Journal articles on the topic 'Immune-related adverse effects (irAEs)'
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Naing, Aung, Joud Hajjar, James L. Gulley, Michael B. Atkins, Gennaro Ciliberto, Funda Meric-Bernstam, and Patrick Hwu. "Strategies for improving the management of immune-related adverse events." Journal for ImmunoTherapy of Cancer 8, no. 2 (December 2020): e001754. http://dx.doi.org/10.1136/jitc-2020-001754.
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With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient’s voice, and sharing evolving data to improve the management of irAEs.
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Reynolds, Kerry Lynn, Justine Vanessa Cohen, Sienna Durbin, Molly Thomas, Michael Dougan, Holly S. Martinson, Alex Faje, et al. "Inpatient admissions related to immune-related adverse effects (irAE) among patients treated with immune checkpoint inhibitors for advanced malignancy: A tsunami is coming, but are we ready?" Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 127. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.127.
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127 Background: Disruption of the immune system with immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude of irAE’s in the real-world, particularly inpatient is unclear. Methods: Data was collected on patients with advanced malignancy who experienced a suspected irAE needing admission to an academic hospital (Feb 2011 to June 2017). Each case was reviewed comprehensively by minimum of two reviewers, including one sub-specialist. In addition, oncologists at our institution were surveyed regarding their confidence about managing patients with irAEs. Results: Over a span of 6 years, there were 343 hospitalizations for suspected irAEs and the majority (65%; N = 223) were confirmed irAEs that required treatment with immunosuppression or therapy stopped as result. The mean length of stay was 6.3 days (range 1 to 31 days), readmission rate for another irAE event 25%, total readmission rate 61.7%, and inpatient mortality 8%. The most common irAEs were enterocolitis (43.9%), pulmonary (16%), hepatic (15%), neurological (8.9%), endocrinopathies (7.1%), rheumatological (4%), dermatological (3%), cardiovascular (3%), renal (1.8%), and allergy (1.3%). Over the past 5 years, there was a significant increase in admissions due to irAEs (admissions in 2016 vs 2011, odds ratio = 3.07; p < 0.01). The Cancer Center survey (N = 26) revealed majority of oncologists do not feel very comfortable managing irAEs, and 48% felt that irAE complications should be managed on a different service. Conclusions: irAEs from immune checkpoint inhibitors can result in prolonged hospitalizations, high rate of readmissions, and mortality. The number of patients admitted due to irAEs has significantly increased by more than three-fold in the recent years, but majority of oncologists do not feel very comfortable managing irAEs. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research program for early detection and intervention.
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Chen, Ru, Min Zhou, and Feng Zhu. "Immune Checkpoint Inhibitors Related to Cardiotoxicity." Journal of Cardiovascular Development and Disease 9, no. 11 (November 3, 2022): 378. http://dx.doi.org/10.3390/jcdd9110378.
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Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancers. Along with development of ICIs, immune-related adverse effects (irAEs) have aroused wide attention. The cardiac irAE, one of the rare but potentially fatal effects, have been reported recently. However, the clinical comprehension of cardiac irAEs remains limited and guidelines are inadequate for cardio-oncologists to tackle the problem. In this review, we have summarized current classifications of, manifestations of, potential mechanisms of, and treatment for ICI-related myocardial injury in order to provide some clues for the understanding of cardiac irAEs in clinical work.
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Kawahira, Machiko, Shuji Kanmura, Keiko Mizuno, Kentaro Machida, Takao Ohtsuka, Masami Sato, Hideki Enokida, et al. "Effects of immune checkpoint inhibitor therapy resumption in patients with malignant tumors after moderate-to-severe immune-related adverse events." PLOS ONE 17, no. 4 (April 28, 2022): e0267572. http://dx.doi.org/10.1371/journal.pone.0267572.
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Background and aims Immune checkpoint inhibitors (ICIs) are used to treat several cancers, but they sometimes induce immune-related adverse events (irAEs). Patients with irAEs often have improved antitumor responses, but discontinuation of ICIs after irAEs is considered necessary. Resuming the use of ICIs after irAEs is preferable, but few studies have investigated the safety of ICI resumption after irAEs. Therefore, we evaluated the factors associated with the recurrence of irAEs after ICI resumption to investigate the safety of this approach. Methods In this observational study, we enrolled patients treated with ICIs from September 2014 to March 2020 at our institution. Patient characteristics, ICIs, grades of irAEs, ICI discontinuation or resumption rates, and recurrence rates of irAEs after ICI therapy were analysed. Results Two-hundred eighty-seven patients were included in the present study, and 76 patients experienced grade 2 or higher irAEs. Forty-two patients underwent ICI resumption after recovering from irAEs, and 13 of them had a recurrence of irAEs. Among those 13 patients, six had a recurrence of the same irAE, and seven experienced other irAEs. Ten of the 13 patients had grade ≥2 irAEs, and none had fatal irAEs. In the grade 2 or higher irAE group, more patients had irAEs associated with multiple organs and of initial grade ≥2 than those in the grade 1 and no recurrent irAEs group. Conclusions Patients with initial multisystemic irAEs and irAEs of grade ≥2 were more likely to experience relapse or develop new grade ≥2 irAEs after ICI resumption.
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Wang, QuanQiu, and Rong Xu. "Immunotherapy-related adverse events (irAEs): extraction from FDA drug labels and comparative analysis." JAMIA Open 2, no. 1 (October 15, 2018): 173–78. http://dx.doi.org/10.1093/jamiaopen/ooy045.
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Abstract Objectives Immune checkpoint inhibitors (ICIs) have dramatically improved outcomes in cancer patients. However, ICIs are associated with significant immune-related adverse events (irAEs) and the underlying biological mechanisms are not well-understood. To ensure safe cancer treatment, research efforts are needed to comprehensively detect and understand irAEs. Materials and methods We manually extracted and standardized irAEs from The U.S Food and Drug Administration (FDA) drug labels for six FDA-approved ICIs. We compared irAE profile similarities among ICIs and 1507 FDA-approved non-ICI drugs. We investigated how irAEs have differential effects on human organs by classifying irAEs based on their targeted organ systems. Finally, we identified broad-spectrum (nontarget-specific) and narrow-spectrum (target-specific) irAEs. Results A total of 893 irAEs were extracted. 31.4% irAEs were shared among ICIs as compared to the 8.0% between ICIs and non-ICI drugs. irAEs were resulted from both on- and off-target effects: irAE profiles were more similar for ICIs with same target than different targets, demonstrating the on-target effects; irAE profile similarity for ICIs with the same target is less than 50%, demonstrating unknown off-target effects. ICIs significantly target many organ systems, including endocrine system (3.4-fold enrichment), metabolism (3.7-fold enrichment), immune system (3.6-fold enrichment), and autoimmune system (4.8-fold enrichment). We identified 21 broad-spectrum irAEs shared among all ICIs, 20 irAEs specific for PD-L1/PD-1 inhibition, and 28 irAEs specific for CTLA-4 inhibition. Discussion and conclusion Our study presents the first effort toward building a standardized database of irAEs. The extracted irAEs can serve as the gold standard for automatic irAE extractions from other data resources and set a foundation to understand biological mechanisms of irAEs.
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Coschi, Courtney H., and Rosalyn A. Juergens. "The Price of Success: Immune-Related Adverse Events from Immunotherapy in Lung Cancer." Current Oncology 28, no. 6 (November 2, 2021): 4392–407. http://dx.doi.org/10.3390/curroncol28060373.
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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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Thapa, Bicky, Joanna Roopkumar, Ann S. Kim, Lorenzo Gervaso, Pradnya Dinkar Patil, Cassandra Calabrese, Alok A. Khorana, and Pauline Funchain. "Incidence and clinical pattern of immune related adverse effects (irAE) due to immune checkpoint inhibitors (ICI)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14151-e14151. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14151.
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e14151 Background: ICIs have revolutionized outcomes in many advanced malignancies, however their use is associated with irAEs. Methods: An IRB-approved, retrospective chart review was done using the Cleveland Clinic pharmacy database. Patients were included who received six FDA approved (nivolumab, ipilimumab, pembrolizumab, atezolizumab, avelumab, or durvalumab) ICIs from July 2015 to December 2017. irAEs were identified from review of electronic medical records. Descriptive analysis was done to evaluate the incidence, pattern, and severity of irAEs. Results: A total of 1091 patients received ICI therapy, 651 (59.7%) were male, 958 (87.4%) white, 95 (8.7%) black. Lung cancer (540, 49.5%) comprised the majority of the cohort, followed by melanoma (152, 13.9%), and renal cell carcinoma (121, 11.1%). About 996 (91.3%) received treatment with only one ICI, 85 (7.8%) with 2 ICIs, and only 10 patients received 3 ICIs. A total of 487 (44.63%) patients encountered irAEs, 128 (11.73%) resulting in treatment cessation. Fatigue (152, 13.9%) was the most common, followed by dermatologic irAEs (131, 12%). Endocrine irAEs occurred in 108 (9.89%), GI toxicities, namely diarrhea and colitis, were seen in 92 (8.4%) and hepatotoxicity in 54 (4.94%). Other irAEs including rheumatologic, pneumonitis, renal, and neurological adverse effects were documented in 6.5%, 5.1%, 2.56%, and 2.01% respectively. Rare irAEs such as ocular toxicity, cardiac toxicity, and vasculitis were seen in 0.8%, 0.73%, and 0.54%, respectively. Compared with a pooled analysis from clinical trials (De Velasco G et al. Comprehensive Meta-analysis of Key irAEs from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients) dermatologic irAEs and fatigue were less frequent; diarrhea/colitis, pneumonitis and rheumatologic irAEs were more frequent. Conclusions: irAEs on ICI therapy are very common. Awareness of the relative frequencies of various irAEs, particularly severe and rare irAEs, in a real-world setting can help improve quality of care for cancer patients receiving ICI. [Table: see text]
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Kapoor, Akhil, Vanita Noronha, Vijay Maruti Patil, Amit Joshi, Nandini Sharrel Menon, and Kumar Prabhash. "Association of immune-related adverse effects and survival in responders treated with immune checkpoint inhibitors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15172-e15172. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15172.
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e15172 Background: The development of immune-related adverse effects (irAEs) can corroborate with the response to immune checkpoint inhibitors (ICIs). However, there is very limited data on the association of irAEs with survival in patients who have shown response to ICIs. Methods: This study is a retrospective audit of prospectively collected database of patients who received ICIs for advanced solid tumors. Responders were defined as patients who attained best response of either complete response (CR) or partial response (PR). Time-to-event analysis was done using Kaplan-Meier estimator and hazard ratio was calculated by using Cox proportional model. Results: A total of 155 patients who received ICI during the specified period were evaluated for this study. The response rate was 19.4%. One year OS for responders was 75.6% (SD 8.8) versus 26.1% (SD 5.1). The median OS for patients who developed irAE was 12.3 months (95% CI: 8.9-15.6) while it was not reached for patients without irAE (HR 10.5, 95% CI 1.2-NR, p=0.007). One-year OS for the corresponding group of patients was 53.6% (SD 15.6) versus 92.9% (SD 6.9), respectively. Conclusions: This study reports negative association of immune-related adverse effects and survival in responding patients of solid tumors treated with immune checkpoint inhibitors. [Table: see text]
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Rodriguez, Benigno, José Fabián Martínez-Herrera, Lorena López Zepeda, Guillermo Olivares, Alberto Villalobos, Fernando Perez, Christian Patricio Camacho Limas, et al. "Association of immune-related adverse events with immune-checkpoint inhibitors and treatment response in melanoma patients." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e21522-e21522. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e21522.
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e21522 Background: Immune-related adverse effects (irAE´s) of immune-checkpoint inhibitors (ICIs) have been linked with a better treatment response in melanoma patients, especially cutaneous toxicities. However, little is known regarding other irAE´s which is important as they can be used as clinical markers of an adequate therapeutical response. Methods: We conducted a retrospective study on patients who were diagnosed with melanoma and received treatment with ICI´s between January 2015 until December 2021, immune related adverse events and their relationship with overall survival in melanoma patients treated with ICIs was the main objective of this study. Results: 53 records of patients with advance melanoma treated with ICIs between january 2016 to december 2021, demographic characteristics were as follow: 64.2% were male, mean age at diagnoses was 60.3 years, 41.5% had smoking history and 15.1% were Jewish. At diagnosis 73.6% of patients had a good functional status (ECOG 0-1). The most common histological subtypes were epithelioid (34%), and nodular (22.6%). Lung metastases was the most common affected site (49.1%), followed by brain 43.4% and non-regional nodes 42.5%. BRAF mutations was determined in 81.1% of the biopsies and 36% of them being V600E mutation. ICI´s was the preferred first line treatment in 83% of cases, median number of administered cycles were 6 (range 1-54 cycles), 60.4% of patients received pembrolizumab, 37.7% nivolumab plus ipilimumab, 20.8% nivolumab monotherapy and 5.7% ipilimumab. Throughout the studied period IrAE´s were reported in 34% of patients with 66.7% of them being grade 1-2 and 33.3% grade 3-4. The most common IrAE’s: vitiligo 38.8%, hypothyroidism22% and 3.8% pneumonitis. Median PFS at 12 months and OS was significantly better in the group of patients with irAE´s: Patients who develop an irAE´s are 7 times more likely to be disease free at 12 months and 4.1 times more likely to have a longer OS regardless of severity and type of toxicity. The impact of developing irAEs is significantly important for PFS (HR: 11.9, CI 95%: 3.28-4.71) as median PFS was not yet reached in this group. Conclusions: Development of irAEs is associated with favorable outcomes to ICIs with patients being 7 times more likely to be 12-month disease free and 4.1 times more likely to have a longer OS. irAEs can be used as clinical markers of an adequate treatment response.[Table: see text]
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Kim, Sarah, A. Dimitrios Colevas, Stephanie Tse, Sandy On, and Edna Cheung. "Immune-related adverse effects of long-term PD-1/PD-L1 inhibtor treatment." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2661. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2661.
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2661 Background: Immune-related adverse effects (irAE) are autoimmune-like toxicities caused by immune checkpoint inhibitor (ICI) treatment and often necessitate interventions such as corticosteroids, treatment interruptions/discontinuation, or hospital admission. Although ICI related irAEs are well described in literature, data on the toxicity profile associated with long-term ICI use remains limited. Since the optimal duration of therapy with ICI agents is currently unknown, it is crucial to assess the risks of long-term ICI use. Methods: This was a retrospective, observational, single-center study of adult oncology patients who received at least 1 year of programed death 1 (PD-1) inhibitor or programmed death ligand-1 (PD-L1) inhibitor treatment. The objective of this study was to characterize late-onset irAEs defined as greater than 1 year with long-term ICI treatment. Clinically significant irAEs were defined as those requiring corticosteroid treatment, hospital admission, treatment interruption or treatment discontinuation. This study included patients who received at least 1 year of nivolumab, pembrolizumab, atezolizumab or durvalumab between January 2016 and September 2021. Disease states included head and neck cancer, renal cell carcinoma, non-small cell lung cancer, and melanoma. Patients with concurrent exposure to other treatment such as chemotherapy, radiation, surgery, tyrosine kinase inhibitors and monoclonal antibodies while on ICI treatment were included in the study. Exclusion criteria included patients with treatment breaks of greater than 6 months, two malignancies undergoing active treatment, and treatment administration outside of the study center. Results: Of 282 patients assessed, 143 met study inclusion criteria. The median ICI treatment duration was 19 months (IQR 14-27). There was a 30% incidence of late-onset irAEs, of which 22% were clinically significant. Most late-onset irAEs were low in severity, as 45 (90%) were grade 1-2 and 5 (10%) were grade 3. The most common late-onset irAEs were pulmonary (8%) and gastrointestinal (7%). Univariate analysis suggests risk factors potentially associated with late-onset irAEs include concurrent exposure to additional therapies during ICI treatment and past medical history of rheumatologic disease. Conclusions: Although the optimal duration of ICI therapy is unknown, this study suggests that long-term ICI use was associated with a low but notable incidence of toxicities, of which most were low in severity. [Table: see text]
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Medina, Patrick, Kate D. Jeffers, Van A. Trinh, and R. Donald Harvey. "The Role of Pharmacists in Managing Adverse Events Related to Immune Checkpoint Inhibitor Therapy." Journal of Pharmacy Practice 33, no. 3 (November 6, 2019): 338–49. http://dx.doi.org/10.1177/0897190019885230.
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Objective: To provide an overview of immune checkpoint inhibitor (ICI) therapy-associated immune-related adverse events (irAEs) and their management, focusing on the key responsibilities for pharmacists in recognizing, distinguishing, and treating irAEs and in educating patients about irAEs and their management. Data Sources: Literature published from January 2000 to March 2018 available from online sources. Study Selection and Data Extraction: Relevant English-language studies, guidelines, and articles. Data Synthesis: ICI therapies have been approved for the treatment of several cancers as single-agent therapies, combined ICI therapies, or in combination with other agents. ICI therapies increase the activity of the immune system and consequently can have autoimmune-like adverse effects that are often termed irAEs. irAE management can be challenging as irAEs can vary in their frequency and severity among patients, according to the specific agent, and can occur at any time during treatment or after therapy discontinuation. Additionally, for patients treated with ICI therapies in combination with other therapies, ICI-associated irAEs must be distinguished from adverse events associated with chemotherapy or targeted therapies, which often require different management. Pharmacists can provide essential support to diagnose and manage irAEs. Relevance to Patient Care and Clinical Practice: Early and accurate diagnosis and prompt management of irAEs by pharmacists are critical to reduce the risk of severe or life-threatening complications and prevent premature ICI discontinuation. Conclusions: Pharmacists have a key role in the recognition, monitoring, and management of irAEs and in educating patients about irAEs associated with ICI therapies and the agents used to manage them.
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Melia, A., E. Fockens, A. Madroszyk, P. Lafforgue, and T. Pham. "OP0278 MUSCULOSKELETAL IMMUNE-RELATED ADVERSE EVENTS IN 927 PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS FOR SOLID CANCER." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 184.1–185. http://dx.doi.org/10.1136/annrheumdis-2022-eular.252.
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BackgroundThe prevalence of the musculoskeletal immune-related adverse events (irAEs) is probably underestimated, as most studies report only severe side effects. The largest prospective study with systematic monitoring by a rheumatologist, for musculoskeletal irAEs, concerned 35 patients.ObjectivesThe main objective was to describe each type of musculoskeletal irAEs: prevalence, clinical features, treatment regimen, ICI drug, time of occurrence and management of musculoskeletal irAEs. The secondary objectives were to describe IrAEs’course ant to investigated tumor response at 3 months after introduction of ICI according to IrAEs’grade, clinical features, pain patterns and the treatments used to manage musculoskeletal irAEs.MethodsWe conducted a retrospective study among patients who received ICI from 07/27/2014 to 05/08/2020 at the medical oncology department of the Institut Paoli-Calmettes, Marseille, France. All medical files were systemically reviewed by a rheumatologist who collected clinical features, time of occurrence, treatment regimen, irAEs management, course, outcomes and tumor response 3 months after introduction of ICI.ResultsIn our cohort of 927 patients treated with ICI for a solid tumor, 118 patients (12.7%) presented a musculoskeletal irAE. Their median age was 66.5, 61% were male, and they mainly had a lung (57.6%) or urological cancer (27.1%). The most frequently involved ICI was an anti PD-1. Arthralgias and myalgias were the most frequent musculoskeletal irAEs (76.3%) and inflammatory rheumatic features were reported in 36 patients (30.5%) with elevated acute phase reactants and negative immunological markers. The median time of onset was 2 months (IC 95% 1.8; 2.7). Musculoskeletal irAEs were mainly mild and no deaths were related. Painkillers were the most widely used treatments (86.4%). Systemic corticosteroids were used in 38 patients (32.2%) with a mean dose of 43 ± 35 milligrams/day. Among the inflammatory rheumatic features, 20 (55.5%) were treated with systemic corticosteroids and 8 with csDMARDs (16.7%). bDMARDs were not used in our cohort. Musculoskeletal irAEs resulted in discontinuation of the responsible ICI in 23 patients (19.5%). The majority of musculoskeletal irAEs (79.7%) resolved within a median time of 3 months (IC 95% 2.2;4.0). Tumor response at 3 months did not differ according to musculo-skeletal irAE severity, type of manifestation (arthralgias/myalgias versus inflammatory rheumatic features), pain patterns (mechanical versus inflammatory) or irAE treatments.ConclusionOur single-center cohort is the largest to our knowledge to describe all musculoskeletal irAEs in patients treated with ICI without focusing on severe or inflammatory manifestations. These musculoskeletal irAEs are frequent, mostly mild and well tolerated, resolving and allowing possible continuation of ICI treatment. Collaboration between oncologists and rheumatologists should be further encouraged to determine whether all musculoskeletal irAEs, even non-severe and non-inflammatory ones, are associated with a good tumor response to ICI.References[1]Kostine M and al, Rheumatology. 2019 Dec 1.[2]Belkhir R and al, Ann Rheum Dis. 2017 Oct.[3]Angelopoulou F and al, Rheumatol Int. 2021 Jan.[4]Kostine M and al, Ann Rheum Dis. 2021 Jan.[5]Cappelli LC and al, Arthritis Care Res. 2017 Nov.[6]Kostine M and al, Ann Rheum Dis. 2018 Mar.[7]Liew DFL and al, Int J Rheum Dis. 2019 Feb.[8]Cappelli LC and al, Seminars in Arthritis and Rheumatism. 2018 Dec.AcknowledgementsWe gratefully thank Patrick SFUMATO and Christophe ZEMMOUR (biostatisticians, Institut Paoli-Calmettes, Marseille), Doctor Frédéric BENIZRI (pharmacist, Institut Paoli-Calmettes, Marseille), Doctor Marie-Caroline GUZIAN (rheumatologist, Montélimar).Disclosure of InterestsNone declared
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Verspohl, Sophia H., Tobias Holderried, Charlotte Behning, Peter Brossart, and Valentin S. Schäfer. "Prevalence, therapy and tumour response in patients with rheumatic immune-related adverse events following immune checkpoint inhibitor therapy: a single-centre analysis." Therapeutic Advances in Musculoskeletal Disease 13 (January 2021): 1759720X2110069. http://dx.doi.org/10.1177/1759720x211006963.
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Background: Immune checkpoint inhibitors (ICIs) improved cancer therapy by inducing a higher immune system activity. This effect can cause rheumatic immune-related adverse events (rh-irAEs), which have not yet been extensively studied. Methods: We analysed 437 patients between 2014 and 2019, treated with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) or pembrolizumab (anti-PD-1) at the Clinic for Internal Medicine III, Oncology, Haematology and Rheumatology at the University Hospital Bonn, Germany. Results: Of the 437 patients 60% were males. Patients were mainly treated for melanoma, lung cancer, head and neck tumour and urothelial carcinoma. At least one immune-related adverse event (irAE) was observed in 163 patients (37.3%), including rh-irAE. Most common side effects were rash, colitis and hepatitis. We identified 19 patients (4.3%) with a minimum of one rh-irAE due to ICI therapy; three of those had a pre-existing rheumatic disease. Arthralgia developed most frequently in eight patients (42.1%). Other rh-irAEs were: arthritis ( n = 7; distinguished in rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and undifferentiated arthritis), myalgia ( n = 2) and myositis ( n = 3). Most rh-irAEs were classified as moderately severe (Common Terminology Criteria of Adverse Events grade 2: 68.4%). Median time between starting ICI therapy and the occurrence of rh-irAE was 109 days (interquartile range 40–420 days). Fifteen patients (78.9%) were treated with glucocorticosteroids. In four cases additional therapy with methotrexate or tocilizumab was required. Even though patients benefited from ICI treatment, therapy had to be discontinued in six of the participants due to rh-irAE. Interestingly, patients with rh-irAE had a significantly higher tumour response compared with patients without rh-irAE (94.4% versus 43.5%; p < 0.0001). Conclusion: Rh-irAEs occur under ICI therapy, especially in patients with higher tumour response. However, they are not the most frequent irAE after ICI exposure: 9.3% of all irAEs were rheumatic (20 rh-irAE cases in 19 patients of a total of 215 irAE cases in 163 patients).
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Zhang, Shuo, Ziyue Zhou, Li Wang, Mengtao Li, Fengchun Zhang, and Xiaofeng Zeng. "Rheumatic immune-related adverse events associated with immune checkpoint inhibitors compared with placebo in oncologic patients: a systemic review and meta-analysis." Therapeutic Advances in Chronic Disease 12 (January 2021): 204062232097699. http://dx.doi.org/10.1177/2040622320976996.
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Objective: We aim to characterize the incidence and relative risk of rheumatic and systemic immune-related adverse effects (irAEs) among immune checkpoint inhibitor (ICI) therapy compared with those after placebo treatment. Methods: Randomized clinical trial studies with placebo control with the following keywords were searched from Embase, PubMed, Cochrane databases: immune checkpoint inhibitors, neoplasms, randomized controlled trials, and adverse effects. Results: Among the 5444 published and 316 registration records, nine placebo-controlled randomized clinical trials met our selection criteria, and included data from 5560 patients. Compared with placebo use, using ICIs increases the risk of overall-rheumatic irAEs. The incidence and relative risk of all-grade rheumatic irAEs were 18.40% [95% confidence interval (CI) 12.16–25.59%, p < 0.01] and 2.30 (95% CI 1.32–4.02), respectively, while musculoskeletal irAEs were 11.30% (95% CI 9.76–12.85%) and 1.01 (95% CI 0.84–1.22). The incidence and relative risk of severe rheumatic irAEs were 5.72% (95% CI 3.92–7.82%), and 8.29 (95% CI 3.75–18.35), respectively. Arthralgia was the most common rheumatic irAE (incidence 11.00%, 95% CI 9.55–12.64%; relative risk 0.99, 95% CI 0.82–1.19), although usually not severe. Colitis (incidence 3.23%, 95% CI 1.27–7.98%; relative risk 6.53, 95% CI 2.66–16.04) and pneumonitis (incidence 3.11%, 95% CI 1.56–6.21; relative risk 4.04, 95% CI 1.65–9.89) were commonly observed and tended to be severe. Hepatitis, hypophysitis, thyroiditis, and myositis were rare and less recorded, yet can be severe and life threatening. Other extremely rare severe rheumatic irAEs included sarcoidosis ( n = 11), autoimmune arthritis ( n = 8), autoimmune uveitis ( n = 3), autoimmune pericarditis, bursitis, osteochondrosis, psoriasis, polymyalgia rheumatica, systemic inflammatory response syndrome, and Sjögren syndrome ( n = 1, each). Conclusion: ICI therapy increased the incidence and relative risk of all-grade and severe rheumatic irAEs. Arthralgia was the most commonly observed non-severe irAE, while colitis and pneumonitis were commonly observed severe irAEs. Rare rheumatic irAEs like hepatitis, hypophysitis, thyroiditis, and myositis warrant special attention.
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Boruah, Abhilasha Pankaj, Kathryn Demski, Pradnya Dinkar Patil, Cassandra Calabrese, and Pauline Funchain. "Implementation and impact of a novel multidisciplinary immune-related adverse events tumor board for patients receiving immune checkpoint inhibitor therapy." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e13541-e13541. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13541.
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e13541 Background: Given the often atypical and diverse presentations of immune-related adverse events, the utilization of an institutional multidisciplinary irAE tumor board is an effective strategy to deliver comprehensive, collaborative, and efficient care to patients experiencing these effects. We report the clinical impact of a multidisciplinary tumor board dedicated towards management of irAEs in patients receiving checkpoint inhibitor therapy. Methods: We completed a retrospective review of patients discussed during our multidisciplinary irAE tumor board at Cleveland Clinic Taussig Cancer Center. Pertinent data collection regarding malignancies, therapies, and reported irAEs was completed through the electronic medical system. Results: Between September 2017-January 2021, 96 patients were discussed in our institutional irAE tumor board. 48 males and 48 females were discussed with the most common primary malignancies being melanoma (53%, 51/96), lung neoplasms (25%, 24/96), and renal cell carcinoma (15%, 14/96). Of the therapies used by these patients, the most frequently associated checkpoint inhibitors were Nivolumab (41%, 39/96), Pembrolizumab (30%, 26/96), and Ipilumumab (17%, 16/96). irAEs affecting the gastrointestinal system such as colitis, hepatitis, and gastritis were most common among discussed patients (40%, 38/96), however several patients also exhibited irAEs targeting the neurological (12.5%, 12/96), rheumatologic (11%, 11/96), dermatologic (8%, 8/96), respiratory (8%, 8/96), and cardiac systems (4%, 4/96). The utilization of tumor board was documented in 41 patients’ notes (43%), with increased documentation over the past year (71%, 24/34), and 70 patients (73%) received a pertinent consult for management of their irAE post tumor board recommendations. Conclusions: Clinical utilization of irAE TB recommendations was high as evidenced by clinical documentation and consequent referrals. Increasing institutional awareness of tumor board over the past year was reflected in a proportionate rise in official documentation. irAE tumor board has the capacity to promote more effective cross-specialty collaboration during treatment of irAEs by both streamlining patient care discussions and encouraging cross-fertilization of therapeutic concepts between multiple subspecialties, and may ultimately increase quality of care for patients experiencing these toxicities.
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Zhang, You-Cheng, Tian-Chen Zhu, Run-Cong Nie, Liang-He Lu, Zhi-Cheng Xiang, Dan Xie, Rong-Zhen Luo, and Mu-Yan Cai. "Association between Early Immune-Related Adverse Events and Survival in Patients Treated with PD-1/PD-L1 Inhibitors." Journal of Clinical Medicine 12, no. 3 (January 17, 2023): 736. http://dx.doi.org/10.3390/jcm12030736.
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Background: Immune-related adverse events (irAEs) are side effects that reflect the activation of patients’ immune systems after treatment with immune checkpoint inhibitors (ICIs). However, there is no meta-analysis on the effect of early irAEs on patient survival. Thus, we assessed the association between early irAEs and the survival of patients treated with ICIs. Methods: PubMed, Embase, and Web of Science were searched from May 2010 to May 2020 for all the retrospective and prospective comparative studies to evaluate the hazard ratios (HRs) for death. A random-effects model was used to calculate the pooled HR for death, and heterogeneity was assessed using I² statistics. The main outcomes were overall survival (OS) and progression-free survival (PFS). Results: A total of 11 reports with 2077 patients were included. A significant association was observed between early irAEs and a favorable clinical outcome. Patients with early irAEs had prolonged OS (HR: 0.62, 95% confidence interval (CI): 0.53–0.74, p < 0.001) and PFS (HR: 0.53, 95% CI: 0.41–0.66, p < 0.001) compared to those without; these results were confirmed using a sensitivity analysis. The irAE types, malignancy types, and sample size were correlated with patients’ clinical outcomes. Conclusions: Early irAEs, especially cutaneous irAEs, correlated with a better clinical outcome in patients treated with ICIs.
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Hamatake, Kiyonori, and Kazuaki Kojima. "Initiatives for immune-related adverse events by the outpatient pharmacist clinic." Trends in Immunotherapy 6, no. 1 (January 10, 2022): 3. http://dx.doi.org/10.24294/ti.v6.i1.1385.
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Early detection is the key in managing side effects because immune-related adverse events (irAEs) are becoming more serious, and their onset time differs. In our hospital, we conducted an outpatient pharmacist clinic for early detection of irAEs by self-care practice for the cases of immune checkpoint inhibitor administration. As a result of a retrospective survey of 207 cases, the percentage of irAEs found by pharmacist’s suggestion of the outpatient pharmacist clinic increased over time, and a high detection ratio was obtained even for irAEs with a late onset time. The incidence of serious irAEs was higher than that in the immediate post-marketing surveillance, and different factors were considered. Although there were some problems, the outpatient pharmacist clinic had a certain effect.
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Walker, Josh, Mena Farag, Debra Josephs, Victoria Williams, and Paul Holmes. "011 A case of a neurological immune-related adverse event associated with ipilimumab/nivolumab." Journal of Neurology, Neurosurgery & Psychiatry 93, no. 9 (August 12, 2022): e2.203. http://dx.doi.org/10.1136/jnnp-2022-abn2.55.
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AbstractWe present an unusual movement disorder due to immune checkpoint inhibitors which responded rapidly to prednisolone.BackgroundImmune checkpoint inhibitors (ICIs) have revolutionised the scope of cancer therapy but can induce autoimmune effects on healthy organs, termed immune-related adverse events (irAEs). Their pathophysiology relies on the same mechanisms that confer anti-tumour activity and can affect any organ in the body. Neurological irAEs (n-irAEs) although rare, are potentially fatal. Differentiating n-irAEs from paraneoplastic syndromes and other neurological disorders can be challenging.CaseWe present a case of n-irAE in a patient with metastatic renal cell carcinoma treated with two cycles of ipilimumab/nivolumab. Following the second cycle, the patient developed subacute onset of postural and rest tremor, predominantly affecting her upper limbs, head and tongue, of variable amplitude, with bradykinesia of foot tapping. Her gait was broad-based. MRI brain was unremarkable. CSF was lymphocytic (WBC 103 cells, 90% lymphocytes) with elevated protein (1.30g/L), normal CSF:serum glucose ratio, negative CSF culture and viral PCR. She was treated for ICI-associated neurotoxicity and responded rapidly to high-dose steroids.ConclusionPhysicians should be aware of the diverse presentations of n-irAEs, including unusual movement disorders. Close collaboration between neurologists and oncologists is imperative in the management of these patients.
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Gnanapandithan, Karthik, Prakash Kharel, Alyssa Grimshaw, and Smith Giri. "Hematologic Immune-Related Adverse Events from Immune Checkpoint Inhibitors: A Systematic Review of Case-Reports and Case-Series." Blood 134, Supplement_1 (November 13, 2019): 3606. http://dx.doi.org/10.1182/blood-2019-132203.
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Introduction: Immune checkpoint inhibitors (ICI) have proven to be a significant breakthrough in modern cancer therapy. However, this has come at a cost of immune-related adverse events (irAE) affecting various organ systems. Hematological irAEs including autoimmune hemolytic anemia (AIHA), pure red cell aplasia (PRCA), immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), hemophagocytic lymphohistiocytosis (HLH), aplastic anemia and pancytopenia, are well recognized side effects of ICI. Due to their rarity, existing literature is confined to case reports and series. We conducted a systematic review of all published case reports and series till date to summarize clinical presentation, risk factors, management, and outcomes of patients who develop hematologic irAEs during ICI treatment. Methods: Using free text and controlled vocabulary (MESH and EMTREE terms), we performed a systematic search of the literature using Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection. Eligibility criteria included any case report or case series describing at least one hematologic irAEs developing during and likely related to ICI therapy for solid/hematologic malignancy. Two authors independently screened the titles, abstracts, and the full text of the selected papers. Patients who had received at least one FDA approved ICI (PD-1, PDL-1 or CTLA-4 inhibitors), and subsequently developed a decline in one or more of cell lines were included. Data regarding clinical presentation, concomitant other irAEs, treatment and clinical outcomes was extracted using a standardized data extraction form and summarized using descriptive statistics. Results: Of the 19856 articles screened, a total of 59 articles were selected for full-text review, and a total of 54 reports describing 57 cases met our eligibility criteria. The median age at the time of presentation was 63 y(interquartile range (IQR) 51-74) yrs, and 29 (50.9%) were males. PD-1 inhibitors were implicated in 35 (61%), CTLA-4 inhibitors in 14 (25%) and PD1/CTLA4 combination therapy in 7 (12%). The most common malignancies included metastatic melanoma (n=32, 56%) and non-small cell lung cancer (n=16, 28%). Only 8 patients (14%) reported a pre-existing history of autoimmune disease and only 11 (19%) had additional irAES involving other organ systems. AIHA (n=16, 28%), ITP (n=12, 21%) and pancytopenia (n=13, 23%) were the three most common subtypes of hematologic irAEs. Two or more cell lines were affected in 13 patients (23%). Twenty-six (46%) of the irAEs were detected on regular laboratory tests. The median number of cycles prior to the onset of hematologic irAEs was 3 (IQR 2-4). Among treatment strategies, corticosteroids were used in most patients (n=50, 88%). Other treatment modalities employed included Intravenous Immunoglobulin (IVIg) (n=14; 25%), hematopoietic growth factors and other supportive treatment were Treatment strategies were based on the actual irAE and the patient's condition. Corticosteroids, transfusion of blood products, hematopoietic growth factors, and other supportive treatment were primarily employed in most patients. Steroids were used in 50 (88%) patients and intravenous immunoglobulins in 14 (25%). Other immunosuppressants, anti-thymocyte globulins, and plasma exchange were used in select patients. Most of the patients (n=44, 77%) were described as having improved or recovered blood counts with treatment. Only 5 (9%) of these patients were rechallenged with the same or other ICI therapy. Among these, the same hematologic irAE recurred in 2 patients (40%). Cytopenia, as an irAE, was directly responsible for the death of 8 patients (14%). Conclusion: Hematologic irAEs are rare but potentially fatal adverse effect of ICI therapy. Although it can have diverse manifestations, AIHA and ITP are the most common subtypes. Almost half of these patients are clinically silent and detected in routine laboratory evaluation. Most hematologic irAEs appear early during the course of therapy and without pre-existing/concomitant irAEs. Most cases report successful resolution with treatment that commonly include high dose corticosteroids, and successful re-challenge has been reported in a few cases. Disclosures No relevant conflicts of interest to declare.
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Morgado, Manuel, Ana Plácido, Sandra Morgado, and Fátima Roque. "Management of the Adverse Effects of Immune Checkpoint Inhibitors." Vaccines 8, no. 4 (October 1, 2020): 575. http://dx.doi.org/10.3390/vaccines8040575.
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By increasing the activity of the immune system, immune checkpoint inhibitors (ICPI) can have adverse inflammatory effects, which are referred to as immune-related adverse effects (irAEs). In this review, we present the recommendations for the appropriate identification and treatment of irAEs associated with ICPI to increase the safety and effectiveness of therapy with these immuno-oncological drugs. Several guidelines to manage irAEs adopted by different American and European societies in the field of oncology were identified. A narrative review of the several strategies adopted to manage irAEs was performed. With close clinical surveillance, ICPI can be used even in patients who have mild irAEs. Moderate to severe events require early detection and appropriate treatment, particularly in patients with a history of transplantation or pre-existing autoimmune disease. In most cases, adverse reactions can be treated with the interruption of treatment and/or supportive therapy, which includes, in serious adverse reactions, the administration of immunosuppressants. The identification and treatment of irAEs in the early stages may allow patients to resume therapy with ICPI. This review is an instrument to support healthcare professionals involved in the treatment and monitoring of patients who are administered ICPI, contributing to the timely identification and management of irAEs.
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Gupta, Samir, Anas Belouali, Neil J. Shah, Michael B. Atkins, and Subha Madhavan. "Automated Identification of Patients With Immune-Related Adverse Events From Clinical Notes Using Word Embedding and Machine Learning." JCO Clinical Cancer Informatics, no. 5 (May 2021): 541–49. http://dx.doi.org/10.1200/cci.20.00109.
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PURPOSE Although immune checkpoint inhibitors (ICIs) have substantially improved survival in patients with advanced malignancies, they are associated with a unique spectrum of side effects termed immune-related adverse events (irAEs). To ensure treatment safety, research efforts are needed to comprehensively detect and understand irAEs. Retrospective analysis of data from electronic health records can provide knowledge to characterize these toxicities. However, such information is not captured in a structured format within the electronic health record and requires manual chart review. MATERIALS AND METHODS In this work, we propose a natural language processing pipeline that can automatically annotate clinical notes and determine whether there is evidence that a patient developed an irAE. Seven hundred eighty-one cases were manually reviewed by clinicians and annotated for irAEs at the patient level. A dictionary of irAEs keywords was used to perform text reduction on clinical notes belonging to each patient; only sentences with relevant expressions were kept. Word embeddings were then used to generate vector representations over the reduced text, which served as input for the machine learning classifiers. The output of the models was presence or absence of any irAEs. Additional models were built to classify skin-related toxicities, endocrine toxicities, and colitis. RESULTS The model for any irAE achieved an average F1-score = 0.75 and area under the receiver operating characteristic curve = 0.85. This outperformed a basic keyword filtering approach. Although the classifier of any irAEs achieved good accuracy, individual irAE classification still has room for improvement. CONCLUSION We demonstrate that patient-level annotations combined with a machine learning approach using keywords filtering and word embeddings can achieve promising accuracy in classifying irAEs in clinical notes. This model may facilitate annotation and analysis of large irAEs data sets.
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Weinmann, Sophia C., and David S. Pisetsky. "Mechanisms of immune-related adverse events during the treatment of cancer with immune checkpoint inhibitors." Rheumatology 58, Supplement_7 (December 1, 2019): vii59—vii67. http://dx.doi.org/10.1093/rheumatology/kez308.
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AbstractImmune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.
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Nasca, Vincenzo, Francesco Barretta, Francesca Corti, Sara Lonardi, Monica Niger, Maria Elena Elez, Marwan Fakih, et al. "Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer." Journal for ImmunoTherapy of Cancer 11, no. 1 (January 2023): e005493. http://dx.doi.org/10.1136/jitc-2022-005493.
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BackgroundImmune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.MethodsWe conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a ‘burden score’ constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.ResultsAmong 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two’s effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, ‘aggregated’ burden scores were developed to distinguish ‘protective’ (endocrine and musculoskeletal) and ‘harmful’ (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.ConclusionsOur results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.
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Cabanillas, Gerardo. "Immune related adverse events and their treatment in melanoma patients receiving ipilimumab." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e14598-e14598. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14598.
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e14598 Background: Ipilimumab is an immune checkpoint inhibitor approved for the treatment of melanoma. Immune-related adverse events (irAEs) may occur as adverse effects. Most reports on irAEs are from clinical trials, which may not reflect community clinical practice and outcomes. We used a health insurance based database to identify irAEs and their treatment among patients with melanoma that received Ipilimumab, as part of regular care. Methods: We identified all melanoma patients aged 18 and older who received Ipilimumab from the Truven Health Analytics Marketscan database between 2011 and 2014. Patients had continuous insurance coverage from the period of six months prior to Ipilimumab and three months after. We further assessed the treatment for each irAEs. IrAEs were defined base on claims with one or more 228 ICD-9 codes; irAEs had to occur within a 6-month window before treatment. We used summary statistics such as means and standard deviations for continuous variables, frequencies and percentages for categorical variables. Results: The cohort included 1225 patients. Median age was 60 years, 62% were male; 343 (35.44%) patients had one or more irAEs, and 48.6% (211) were treated at least once. Young age and female gender were associated with a higher likelihood of having an irAEs. Endocrinopathies and gastrointestinal diseases were the most common irAEs. The most frequent irAEs was colitis in 27% of patients, followed by hypothyroidism 26%. Six different drugs were used to treat irAEs, and corticosteroids being the most frequently prescribed. Few patients with colitis received Infliximab 14%; and cyclosporine was prescribed in one patient with pancreatitis Conclusions: One third of the patients with melanoma treated with Ipilimumab in the community developed irAEs. Corticosteroids were the most frequent drugs used to treat irAEs. Our results show that toxicity remains high with the use of this agent in clinical practice.
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Kulkarni, Ajinkya, Mrunal Kulkarni, Vinay Edlukudige Keshava, Rithikaa Ellangovan, and Rajesh Thirumaran. "Awareness of immune-related adverse events among medical residents in a community hospital." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15154-e15154. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15154.
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e15154 Background: Immunotherapy has paved the way for new frontiers in the management of certain advanced cancers. Immune checkpoint inhibitors (ICI) have substantially improved prognosis in patients with advanced malignancy. Primary targets for ICIs include programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1) and Cytotoxic T-lymphocyte-associated antigen 4(CTLA-4). These treatments have a wide range of adverse effects distinct from traditional chemotherapy regimens. We conducted a survey to assess the awareness of immune-related adverse events (IRAE) among medical residents in a community hospital. Methods: Internal medicine residents in a community hospital were given a survey of 10 questions related to IRAEs. A total of 40 responses were collected and analyzed. Results: 22.50% respondents were aware that nephrotoxicity is not a common side effect of immunotherapy. 35% were aware that cutaneous toxicities are the most common IRAEs. 42.50% were aware that hair loss is not a common side effect of ICIs. 42.50% were aware that patients do not need pretreatment with anti-emetics before immunotherapy. 45% were aware that the onset of hepatotoxicity is usually not seen within the first week of starting immunotherapy. 50% were aware that immunotherapy is associated with the development of pneumonitis. 62.5% were aware that steroids formed mainstay of treatment in IRAEs. 65% were aware that immunotherapy is associated with thyroid-related side effects. 67.5% were aware that patients with pre-existing autoimmune conditions are at greater risk for immune-related adverse effects. 70% were aware that immune related colitis was not treated with antibiotics. Conclusions: With the rapid advancement and use of immunotherapy the incidence of IRAEs is increasing. Involvement of single or multiple organ systems as well as flare of previously well controlled autoimmune disease can add to the challenge. As we gain more experience, long term data will emerge to help predict at-risk patients. This is a dynamic area of research and new treatments are under development. 6/10 questions were answered correctly by less than 50% respondents and 4/10 were answered correctly by 50-70% respondents. At present no data is available to gauge awareness regarding IRAEs among internists. Our survey suggests a lack of awareness among medical residents on many fronts. Lack of awareness leads to inappropriate treatment and prolonged hospital stay. Active efforts need to be taken to educate residents regarding immunotherapy and IRAEs to achieve better patient outcomes.
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Weber, Jeffrey S. "Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein Antibodies for the Oncologist." American Society of Clinical Oncology Educational Book, no. 32 (June 2012): 174–77. http://dx.doi.org/10.14694/edbook_am.2012.32.79.
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Overview: Monoclonal antibodies directed against immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1), can boost endogenous immune responses directed against tumor cells. Recently, ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma, and the anti-PD-1 antibody BMS-936558 has shown promising results in patients with melanoma, non-small cell lung cancer, and renal cell cancer. During treatment with these antibodies, a unique set of toxicities occur called immune-related adverse events (irAEs). These irAEs may occur at any time during treatment and include colitis characterized by a mild to moderate but occasionally severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab, and a subset of those side effects has also been observed with BMS-936558. Patient and physician education as well as good patient–caretaker communication are keys to limiting the morbidity of irAEs. Early recognition of these irAEs and initiation of treatment are critical to reduce the risk of complications, since virtually all irAEs are reversible with the use of steroids and other immune suppressants. The onset of grade 3 to 4 irAEs correlated with treatment response in some ipilimumab studies. This article provides detailed description and recommendations for practicing oncologists to manage the common irAEs associated with antibodies against immune checkpoint blockade.
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Kalinich, Mark, William Murphy, Shannon Wongvibulsin, Vartan Pahalyants, Kun-Hsing Yu, Feicheng Wang, Leyre Zubiri, et al. "854 Prediction of severe immune-related adverse events in patients on immune checkpoint inhibitors: study of a population level insurance claims database from the United States." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A907. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0854.
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BackgroundImmune-related adverse events (irAEs) are serious side effects of immune checkpoint inhibitors (ICIs) for patients with advanced cancer. Understanding the epidemiology and risk factors for severe irAEs would be beneficial for patients and clinicians.MethodsWe performed a retrospective review of cancer patients treated with ICIs using un-identifiable claims data from a nationwide US health insurance plan from January 3rd, 2011 to December 31st, 2019. Patients with an identified primary cancer and at least one administration of an ICI were included in the study. We defined severe irAE as any inpatient hospitalization with new immunosuppression within 2 years after initiation of ICI. The main outcomes were incidence of severe irAE in ICI therapy and factors associated with severe irAE occurrence. Multivariable logistic regression, including Charlson comorbidity index, age, gender, primary cancer, region, and zip code average income and unemployment, was used to model risk factors for severe irAE (table 1).ResultsThere were 14,378 patients followed over 19,177 patient-years identified with a primary cancer and at least 1 administration of ICI. 504 (3.5%) patients developed a severe irAE. The incidence of severe irAEs per patient ICI treatment year was 2.6%, rising from 0% (0/71) in 2011 to 3.7% (93/2486) in 2016 (figure 1). Combination immunotherapy (OR: 2.44, p < 0.001) and younger age (OR: 0.77, p < 0.001) were associated with increased odds of developing severe irAEs, whereas patients with non-lung cancer were associated with decreased odds of irAEs (melanoma OR: 0.70, p = 0.01, renal cell carcinoma OR: 0.71, p = 0.03, other cancers OR: 0.50, p < 0.001; figure 1). Sex, region, zip code income, and zip-code imputed unemployment were not associated with severe irAE incidence. Prednisone (72%) and methylprednisone (25%) were the most common immunosuppressive treatments identified in irAE hospitalizations.Abstract 854 Table 1Multivariate Regression Results for Incidence of Severe irAEAbstract 854 Figure 1irAE hospitalizations vs. Total HospitalizationsConclusionsWe found that 3.5% of patients initiating ICI therapy experienced severe irAEs requiring hospitalization and immunosuppression. The odds of severe irAEs were higher with younger age, treatment with combination ICI therapy (CTLA-4 and PD-1 or PD-L1), and lower for other cancers compared with patients on PD-1 or PD-L1 inhibitors with lung cancer. This evidence from the first nationwide study of severe irAEs in the US identified the real-world epidemiology, risk factors, and treatment patterns of severe irAEs in the US which may guide treatment selection and decisions for patients and clinicians.
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Stelmachowska-Banaś, Maria, and Izabella Czajka-Oraniec. "Management of endocrine immune-related adverse events of immune checkpoint inhibitors: an updated review." Endocrine Connections 9, no. 10 (October 2020): R207—R228. http://dx.doi.org/10.1530/ec-20-0342.
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Immune checkpoint inhibitors (ICIs) belong to a new group of anticancer drugs targeting T-cell proteins involved in the activation of immune response toward malignancies. Their introduction into clinical practice was a milestone in modern cancer treatment. However, the significant advantage of ICIs over conventional chemotherapy in terms of therapeutic efficacy is accompanied by new challenges related to specific side effects. ICI-induced immune system activation could lead to the loss of self-tolerance, presenting as autoimmune inflammation and dysfunction of various tissues and organs. Thus, the typical side effects of ICIs include immune-related adverse events (irAEs), among which endocrine irAEs, affecting numerous endocrine glands, have been commonly recognized. This review aimed to outline the current knowledge regarding ICI-induced endocrine disorders from a clinical perspective. We present updated information on the incidence and clinical development of ICI-induced endocrinopathies, including the most frequent thyroiditis and hypophysitis, the rarely observed insulin-dependent diabetes mellitus and primary adrenal insufficiency, and the recently described cases of hypoparathyroidism and lipodystrophy. Practical guidelines for monitoring, diagnosis, and treatment of ICI-related endocrine toxicities are also offered. Rising awareness of endocrine irAEs among oncologists, endocrinologists, and other health professionals caring for patients receiving ICIs could contribute to better safety and efficacy. As immunotherapy becomes widespread and approved for new types of malignancies, increased incidences of endocrine irAEs are expected in the future.
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Tyan, Kevin, Joanna Baginska, Martha Brainard, Anita Giobbie-Hurder, Mariano Severgnini, Michael Manos, Rizwan Haq, et al. "648 Cytokine changes during immune-related adverse events and steroid treatment in melanoma patients receiving immune checkpoint inhibitors." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A685—A686. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0648.
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BackgroundImmune checkpoint inhibitors (ICIs) often lead to immune-related adverse events (irAEs) with effects ranging from treatment interruption to mortality.1 2 Most irAEs are treated with corticosteroids despite mounting evidence to suggest that corticosteroid treatment may blunt antitumor efficacy.3–5 There is a paucity of data on biomarkers that predict irAEs or characterize inflammatory changes during irAEs or steroid use. We sought to identify changes in cytokines that correlate with irAEs and may suggest inflammatory mechanisms that enable rational therapies. We also aimed to study the impact of steroid treatment on cytokine levels to better understand their immunomodulatory effect.MethodsWe analyzed longitudinal levels of 34 cytokines in 52 melanoma patients receiving ICIs who developed irAEs. Luminex assay was performed on serum at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels were compared with incidence and grade of irAEs. Cytokine fold-change was compared between patients who did not develop irAEs, patients who developed irAEs without receiving steroids, and patients who developed irAEs who received steroids during the longitudinal profiling period.Results33/52 (63.5%) patients were male and median age was 70.5 years. 47 patients (90.4%) received anti-PD1 monotherapy, 4 patients (7.7%) received anti-CTLA-4 monotherapy and one patient received combination therapy (1.9%). Twenty-eight patients (53.8%) developed grade 1–2 irAEs and 24 patients (46.2%) developed grade 3-4 irAEs. There were no differences in cytokine levels between patients with grade 1-2 vs. grade 3-4 irAEs. Patients with dermatitis (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005, figure 1A). Patients with pneumonitis (N = 4) had significantly higher baseline IL-17 (p = 0.009, figure 1B). There was a trend towards lower GCSF levels in patients developing colitis (N = 8, p = 0.08, figure 1C). We observed a harmonization of cytokine fold-change in patients who developed irAEs without receiving steroids: 269/276 (97.5%) of pairwise comparisons exhibited fold-change in the same upwards or downwards direction (figure 2). In contrast, corticosteroid treatment in patients with irAEs appeared to alter cytokine fold-change to a discordant pattern (214/276, 77.5%) mirroring patients who did not develop irAEs during the longitudinal profiling period (213/276, 77.2%). Example patient timelines are shown in figure 3.Abstract 648 Figure 1Baseline cytokine level differences in patients with irAEs(A) Baseline levels of Ang-1 (median 16,375 vs. 11,604 pg/mL, p = 0.005) and CD40L (median 3,840.2 vs. 2433.8 pg/mL, p = 0.006) was higher in patients who developed dermatitis during ICI treatment. (B) Baseline levels of IL-17 was higher (median 2.8 vs. 0.0 pg/mL, p = 0.009) in patients who developed pneumonitis during ICI treatment. (C) There was a trend towards lower baseline levels of GSCF (median 0.0 vs. 11.9 pg/mL, p = 0.08) in patients who developed colitis during ICI treatment.P-values for baseline comparisons were obtained through Wilcoxon rank-sum test. The solid black line indicates median. Violins show range and kernel density estimate distributions of each group. (*) p < 0.05, (**) p < 0.01.Abstract 648 Figure 2Spearman’s correlation analysis of cytokine changesSpearman’s correlation analysis of cytokine changes in patients who did not develop irAEs (A), developed irAEs without steroid treatment (B), and developed irAEs with steroid treatment (C) during the cytokine profiling period. Spearman’s correlation heatmap show changes in cytokine fold-change relative to each another. Blue indicates fold-change of two cytokines in the same direction, red indicates fold-change of two cytokines moving in opposite directions. Cytokine fold-change is based on changes in serum levels between baseline and the event of interest (irAE onset or irAE onset with steroid treatment).(A) Patients who did not develop irAEs during the cytokine profiling period had a discordant pattern of cytokine fold-change, with 213/276 (77.2%) pairwise comparisons changing in the same direction. (B) Patients who developed irAEs without receiving steroid treatment demonstrated a harmonized pattern of cytokine fold-change, with 269/276 (97.5%) pairwise comparisons showing concordant direction of fold-change. (C) Patients who developed irAEs and received steroid treatment exhibited a discordant pattern of cytokine fold-change similar to patients without irAEs, with 214/276 (77.5%) pairwise comparison changing in the same direction.Abstract 648 Figure 3Example patient timelinesThe log2 fold-change of all cytokines over time were graphed for each patient. Timelines below each graph indicate ICI regimen (blue), irAEs (red), steroid treatment for irAEs (green), and RECIST response status (yellow). Black arrows indicate each ICI dosage cycle. A representative timeline is shown for a patient (#1) who did not develop irAEs during the Luminex profiling period, a patient (#29) who developed grade 1 dermatitis without receiving steroid treatment, and a patient (#44) who developed grade 2 arthralgia and received prednisone and methylprednisolone.ConclusionsBaseline cytokine levels correlate with specific irAEs in melanoma patients receiving ICIs. irAEs appear to drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid administration. These findings should be validated in larger cohorts.Ethics ApprovalPatients were identified from DFCI’s melanoma bio-specimen banking protocol (DFCI protocol 05-042)ReferencesRahma OE, Ott PA. General Principles of Immune-Related Toxicities. In: Enrstoff M, Puzanov I, Robert C, Diab A, Hersey P, ed. SITC’s Guide to Managing Immunotherapy Toxicity. Society for Immunotherapy of Cancer; 2018: Chapter 5.Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723.Faje AT, Lawrence D, Flaherty K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer 2018;124(18):3706–3714.Arbour KC, Mezquita L, Long N, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2018;36(28):2872–2878.Libert C, Dejager L. How Steroids Steer T Cells. Cell Reports 2014;7(4):938–939.
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Luo, Jia, Jason Beattie, Paige Fuentes, Hira Rizvi, Jacklynn V. Egger, Jeffrey Kern, Donald Y. M. Leung, et al. "Beyond steroids: Immunosuppressants in steroid-refractory/resistant immune related adverse events." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9092. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9092.
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9092 Background: The optimal management for immune related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants based on case reports and expert opinion. Methods: We examined patients with advanced lung cancers at MSK treated with immune checkpoint blockade (ICB) from 2011-2020. Pharmacy records were queried to identify patients who received systemic steroids as well as an additional immunosuppressant (eg TNFα inhibitor, mycophenolate mofetil). Patient records were manually reviewed to examine baseline characteristics, management, and outcomes. Results: Among 2,750 patients with lung cancers treated with ICB, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (TNFα inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (5/6) and colitis (18/27) but less common in neuromuscular (1/5) and pneumonitis (3/10). All patients with hepatitis received mycophenolate mofetil 500-1000mg BID for a median of 3 months, range 2-5 months. Of the 18 patients with colitis who improved with a TNFα inhibitor, 10 needed just one dose. Of 13 patients who died, 4 were related to toxicity from immunosuppression (3, infection-related deaths; 1, drug-induced liver injury leading to acute liver failure). Those who died from immunosuppressive therapy received higher amounts of systemic steroids than those who did not (max median 525 vs 132 mg prednisone equivalent, Mann Whitney U p = 0.004, total median 5.9k vs 2.3k mg prednisone equivalent, p = 0.004). Of 31 patients who received at least 3 weeks of prednisone ≥ 20mg, most (90%, 28/31) had at least one side effect that was brought to clinical attention (most commonly altered mood/ sleep, 52%, increase in BMI > 1kg/m2, 45%, and infection, 32%). Conclusions: Steroid-refractory/resistant immune related adverse events are rare. While existing treatments help patients with hepatitis and colitis, most patients with other irAEs remain refractory and/or experience toxicities from immunosuppression. Systemic steroid use likely contributed to side effects and mortality. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically informed treatment regimens for severe irAEs to realize the true benefit of ICB therapy.
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Fa'ak, Faisal, Chrystia M. Zobniw, Maryam Buni, Linda Lu, Adewunmi Falohun, VanAnh Trinh, Muhammad Osama Awiwi, et al. "816 Selective immune suppression using interleukin-6 blockade in immune related adverse events." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A853. http://dx.doi.org/10.1136/jitc-2021-sitc2021.816.
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BackgroundManaging immune-related adverse events (irAEs) has become a critical challenge with the increasing implementation of immune-checkpoint inhibitors (ICIs) in cancer treatment. IrAEs may cause treatment interruption or discontinuation, the rate of which is higher with multi-agent ICI regimen needed to overcome resistant tumor microenvironment. Herein, we describe our clinical experience using interleukin-6 receptor antagonists (IL-6RA) to manage irAEs in cancer patients receiving ICIs.MethodsWe conducted a retrospective, multi-center study to evaluate the safety and efficacy of IL-6RA for irAE management. Eligible patients were identified from the institutional databases (pharmacy records, tumor registries, oncology and specialty clinic records for diagnosis and management of irAEs). The primary objective was assessing changes in irAE symptoms. The secondary objective was assessing overall response rate (ORR) before and after IL-6RA treatment.ResultsA total of 81 patients received an IL-6RA (tocilizumab or sarilumab); median age was 66 years, 41% were females, 70% received single-agent anti-PD-1 and 23% received nivolumab plus ipilimumab. Cancer types were primarily melanoma (44%), genitourinary cancer (37%), and lung cancer (8.6%). Indications for using IL-6RA were inflammatory arthritis (74%), polymyalgia rheumatica (6%), myositis/myocarditis/myasthenia gravis (5%) encephalitis (5%), and 1% each with pneumonitis, colitis, hepatitis, central nervous system vasculitis, oral mucositis, and flare of pre-existing myasthenia gravis, psoriasis, and Crohn's disease. Notably, 83 % of patients received corticosteroids as first-line therapy, and 29% received disease-modifying antirheumatic drugs, without improvement. After initiation of IL-6RA, improvement of irAEs was observed in 78% after a median of 2.1 months. Of evaluable patients with inflammatory arthritis, the median clinical disease activity index (CDAI) at IL-6RA initiation was 28, indicating high disease activity, and dropped to 6 after treatment, indicating low disease activity. The median CRP level at IL-6RA initiation was 59.5 mg/L and dropped to 1.5 mg/L within 10 weeks of treatment. Seventy-two patients tolerated IL-6RA, and nine stopped treatment due to side effects. Thirty-eight patients were evaluated for tumor response by RECIST 1.1 criteria; the ORR was 58% prior to IL-6RA and 66% after treatment. Of 21 evaluable melanoma patients, the ORR was 62% prior to IL-6RA compared to 71% after treatment (figure 1).ConclusionsOur study demonstrated that targeting IL-6R could be an effective approach to mitigate autoimmunity while maintaining and possibly boosting tumor immunity. Clinical trials are currently evaluating the safety and efficacy of tocilizumab in combination with ICIs in patients with melanoma, non-small cell lung cancer, and urothelial carcinoma (NCT04940299, NCT03999749).Ethics ApprovalThe study was approved by The University of Texas MD Anderson Cancer Center intuition's Ethics Board, approval number PA19-0089Abstract 816 Figure 1A patient with sinonasal malignant melanoma involving the ethmoid air cells. (A) Baseline maximum intensity projection (MIP) PET image at 1 month before initiation of ICI (ipilimumab and nivolumab) shows avid FDG uptake of the tumor at the ethmoid air cells (arrow). (B) MIP PET image at 7 months after ICI initiation shows resolution of the FDG uptake at the site of the tumor, consistent with complete response. (C) Concurrent MIP PET and corresponding fused PET-CT images 7 months after initiation of ICI show avid radiotracer uptake at the knee joints, suggestive of arthritis. (D) MIP PET image at 10 months after concomitant therapy with IL6R antagonist and nivolumab shows persistent absence of hypermetabolic radiotracer activity at the paranasal sinuses, consistent with complete response. (E) Concurrent MIP PET and corresponding fused PET-CT images show physiologic radiotracer uptake at the knee joints, consistent with resolving arthritis.
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Ou, Qiyun, Yunfang Yu, Haitao Zhong, Anlin Li, Yongjian Chen, HaiYu Zhou, Shaopeng Zheng, Luyu Huang, and Herui Yao. "Association of immune-related adverse events with immune checkpoint inhibitor efficacy in pancancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14087-e14087. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14087.
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e14087 Background: Immune-related adverse events (irAEs) have been shown to be associated with the efficacy of immune checkpoint inhibitors in patients with advanced cancer, but the reported effect sizes have varied greatly in previous trials. We did a meta-analysis to assess immune checkpoint inhibitors efficacy and further explored the correlation of irAEs with efficacy in cancer. Methods: We systematically searched database inception to January, 2019 for randomized trials of immune checkpoint inhibitor in patients with advanced cancer that had available data for overall survival (OS) and progression-free survival (PFS), and irAEs. We calculated the pooled hazard ratios (HRs) and 95% confidence intervals [CIs] using a random-effects model, and assessed the association between the irAEs and PFS or OS using coefficient of determination ( R²). The PROSPERO registry number is CRD42017075610. Results: Thirty eight trials with 19,521 patients were included. Compared with conventional therapy, anti-PD-1 or PD-L1 combined with conventional therapy significantly enhanced survival (HR = 0.62, 95% CI 0.53 to 0.72 for PFS; HR = 0.71, 95% CI 0.58 to 0.87 for OS), and anti-PD1 or PD-L1 combined with anti-CTLA4 (HR = 0.75, 95% CI 0.63 to 0.90 for PFS). Anti-CTLA4 plus conventional therapy prolonged PFS (HR = 0.80, 95% CI 0.72 to 0.89) and OS (HR = 0.80, 95% CI 0.66 to 0.96) than conventional therapy alone. Anti-PD1 or PD-L1 outperformed anti-CTLA4 on OS (HR = 0.68, 95% CI 0.57 to 0.81). Significant correlation between treatment efficacy and irAEs was only identified in pneumonitis ( R2 0.59, P = 0.026 for PFS) and diarrhea ( R2 0.22, P = 0.006 for OS). Conclusions: We recommended the concurrent use of immune checkpoint inhibitor and conventional therapy or dual immunotherapy as the most appropriate regimens for advanced cancer. Furthermore, development of pneumonitis and diarrhea were associated with survival outcome of immune checkpoint inhibitors in patients with advanced cancer.
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Gandy, Nemi, Mubarik A. Arshad, Kathryn L. Wallitt, Suraiya Dubash, Sameer Khan, and Tara D. Barwick. "Immunotherapy-related adverse effects on 18F-FDG PET/CT imaging." British Journal of Radiology 93, no. 1111 (July 2020): 20190832. http://dx.doi.org/10.1259/bjr.20190832.
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18F-Fluorodeoxyglucose positron emission tomography/CT imaging plays a key role in oncological imaging including in staging, radiotherapy planning, treatment response and recurrence assessment. Immunotherapies represent a major advance in cancer therapy for a number of tumours with resulting survival benefit. However, a wide range of immune related adverse events (irAEs), some of which can be apparent on imaging, have been reported. These involve many organ systems but particularly endocrine, cutaneous and gastrointestinal systems. Early detection of irAEs is essential to aid diagnosis and management of patients and to reduce associated morbidity. In addition, it is important to not mistake treatment related effects for disease. This pictorial review aims to identify common irAEs and changes seen on 18F-fluorodeoxyglucose positron emission tomography/CT.
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Offin, Michael, Jacklynn V. Egger, Caroline G. McCarthy, Vasilisa Rudneva, Jason Beattie, Michelle S. Ginsberg, Jennifer L. Sauter, et al. "Improved survival among patients with malignant pleural mesotheliomas who develop immune-related adverse events on immunotherapy." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 8556. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.8556.
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8556 Background: While immune checkpoint inhibitors (ICI) are a standard option for patients with malignant pleural mesotheliomas (MPM), there is limited data on the rate of immune related adverse events (irAEs) and effects on clinical outcomes. Methods: 61 patients with MPM who received ICI between January 2016 and October 2020 were assessed and followed through November 2020. irAEs (CTCAE v5.0) were noted along with the time from ICI start to irAE onset. Patients were grouped into irAE ever versus never. Clinicopathologic characteristics, prior treatments, and investigator assessed clinical benefit rate (CBR; partial response [PR] + stable disease [SD]) were compared by Fisher’s Exact and Mann-Whitney Tests. Overall survival (OS) and investigator assessed progression free survival (PFS) from ICI start were compared using Kaplan Meier. In consented patients (n = 56), next generation sequencing (MSK-IMPACT) was performed with HLA genotyping analysis by POLYSOLVER software and alleles for the three major MHC class I (HLA-A, -B, -C) genes were obtained from whole exome recapture. Results: Most patients were male (72%), smokers (55%), > 70 years old (median 72, range 34-90), and had epithelioid histology (67%). No patients had baseline autoimmune disease. The median line of prior systemic therapies to ICI start was 2 (range 1-5). 17 patients (28%) developed an irAE on therapy including 7 (11%) with grade 3 to 5 events (pneumonitis, myositis, pancreatitis, nephritis, encephalitis and adrenal insufficiency). The median time from ICI start to irAE was 2.5 months (range 2 days – 5.8 months). There was no association with dual ICI (n = 6) vs single agent (n = 11) and sooner onset (2.1 vs 4.0 months; p = 0.10) nor higher grade (median grade 2 vs 3; p = 0.31) of irAEs. 1 patient developed grade 5 pneumonitis with onset 2 days after initial dose of dual-ICI. Comparing patients with irAEs to those without, there was no difference in distribution of epithelioid histology (n = 10 vs 31; p = 0.54), median age (71 vs 72 years old; p = 0.43), nor prior thoracic radiation (n = 5 vs 11; p = 0.75).There was no difference in HLA type nor the fraction of HLA alleles of individual genes amongst the groups. Patients who had an irAE were on ICI longer than those that did not (median time on ICI 5.4 vs 0.9 months, respectively; p = 0.02). OS was higher in patients with irAEs compared to those without (21.1 vs 4.7 months; p = 0.003) as was PFS (6.8 vs 1.7 months; p = 0.01). There was a significant increase in the CBR between those that had an irAE (65%; 5 PR, 6 SD) and those that did not (27%; 2 PR, 10 SD; p = 0.006). Conclusions: 28% of patients with MPM who received ICIs developed an irAE and onset tended to be early in the course of treatment. There was no clear predictive clinicopathologic feature that correlated with the occurrence of irAE. There was a significant increase in OS, PFS, and CBR in patients that had an irAE compared to those that did not.
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Kozono, David E., Elad Sharon, Jennifer Le-Rademacher, Erin Twohy, Tyler J. Zemla, Yujia Wen, Mark Watson, et al. "Alliance A151804: Establishment of a national biorepository to advance studies of immune-related adverse events." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS3154. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3154.
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TPS3154 Background: Immune-related Adverse Events (irAEs) are rare but serious sequelae of treatment with immuno-oncology (IO) therapeutics. These therapeutics, including monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have had transformative effects on outcomes for patients (pts) with advanced cancers. Although most pts tolerate the therapies well, a few experience irAEs ranging in severity up to life-threatening. These irAEs involve diverse organs including the heart, kidney, liver and lung, and gastrointestinal, musculoskeletal, central and peripheral nervous systems. Because of the relatively low incidence and wide variety of irAEs due to various immunotherapies for multiple tumor types, establishment of an efficient centralized repository for acquisition and organized distribution of well-annotated biospecimens is vital for translational studies that improve understanding of the molecular pathogenesis and treatment of these significant toxicities. Methods: This multi-institutional study is open at sites across the National Clinical Trial Network to pts who received ≥ 1 IO therapeutics (e.g., CTLA-4, PD-1 or PD-L1 inhibitor) and experienced 1) ≥ 1 serious (grade 3–5) adverse events that are likely immune-related, 2) rare infection or 3) tumor hyperprogression. IrAEs of interest include myocarditis, colitis, hepatitis, nephritis, myositis, pneumonitis, meningitis/encephalitis, dermatitis, endocrinopathies and neuropathy. Pts may be on an NCTN or non-NCTN IO trial or be receiving standard-of-care therapy. Registration must occur ≤ 72 hours after confirmation of the irAE event. Clinical data are collected at registration, 1 month after registration and for up to 1 year. Biospecimens (tumor blocks, biopsies of inflammatory tissues used to establish irAE diagnosis, and serial blood samples for isolation of plasma, serum and peripheral blood mononuclear cells) are collected at 1-2 timepoints. Stool samples are collected from pts experiencing colitis. Imaging data are collected for pts with hyperprogression or pneumonitis. Goal accrual is 240 pts. Biospecimens and data will be made available to investigators following future submission and approval of proposals. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180820 (ECOG-ACRIN); U10CA180888 (SWOG); U10CA180868 (NRG); https://acknowledgments.alliancefound.org; Clinical trial information: NCT04242095 .
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Patwari, Anannya, Vineel Bhatlapenumarthi, Antoine Joseph Harb, and Adam Curtis. "Immune related adverse effects (IRAEs) in patients with cancer who received immune checkpoint inhibitors (ICIs): A single center experience from rural Maine." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e19265-e19265. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19265.
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e19265 Background: ICIs are used for a variety of malignancies and have shown to improve survival, but they are associated with IRAEs. We aim to identify the frequency and severity of new IRAEs and flares of preexisting autoimmune (AI) disorders excluding thyroid disorders in cancer patients treated with ICIs at our institution. Methods: We conducted a retrospective chart review analysis of all cancer patients who received ICIs: nivolumab, pembrolizumab, atezolizumab and durvalumab at the Northern Light Cancer Institute from June 2015 to March 2019. We excluded patients who received ipilimumab. We then studied those who developed IRAEs. Results: Out of 465 who received ICIs, 115(24.7%) developed IRAEs. 83 out of 298 (27.9%) nivolumab recipients, 20/121 (15.7%) pembrolizumab recipients, 5/26 (19.2%) atezolizumab and 7/20 (35%) durvalumab recipients developed IRAEs. Some patients had multiple toxicities. Median age at cancer diagnosis was 66 years, evenly split among males and females. Majority (63%) were treated for Lung cancer, followed by melanoma (20%) and genitourinary cancers (12%). Summary of new IRAEs are as noted in the table below. In patients with new IRAEs treatment was held in 29(6%) for a median duration of 7.2 wks. Upon rechallenge with the same ICI in 27 patients, 20(74%) tolerated and 7 did not leading to permanent discontinuation. Majority were treated with steroids and some required immunomodulators. Interestingly 39(8%) patients with underlying AI condition received ICIs. Of these 11(28.2%) developed flares, resulting in permanent discontinuation of drug in 4. The majority tolerated the treatment well. Treatment was permanently discontinued in 70(15%), 26(6%) required hospital admission for IRAEs. Pneumonitis was the most common toxicity necessitating treatment discontinuation and hospital stay. Conclusions: In real world setting the frequency and severity of IRAEs was more than the reported literature data, leading to higher rates of permanent discontinuation of treatment. [Table: see text]
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Bayless, Nicholas L., Jeffrey A. Bluestone, Samantha Bucktrout, Lisa H. Butterfield, Elizabeth M. Jaffee, Christian A. Koch, Bart O. Roep, et al. "Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR." Journal for ImmunoTherapy of Cancer 9, no. 9 (September 2021): e002627. http://dx.doi.org/10.1136/jitc-2021-002627.
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Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.
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Morales-Barrera, Rafael, Cristina Suarez Rodriguez, Macarena Gonzalez, Javier Ros, Maria Eugenia Semidey, Ester Serra Hernandez, Joaquin Mateo, et al. "Impact of immune-related adverse events on survival in patients with metastastic urothelial carcinoma treated with immune-checkpoint inhibitors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 4531. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4531.
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4531 Background: Immune-checkpoints inhibitors (ICIs) represents the standard of care for platinum-pretreated advanced urothelial cancer patients (pts). By enhancing T-cell activation, a unique spectrum of inflammatory side effects has emerged, also known as immune-related adverse events (irAEs). Data regarding the association between irAEs and pts outcomes are conflicting. Here we conducted a retrospective analysis to investigate the association between irAEs profile and disease outcome in metastastic urothelial carcinoma (mUC) pts. Methods: Medical records from pts with mUC included in clinical trials between July 2013 and June 2018 and treated with ICIs were reviewed. Pts previously treated with platinum-based chemotherapy or cisplatin ineligible pts who had not been previously treated with chemotherapy were included. Clinical responses were assessed as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to RECIST v1.1. Adverse events were graded based CTCAE v4.03. Overall survival (OS) was calculated from the date of initiation of ICI to the date of death. X2 test was used to determine differences in rates. OS was estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: From a total of 52 pts, 44 (84.6%) were treated with ICI monotherapy and 8 (15.3%) in combination (anti-CTLA4 or targeted therapy). Median age was 65 years, 42 pts (80.8%) were male, 44 patients (84.6%) had ECOG PS 0-1, 14 pts (26.9%) had liver metastasis. Overall irAEs were observed in 30 pts (57.7%) and 10 pts (19.2%) developed grade 3/4 irAES. Most common grade 3/4 irAEs were diarrhea (6.6%), rash (6.6%) and hepatitis (6.6%). Disease control rate (CR [26%]+PR[33%]+SD[20%]) was higher for patients with irAEs compared to those patients who did not developed irAEs (CR [13.6%]+PR[0%]+SD[22.7%], this difference was statically significant (P = 0.002). Median OS was 11.23 mo (CI 95%, 3.76-18.70) for the overall cohort, while median OS was 21.91 mo for those patients with irAEs compared to 6.47 mo in patients who did not developed irAEs (P = 0.004). Conclusions: In this analysis we found that the development of irAEs was a strong predictor of improved OS in mUC patients treated with ICI.
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Weber, Jeffrey S., Katharina C. Kähler, and Axel Hauschild. "Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab." Journal of Clinical Oncology 30, no. 21 (July 20, 2012): 2691–97. http://dx.doi.org/10.1200/jco.2012.41.6750.
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Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)—ipilimumab and tremelimumab—have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.
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Borówka, Maciej, Stanisław Łącki-Zynzeling, Michał Nicze, Sylwia Kozak, and Jerzy Chudek. "Adverse Renal Effects of Anticancer Immunotherapy: A Review." Cancers 14, no. 17 (August 23, 2022): 4086. http://dx.doi.org/10.3390/cancers14174086.
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Modern oncological therapy utilizes various types of immunotherapy. Immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cells (CAR-T) therapy, cancer vaccines, tumor-targeting monoclonal antibodies (TT-mAbs), bispecific antibodies and cytokine therapy improve patients’ outcomes. However, stimulation of the immune system, beneficial in terms of fighting against cancer, generates the risk of harm to other cells in a patient’s body. Kidney damage belongs to the relatively rare adverse events (AEs). Best described, but still, superficially, are renal AEs in patients treated with ICIs. International guidelines issued by the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) cover the management of immune-related adverse events (irAEs) during ICI therapy. There are fewer data concerning real occurrence and possible presentations of renal adverse drug reactions of other immunotherapeutic methods. This implies the need for the collection of safety data during ongoing clinical trials and in the real-life world to characterize the hazard related to the use of new immunotherapies and management of irAEs.
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López Gallego, Javier, Pablo Ayala de Miguel, Itziar Gorospe García, Pablo René Rivera Vargas, Andrea Posada Restrepo, Jonathan Aires Machado, Rubén Alonso Calderón, et al. "Immune-related adverse events and outcomes during treatment with immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e21662-e21662. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e21662.
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e21662 Background: Immunotherapy of cancer has changed the paradigm of treatment of many tumours, specially non-small cell lung cancer (NSCLC). The use of immune-checkpoint inhibitors (ICI) is associated in some patients with the development of new immune-related adverse events (irAEs). Our aim was to study if there is any correlation between the appearence of irAEs and the efficacy of ICI. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included and univariate and multivariate Cox regression analysis were performed. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. irAEs occured in 65% of patients; 12% developed grade 3 to 4 toxicities. More frequent irAEs were fatigue (54%) and rash (27%). Significant statistical variables in univariate analysis were included in multivariate analysis by Cox regression. The appearence of any grade of iRAE was associated with improved progression-free survival (PFS) (median 17.9 months vs 5.1 months; HR 7.12; p = 0.008). Those patients who experimented any grade of irAE were more likely to achieve stabilization or response than those who suffered progression of disease (HR 13.00; p < 0.001; 95% CI [3.47-48.78]. The use of corticosteroids during treatment with ICI was not related to the benefit of treatment. Conclusions: Appearence of immune-related adverse effects during treatment with ICI was associated with better outcomes in our population. The use of corticosteroids during immunotherapy didn´t have any deleterious effect on the efficacy of treatment.
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Tarhini, Ahmad. "Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management." Scientifica 2013 (2013): 1–19. http://dx.doi.org/10.1155/2013/857519.
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Immunomodulation with the anti-CTLA-4 monoclonal antibody ipilimumab has been shown to extend overall survival (OS) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Blockade of CTLA-4 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation, thus amplifying T-cell-mediated immunity and the patient's capacity to mount an effective antitumor immune response. While this immunostimulation has unprecedented OS benefits in the melanoma setting, it can also result in immune-mediated effects on various organ systems, leading to immune-related adverse events (irAEs). Ipilimumab-associated irAEs are common and typically low grade and manageable, but can also be serious and life threatening. The skin and gastrointestinal tract are most frequently affected, while hepatic, endocrine, and neurologic events are less common. With proper management, most irAEs resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams. Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities.
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Mujumdar, Urvi, Huifen Wang, Elizabeth Lawler, Victoria Lanzarini, Maria Lowe, Nataliya Trunova, Alyssa B. Klein, and Cathy Emmas. "Immune-related adverse event (irAE) education, self-efficacy, and potential irAE experiences in patients treated with immunotherapy for non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 76. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.76.
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76 Background: Immunotherapy presents new challenges for effective patient engagement to ensure that irAEs are reported and treated appropriately. This study directly assesses how NSCLC patients in an online community perceived their irAE education and experience of potential irAEs. Methods: PatientsLikeMe is an online community for patients to track and share their experiences with the goal of improving health outcomes across all conditions. For this study, US residents ≥ 18, with self-reported immunotherapy treatment for NSCLC were invited to a baseline survey at enrollment and follow-up survey after 3 months (Dec 2017-Aug 2018). Quantitative and qualitative analyses were performed. Results: Respondents (N = 72) were female (69%), white (94%), and mean age of 64.3 (SD 9.3). Current immunotherapy use was reported by 60 (83%) patients and prior use by 12. Most (66 [92%]) reported that a healthcare provider (HCP) shared information about irAEs before they started treatment and 47 (71%) sought additional information. 43 (60%) reported experiencing a potential irAE while on treatment, 34 (79%) of whom indicated reporting this to a HCP. Free-text responses revealed a need for more clarity on side effects and severity, and that lapses in patient-provider communication sometimes occurred. The 3-month follow-up survey was completed by 39/72 patients; 28 (72%) remained on immunotherapy, and 8 (21%) had stopped since baseline. Of the 20 patients (51%) who reported experiencing a potential irAE in the past 3 months, 15 had also reported this at baseline, and 13 reported this to a HCP. Free-text responses revealed that many patients opted to wait until the next scheduled appointment to report irAEs or they self-managed minor side effects. Conclusions: Patients reported satisfaction with information received and responded appropriately to potential irAEs, but also suggested a need to improve information and communication with care teams. As patients become more accustomed to their treatment, there may be changes in reporting of irAEs. As this data is from a self-selected convenience sample of patients, results may be limited in generalizability.
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Chmielewska, Izabela, Marta Dudzińska, Michał Szczyrek, Joanna Świrska, Kamila Wojas-Krawczyk, and Agnieszka Zwolak. "Do endocrine adverse events predict longer progression-free survival among patients with non-small-cell lung cancer receiving nivolumab?" PLOS ONE 16, no. 9 (September 29, 2021): e0257484. http://dx.doi.org/10.1371/journal.pone.0257484.
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The aim of the study was to assess the occurrence and nature of immune-related endocrine adverse events (irAEs) among patients with non-small-cell lung cancer (NSCLC) treated with nivolumab. Methods: The study group included 35 patients (15 women, 20 men, 65.8 ± 7.1 years) with NSCLC in stage IIIB (n = 16, 45.7%) and IV (n = 19,54.3%) who were treated with nivolumab. Results: Of the studied patients, 34.3% (n = 12) developed endocrine irAEs (irAE group): 22.9% (n = 8) hyperthyroidism and 8.6% (n = 3) hypothyroidism, and in one case, hypophysitis was observed. The median irAEs onset time was 2 months. In the group of patients with thyroid disorders, permanent hypothyroidism eventually developed in 58.3%. The severity of the analyzed irAEs ranged from mild to moderate (Grade 1–2); the case of hypophysitis was estimated as Grade 3. The comparison of progression-free survival time (PFS) between the two groups showed longer PFS in patients in the irAE group (p = 0.021). Patients with irAE were treated significantly longer with nivolumab and they received more doses of nivolumab, however in Cox analysis we did not find patients with irAE to experience progression later than patients without them. Conclusions: Nivolumab therapy is associated with an increased risk of endocrine adverse effects, particularly thyroid dysfunction. Endocrine adverse effects can be successfully treated pharmacologically and usually do not require discontinuation of immunotherapy. The relationship between a better cancer prognosis in patients who developed endocrine irAE has not been found.
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Inaba, Hidefumi, Hiroyuki Ariyasu, Hisako Okuhira, Yuki Yamamoto, Hiroaki Akamatsu, Masahiro Katsuda, Masatoshi Jinnin, Isao Hara, and Takashi Akamizu. "Endocrine dysfunctions during treatment of immune-checkpoint inhibitors." Trends in Immunotherapy 4, no. 1 (June 7, 2020): 18. http://dx.doi.org/10.24294/ti.v4.i1.606.
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Immune-checkpoint inhibitors (ICIs) are novel agents directed to various malignant tumors. During ICI therapy, however, immune related adverse effects (irAEs) including endocrine dysfunctions have been reported. Dysfunctions in the pituitary gland and the thyroid gland by ICI are often observed, and those in the adrenal glands and the pancreas are less frequent. Positive correlation of the prevalence of endocrine irAEs to clinical antitumor effectiveness during ICI therapy has been reported. The mechanisms of endocrine irAEs by ICI, however, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. This review describes possible mechanisms involved in ICI-related immunity, and discusses clinical management of endocrine irAEs during ICI therapy.
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Cheung, Yee-Ming Melody, Wei Wang, Bradley McGregor, and Ole-Petter Hamnvik. "RF05 | PSUN354 Associations between immune-related thyroid dysfunction and efficacy of immune checkpoint inhibitors – A systematic review and meta-analysis." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A891—A892. http://dx.doi.org/10.1210/jendso/bvac150.1846.
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Abstract Background There is growing evidence suggesting that the occurrence of immune-related adverse events (irAEs) may be a predictor of immune checkpoint inhibitor (ICI) efficacy. Whether this association extends to all irAEs or just those within particular organs/systems is yet to be resolved. As immune-related thyroid dysfunction (thyroid irAE) is one of the most commonly reported irAEs, this study aims to summarize the available data and determine if thyroid irAE is a surrogate marker for improved cancer outcomes during ICI therapy. Methods PubMed, EMBASE and Cochrane Library were searched up to July 1st 2021 for studies assessing the relationship between thyroid irAE development during ICI therapy and cancer outcomes. Outcome measures of interest include overall survival (OS) and progression free survival (PFS). Sub-group analyses based on cancer type and adjustment for immortal time bias (ITB) were also performed. Results Forty-seven studies were included in the systematic review. Twenty-one studies were included in the OS meta-analysis whilst 15 were included in the PFS meta-analysis. Development of thyroid irAE during ICI therapy was associated with improved OS and PFS (OS: HR 0.52, CI 0.43-0.62, p<0.001; PFS: HR 0.58, CI 0.50-0.67, p<0.001). Sub-group analyses involving non-small cell lung cancer populations and studies where ITB was accounted for, observed similar results (HR 0.37, CI 0.24-0.57, p<0.001) and (HR 0.51, CI 0.39-0.69, p<0.001), respectively. Conclusion Despite the heterogeneity and biases identified, the evidence does suggest that the development of thyroid irAE is associated with anti-tumor effects of ICIs and therefore, can be used as a surrogate marker for clinical response. Presentation: No date and time listed
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Patil, Pradnya Dinkar, Alexia Zagouras, Wei (Auston) Wei, and Nathan A. Pennell. "Incidence and patterns of immune related adverse events (irAEs) during chemoimmunotherapy (ChemoIO) in patients with advanced nonsquamous NSCLC." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e20705-e20705. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e20705.
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e20705 Background: Based on superior outcomes noted in KEYNOTE-189 with the addition of pembrolizumab to platinum doublet chemotherapy, a majority of pts with nonsquamous NSCLC are now treated with chemoIO. irAEs can cause significant morbidity and occasionally mortality in pts treated with immunotherapy. Since chemotherapy is immunosuppressive, it is plausible that incidence of irAEs would be lower in pts receiving chemoIO compared to immunotherapy. The incidence of irAEs in KEYNOTE-189 was 22.7% vs 29.2% in KEYNOTE-024 with pembrolizumab monotherapy. We sought to evaluate the incidence and patterns of irAEs in pts with advanced nonsquamous NSCLC treated with chemoIO at our institution and to determine if the rate varied with the intensity of chemotherapy [carboplatin/ pemetrexed/ pembrolizumab (CPP) vs pemetrexed/ pembrolizumab (PP)]. Methods: We retrospectively reviewed the charts of 73 pts with advanced nonsquamous NSCLC who received CPP followed by maintenance PP. In addition to clinicopathologic variables, we noted the date, incidence, type and grade of irAEs. Descriptive statistics were used to report the incidence and patterns of irAEs. McNemar’s test was used to determine if there was a significant difference in rate of irAEs during CPP vs PP. Results: Of the 73 pts, 52% were females, 67% former smokers, 49% had previously received radiation and 11% had a history of autoimmune disease. 35 pts received 4 cycles of CPP. 21 patients (28%) developed irAEs, of which 6 had irAEs during CPP and 15 developed irAEs on PP. The rate of irAEs was significantly higher after stopping carboplatin (p = 0.049). 10 pts (13%) stopped pembrolizumab due to irAEs. Organ systems involved and grade of irAEs are listed below. Conclusions: The immunosuppressive effects of intensive chemotherapy may be protective against irAEs in pts receiving chemoIO. [Table: see text]
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Shore, Neal. "Diagnosis and Management of Checkpoint Inhibitor Side Effects in Patients with Bladder Cancer: the Urologist’s Perspective." Bladder Cancer 6, no. 4 (December 14, 2020): 425–33. http://dx.doi.org/10.3233/blc-200362.
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From 2016 through the present day, we have witnessed extraordinarily rapid advances and regulatory approvals of immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway, which has significantly improved survival among patients with advanced and metastatic urothelial carcinoma (mUC). Although these agents usually are well tolerated, their unique mechanism of action may enhance cytotoxic T-cell mediated immunity, evoking unique side effects that differ from conventional chemotherapy or molecularly targeted agents. The most common immune-related adverse events (irAEs) are dermatitis, colitis, pneumonitis, thyroid dysfunction, and transaminitis, but any organ system permeated by the lymphatic vasculature can be affected; also, neuropathies and arthralgias may occur. Immune-mediated events of any grade require prompt recognition and appropriate management to mitigate the risk of irAE exacerbation. Most patients with mild (grade 1) irAEs may continue checkpoint inhibitor treatment with careful monitoring. For grade 2 irAEs, it is appropriate to suspend treatment, initiate corticosteroid therapy, and only resume treatment if the irAE resolves to < grade 1. Events classified as > grade 3 may require permanent treatment cessation and high-dose corticosteroid therapy. In clinical trials of PD-1/PD-L1 inhibitors across multiple cancer types, approximately 15% of patients with mUC developed irAEs requiring corticosteroid therapy. Training physicians and nurse providers and counseling patients regarding the early recognition of irAEs are mandatory to ensure timely irAE detection and optimized patient management. Hence, operationalizing an advanced bladder cancer clinic requires collaboration and coordination amongst urologists, medical and radiation oncologists, and other medical specialists who participate in the increasingly multimodal and multidisciplinary care of patients with bladder cancer.
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Grizzi, Giulia, Fausto Petrelli, Michele Ghidini, Antonio Ghidini, Margherita Ratti, Stefano Panni, Mary Cabiddu, et al. "Immune-related adverse events (irAEs) and survival in solid tumors treated with immune checkpoint inhibitors (ICIs): A systematic review and meta-analysis." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14130-e14130. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14130.
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e14130 Background: irAEs are autoimmune-toxic effects associated with ICIs used for treatment of advanced solid tumors. The correlation of these irAEs with survival is presently unknown. The objective of this meta-analysis is to assess the outcome of cancer patients treated with ICIs who develop irAEs. Methods: Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane library database from their inception to November 2018. Studies were selected if: 1) they reported correlation of irAEs (any) with outcome, 2) they included patients with solid tumors; 3) they included treatment with anti-PD-(L)1 or anti-CTLA-4 agents, 4) patients had no previous history of autoimmune disorders, 5) they were published in English language, and 6) they provided availability of adequate data to calculate hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs). Data were pooled using HRs for overall survival (OS) or progression-free survival (PFS) or ORs for overall response rate (ORR) of irAEs vs no irAEs according to fixed or random effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. Hazard ratio for PFS and ORs for ORR were secondary endpoints. Results: A total of 29 studies for a total of 4242 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death (HR = 0.52, p < .001). Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR = 0.51, p < .001). The combined odds of response was 4.87 (p < .001). Conclusions: In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T cell activation. Patients showing any form of irAEs can be informed about the positive prognostic effect, and physicians can detect patients with favorable outcome to ICIs.
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Pender, Lori Keys, Haleh Kadkhoda, Katie S. Lucero, Patti Repetto, Charlotte Warren, Jacqueline Gearhart, and Jeffrey S. Weber. "Effects of online education on the identification and management of immune-related adverse events over time." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e18224-e18224. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18224.
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e18224 Background: Immune checkpoint inhibitors (ICIs) are increasingly used in oncology care and produce a wide variety of immune-related adverse events (irAEs) that differ from toxicities of other systemic therapies. The objective of this study was to assess trends over time in oncologists’ knowledge, competence, and confidence managing irAEs. Methods: A series of online continuing medical education (CME) activities addressing irAEs was launched beginning in April 2014; 39 included multiple-choice knowledge/competence questions and a confidence question assessed on a 5-point Likert-type scale before and immediately after the activity. Activities that had at least 30 oncologists participate pre/post are included in this analysis. A pre-/post-assessment study design was used, and educational effect was assessed with chi-square tests. Analyses were conducted to examine trends in knowledge, competence, and confidence recognizing, identifying, and managing irAEs over four years on a quarterly basis. Weighted averages in each of the outcomes were calculated by quarter. Results: A total of 187,800 learners participated from April 2014-March 2018, including 96,177 physicians, of whom 25,127 were oncologists. The average increase pre- to post-test for 22 activities that asked a knowledge-based question was 18% (P < 0.001). The absolute increase from pre-test in 2014 (67%) to post-test in 2018 (87%) was 20 percentage points. For 16 activities with competence questions, the average increase from pre- to post-test was 8% (P < 0.001), and the absolute increase from pre-test in 2014 (39%) to post-test in 2017 (87%) was 48 percentage points. For 5 activities with a confidence question, the average increase from pre- to post-test was 8% (P < 0.05), and the mean rating pre-test in 2016 was 2.85 versus 3.53 post-test in 2018. Conclusions: Online CME is effective to improve oncologists’ knowledge, competence, and confidence managing irAEs; however, pre-test outcomes in 2018 demonstrate ongoing knowledge and competence gaps that should be addressed, and post-test confidence data indicate a persistent lack of confidence among oncologists even after participating in online CME.