Endocrine Side Effects Induced by Immune Checkpoint Inhibitors

Corsello, Salvatore Maria; Barnabei, Agnese; Marchetti, Paolo; Vecchis, Liana De; Salvatori, Roberto; Torino, Francesco

doi:10.1210/jc.2012-4075

Cited by 374 publications

(375 citation statements)

References 105 publications

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“…Hypophysitis secondary to ipilimumab administration, first reported in 2003 [13], is now well described, but the mechanism of pituitary injury remains unknown. It is still unclear whether the effects result from T cells specifically acting against antigens shared by tumour and normal cells or from the concomitant activation of multiple T cell populations with separate anti-host and anti-tumour activity [11][12][13].…”

Section: Discussionmentioning

confidence: 99%

Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports

et al. 2014

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“…Hypothyroidism is the second most common endocrinological irAE [36]. It is more common with the combination of Nivolumab and Ipilimumab (15%) and anti-PD-1 agents alone (4-10%) compared to Ipilimumab alone (2-4%) [2,4,19,25].…”

Section: Thyroid Dysfunctionmentioning

confidence: 99%

Section: Thyroid Dysfunctionmentioning

confidence: 99%

“…The management of irreversible hypothyroidism involves hormone replacement with levothyroxine which can be initiated at a dose of 1-1.5 mcg/kg /day and the immunotherapy can be continued with no discontinuation [5,7,36]. Symptomatic hyperthyroidism with tremor and tachycardia can be treated with beta-blockers or corticosteroids.…”

Section: Thyroid Dysfunctionmentioning

confidence: 99%

“…Subclinical or mild hypothyroidism is more common with a less than 1% of patients developing severe and life-threatening symptoms [2,4,19,25,36]. Most cases present as silent thyroiditis secondary to antithyroglobulin and antithyroperoxidase antibodies and hypothyroidism or after transient subclinical hyperthyroidism [33,36] and very rarely as a thyroid storm [37].The management of irreversible hypothyroidism involves hormone replacement with levothyroxine which can be initiated at a dose of 1-1.5 mcg/kg /day and the immunotherapy can be continued with no discontinuation [5,7,36]. Symptomatic hyperthyroidism with tremor and tachycardia can be treated with beta-blockers or corticosteroids.…”

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confidence: 99%

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2016

JCPCR

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Background: Over the last 5 years ever since Ipilimumab received FDA approval for the treatment of metastatic melanoma, immunotherapy as a treatment modality is making its presence felt in oncology clinics across the globe. While initially approved for the treatment of metastatic melanoma alone, the immunotherapy repertoire is ever expanding with its' utility being assessed for in the metastatic and adjuvant setting. The adverse effect profile from immunotherapy drugs differs from that of conventional chemotherapy that oncological services have trained in managing over the last few decades. This raises the need for educating health care professionals as the scenarios that patients present with at acute admissions or in clinic secondary to immune related adverse effects (iRAEs) can often be misleading. Aims:This review aims to synopsise the common and less common iRAEs and highlight their varied presentations, in addition to stressing the need to institute timely immunosuppression, which forms the cornerstone in the management of iRAEs.Recommendations: iRAEs have been recognised more frequently and in greater severity in dose dense and combination treatment regimens. While dermatological, gastrointestinal, hepatic toxicities in addition to endocrinopathies are the most commonly encountered iRAEs though other organ systems can be involved. The appropriate grading of an iRAEs' severity, delaying or discontinuing immunotherapy based treatment, supportive care, commencement of immunosuppression (with corticosteroids and/or steroid sparing agents) and a multidisciplinary approach are key constituents in the treatment pathway of iRAEs. Conclusion:Early recognition of iRAEs and timely commencement of appropriate immunosuppression is imperative in order to reduce the risk of significant morbidity and potential mortality. The management of iRAEs warrants a multidisciplinary approach which would be aided by the development of local guidelines and educational activities directed at providing health care professionals with the information and tools required to recognise and appropriately treat iRAEs. IntroductionOver the last few decades there has been an increasing interest in the field of cancer immunotherapy. The manipulation of the immune system using immunotherapeutic interventions has changed the therapeutic landscape in many type of cancers [1][2][3][4]. However, immunotherapy carries immune-related adverse effects (irAEs) which can be significant [5][6][7]. irAEs are usually reversible but occasionally can be life-threatening [5][6][7]. A retrospective study on the irAEs of Ipilimumab showed that 85% of patients experienced irAEs of any grade of whom 19% discontinued therapy [8]. 35% patients required systemic corticosteroids and 10% required anti-TNF therapy for irAEs [8]. There were no significant differences in overall survival in those with and without irAEs or between those who received corticosteroids or not [8,9]. Hence, this requires the development of treatment protocols and training of the healthcar...

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Melanoma and a Headache

2015

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A 60-year-old man with advanced melanoma presented with headaches and increasing fatigue during treatment with ipilimumab. Several months earlier, he presented to the emergency department with shortness of breath. Imaging revealed pulmonary emboli and incidental groin lymphadenopathy. Biopsy of a lymph node showed melanoma. He then underwent inguinal lymph node dissection and was found to have 9 lymph nodes involved with melanoma (stage IIIC melanoma).He was then treated with ipilimumab (3 mg/kg), a monoclonal antibody to cytotoxic T lymphocyte antigen-4 (CTLA-4), every 3 weeks, as part of an investigational adjuvant therapy clinical trial. When presenting for his fourth and final dose of ipilimumab, he reported central headaches, severe fatigue, poor appetite, intermittent nausea, and a mild rash. On examination, vital signs were within normal limits. Physical examination had largely unremarkable results except for a slightly red, raised rash over his chest and proximal extremities.Laboratory testing showed the following: thyrotropin, 0.02 mIU/L (reference range, 0.3-5.0 mIU/L), and free thyroxine, less than 0.25 ng/dL (reference range, 0.5-1.2 ng/dL; to convert to picomoles per liter, multiply by 12.871). Cosyntropin stimulation test showed a cortisol peak level of 0.9 μg/dL (reference range, >20 μg/dL; to convert to nanomoles per liter, multiply by 27.588). He had low corticotropin (<5 pg/mL; reference range, 7-51 pg/mL; to convert to picomoles per liter, multiply by 0.22) and testosterone levels (<0.1 ng/mL; reference range, 2-11 ng/mL; to convert to nanomoles per liter, multiply by 0.0347). Magnetic resonance imaging (MRI) of the brain is shown in the Figure.

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Endocrine Side Effects Induced by Immune Checkpoint Inhibitors

Abstract: Although reports of endocrine side effects caused by cancer immune therapy are abundant, their exact prevalence and mechanism are unclear. Well-designed correlative studies oriented to finding and validating predictive factors of autoimmune toxicity are urgently needed.

Cited by 374 publications

References 105 publications

Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports

Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports

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Melanoma and a Headache

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