Immune Checkpoint Inhibitors as a Threat to the Hypothalamus–Pituitary Axis: A Completed Puzzle

Barnabei, Agnese; Corsello, Andrea; Paragliola, Rosa Maria; Iannantuono, Giovanni Maria; Falzone, Luca; Corsello, Salvatore Maria; Torino, Francesco

doi:10.3390/cancers14041057

Cited by 6 publications

(4 citation statements)

References 81 publications

(245 reference statements)

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“…The spectrum of ICI-induced hypothalamus–pituitary autoimmunity includes the anterior hypophysitis, infundibulo-neurohypophysis, panhypophysitis, and hypothalamitis, among which the anterior hypophysitis is the most common entity [ 66 ]. The higher incidence of anterior pituitary deficiency as compared with the rare manifestation of posterior pituitary dysfunction in ICI-induced hypophysitis may be attributed to the rich vascularity of the anterior pituitary gland with higher exposure to systemic therapy and its associated toxicities [ 57 ].…”

Section: Literature Review Resultsmentioning

confidence: 99%

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

Mytareli

Ziogas

Karampela

et al. 2023

Cancers

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Immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancers, either in adjuvant or metastatic settings. Regarding safety, endocrine adverse events (AEs) are some of the most common AEs in ICI-treated patients, with thyroid dysfunction and hypophysitis being the most frequent disorders. However, there are also some rare and very rare immune-related (ir) endocrine complications (incidence between ≥1/10,000 to <1/1000 and <1/10,000, respectively, according to the established classification) that have been reported in isolated case reports, with limited data about their management. In this systematic review, we summarize all published cases with primary adrenal insufficiency, central diabetes insipidus, primary hypoparathyroidism, lipodystrophy, osteoporosis, hypergonadotrophic hypogonadism, or Cushing disease and discuss their diagnostic and therapeutic approaches as well as the current knowledge on their pathophysiology. In these ICI-treated cancer patients, the presentation of symptoms unrelated to their underlying malignancy has led to further diagnostic tests, including hormonal profile and functional assays which subsequently confirmed endocrinopathy, while the assessment of autoantibodies was rarely available. In most of these cases, the exact pathogenesis remained unknown, and the endocrine dysfunction was permanent, requiring lifelong supplementation. Although endrocine irAEs are rare, physicians must be aware of these irAEs to recognize them on time and treat them appropriately.

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Section: Literature Review Resultsmentioning

confidence: 99%

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

Mytareli

Ziogas

Karampela

et al. 2023

Cancers

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“…More records should be screened to further confirm the application value of the trigger. L21 and L22 are mainly used for the adverse events of pituitaritis caused by the new antitumor drug PD-1/PD-L1 preparation, which is a common irAE in patients with cancer treated with PD-1/PD-L1 ( 27 ). The failure to be identified may be related to the insufficient application of PD-1/PD-L1 preparation in our hospital.…”

Section: Discussionmentioning

confidence: 99%

The application of Global Trigger Tool in monitoring antineoplastic adverse drug events: a retrospective study

Liu,

Xia

et al. 2024

Front. Oncol.

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ObjectiveThis study aimed to establish an antineoplastic drugs trigger tool based on Global Trigger Tool (GTT), to examine the performance by detecting adverse drug events (ADEs) in patients with cancer in a Chinese hospital (a retrospective review), and to investigate the factors associating with the occurrence of antineoplastic ADEs.MethodsBased on the triggers recommended by the GTT and those used in domestic and foreign studies and taking into account the scope of biochemical indexes in our hospital, some of them were adjusted. A total of 37 triggers were finally developed. Five hundred medical records of oncology patients discharged in our hospital from 1 June 2020 to 31 May 2021 were randomly selected according to the inclusion and exclusion criteria. These records were reviewed retrospectively by antineoplastic drugs trigger tool. The sensitivity and specificity of the triggers were analyzed, as well as the characteristics and risk factors for the occurrence of ADEs.ResultsThirty-three of the 37 triggers had positive trigger, and the sensitivity rate was 91.8% (459/500). For the specificity, the positive predictive value of overall ADEs was 46.0% (715/1556), the detection rate of ADEs was 63.0% (315/500), the rate of ADEs per 100 admissions was 136.0 (95% CI, 124.1–147.9), and the rate of ADEs per 1,000 patient days was 208.33 (95% CI, 201.2–215.5). The top three antineoplastic drugs related to ADEs were antimetabolic drugs (29.1%), plant sources and derivatives (27.1%), and metal platinum drugs (26.3%). The hematologic system was most frequently involved (507 cases, 74.6%), followed by gastrointestinal system (89 cases, 13.1%). Multivariate logistic regression analysis showed that the number of combined drugs (OR = 1.14; 95% CI, 1.07–1.22; P < 0.001) and the previous history of adverse drug reaction (ADR) (OR = 0.38; 95% CI, 0.23–0.60; P < 0.001) were the risk factors for ADEs. The length of hospital stay (OR = 0.40; 95% CI, 0.14–1.12; P < 0.05) and the previous history of ADR (OR = 2.18; 95% CI, 1.07–4.45; P < 0.05) were the risk factors for serious adverse drug events (SAE).ConclusionThe established trigger tool could be used to monitor antineoplastic drugs adverse events in patients with tumor effectively but still needs to be optimized. This study may provide some references for further research in order to improve the rationality and safety of antineoplastic medications.

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“…An inverse signal indicates may work in an inhibitory manner [38]. Among the pituitary-related adverse events caused by ICIs, diabetes insipidus is rare, occurring only 0.7% of the time, and has been reported to result from panhypopituitarism, a selective injury to the posterior pituitary gland or hypothalamus [39]. The mechanism underlying the higher prevalence of ICI-induced adverse events in the anterior pituitary than in the posterior pituitary or hypothalamus remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Pituitary-Related Adverse Events and Onset Patterns Caused by Immune Checkpoint Inhibitors: Analysis Using the Japanese Adverse Drug Event Report Database

Asano,

Noguchi,

Kimura

et al. 2023

Medicina

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Background and Objectives: One type of immune-related adverse event caused by immune checkpoint inhibitors (ICIs) is pituitary-related adverse events. The management of pituitary-related adverse events is important because they can be fatal if not treated promptly. Therefore, this study was conducted to investigate the onset of pituitary-related adverse events using the Japanese Adverse Drug Report (JADER) database. Materials and Methods: Cases registered in the JADER database from 2004 to 2019 were used. The target drugs were ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab, and the target adverse events were the high-level terms “Anterior pituitary hypofunction,” “Anterior pituitary hyperfunction,” “Posterior pituitary disorder,” and “Pituitary neoplasm” in the Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J). The information component (IC) was used for signal detection and IC delta (ICΔ) was used for women-related signals. Onset timing and patterns were analyzed using the Weibull distribution. Results: Signals were detected with ipilimumab, nivolumab, pembrolizumab, and atezolizumab in “Anterior pituitary hypofunction,” with ICs and 95% credible intervals (95%CrI) of 5.53 (5.30–5.69), 4.96 (4.79–5.08), 4.04 (3.76–4.25), and 2.40 (1.53–3.00). Significant signals were detected in women, except for atezolizumab. Additionally, the time of onset was classified as the wear-out failure type. Inverse signals were detected with ipilimumab and nivolumab in “Posterior pituitary disorder,” with ICs (95%CrI) of −1.24 (−2.80–−0.26), and −0.89 (−1.64–−0.37). Conclusions: Anterior pituitary hypofunction is likely to occur with the long-term administration of ipilimumab, nivolumab, and pembrolizumab. Further investigation is needed to determine the differences in the tendencies to detect signals in the anterior and posterior pituitaries between ipilimumab and nivolumab.

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Immune Checkpoint Inhibitors as a Threat to the Hypothalamus–Pituitary Axis: A Completed Puzzle

Cited by 6 publications

References 81 publications

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

The Uncharted Landscape of Rare Endocrine Immune-Related Adverse Events

The application of Global Trigger Tool in monitoring antineoplastic adverse drug events: a retrospective study

Pituitary-Related Adverse Events and Onset Patterns Caused by Immune Checkpoint Inhibitors: Analysis Using the Japanese Adverse Drug Event Report Database

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