Distinct clinical features and prognosis between persistent and temporary thyroid dysfunctions by immune-checkpoint inhibitors

Immune checkpoint inhibitors block the checkpoint molecules. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). We collect recent published results about autoimmune endocrine dysfunctions associated with cancer antibody immunotherapies. These agents cause a raised immune response leading to immune-related adverse events (irAEs), varying from mild to fatal, based on the organ system and severity. Immune-related endocrine toxicities are usually irreversible in 50% of cases, and include hypophysitis, thyroid dysfunctions, type 1 diabetes mellitus, and adrenal insufficiency. Anti-PD-1-antibodies are more frequently associated with thyroid dysfunctions (including painless thyroiditis, hypothyroidism, thyrotoxicosis, or thyroid storm), while the most frequent irAE related to anti-CTLA-4-antibodies is hypophysitis. The combination of anti-CTLA-4 and anti-PD-1 antibodies is associated with a 30% chance of irAEs. Symptoms and clinical signs vary depending on the target organ. IrAEs are usually managed by an oncological therapist, but in more challenging circumstances (i.e., for new onset insulin–dependent diabetes, hypoadrenalism, gonadal hormones dysfunctions, or durable hypophysitis) an endocrinologist is needed.

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Patterns of thyroid dysfunctions during treatment with immune checkpoint inhibitors (ICI) in 59 solid cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18567 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18567-e18567

Author(s):

Yong Jiang ◽

Li Yang ◽

Yin Han ◽

Yongshen Zhang ◽

Feng-Ming Kong

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Thyroid Function ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Thyroid Dysfunction ◽

Checkpoint Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Thyroid Dysfunctions

e18567 Background: Immune checkpoint inhibitors (ICI) have now become the mainstay treatment in patients with many kinds of cancers. Thyroid dysfunction as the most common endocrine toxicity is poorly understood. This study aimed to report hypothyroidism and exam its changing dynamtic in our first series of patients treated with ICI. Methods: This is a retrospective study. Patients received nivolumab or pembrolizumab between July 2018 and December 2019 were considered. Patient must have euthyroidism within the 3 months before immunotherapy and those had previous use of levothyroxine were excluded. They were monitored by thyroid function tests every cycle until stopping ICI. Patients must have received at least 3 cycles of antibody treatment. Results: Among 89 patients treated, 59 met the inclusion criteria. There were 33 males, 26 females, including 26 (44.1%) nivolumab, and 33 (55.9%) pembrolizumab. Median age was 62 years [range: 27-88]). Cancer diagnoses observed were non small cell lung cancer 17(28.8%), small cell lung cancer 4 (6.8%),liver cancer 9 (15.3%), head and neck cancer 5 (8.5%), esophageal cancer4 (6.8%) colon cancer 3 (5.1%), nasopharygeal carcinoma 3 (5.1%) melanoma 3 (5.1%) and other cancers 11(18.6%). There were 9 patients (15.3%) developed a thyroid dysfunction, including 5 females. Four patients had thyrotoxicosis (median onset: 8 weeks) followed by hypothyroidism. There were three types of thyroid dysfunctions: the first type patients 3 (33.3%) had a brief time period of TSH flair (peak 17.4-57.8) after the first cycle of ICI, followed by TSH dramatic drop companied with rising fT4, which usually returned to normal level during 3-4 cycles of . The other 4 patients (44.4%) with thyroid dysfunction presented with remarkably elevated TSH (15.43-125.2) after 3.5-10 months’ treatment, followed by hypothyroidism development with a need of levothyroxine. The remaining 1 patient had a third type of thyroid dysfunction with elevated TSH, elavated more while the treatment continue, the patient should be given levothyroxine as soon as possible. Additionally, 1 patient developed hypopituitarism presented with both low level of TSH and fT4 after 10 month treatment. There was no significant difference in patient characteristics between patients with hypothyroidism and those without. Conclusions: There are heterogeneity in thyroid function and hypothyroidism after ICI. Before more experience is gained, frequent monitoring of thyroid function during ICI is warranted for prompt management of the hypothyroidism.

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Clinical Features of Liver Injury Induced by Immune Checkpoint Inhibitors in Japanese Patients

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2019/6391712 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Koji Imoto ◽

Motoyuki Kohjima ◽

Tomonobu Hioki ◽

Tomoyuki Kurashige ◽

Miho Kurokawa ◽

...

Keyword(s):

Liver Injury ◽

Liver Biopsy ◽

Clinical Features ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Case Series ◽

Japanese Patients ◽

Malignant Neoplasms ◽

Drug Induced

Aim. Immune checkpoint inhibitors (ICIs) have improved the survival rate of patients carrying various malignant neoplasms. Despite their efficacy, ICIs occasionally induce liver injury as an immune-related adverse event (irAE). This study aimed to reveal the clinical features of the hepatic irAE in Japanese patients. Methods. Among 387 patients treated with ICIs, those who developed drug-induced liver injury were investigated. We also describe the histological findings and clinical courses of four patients with hepatic irAE who underwent liver biopsy. Results. Among the 56 patients with all-grade liver injury, only 11 (19.6%) showed hepatocellular-type liver injury, which resembled autoimmune hepatitis. Thirty-four patients (60.7%) developed cholestatic or mixed-type liver injury, although only one patient showed abnormal image findings in the bile duct. Most patients with grade ≤2 liver injury improved spontaneously, while two patients with biliary dysfunction required ursodeoxycholic acid or prednisolone. Among eight patients with grade ≥3 liver injury, three required no immunosuppressants and five were treated with prednisolone (three of five patients required other types of immunosuppressants). Four patients in the case series showed diverse clinical features in terms of hepatotoxic pattern, symptoms, and the interval time between the initiation of immunotherapy and the onset of the hepatic irAE. Conclusions. Our findings suggest that ICIs could cause microscopic biliary disorder without any abnormal image finding. Because the hepatic irAE presents diverse clinical features, liver biopsy is recommended to provide appropriate treatments.

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Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-020-03448-8 ◽

2020 ◽

Author(s):

Atsushi Yamamoto ◽

Yoshihiko Yano ◽

Yoshihide Ueda ◽

Eiichiro Yasutomi ◽

Yuri Hatazawa ◽

...

Keyword(s):

Clinical Features ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Mediated

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Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune‐checkpoint inhibitors

Cancer Science ◽

10.1111/cas.14363 ◽

2020 ◽

Vol 111 (5) ◽

pp. 1468-1477 ◽

Cited By ~ 4

Author(s):

Chiaki Kurimoto ◽

Hidefumi Inaba ◽

Hiroyuki Ariyasu ◽

Hiroshi Iwakura ◽

Yoko Ueda ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Thyroid Dysfunctions

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Clinical features affecting efficacy of immune checkpoint inhibitors in pretreated patients with advanced NSCLC: a Danish nationwide real-world study

Acta Oncologica ◽

10.1080/0284186x.2021.2023213 ◽

2022 ◽

pp. 1-8

Author(s):

Mette T. Mouritzen ◽

Karen F. Junker ◽

Andreas Carus ◽

Morten Ladekarl ◽

Peter Meldgaard ◽

...

Keyword(s):

Clinical Features ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Advanced Nsclc ◽

Checkpoint Inhibitors ◽

Pretreated Patients

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Molecular and clinical features of hospital admissions and immunotherapy related adverse events of immune checkpoint inhibitors in thoracic malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18192 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18192-e18192

Author(s):

Dan Zhao ◽

Isa Mambetsariev ◽

Chen Chen ◽

Haiqing Li ◽

Jeremy Fricke ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Clinical Features ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Hospital Admissions ◽

Checkpoint Inhibitors ◽

Wilcoxon Test ◽

Thoracic Malignancies

e18192 Background: Immunotherapy related adverse events (irAEs) and hospital admissions with Immune Checkpoint Inhibitors (ICIs) in thoracic malignancies remain poorly characterized. Methods: Admissions after ICIs in all thoracic malignancies patients received ICIs at City of Hope (total 384) were identified as of 11/8/2018. IrAEs, outcomes, pathology and next-generation sequencing (NGS) data were collected, including Tumor mutation burden (TMB) and PD-L1 (22C3). Length of stay (LOS) and overall survival (OS) was calculated. Unpaired T-tests if data passed normality test, Chi-square and Fisher’s exact test, Gehan-Breslow-Wilcoxon test were used for comparison between 2 groups (irAEs VS no irAEs) for LOS, demographics and genetics, and survival respectively. Results: 100 patients had hospital admissions after ICIs therapy and 90 patients (41 women, 49 men) had stage IV disease (63 lung adenocarcinomas, 14 squamous cell lung cancer, 5 small cell lung cancer, 8 others). 28 out of 90 patients had irAEs (10 pneumonitis/pneumonia, 4 adrenal insufficiencies, 4 colitis, 3 liver toxicities, 2 nephritis, 1 heart failure, 1 pancreatitis, 1 diabetic ketone acidosis, and others including multiple irAEs). There was no difference between the patients who had irAEs VS no irAEs in LOS (median 7 days VS 6 days, P = 0.57). Patients with irAEs had more invasive diagnostic procedures than no irAEs (53.6% VS 25.8%, P = 0.02). There was a trend of longer OS in irAEs patients (median 16.4 months VS 6.8 months, P = 0.13) than no irAEs. Male gender (71.4% (20/28) VS 46.8% (29/62), OR = 2.85, P = 0.04) and smoking exposure (89.3% (25/28) VS 58.1% (36/62), OR = 6.0, P < 0.01) were associated with irAEs patients. Genetic alterations of LRP1B gene (83.3% (5/6) VS 26.9% (7/26), OR = 13.6, P = 0.02) and MLL3 gene (66.7% (4/6) VS 19.2% (5/26), OR = 8.4, P = 0.04) were associated with patients who had irAES. No difference was found in age, lines of therapy, TP53, KRAS, EGFR, STK11, PIK3CA, TMB, PD-L1 between the irAEs and no irAEs patients. Conclusions: Hospitalized patients who had irAEs had similar LOS compared with patients without irAEs but potentially longer OS. Gender, smoking status and genes associated with irAEs and ICIs outcomes were explored. Larger dataset for molecular and clinical features was planned.

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