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Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research.
Johnson DB, Reynolds KL, Sullivan RJ, Balko JM, Patrinely JR, Cappelli LC, Naidoo J, Moslehi JJ
(2020) Lancet Oncol 21: e398-e404
MeSH Terms: Antineoplastic Agents, Immunological, Humans, Medical Oncology, Neoplasms, Patient Care, Patient Education as Topic
Show Abstract · Added September 29, 2020
Immune checkpoint inhibitors (ICIs) have now been approved in numerous and diverse cancer types and combination regimens. Effective recognition and treatment of ICI toxicities, which might occur acutely, affect any organ system, and produce many distinct clinical syndromes, have emerged as essential goals of ICI management. Thus, developing robust diagnostic and management approaches for ICI toxicity across the health-care system is an urgent and unmet clinical need. In this Personal View, we describe barriers to high-quality care that have constrained the most effective management of patients with cancer receiving ICI treatment. We review education initiatives to enhance patient and physician awareness, which is necessary given the broad spectrum of ICI toxicities often experienced by patients, and assess various systems-based approaches that maximise the chances of appropriate management. In addition, we describe research pipelines that broaden evidence-based approaches and the pathobiology of these novel events. Developing effective, systematic approaches for the recognition and treatment of ICI toxicities will continue to grow in importance as these agents proliferate in cancer care.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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Survivorship in immune therapy: Assessing toxicities, body composition and health-related quality of life among long-term survivors treated with antibodies to programmed death-1 receptor and its ligand.
Patrinely JR, Young AC, Quach H, Williams GR, Ye F, Fan R, Horn L, Beckermann KE, Gillaspie EA, Sosman JA, Friedman DL, Moslehi JJ, Johnson DB
(2020) Eur J Cancer 135: 211-220
MeSH Terms: Aged, Antineoplastic Agents, Immunological, B7-H1 Antigen, Body Composition, Female, Functional Status, Humans, Immune Checkpoint Inhibitors, Male, Middle Aged, Neoplasms, Nutritional Status, Programmed Cell Death 1 Receptor, Progression-Free Survival, Quality of Life, Retrospective Studies, Survivors, Time Factors
Show Abstract · Added September 29, 2020
AIM - Antibodies to programmed death-1 receptor and its ligand (anti-PD-1/PD-L1) produce durable responses in many cancers. However, the long-term effects of anti-PD-1/PD-L1 blockade are not well defined. We identified the toxicities, health outcomes and health-related quality of life (HRQoL) amongst long-term survivors treated with anti-PD-1/PD-L1.
METHODS - We assessed 217 patients who received anti-PD-1/PD-L1 for melanoma, renal cell carcinoma or non-small-cell lung carcinoma between 2009 and 2017, with survival greater than two years after treatment. Patient and tumour characteristics, immune-related adverse events (irAEs), cardiometabolic parameters (glucose, blood pressure, body mass index [BMI]), body composition (using automated body composition analyser, computed tomography and Slice-o-matic software) and HRQoL outcomes were tracked.
RESULTS - Among the included patients, most were men (70.3%) and at anti-PD-1/PD-L1 initiation had an average age of 61.0 years and median BMI of 28.5. Median overall survival was not reached; 33 (15.2%) died during the follow-up primarily from progressive cancer (n = 28). At the last follow-up, most patients' Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (41%). There was no difference in blood pressure, glucose or BMI from baseline to two years after treatment initiation. Body composition showed increased adiposity (p = 0.05), skeletal muscle mass (p = 0.03) and skeletal muscle gauge (p = 0.04). We observed chronic irAEs at the last follow-up including hypothyroidism (10.6%), arthritis (3.2%), adrenal insufficiency (3.2%) and neuropathy (2.8%). New diagnoses of type 2 diabetes (6.5%) and hypertension (6.0%) were observed, with uncertain relationship to anti-PD-1/PD-L1. Patient-reported outcomes compared favourably with cancer and general populations, although younger age (p = 0.003) and need for subsequent therapy (p = 0.03) were associated with worse HRQoL outcomes.
CONCLUSION - Durable responses to anti-PD-1/PD-L1 therapy and favourable HRQoL outcomes are encouraging. Chronic events may be more common than previously thought although no clear chronic adverse cardiometabolic effects were observed.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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18 MeSH Terms
Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities.
Allenbach Y, Anquetil C, Manouchehri A, Benveniste O, Lambotte O, Lebrun-Vignes B, Spano JP, Ederhy S, Klatzmann D, Rosenzwajg M, Fautrel B, Cadranel J, Johnson DB, Moslehi JJ, Salem JE
(2020) Autoimmun Rev 19: 102586
MeSH Terms: Antineoplastic Agents, Immunological, Bayes Theorem, Humans, Myositis, Pharmacovigilance, Retrospective Studies
Show Abstract · Added September 29, 2020
BACKGROUND - In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.
PATIENTS METHODS - We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC (lower end of the IC 95% credibility interval) >0 is deemed significant.
RESULTS - We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).
CONCLUSIONS - Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.
Copyright © 2020 Elsevier B.V. All rights reserved.
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COVID-19 and immune checkpoint inhibitors: initial considerations.
Sullivan RJ, Johnson DB, Rini BI, Neilan TG, Lovly CM, Moslehi JJ, Reynolds KL
(2020) J Immunother Cancer 8:
MeSH Terms: Antineoplastic Agents, Immunological, COVID-19, Coronavirus Infections, Humans, Molecular Targeted Therapy, Neoplasms, Pandemics, Pneumonia, Viral, Programmed Cell Death 1 Receptor
Show Abstract · Added May 29, 2020
COVID-19 infections are characterized by inflammation of the lungs and other organs that ranges from mild and asymptomatic to fulminant and fatal. Patients who are immunocompromised and those with cardiopulmonary comorbidities appear to be particularly afflicted by this illness. During pandemic conditions, many aspects of cancer care have been impacted. One important clinical question is how to manage patients who need anticancer therapy, including immune checkpoint inhibitors (ICIs) during these conditions. Herein, we consider diagnostic and therapeutic implications of using ICI during this unprecedented period of COVID-19 infections. In particular, we consider the impact of ICI on COVID-19 severity, decisions surrounding continuing or interrupting therapy, diagnostic measures in patients with symptoms or manifestations potentially consistent with either COVID-19 or ICI toxicity, and resumption of therapy in infected patients. While more robust data are needed to guide clinicians on management of patients with cancer who may be affected by COVID-19, we hope this commentary provides useful insights for the clinical community.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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9 MeSH Terms
Demographic Factors Associated with Toxicity in Patients Treated with Anti-Programmed Cell Death-1 Therapy.
Shah KP, Song H, Ye F, Moslehi JJ, Balko JM, Salem JE, Johnson DB
(2020) Cancer Immunol Res 8: 851-855
MeSH Terms: Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, CTLA-4 Antigen, Female, Hospitalization, Humans, Immunologic Factors, Immunotherapy, Length of Stay, Male, Melanoma, Middle Aged, Programmed Cell Death 1 Receptor, Risk Factors, Young Adult
Show Abstract · Added May 29, 2020
Immune checkpoint inhibitors (ICI) are now routinely used in multiple cancers but may induce autoimmune-like side effects known as immune-related adverse events (irAE). Although classical autoimmune diseases have well-known risk factors, including age, gender, and seasonality, the clinical factors that lead to irAEs are not well-defined. To explore these questions, we assessed 455 patients with advanced melanoma treated with ICI at our center and a large pharmacovigilance database (VigiBase). We found that younger age was associated with a similar rate of any irAEs but more frequent severe irAEs and more hospitalizations (OR, 0.97 per year). Paradoxically, however, older patients had more deaths and increased length of stay (LOS) when hospitalized. This was partially due to a distinct toxicity profile: Colitis and hepatitis were more common in younger patients, whereas myocarditis and pneumonitis had an older age distribution both in our center and in VigiBase. This pattern was particularly apparent with combination checkpoint blockade with ipilimumab and nivolumab. We did not find a link between gender or seasonality on development of irAEs in univariate or multivariate analyses, although winter hospitalizations were associated with marginally increased LOS. This study identifies age-specific associations of irAEs.
©2020 American Association for Cancer Research.
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19 MeSH Terms
An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.
Sherry AD, Bezzerides M, Khattab MH, Luo G, Ancell KK, Kirschner AN
(2020) Strahlenther Onkol 196: 664-670
MeSH Terms: Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Autoimmune Diseases of the Nervous System, Axilla, Carboplatin, Carcinoma, Merkel Cell, Combined Modality Therapy, Deglutition Disorders, Etoposide, Fatal Outcome, Fingers, Hallucinations, Humans, Lymphatic Metastasis, Male, Neuralgia, Palliative Care, Paraneoplastic Syndromes, Nervous System, Parenteral Nutrition, Total, Pneumonia, Aspiration, Positron Emission Tomography Computed Tomography, Radioimmunotherapy, Radiotherapy, High-Energy, Radiotherapy, Intensity-Modulated, Skin Neoplasms
Show Abstract · Added March 3, 2020
PURPOSE - Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae.
METHODS - Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab.
RESULTS - After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration.
CONCLUSION - This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.
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27 MeSH Terms
Cancer Treatment-Associated Pericardial Disease: Epidemiology, Clinical Presentation, Diagnosis, and Management.
Ala CK, Klein AL, Moslehi JJ
(2019) Curr Cardiol Rep 21: 156
MeSH Terms: Antineoplastic Agents, Immunological, Cardiotoxicity, Cardiovascular Diseases, Humans, Immunotherapy, Neoplasms, Pericarditis, Pericardium, Risk Factors
Show Abstract · Added January 15, 2020
PURPOSE OF REVIEW - Cancer therapeutics have seen tremendous growth in the last decade and have been effective in the treatment of several cancer types. However, with advanced therapies like kinase inhibitors and immunotherapies, there have been unintended consequences of cardiotoxicities. While traditional chemotherapy and radiation-induced cardiotoxicity have been well studied, further research is needed to understand the adverse effects of newer regimens.
RECENT FINDINGS - Both immune-mediated and non-immune-medicated cytotoxicity have been noted with targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. In this manuscript, we describe the pericardial syndromes associated with cancer therapies and propose management strategies. Pericardial effusion and pericarditis are common presentations in cancer patients and often difficult to diagnose. Concomitant myocarditis may also present with pericardial toxicity, especially with immunotherapies. In addition to proper history and physical, additional testing such as cardiovascular imaging and tissue histology need to be obtained as appropriate. Holding the offending oncology drug, and institution of anti-inflammatory medications, and immunosuppressants such as steroids are indicated. A high index of suspicion, use of standardized definitions, and comprehensive evaluation are needed for early identification, appropriate treatment, and better outcomes for patients with cancer treatment-associated pericardial disease. Further research is needed to understand the pathophysiology and to evaluate how the management of pericardial conditions in these patients differ from traditional management and also evaluate new therapies.
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9 MeSH Terms
Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors.
Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE
(2019) Eur J Cancer 123: 112-115
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, CTLA-4 Antigen, Chemical and Drug Induced Liver Injury, Child, Databases, Factual, Female, Hepatitis, Autoimmune, Humans, Ipilimumab, Male, Massive Hepatic Necrosis, Middle Aged, Neoplasms, Nivolumab, Programmed Cell Death 1 Receptor, World Health Organization, Young Adult
Added November 12, 2019
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Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study.
Ornstein MC, Pal SK, Wood LS, Tomer JM, Hobbs BP, Jia XS, Allman KD, Martin A, Olencki T, Davis NB, Gilligan TD, Mortazavi A, Rathmell WK, Garcia JA, Rini BI
(2019) Lancet Oncol 20: 1386-1394
MeSH Terms: Aged, Algorithms, Antineoplastic Agents, Antineoplastic Agents, Immunological, Axitinib, Carcinoma, Renal Cell, Dehydration, Diarrhea, Fatigue, Female, Humans, Hypertension, Ipilimumab, Kidney Neoplasms, Male, Middle Aged, Nivolumab, Progression-Free Survival, Response Evaluation Criteria in Solid Tumors, Retreatment
Show Abstract · Added October 30, 2019
BACKGROUND - Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor.
METHODS - We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811.
FINDINGS - Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2).
INTERPRETATION - Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting.
FUNDING - Pfizer.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology
Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, Stewart GC, Choueiri TK, Di Carli M, Allenbach Y, Kumbhani DJ, Heinzerling L, Amiri-Kordestani L, Lyon AR, Thavendiranathan P, Padera R, Lichtman A, Liu PP, Johnson DB, Moslehi J
(2019) Circulation 140: 80-91
MeSH Terms: Antineoplastic Agents, Immunological, Cardiology, Clinical Trials as Topic, Humans, Immunotherapy, Medical Oncology, Myocarditis, Neoplasms
Show Abstract · Added November 12, 2019
Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.
© 2019 American Heart Association, Inc.
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8 MeSH Terms