Immune-mediated adverse events following influenza vaccine in cancer patients receiving immune checkpoint inhibitors

Objectives The emergence of immune checkpoint inhibitors has transformed treatment paradigms for various malignancies. Patients with cancer are at increased risk of complications and hospitalizations from influenza; therefore, it is recommended that they receive inactivated influenza vaccination. However, efficacy and safety of inactivated influenza vaccination in patients receiving immune checkpoint inhibitors is uncertain. The objective of this prospective case series was to evaluate the incidence of immune-mediated adverse events (imAEs) following inactivated influenza vaccination in patients receiving immune checkpoint inhibitors. Changes in cytokine and chemokine levels were also evaluated. Methods Patients receiving immune checkpoint inhibitors during the 2017–2018 influenza season were eligible for study participation. Peripheral blood samples were collected prior to administration of inactivated influenza vaccine and two post-vaccination time points. Evaluation of new or worsening imAEs occurred via patient questionnaire and review of medical records for 60 days following inactivated influenza vaccination. Baseline imAEs were evaluated from review of medical records for 60 days prior to inactivated influenza vaccination. Serum cytokines and chemokines were measured using a multiplex Luminex assay. Results Twenty-four patients were enrolled in this study. Seven patients experienced any grade imAE (one patient having 2) within 60 days following inactivated influenza vaccination. The majority were Grades 1–2, including rash ( n = 3), hypothyroidism, myalgia, and colitis ( n = 1 each). Two patients experienced severe imAEs (grade 3 nephritis and grade 4 diabetes). No significant changes ( p > 0.05) in serum cytokine or chemokine concentrations were observed. Conclusions Although small, our study suggests that inactivated influenza vaccine may be safely administered to patients receiving immune checkpoint inhibitors. The majority of imAEs following inactivated influenza vaccination were Grades 1-2 and did not require changes in immune checkpoint inhibitor therapy.

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Effect of influenza vaccination on immune-related adverse events in patients receiving single-agent immune checkpoint inhibitors for the treatment of cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18763 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18763-e18763

Author(s):

Naga Malleswari Vutukuri ◽

Calette Corcoran ◽

Jill Comeau ◽

Elizabeth Stephenson ◽

Kavitha Beedupalli ◽

...

Keyword(s):

Adverse Events ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Secondary Outcome ◽

Number Of Patients ◽

Influenza Vaccinations

e18763 Background: Recent single-center, retrospective reviews have evaluated the effect of influenza vaccinations on the incidence and severity of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICI). Methods and outcomes in these studies vary. The most common medication investigated was ipilimumab, an Anti-CTLA-4 monoclonal antibody. There is limited data evaluating the incidence of irAEs in those receiving the specific ICIs, program death-1 (PD-1) and program death ligand-1 (PD-L1) inhibitors. Methods: A retrospective chart review was conducted including patients 18 to 89 years old who received single-agent pembrolizumab, nivolumab, atezolizumab, or durvalumab at an academic medical center from August 2015 to August 2019. The primary objective was to evaluate the incidence of irAEs in those who received an influenza vaccine compared to those who did not. Electronic health records, and the Louisiana Immunization Network for Kids (LINKS), which now collects adult information, were utilized for data collection. Chi-square tests were used to evaluate all endpoints. Results: Of the 217 charts screened, 133 were included in this study Fifty-three patients were included in the influenza vaccination group and 80 patients in the group that did not receive influenza vaccinations. The median age in those who received an influenza vaccine and in those who did not were 61 years and 62 years, respectively. The most common cancer diagnoses were lung cancer and melanoma. Ninety-one percent of patients in the vaccination group versus 81% in the group who did not receive an influenza vaccine received either nivolumab or pembrolizumab (PD-1 inhibitors). There was no statistical difference in irAEs in those who received an influenza vaccine versus those who did not (30% versus 45%, p = 0.15). The only significant secondary outcome found was the rate of irAEs in patients receiving a PD-1 inhibitor versus a PD-L1 inhibitor regardless of vaccination (42.2% versus 11.1%, p = 0.03). The majority of irAEs were grade 1 or 2. Conclusions: Based on this study, receiving an influenza vaccine does not have an influence on the risk of irAEs in those receiving ICI, specifically PD-1 and PD-L1 inhibitors. These outcomes may have been affected by adherence issues with yearly influenza vaccinations, inaccurate vaccine records, and receiving vaccines out of state. The statistically significant secondary outcome may have been affected by the disproportionate number of patients who were receiving a PD-1 inhibitor in this study. Larger population studies are needed to validate these findings and identify both the risk and benefit of patients receiving their yearly influenza vaccine while receiving ICI.

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Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors

BMC Cancer ◽

10.1186/s12885-021-08006-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Luisa Maria Griewing ◽

Claudia Schweizer ◽

Philipp Schubert ◽

Sandra Rutzner ◽

Markus Eckstein ◽

...

Keyword(s):

Adverse Events ◽

Cancer Patients ◽

Weight Change ◽

Immune Checkpoint ◽

Detection Rate ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Patient Questionnaire ◽

Organ Specific ◽

Tumor Entities

Abstract Background Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. Methods The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. Results Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were “weight change”, “difficulty to grip things”, “bloody or mucous stool” and “insomnia”. Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. Conclusion Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on “weight change” and “insomnia” may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. Trial registration ClinicalTrials.gov, NCT03453892. Registered on 05 March 2018.

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Immuno-related endocrinopathy in patients treated with immune checkpoint inhibitors

Medical Council ◽

10.21518/2079-701x-2020-9-16-24 ◽

2020 ◽

pp. 16-24

Author(s):

D. I. Yudin ◽

K. K. Laktionov ◽

K. A. Sarantseva ◽

O. I. Borisova ◽

V. V. Breder ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Clinical Practice ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Serious Adverse Events ◽

Immune Mediated ◽

Discontinuation Of Treatment ◽

The Russian Federation

Recently immune checkpoint inhibitors amazingly changed the landscape of cancer therapy worldwide. The number of immune checkpoint molecules in clinical practice is constantly increasing. There are some monoclonal antibodies recently registered in the Russian Federation: anti-PD1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab). Immune-mediated endocrinopathies are some of the most common complications of immunotherapy. According to the results of clinical studies, the incidence of serious endocrine immuno-mediated adverse events with anti-PD1 monoclonal antibodies is low (3.5–8%). The use of anti-CTLA4 antibodies, combined regimens, and the use of immunotherapy after chemoradiotherapy significantly increase the incidence of serious adverse events to 30%. In clinical practice of N.N. Blokhin Cancer Research Center among 245 non-small cell lung cancer and hepatocellular carcinoma patients treated with immunotherapy, 22 (8,9%) developed an immune-mediated endocrinopathy. Most patients developed adverse events of 1–2 degrees, in two patients – 3 degrees, requiring discontinuation of treatment. The aim of this article was to provide useful information and recommendations regarding the management of common immuno-related endocrine adverse events (including hypothyroidism, hyperthyroidism, pituitary, adrenal insufficiency) for clinical oncologists.

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Immune-mediated adverse events in immune checkpoint inhibitors therapy: literature review

Modern Oncology ◽

10.26442/18151434.2021.2.200502 ◽

2021 ◽

Vol 23 (2) ◽

pp. 319-326

Author(s):

Marina A. Lyadova ◽

Vladimir K. Lyadov

Keyword(s):

Adverse Events ◽

Interstitial Nephritis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Acute Interstitial Nephritis ◽

Early Symptom ◽

Immune Mediated ◽

Cutaneous Rash ◽

Pancreatic Dysfunction

Immune-mediated adverse events (imAEs) are complications of therapy with immune checkpoint inhibitors, which arise as a result of autoimmune inflammation. The article summarizes systemic (fatigue, fever), cutaneous (rash, itching), gastrointestinal (diarrhea, colitis, hepatitis, pancreatic dysfunction), endocrinological (hypothyroidism, hypophysitis, adrenal insufficiency, diabetes mellitus), pulmonary (pneumonitis, pleuritis), rheumatological (arthralgia), neurological (headache, sensory and motor disorders), renal (acute interstitial nephritis, lupus-like nephritis, granulomatous nephritis, diffuse interstitial nephritis and minimal change disease), hematological (anemia, cytopenia), cardiovascular (myocarditis) and ocular (conjunctivitis, episcleritis, ceratitis, blepharitis and uveitis) imAE. Pathogenetic mechanisms and treatment approaches (in accordance with toxicity grade and clinical recommendations) are discussed. Early symptom recognition, patient education and timely intervention are crucial for imAE correction.

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Liver injury by immune checkpoint inhibitors in patients with hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.341 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 341-341 ◽

Cited By ~ 1

Author(s):

Nicola Personeni ◽

Tiziana Pressiani ◽

Antonio Capogreco ◽

Arianna Dal Buono ◽

Antonio D'Alessio ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Injury ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Subsequent Treatment ◽

Drug Induced ◽

Increased Risk ◽

Grade 3

341 Background: In patients with hepatocellular carcinoma (HCC) and baseline liver dysfunction, hepatic immune-related adverse events (HIRAEs) during immunotherapy have not been adequately characterized and their impact on subsequent treatment outcomes is not known. Methods: 40 patients with advanced/unresectable HCC and Child Pugh score A have been enrolled in first and second-line clinical trials of anti-programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs). HCC etiologies were: hepatitis C (32.5%), hepatitis B (7.5%), alcohol abuse (27.5%), other (32.5%). 7 received anti-PD-1 mAbs alone and 33 received combined regimens that included anti-PD-1 mAbs plus either anti-cytotoxic T lymphocyte antigen 4 (30.4%) or tyrosine kinase inhibitors (TKIs) (54.5%), or both (15.1%). We reviewed their liver function tests and HIRAEs onset was related to time to treatment failure (TTF). Results: Overall, 12 patients (30%) developed grade ≥ 3 hepatitis according to Common Toxicity Criteria for Adverse Events v. 4.03, resulting in 4 cases of grade 2 drug-induced liver injury per DILI Working Group criteria. Time between therapy initiation and hepatitis onset was 1.4 months (0.4-2.8) and median peak aminotransferase (AT) level was 258 IU/L (85-869). Out of 6 permanent treatment discontinuations due to adverse events (AEs), 4 were linked to hepatitis. Higher AT median levels at baseline were significantly linked to grade ≥ 3 hepatitis compared with lower grades (95 IU/L vs. 36 IU/L, respectively; p = 0.008). Etiology, age, treatment did not predict HIRAEs onset. TTF in patients in patients with grade ≥ 3 hepatitis was shorter than in the whole cohort (1.4 vs. 3.8 months, p = 0.041), while overall survival did not differ (p = 0.125). Conclusions: We observed a 30% incidence of clinically significant HIRAEs. HIRAEs represent the most frequent AEs leading to treatment discontinuation in patients with HCC undergoing treatments with immune checkpoint inhibitors. Baseline AT levels may identify patients at increased risk of grade ≥ 3 hepatitis.

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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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An Evaluation of the Use of Corticosteroids for the Management of Immune-Mediated Adverse Events in Cancer Patients Treated With Immune Checkpoint Inhibitors

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.2.2 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Adrian Tsui, PharmD ◽

Linday Edmondson, PharmD, BCOP ◽

Justin Julius, PharmD

Keyword(s):

Adverse Events ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Retrospective Chart Review ◽

Prescribing Practices ◽

Immune Mediated ◽

Number Of Patients ◽

Secondary Endpoints

Immune checkpoint inhibitors (ICIs) have gained prominence for the treatment of a variety of malignancies. However, they are associated with the development of immune-mediated adverse events (IMAEs). Appropriate management of IMAEs and subsequent rechallenging of patients with ICI therapy remains an important area of research. The primary endpoint of this study was to evaluate the efficacy of current prescribing practices and adherence to guideline recommendations for IMAE management. The incidence of symptom resolution, number of patients reinitiated with ICI therapy, and IMAE recurrence upon ICI therapy reinitiation were explored as secondary endpoints. A retrospective chart review within the Allegheny Health Network was conducted in cancer patients treated with ICI therapy who developed a documented ICI-associated IMAE and subsequently received corticosteroid therapy. IRB approval was obtained for this study. Descriptive statistics were used to analyze both primary and secondary endpoints. The study sample was made up of 81 patients. Overall, 50 out of 81 patient cases (62%) were found to be discordant with guideline recommendations; the primary factors identified were inappropriate starting corticosteroid dosing (64%), initiation of a corticosteroid taper prior to IMAE resolution to at least grade 1 severity, and condensed corticosteroid taper (74%). The main IMAEs identified were colitis (28%), pneumonitis (27%), and skin-related inflammation (12%). 76 out of the 81 patients (94%) achieved IMAE resolution; 41 patients (54%) were rechallenged with ICI therapy, of which 14 patients (34%) developed IMAE recurrence. Future studies may focus on evaluating different immunosuppression strategies to optimize IMAE management.

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Pathogenesis, Clinical Manifestations and Management of Immune Checkpoint Inhibitors Toxicity

Tumori Journal ◽

10.5301/tj.5000625 ◽

2017 ◽

Vol 103 (5) ◽

pp. 405-421 ◽

Cited By ~ 11

Author(s):

Alessandro Inno ◽

Giulio Metro ◽

Paolo Bironzo ◽

Antonio M. Grimaldi ◽

Elisabetta Grego ◽

...

Keyword(s):

Clinical Practice ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Manifestations ◽

Know How ◽

Immune Mediated ◽

Medical Oncologists ◽

Tumor Types

Immune checkpoint inhibitors have emerged as an effective treatment for several tumor types and their use in clinical practice is expected to further increase in the immediate future. Although these agents are well tolerated, they are associated with a peculiar spectrum of toxicity, which is immune mediated and may potentially affect every organ. However, immune-related adverse events are mostly reversible if promptly diagnosed and adequately treated. Therefore, it is crucial that medical oncologists know how to diagnose and treat immune-related adverse events. This review focuses on the pathogenesis, clinical manifestations and management of immune-related toxicity of anti-CTLA-4 and anti-PD-1 antibodies.

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