Incidence of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors, Case Series from Two Tertiary Care Centeers in Dubai, UAE

Introduction: Immune checkpoint inhibitors (ICI) represent a major component of systemic therapy in advanced malignancy. Studies have reported unique spectrum of toxicity profile of ICI as compared to systemic chemotherapy. Aim of this study is to evaluate toxicities of ICI in our population and to compare this with published data. Material and Methods: We retrospectively reviewed medical records of patients treated with ICI at Dubai hospital and American hospital Dubai from November 2015 to April 2019. After patient identification from hospitals cancer registry, data regarding patients’ demographics, cancer type, type of ICI, adverse events, and duration of treatment were collected. Results: Forty-Five patients were identified with median age of 60 (27-80) years. 27 (60%) patients were male and 18 (40%) were female. Underlying diagnosis was lung cancer (n=25), renal cell cancer (n=6), melanoma (n=5), bladder cancer (n=3), Hodgkins lymphoma (n=3) and other malignancies (n=3). Majority of patients received Nivolumab (n=20, 44%) followed by Pembrolizumab (n=19, 42%), Atezolizumab (n=4, 9%) and Durvalumab (n=2, 5%) respectively. Thyroid dysfunction was the most common side effect observed in 17 (38%) patients including hypothyroidism (n=12, 27%) and hyperthyroidism (n=5, 11%). 53 % patients treated with Nivolumab developed thyroid dysfunction as compared to Pembrolizumab (22%). 7 patients (16%) had elevated liver enzymes. Grade II and III hepatotoxicity was noted in 1 patient (2.2 %) each. One patient (2.2 %) developed grade II skin toxicity. One patient (2.2 %) developed grade III colitis. Grade II, III and IV pneumonitis was observed in 2 (4.4 %), 1 (2.2%) and 1 (2.2%) patient respectively. Immune mediated adverse events were managed according to standard guidelines and 2 patients (4.4 %) had treatment discontinuation due to grade IV Pneumonitis and grade III Colitis. Conclusion: Our study reports relatively higher incidence of thyroid adverse events in patients treated with ICI. The incidence of grade III-IV immune related toxicity remains low. Overall treatment with ICI was tolerated reasonably well and toxicity was manageable.

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Autoimmune encephalitis associated with Ma2 antibodies and immune checkpoint inhibitor therapy

Practical Neurology ◽

10.1136/practneurol-2019-002464 ◽

2020 ◽

Vol 20 (3) ◽

pp. 256-259 ◽

Cited By ~ 1

Author(s):

Shane Lyons ◽

Ronan Joyce ◽

Patrick Moynagh ◽

Luke O'Donnell ◽

Silive Blazkova ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Autoimmune Encephalitis ◽

Advanced Malignancy ◽

Temporal Lobes ◽

Stage 4 ◽

Fluid Attenuated Inversion Recovery ◽

Checkpoint Inhibitor Therapy

Immune checkpoint inhibitors have transformed the treatment of advanced malignancy, while increasing the risk of immune-related adverse events. A 56-year-old woman who had received nivolumab for stage 4 renal cell carcinoma subsequently developed altered behaviour, memory deficits and worsening of previously stable epilepsy. MR scan of the brain showed bilateral FLAIR (fluid-attenuated inversion recovery) hyperintensity of the mesial temporal lobes, and there were anti-Ma2 antibodies in both serum and cerebrospinal fluid. She was treated with corticosteroids but developed further clinical relapses requiring immunoglobulin and rituximab. The immune-related adverse events relating to immune checkpoint inhibitors are an emerging challenge for the neurologist. Some cases are refractory and require serial immunosuppression.

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Association between the type of thyroid dysfunction induced by immune checkpoint inhibitors and prognosis in cancer patients

10.21203/rs.3.rs-841797/v1 ◽

2021 ◽

Author(s):

Han-sang Baek ◽

Chaiho Jeong ◽

Kabsoo Shin ◽

Jaejun Lee ◽

Dong-Jun Lim ◽

...

Keyword(s):

Subclinical Hypothyroidism ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Thyroid Dysfunction ◽

Checkpoint Inhibitors ◽

Hazard Ratio ◽

Cancer Type ◽

Significant Difference ◽

The Difference ◽

Lower Hazard

Abstract Background Immune checkpoint inhibitors (ICIs) cause thyroid immune-related adverse effects (irAEs). However, associations between each type of thyroid immune-related adverse effect (irAE) and the anti-tumor effect of ICI remains unknown. This study aimed to determine the effects of each type of thyroid dysfunction on patient survival. Methods Patients who initiated ICI treatment from January 2015 to December 2019 in Seoul St. Mary’s Hospital were retrospectively analyzed. Thyroid dysfunction was classified into four types: newly developed overt or subclinical hypothyroidism, thyrotoxicosis, worsened hypothyroidism, and subclinical hyperthyroidism. Patients were divided into two groups according to the presence or absence of thyroid dysfunction. Results Among the 196 patients, 66 (33.7%) developed thyroid irAEs. There was no significant difference in age, sex, or cancer type between the two groups. The overall survival in patients with thyroid irAEs was significantly higher than that in patients without thyroid irAEs (38 months vs. 13 months, respectively, p = 0.005). After adjusting for confounding factors, the hazard ratio for mortality in the thyroid irAE group compared to the no thyroid irAE group was 0.520 (p = 0.007). Newly developed overt or subclinical hypothyroidism patients showed a significantly lower hazard ratio for morbidity of 0.309 (p = 0.001). Patients with thyrotoxicosis showed a worse hazard ratio for morbidity than those without thyroid irAE, although the difference was not statistically significant. Conclusions It was verified that ICI treatment-induced thyroid dysfunction was associated with better survival, even in the real-world practice. Thus, endocrinologists should cooperate with oncologists to monitor patients treated with ICIs.

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639 Immune-related thyroid dysfunction in patients with existing thyroid dysfunction

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0639 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A675-A675

Author(s):

Francois Kaleta ◽

Heather Brody ◽

Praveen Namireddy

Keyword(s):

New York ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Thyroid Dysfunction ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Increased Risk ◽

Endocrinological Investigation

BackgroundThyroid dysfunction is a well known side effect of immune checkpoint blockade (ICB) and is one of the most common causes of immune-related adverse events (IRAE). The incidence varies with each individual therapy but generally estimated to be in the range between 6–18% per one study. Hypothyroidism and thyroiditis are the most common manifestations. Initial hyperthyroidism followed by hypothyroidism is another manifestation. Hypothyroidism is more common with an incidence of 10% whereas hyperthyroidism has an incidence of 5%. Less is known about the incidence of worsening thyroid dysfunction in patients with pre-existing thyroid dysfunction treated with ICB.MethodsA retrospective analysis was collected on 370 patients who received immunotherapy from April 2015 to April 2019. Of those, 212 had abnormal thyroid function tests. We analyzed a subgroup of these patients who had baseline thyroid dysfunction for worsening thyroid dysfunction after they were given ICB. Fifty-three patients were included in the analysis and had an abnormal baseline TSH at the start of immunotherapy. Type of immunotherapy, worst TSH, duration between initiation of immunotherapy to worst TSH, treatment type, and grade of abnormality as per Immune Checkpoint Inhibitor Related Adverse Events Common Terminology Criteria for Adverse Events (IRAE-CTCAE) were also recorded. Analysis was done for patients to compare likelihood of worsening TSH resulting in change in treatment for thyroid disorder.ResultsOf the identified patients (N=53) with abnormal TSH screening values outside of the institution’s normal reference range 0.35 - 4.95 uIU/ml, 45.7% (N=16) were hypothyroid and 54.3% (N=19) were hyperthyroid at baseline. Of those who were hypothyroid, 50% (N=8) had worsening TSH and 50% (N=8) had unchanged TSH during treatment. Of those who were hyperthyroid, 31.6% (N=6) had unchanged TSH, 52.6% (N=10) had worsened TSH, and 15.8% (N=3) had normalization of TSH compared to baseline. Overall 26.4% had worsening and of those 11.3% required treatment change.ConclusionsThyroid dysfunction is one of the most common IRAE’s associated with immune checkpoint inhibitors. Little is known about the impact of immunotherapy on patients with existing thyroid dysfunction. Patients who have underlying thyroid dysfunction are at an increased risk for worsening thyroid dysfunction with the use of ICB but though not unduly above the risk general population. Of those with change, only a modest percentage required an alteration of their endocrine therapy. Of interest, our data suggests a potential increased risk in patients with baseline hyperthyroidism compared to hypothyroidism which may be clinically relevant.Ethics ApprovalThe study was approved by ECU Brody School of Medicine Institution’s Ethics Board, approval number 19-000710.ReferencesBarroso-Sousa R, Barry WT, Garrido-Castro AC, et al. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA oncology. 2018;4:173–182.Fessas P, Possamai LA, Clark J, et al. Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms. Immunology. 2019; 2020;159:167–177.Brody HM, Macherla S, Bulumulle A, Namireddy P, Cherry CR. The real-world incidence of immunotherapy-related thyroid dysfunction: A retrospective analysis of a single center’s experience over five years. Journal of clinical oncology. 2020;38:98–98.Iyer PC, Cabanillas ME, Waguespack SG, et al. Immune-Related Thyroiditis with Immune Checkpoint Inhibitors. Thyroid (New York, N.Y.). 2018;28:1243–1251.Presotto EM, Rastrelli G, Desideri I, et al. Endocrine toxicity in cancer patients treated with nivolumab or pembrolizumab: results of a large multicentre study. Journal of endocrinological investigation. 2019; 2020;43:337–345.Chalan P, Di Dalmazi G, Pani F, De Remigis A, Corsello A, Caturegli P. Thyroid dysfunctions secondary to cancer immunotherapy. Journal of endocrinological investigation. 2017; 2018;41:625–638.Mangla A, Paydary K, Yadav U, Liu J, Lad TE. Predictors and outcomes of thyroid dysfunction with immunotherapy: A single institution observational experience. Journal of clinical oncology. 2019;37:e14134-e14134.Basak EA, van der Meer, Jan W M, Hurkmans DP, et al. Overt Thyroid Dysfunction and Anti-Thyroid Antibodies Predict Response to Anti-PD-1 Immunotherapy in Cancer Patients. Thyroid (New York, N.Y.). 2020;30:966–973.Kassi E, Angelousi A, Asonitis N, et al. Endocrine-related adverse events associated with immune-checkpoint inhibitors in patients with melanoma. Cancer medicine (Malden, MA). 2019;8:6585–6594.

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Association of Blood Biomarkers and Autoimmunity with Immune Related Adverse Events in Patients with Cancer treated with Immune Checkpoint Inhibitors

10.21203/rs.3.rs-136849/v1 ◽

2021 ◽

Author(s):

Despina Michailidou ◽

Ali Khaki ◽

Maria Morelli ◽

Leonidas Diamantopoulos ◽

Namrata Singh ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Performance Status ◽

Cancer Type ◽

Blood Biomarkers ◽

Lymphocyte Ratio ◽

Patients With Cancer ◽

History Of

Abstract Background: Patients with cancer treated with immune checkpoint inhibitors (ICIs) develop immune related adverse events (irAEs), however biomarkers are lacking. We hypothesized that clinicopathologic and laboratory factors would be associated with irAE risk and overall survival (OS) in this population.Methods: In a retrospective study of patients treated with ICIs we collected clinicopathologic, laboratory, irAEs and outcomes data. The association between baseline blood biomarkers, clinicopathologic features and irAEs was assessed by logistic regression adjusting for age, sex, smoking, cancer type, performance status, concomitant other systemic therapy, history of autoimmune disease (AD) and chronic infection. Optimal cutoff values of biomarkers were identified by recursive partitioning analysis.Results: 470 patients were identified; 156 (33%) developed irAEs, which were associated with baseline absolute lymphocyte count >2.6k/ul (adjusted [a]OR:4.12), neutrophil to lymphocyte ratio (NLR) ≤5.3 (aOR:2.08) and monocyte to lymphocyte ratio (MLR)≤0.73 (aOR:3.11). Patients with pre-existing AD (aOR:2.81), family history of AD (aOR:5.86), and ICI combination (aOR:2.26) had higher odds of irAEs. Baseline NLR≤5.3 (aHR:0.68) and MLR≤0.73 (aHR:0.43) were associated with longer OS.Conclusion: irAE were associated with autoimmune history, ICI combination and baseline laboratory measurements. Lower NLR and MLR may have favorable prognostic value. Our hypothesis-generating findings require validation in larger prospective studies.

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Immortal time bias in the association between toxicity and response for immune checkpoint inhibitors: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15080 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15080-e15080

Author(s):

Filippo G. Dall'Olio ◽

Alessandro Rizzo ◽

Veronica Mollica ◽

Maria Massucci ◽

Ilaria Maggio ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Prognostic Impact ◽

Cancer Type ◽

Landmark Analysis ◽

Immortal Time Bias ◽

Number Of Patients

e15080 Background: A number of studies have addressed the association between Immune related Adverse Events (IrAE) and outcome in patients treated with Immune Checkpoint Inhibitors (ICI). Only a minority of them considered the effect of immortal time bias (ITB), and results of these papers are conflicting. The aim of our meta-analysis was to assess the relationship between IrAE and outcomes for patients treated with ICIs, with a focus on ITB in weighing the role of this association. Methods: PubMed, Embase (Ovid), and Scopus were searched through January 2, 2020. Studies reporting the prognostic impact of IrAE development on outcome in advanced cancer patients treated with anti PD-1 or PD-L1.Two investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Author name, cancer type, PD-1 and PD-L1 inhibitor used, number of patients, number and type of all adverse events, presence of a landmark analysis, median OS and PFS and difference between patient with or without IrAE in terms of OS and PFS (Hazard Ratio) and ORR (Odds Ratio) were extracted. Data were pooled using a random-effects model. Main outcome were Overall Survival (OS), Progression Free Survival (PFS) and Overall Response Rate (ORR). Analysis was performed with dedicated software (R studio version 1.2.1335, metafor package). Results: A total of 29 articles comprising 7430 patients were included. 7 papers published the results of survival analysis according to landmark analysis, 2 papers published only the naïve analysis while stating that a landmark analysis resulted non significant, and the others did not perform a landmark analysis. IrAEs were associated with improved outcomes with high heterogeneity ( I2 70.8%, p < 0.001 for OS; 65.7%, p 0.002 for PFS; 62.1%, p 0.001 for ORR). When subgroup analysis was performed according to the adoption of a landmark approach, the association between IrAE and outcome remains significant for OS, PFS and ORR but the effect size was smaller ( HR 0.61 vs 0.41 for OS, ANOVA Q-test for difference between subgroup p = 0.015; HR 0.66 vs 0.47 for PFS, ANOVA Q-test p 0.029; OR 2.59 vs 6.77 for ORR, ANOVA Q-test p < 0.001) while heterogeneity was substantially reduced (I2 for papers using LM 43% for OS, p 0.115; 9.7% for PFS, p 0.355; 0.0% for ORR, p 0.556). Conclusions: Our analysis suggests a significant confounding effect of ITB as well as a real effect of IrAE development on outcome.

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Association of blood biomarkers and autoimmunity with immune related adverse events in patients with cancer treated with immune checkpoint inhibitors

Scientific Reports ◽

10.1038/s41598-021-88307-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Despina Michailidou ◽

Ali Raza Khaki ◽

Maria Pia Morelli ◽

Leonidas Diamantopoulos ◽

Namrata Singh ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cancer Type ◽

Monocyte Count ◽

Blood Biomarkers ◽

Lymphocyte Ratio ◽

Patients With Cancer ◽

History Of

AbstractPatients with cancer treated with immune checkpoint inhibitors (ICIs) develop immune related adverse events (irAEs), however biomarkers are lacking. We hypothesized that clinicopathologic and laboratory factors would be associated with irAE risk and overall survival (OS) in this population. In a retrospective study of patients treated with ICIs we collected clinicopathologic, laboratory, irAEs and outcomes data. The association between baseline blood biomarkers, clinicopathologic features and irAEs was assessed by logistic regression adjusting for age, sex, smoking, cancer type, performance status, concomitant other systemic therapy, history of autoimmune disease (AD), chronic infection and pre-existing systemic steroid use (regardless of dose). Optimal cutoff values of biomarkers were identified by recursive partitioning analysis. 470 patients were identified; 156 (33%) developed irAEs, which were associated with baseline absolute lymphocyte count > 2.6 k/ul (adjusted [a]OR: 4.30), absolute monocyte count > 0.29 k/ul (aOR: 2.34) and platelet count > 145 k/ul (aOR: 2.23), neutrophil to lymphocyte ratio (NLR) ≤ 5.3 (aOR: 2.07) and monocyte to lymphocyte ratio (MLR) ≤ 0.73 (aOR: 2.96), as well as platelet to lymphocyte ratio ≤ 534 (aOR: 5.05). Patients with pre-existing AD (aOR: 2.57), family history of AD (aOR: 5.98), and ICI combination (aOR: 2.00) had higher odds of irAEs. Baseline NLR ≤ 5.3 (aHR: 0.68), MLR ≤ 0.73 (aHR: 0.43), PLT > 145 (aHR: 0.48) and PLR ≤ 534 (aHR: 0.48) were associated with longer OS. irAEs were associated with autoimmune history, ICI combination and baseline laboratory measurements. Lower NLR, MLR and PLR may have favorable prognostic value. Our hypothesis-generating findings require validation in larger prospective studies.

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Characteristics of hospitalizations among patients receiving immune checkpoint inhibitors at a community teaching hospital

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219836155 ◽

2019 ◽

Vol 26 (1) ◽

pp. 60-66

Author(s):

Brendan Rasor ◽

Rachel Henderson ◽

Kin Chan

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Cancer Type ◽

Preventable Admissions ◽

The Impact ◽

Reason For Admission

Purpose As immune checkpoint inhibitors continue to acquire new indications, it is important to understand the impact their use has on patients. This study adds to current literature by presenting an analysis of hospitalizations in this population. The primary objective was to assess the reasons for an emergency department visit or hospital admission in patients who receive immune checkpoint inhibitors. Secondary objectives included identifying the frequency of suspected or confirmed immune related adverse events, types of immune related adverse events, number of preventable admissions, duration of immunotherapy, and length of stay. Methods This study was a retrospective, multi-center, chart review of patients hospitalized after receiving an immune checkpoint inhibitor. The population included patients aged 18 and above who received at least one dose of an immune checkpoint inhibitor at a network facility and had a documented admission within one year following the initiation of immunotherapy. Descriptive statistics were performed along with inferential comparisons and a Poisson regression to determine if the immune checkpoint blocker or cancer type predicted admission or reason for admission. Results The 99 patients who met inclusion criteria had a total of 202 admissions. Of these patients, 56 (56.6%) had multiple admissions within the year following initiation of immunotherapy. The most common diagnoses on initial admissions were shortness of breath, pain, and pneumonia. A total of 104 admissions (51.5%) were considered potentially preventable. Suspected or confirmed immune related adverse events were identified in 15.6% of all admissions. There were no significant predictors of admissions or reason for admission. Conclusion Reasons for admission in the study population were comparable to those identified in the general cancer population, with immune related adverse events being associated with a minority of both total and potentially preventable admissions.

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Evaluation of emergency department visits in patients treated with immune checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e24160 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e24160-e24160

Author(s):

Deniz Can Guven ◽

Taha Koray Sahin ◽

Seren Aksun ◽

Hakan Taban ◽

Oktay Halit Aktepe ◽

...

Keyword(s):

Emergency Department ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Hospital Admissions ◽

Checkpoint Inhibitors ◽

Emergency Department Visits ◽

Cancer Type ◽

Common Diagnosis ◽

Ed Visits

e24160 Background: Immune checkpoint inhibitors (ICIs) are the main drugs for immunotherapy. Their efficacy comes at the expense of adverse events including immune-related adverse events (IRAEs). The emergency department (ED) is an important encounter point in the cancer care. However, the data on the causes of ED visits is scarce. Therefore, we evaluated the ED visits of patients treated with ICIs and tried to determine the predisposing factors. Methods: We performed a retrospective review of adult cancer patients treated with ICIs for any cancer type between 09/2014 and 06/2019 in Hacettepe University Cancer Center. The data about ED visits after the first dose of ICIs to six months after the last dose of ICIs was collected from the hospital registries. Baseline characteristics, stages and types of patients’ tumors, types of ICI, causes for emergency visits and hospital admissions were recorded. Results: A total of 221 patients were included. The median age was 60.7 years (18-86) and 65.6% of patients were males. Median follow-up was 9 months (0.2-55). Nivolumab was the most common immunotherapy (67.9%). Melanoma was the most common diagnosis (27.6%) followed by kidney and lung cancer. 90% of patients had advanced disease and more than half of patients were treated with two or more lines of therapy. The 83 patients (37.6%) had at least one emergency department (ED) visit. Half of these visits resulted in hospital admissions. Thirty-eight patients had more than one ED visits with 14 patients having three or more ED visits. Immune-related adverse events comprised less than 10% of the ED visits with most of the ED visits were related to symptoms attributable to disease burden itself. The median time to ED visit after the first dose of ICI was 126 days. While baseline ECOG status, age, polypharmacy (defined as the regular use of five or more drugs), concomitant chemotherapy, eosinophilia and lactate dehydrogenase levels didn’t significantly increase the risk, patients with regular opioid use and baseline neutrophilia ( > 8000) had a statistically significant risk of ED visits (p values 0.001 and 0.19 respectively). These two factors remained significant in the multivariate analyses. Conclusions: In this study, almost 40% of ICI treated patients had ED visits. Recognition and addressing of this patient group’s problems in the ED is very important as evidenced by ability to discharging half of patients from the ED. Collaboration between the other specialists like emergency medicine specialists is vital for improving the care of patients treated with immunotherapy.

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The Price of Success: Immune-Related Adverse Events from Immunotherapy in Lung Cancer

Current Oncology ◽

10.3390/curroncol28060373 ◽

2021 ◽

Vol 28 (6) ◽

pp. 4392-4407

Author(s):

Courtney H. Coschi ◽

Rosalyn A. Juergens

Keyword(s):

Immune Response ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Low Grade ◽

Cancer Type ◽

Immune System Activation ◽

Cancer Types ◽

System Activation

Cancer immunotherapy has the goal of enhancing a patient’s intrinsic immune processes in order to mount a successful immune response against tumor cells. Cancer cells actively employ tactics to evade, delay, alter, or attenuate the anti-tumor immune response. Immune checkpoint inhibitors (ICIs) modulate endogenous regulatory immune mechanisms to enhance immune system activation, and have become the mainstay of therapy in many cancer types. This activation occurs broadly and as a result, activation is supraphysiologic and relatively non-specific, which can lead to immune-related adverse events (irAEs), the frequency of which depends on the patient, the cancer type, and the specific ICI antibody. Careful assessment of patients for irAEs through history taking, physical exam, and routine laboratory assessments are key to identifying irAEs at early stages, when they can potentially be managed more easily and before progressing to higher grades or more serious effects. Generally, most patients with low grade irAEs are eligible for re-challenge with ICIs, and the use of corticosteroids to address an irAE is not associated with poorer patient outcomes. This paper reviews immune checkpoint inhibitors (ICIs) including their mechanisms of action, usage, associated irAEs, and their management.

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SAT-463 Thyrotoxicosis from Nivolumab in a Patient with Preexisting Graves’ Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1351 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Preethi Polavarapu ◽

Padmaja Akkireddy

Keyword(s):

Adverse Events ◽

Thyroid Function ◽

Autoimmune Thyroiditis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Thyroid Dysfunction ◽

Checkpoint Inhibitors ◽

Graves Disease ◽

Thyroid Function Tests ◽

Free T4

Abstract Introduction Thyroid dysfunction is one of the common immune-related adverse events associated with immune checkpoint inhibitors like Nivolumab. Thyroiditis or primary hypothyroidism is the most commonly reported presentation. Graves’ disease is less frequently reported. We report a case of preexisting Graves’ disease patient, on antithyroid meds who developed thyrotoxicosis followed by hypothyroidism after receiving Nivolumab therapy. Case 66 y/o female patient with newly diagnosed metastatic melanoma presented to us for evaluation of abnormal thyroid test after her second cycle of Nivolumab. She has a long-standing history of Graves’ disease and has been on methimazole since her diagnosis. Her baseline thyroid labs before the start of Nivolumab were within normal limits (on methimazole 2.5 mg daily). She presented with weight loss, palpitations, and tremors four weeks after the start of Nivolumab. On exam, she was tachycardic with tremors noted to outstretched hands and had diffusely enlarged thyroid. Repeat lab work done before her second cycle revealed suppressed TSH 0.02 (0.4-4.5 uIU/ml) with elevated free T4 and T3. Her TSI titers were elevated. Methimazole dose was increased to 10 mg daily, and follow up labs done in a month revealed TSH of 89 uIU/ml, Free T4 0.16 (0.76-1.8 ng/dl). Methimazole was completely stopped at this time. She continued to have elevated TSH despite being off of methimazole for more than a month, concerning for the development of hypothyroidism. She was started on levothyroxine, after which labs returned to normal. The patient continued on immunotherapy during this period. Discussion Immune checkpoint inhibitors have been increasingly used for cancer therapy. Endocrinopathies are the most common immune-related adverse events associated with the use of these agents, with thyroid dysfunction being more common. Our patient had well-controlled Graves’ disease and was on a stable dose of methimazole for years. She developed autoimmune thyroiditis four weeks after receiving immunotherapy and subsequently developed hypothyroidism. The literature search did not reveal cases of autoimmune thyroiditis in a patient with preexisting Graves’ disease. One study reported that the timeline for developing the thyrotoxic phase is five weeks, which is followed by the rapid development of either euthyroid or hypothyroid phase. Management during the thyrotoxic phase is usually beta-blockers. Current guidelines recommend checking thyroid function test before initiation of therapy and every two weeks after the diagnosis of thyrotoxicosis until they become euthyroid or hypothyroid. Our case illustrates that patients with preexisting Graves’ disease can develop thyroiditis after receiving immune checkpoint inhibitors, and hence, frequent monitoring with thyroid function tests is needed.

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