemmed MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe
title_short MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe
title_sort mon-290 ipilimumab immune-related acth deficiency is of acute onset and severe
topic Neuroendocrinology and Pituitary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208295/
http://dx.doi.org/10.1210/jendso/bvaa046.1486
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