Management Of irAEs Research Articles

Checkpoint inhibitor immunotherapy induced inflammatory arthritis secondary to Nivolumab and Ipilimumab: a pediatric first

BackgroundImmune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature.Case PresentationA 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy.ConclusionsTo our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children.

Impact of immunosuppressive agents on the management of immune-related adverse events of immune checkpoint blockers

BackgroundImmune checkpoint blockers (ICBs) can induce immune-related adverse events (irAEs) whose management is based on expert opinion and may require the prescription of steroids and/or immunosuppressants (ISs). Recent data suggest that these treatments can reduce the effectiveness of ICBs. ObjectiveTo investigate the relationship between the use of steroids and/or ISs and overall survival (OS) and progression-free survival (PFS) among ICB-treated patients with an irAE. MethodsWe prospectively collected data from the medical records of patients with solid tumors or lymphoma in the French REISAMIC cohort and who had been treated with ICBs between June 2014 and June 2020. Results184 ICB-treated patients experienced at least one Common Terminology Criteria for Adverse Events grade ≥ 2 irAE. 107 (58.2%) were treated with steroids alone, 20 (10.9%) with steroids plus IS, 57 (31.0%) not received steroids or IS. The median OS was significantly shorter for patients treated with steroids alone (25.2 months [95% confidence interval (CI): 22.3–32.4] than for patients treated without steroids or IS (63 months [95%CI: 40.4-NA]) and those receiving an IS with steroids (53.4 months [95%CI: 47.3-NA]) (p < 0.001). The median PFS was significantly shorter for patients treated with steroids alone (17.0 months [95%CI: 11.7–22.9]) than for patients treated without steroids or IS (33.9 months [95%CI: 18.0-NA]) and those receiving an IS with steroids (41.1 months [95%CI: 26.2-NA]) (p = 0.006). There were no significant intergroup differences in the hospital admission and infection rates. ConclusionIn a prospective cohort of ICB-treated patients, the use of IS was not associated with worse OS or PFS, contrasting with the use of steroids for the management of irAEs.

Expert consensus on the clinical application of immunotherapy in breast cancer: 2024.

Significant progress has been made in immunotherapy of breast cancer (BC) with the approval of multiple immune checkpoint inhibitors (ICIs), particularly in early and metastatic triple-negative breast cancer (TNBC) settings. Most guidelines have recommended immune therapy as the important approach in BC, yet several critical aspects still require further clarification, including proper patient selection, treatment duration, optimized chemotherapy partner, predictive biomarkers, and specific considerations for Chinese patients. (I) Establishment of expert group: the expert group consists of 32 experts from departments such as medical oncology, breast surgery, and pathology; (II) literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) and Chinese databases (such as China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang Database), with a search cutoff date of April 23, 2024; (III) assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines; (IV) consensus formulation: on the March 2, 2024, through online consensus meeting, the consensus content is thoroughly discussed, and opinions from all experts are solicited. The consensus meeting has resulted in 15 detailed recommendations, providing clearer guidance on the clinical application of immunotherapy in BC management. The core suggestions are as follows: for early-stage II-III TNBC and metastatic TNBC (mTNBC) in the first-line setting, programmed cell death protein 1 (PD-1) inhibitors can be considered. However, for hormone receptor-positive/human epidermal growth factor receptor 2-negative BC (HR+/HER2- BC), HER2+ BC, and mTNBC in later lines of therapy, evidence is lacking to support the use of immunotherapy. This consensus provides a comprehensive overview of BC immunotherapy, including immunotherapy for early-stage BC and late-stage BC, immune related adverse event (irAE) management, biomarkers of immunotherapy, and future directions. The consensus consolidates these deliberations into 15 evidence-based recommendations, serving as a practical guide for clinicians to more scientifically and systematically manage the clinical application of immunotherapy.

Occurrence and Management of Immunotherapy-Associated Adverse Events in Patients with Gynecological Cancers.

Immune checkpoint inhibitors (ICIs) have emerged as an essential therapeutic approach in treating many solid tumors. ICIs enhance the body's anti-tumor T-cell activity, resulting in a novel spectrum of immunotherapy-related side effects. This novel spectrum of adverse events differs significantly from the side effects of conventional chemotherapy. It, therefore, requires special attention in the diagnosis and management of immunotherapy-related adverse events (irAEs). The present study aimed to retrospectively analyze the incidence, diagnosis, and management of irAEs in patients with gynecologic malignancies who received ICIs and to discuss these findings in the context of the recent literature. In the present retrospective overview, we evaluated patients with gynecologic malignancies (breast, endometrial, cervical, ovarian) who received ICIs with regard to the incidence, type, and time to onset of irAEs. A total of 61 patients treated at the Department of Gynecology and Obstetrics, University Medical Center Mainz, Germany, between 2018 and 2023 were included in the analysis. A total of 32.8% of patients developed an irAE of any grade or type. The median time to irAE was 24 weeks. The most frequently observed irAEs were grade 1 (20%) or 2 (35%). Immunotherapy-related grade 3 or 4 adverse events occurred in 45% of patients (40% grade 3, 5% grade 4). The most common type of irAE in our cohort was hypothyroidism, followed by hepatitis and colitis. Cox regression analysis identified the duration of ICI therapy as the only significant factor influencing the incidence of irAEs (p = 0.004). The broad spectrum of irAEs and the onset time of irAEs are important challenges of therapy with ICIs, requiring proactive monitoring and tailored management strategies to optimize the safety and efficacy of immunotherapy.

Update on Neuro-ophthalmic Manifestations of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitor (ICI) use has been on the rise for treatment of many different malignancies. Subsequently, more has been learned about immune-related adverse events (irAEs) that occur up to 12months after treatment. This review summarizes the latest findings and management of neuro-ophthalmic associated irAEs. irAEs can affect the afferent and efferent neuro-ophthalmic pathways, thereby targeting central and peripheral nervous systems. As more cases are being reported, it is becoming apparent that neuro-ophthalmic irAEs often present with atypical features when compared to their spontaneous autoimmune counterparts. These neuro-ophthalmic presentations can also be signs of a more extensive inflammatory process that spans other organ systems, such as myopathies, endocrinopathies, and paraneoplastic syndromes. Awareness of neuro-ophthalmic irAEs and their atypical presentations can lead to early detection, termination of ICI treatment, and immunosuppressant therapy initiation.

Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade

BackgroundTumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity.MethodsMultiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens.ResultsWhile genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient.ConclusionsThis comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Knowledge domains and emerging trends in immune-related adverse events from immune checkpoint inhibitors: A bibliometrics and visualized analysis

ObjectiveThe primary objective of this paper is to investigate the research hotspots and future trends of immune-related adverse events induced by immune checkpoint inhibitors, offering valuable insights for researchers in this field. MethodologyUsing the visual analysis software, this study conducted quantitative statistics and visualization research on the relevant literature concerning immune-related adverse events caused by immune checkpoint inhibitors in the Web of Science Core Collection Database. By evaluating the publication trends, countries, institutions, keywords, research status, cited documents, and document co-citations, among several others, the discussion revolved around the hot spots and future development trends in this field and provided references for future research. Findings and conclusionsA total of 514 English articles were included, and the top three countries in the research field at the time of this study were the United States, Japan, and China. More specifically, the University of Texas MD Anderson Cancer Center, Dana-Farber Cancer Institute, and Massachusetts General Hospital have been the top three research institutes with more than 10 publications. The frequency of keyword use linked to immune-related adverse events caused by immune checkpoint inhibitors in literature research has been steadily growing over the years. Additionally, the research with respect to the disease focuses on melanoma, cell lung cancer, hepatocellular carcinoma, and breast cancer. In the context of drugs, cancer-related research has mainly focused on the combined use of nivolumab, pembrolizumab, ipilimumab, and immune checkpoint inhibitors. Meanwhile, research on adverse events has delved into the immune checkpoint inhibitors causing vitiligo, thyroid dysfunction, pancreatitis, cholangitis, and rheumatism. Related studies cover acute arthritis, myositis, acute kidney injury, as well as the combination therapy of immune checkpoint inhibitors and docetaxel, management of irAEs in cancer immunotherapy, and biomarkers of immune adverse reactions of immune checkpoint inhibitors. Finally, case report studies of immune adverse reactions caused by immune checkpoint inhibitors could serve as research hotspots in the future.

Circulating biomarkers in the diagnosis and prognosis of immune checkpoint inhibitor-related myocarditis: time for a risk-based approach.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune checkpoints and therefore activate immune cells, allowing them to recognize and attack cancer cells. ICIs have revolutionized oncology practice, but their use has been complicated by immune-related adverse events (irAEs). Of cardiovascular (CV) irAEs, ICI-related myocarditis has received significant attention due to high mortality rates, ranging from 25% to 50%, despite its overall low incidence. Establishing the early diagnosis of ICI-myocarditis is important for early initiation of steroids and consideration of hospitalization in patients who are at risk for hemodynamic compromise and need high acuity care in a tertiary setting. In this review, we summarize the diagnostic and prognostic tools for ICI-myocarditis, including electrocardiography, echocardiography, cardiac magnetic resonance imaging, with emphasis on circulating biomarkers. Cardiac troponins (cTns) are an essential component of the diagnosis of ICI-myocarditis, and we provide a summary of the recent studies that utilized different assays (cTnI vs. cTnT) and outcomes (diagnosis vs. prognosis including major adverse cardiac outcomes). With the exponential increase in ICI use across different oncology indications, there is a major need to include biomarkers in risk stratification to guide diagnosis and treatment. Our review proposes a framework for future multisite registries, including cTn evaluation at baseline and at the time of irAE suspicion, with development of central biobanking to allow head-to-head evaluation and clinical validation of different biomarker assays in ICI-myocarditis. This approach, with the inclusion of CV biomarkers into clinical and pragmatic oncology trials, holds promise to improve the early recognition and management of ICI-myocarditis and CV irAEs, thus leading to better outcomes.

Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer

Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3–4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn’s disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3–5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.

Practice Changes in Checkpoint Inhibitor-Induced Immune-Related Adverse Event Management at a Tertiary Care Center.

Understanding of immune-related adverse events (irAEs) has evolved rapidly, and management guidelines are continually updated. We explored temporal changes in checkpoint inhibitor-induced irAE management at a tertiary cancer care center to identify areas for improvement. We conducted a single-center retrospective study of patients who developed a gastrointestinal, pulmonary, renal, or cardiac irAE between July and 1 October in 2019 or 2021. We collected patient demographic and clinical information up to 1 year after toxicity. Endoscopic evaluation and specialty follow-up after discharge for patients with gastrointestinal irAEs declined between the 2019 and 2021 periods. Symptom duration and steroid taper attempts also declined. For pulmonary irAEs, rates of specialty consultation, hospital admission and readmission, and mortality improved in 2021 compared with 2019. Follow-up rates after hospital discharge were consistently low (<50%) in both periods. For cardiac irAEs, consultation with a cardiologist was frequent and prompt in both periods. Outpatient treatment and earlier specialty consultation improved outcomes with gastrointestinal irAEs. Our study exploring irAE practice changes over time identified areas to improve management; specifically, timely specialty consultation was associated with better outcomes for gastrointestinal irAEs. These findings can help improve the quality of management algorithms at our institution and may inform policies in other institutions.

Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis: Overview of Therapies and a Personalized Approach to Optimized Combined Therapy.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4, anti-programmed cell death 1, and anti-programmed cell death ligand 1 (PD-L1) antibodies, are currently widely used in oncology clinical practice, achieving considerable success in improving disease outcomes. New checkpoint targets are being discovered and investigated through basic science research and clinical trials. ICI remove negative regulatory immune signals on T cells, leading to immune activation and induction of antitumor immunity. Patients who receive ICI, however, are at risk for developing immune-related adverse events (irAEs), which are attributed to increased T cell activity against antigens in both tumors and in healthy tissues, to increased inflammatory cytokine levels, to increased levels of preexisting autoantibodies, and to enhanced complement-mediated inflammation. Arthritis is one of the most common irAEs. ICI-induced rheumatic irAEs are categorized by levels of severity which guide the choice of treatment options. Management of ICI-induced rheumatic irAEs includes the use of glucocorticoids, disease-modifying antirheumatic drugs (mainly methotrexate), and biological agents (e.g., tumor necrosis factor, interleukin-6 receptor, and CD20 inhibitors). This review aims to summarize the current ICI subtypes, their role in rheumatic irAEs development, and therapies currently used in clinical practice to manage irAEs. In addition, we propose to use an ex vivo personalized diagnostic assay for the selection of the most effective ICI with antirheumatic drugs combinations that will inhibit the advancement of ICI-induced adverse events.

Uncovering the flip side of immune checkpoint inhibitors: a comprehensive review of immune-related adverse events and predictive biomarkers.

Immune checkpoint inhibitors (ICIs) have generated considerable excitement as a novel class of immunotherapeutic agents due to their remarkable efficacy in treating various types of cancer. However, the widespread use of ICIs has brought about a number of safety concerns, especially the development of immune-related adverse events (irAEs). These serious complications could result in treatment discontinuation and even life-threatening consequences, making it critical to identify high-risk groups and predictive markers of irAEs before initiating therapy. To this end, the current article examines several potential predictive markers of irAEs in important organs affected by ICIs. While retrospective studies have yielded some promising results, limitations such as small sample sizes, variable patient populations, and specific cancer types and ICIs studied make it difficult to generalize the findings. Therefore, prospective cohort studies and real-world investigations are needed to validate the potential of different biomarkers in predicting irAEs risk. Overall, identifying predictive markers of irAEs is a crucial step towards improving patient safety and enhancing the management of irAEs. With ongoing research efforts, it is hoped that more accurate and reliable biomarkers will be identified and incorporated into clinical practice to guide treatment decisions and prevent the development of irAEs in susceptible patients.

High Dose Cyclophosphamide for the Treatment of Severe Immune Checkpoint Inhibitor Related Adverse Events.

Immune-related adverse events (irAEs) are a group of autoimmune syndromes that arise following therapy with immune checkpoint inhibitors (ICIs) and are characterized by disinhibition of cell-mediated immunity and decreased self-tolerance. First line treatment of irAEs is typically steroids. Severe irAEs that are refractory to steroids can be life threatening and treatment protocols are an area of unmet need. Standardized clinical guidelines for management of severe corticosteroid refractory irAEs are currently not available and thus are an area of unmet need. We present two patients who were treated with nivolumab and subsequently developed steroid refractory irAEs in the forms of transverse myelitis, arthritis, and peri-engraftment respiratory distress syndrome. Treatment with a single high dose of cyclophosphamide resulted in rapid and sustained clinical improvements in two patients experiencing steroid refractory irAEs following ICI therapy. Cyclophosphamide may benefit patients with wide spectrum of irAEs while having a favorable toxicity profile.

Mucous membrane pemphigoid involving palmoplantar lesions that developed during adjuvant nivolumab for malignant melanoma: A rare case and literature review

Immune checkpoint inhibitors (ICIs), such as nivolumab, which target anti‐programmed cell death-1 (PD-1), have been applied to a variety of cancers and have caused immune‐related adverse events (irAEs). Although an association between ICIs and bullous pemphigoid and mucosal pemphigoid (MMP) has been reported, the complex mechanisms underlying PD-1 inhibition‐induced autoantibody production and autoimmunity remain unelucidated. In this report, we present a unique case of MMP involving the palmoplantar lesions during adjuvant nivolumab therapy. A Japanese woman in her 70s was treated with nivolumab for postoperative vulvar malignant melanoma; after the 12th cycle of treatment, ulcers were seen in the oral cavity, and 4 months later, tense palmoplantar blisters appeared. Microscopic examination of the palmar blister revealed subepidermal vesicles characterized by eosinophil infiltration. Immunofluorescence analysis revealed linear IgG and C3 deposits along the basement membrane; ELISA testing confirmed the presence of anti‐BP180 NC16A IgG antibody, and MMP was diagnosed. The patient’s condition gradually improved with a therapeutic regimen of corticosteroids and immunoglobulins. A review of 10 cases of ICI‐associated MMP, including the present case, revealed clinical similarities to conventional MMP; in cases of persistent oral erosions due to ICI, it is most important to consider mucositis and MMP in the framework of differential diagnosis. Besides, we suggest that we can be more suspicious of MMP by paying attention to examining the palms and soles when the patient receiving ICIs has refractory oral ulcers. This report underscores the importance of careful observation and prompt management of irAE as cancer immunotherapy evolves.

IBC‐Ab002 Fc modifications for fast clearance are associated with advantageous safety profile

AbstractBackgroundImmune checkpoint inhibitors (ICI) have been suggested as a unique therapy for treating neurodegenerative diseases. IBC‐Ab002 is a novel fully human anti‐PD‐L1 monoclonal antibody developed by ImmunoBrain Checkpoint (IBC) for the treatment of Alzheimer’s disease (AD).In cancer patients, ICI treatments are often associated with immune‐related adverse events (irAEs), which are side effects that manifest as either temporary or permanent autoimmune conditions caused by drug administration. One example of such an event is T cell‐mediated pancreatic tissue damage leading to autoimmune diabetes. The management of irAE often involves treatment discontinuation until symptoms relief, which has unwanted impact on the effectiveness of therapies that depend on continuous drug exposure.Unlike common ICI used in oncology, PD‐L1 blockade mechanism of action in mouse models of neurodegenerative diseases was shown to be dependent on transient immune system stimulation. Accordingly, IBC‐Ab002 antibody was designed with modifications on its Fc backbone that shorten its circulation half‐life, to meet the pharmacokinetic and pharmacodynamic characteristics needed for treating AD.MethodSurrogate antibodies that block mouse PD‐L1 and share the same hIgG1 Fc‐modifications as IBC‐Ab002 were generated and tested for their propensity to accelerate the onset of autoimmune diabetes in NOD transgenic mice, which spontaneously develop type 1 diabetes. Mice were monitored for their blood‐glucose levels, weight, and survival – for both the acute and long‐term duration following antibody administration.ResultWe found that administration of a therapeutically effective dose of IBC‐Ab002’s surrogate antibody led to fewer cases of premature diabetes onset in NOD mice, when compared with an antibody variant that contains no Fc‐modifications. Furthermore, no excessive weight loss, change in the time‐course of spontaneous diabetes onset or early mortality, were found following IBC‐Ab002’s surrogate treatment, compared with isotype‐control treated mice, in a 200‐days follow‐up assessment.ConclusionWe demonstrate that the clearance rate of the antibody inversely‐relates to the probability of developing an adverse immune response, and that no delayed long‐term irAEs are expected once full clearance of the antibody was achieved. Overall, these findings suggest that shortening the half‐life of anti‐PD‐L1 antibodies in treatments that do not necessitate continuous exposure can considerably increase the safety profile.

Effects of glucocorticoid use on survival of advanced non-small-cell lung cancer patients treated with immune checkpoint inhibitors.

Lung cancer is the second most common cancer worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of cases. Patients with NSCLC have achieved great survival benefits from immunotherapies targeting immune checkpoints. Glucocorticoids (GCs) are frequently used for palliation of cancer-associated symptoms, as supportive care for non-cancer-associated symptoms, and for management of immune-related adverse events (irAEs). The aim of this study was to clarify the safety and prognostic significance of glucocorticoid use in advanced patients with NSCLC treated with immune checkpoint inhibitors (ICIs). The study searched publications from PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine disc, Chinese National Knowledge Infrastructure, Wanfang Data, and Chinese Science and Technology Journal Database up to March 1st, 2022, and conducted a meta-analysis to assess the effects of glucocorticoid use on overall survival (OS) and progression-free survival (PFS) in NSCLC patients treated with ICIs through the available data. The study calculated the pooled hazard ratios (HRs) and 95% confidence intervals (CIs). This study included data from 25 literatures that were mainly retrospective, with 8713 patients included. Patients taking GCs had a higher risk for tumor progression and death compared with those not taking GCs (PFS: HR = 1.57, 95% CI: 1.33-1.86, P <0.001; OS: HR = 1.63, 95% CI: 1.41-1.88, P <0.001). GCs used for cancer-associated symptoms caused an obviously negative effect on both PFS and OS (PFS: HR = 1.74, 95% CI: 1.32-2.29, P <0.001; OS: HR = 1.76, 95% CI: 1.52-2.04, P <0.001). However, GCs used for irAEs management did not negatively affect prognosis (PFS: HR = 0.68, 95% CI: 0.46-1.00, P = 0.050; OS: HR = 0.53, 95% CI: 0.34-0.83, P = 0.005), and GCs used for non-cancer-associated indications had no effect on prognosis (PFS: HR = 0.92, 95%CI: 0.63-1.32, P = 0.640; OS: HR = 0.91, 95% CI: 0.59-1.41, P = 0.680). In advanced NSCLC patients treated with ICIs, the use of GCs for palliation of cancer-associated symptoms may result in a worse PFS and OS, indicating that they increase the risk of tumor progression and death. But, in NSCLC patients treated with ICIs, the use of GCs for the management of irAEs may be safe, and the use of GCs for the treatment of non-cancer-associated symptoms may not affect the ICIs' survival benefits. Therefore, it is necessary to be careful and evaluate indications rationally before administering GCs in individualized clinical management.

Insights from a Veterans Health Administration Database Analysis: Immune-Related Adverse Effects of Immunotherapy in Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: Despite the high success rates in treating Classical Hodgkin lymphoma (cHL), a specific group of patients still experience relapsed or refractory (R/R) disease, affecting approximately 10-20% of cases. The use of immunotherapy with checkpoint inhibitors (CPIs) has emerged as a promising approach, demonstrating impressive efficacy in R/R cHL patients [2,3]. However, there is a lack of real-world evidence regarding the immune-related adverse effects (irAEs) associated with immunotherapy in this relatively rare patient population. To address this gap, this study leverages the Veterans Health Administration (VHA) database to investigate irAEs, providing valuable insights to optimize treatment decisions. Methods: A retrospective analysis was conducted on Hodgkin lymphoma patients who received immunotherapy from the VHA Corporate Data Warehouse from 2014-2022. Patients came from all 18 Veterans Integrated Service Networks, spanning all 50 states and US territories. Data was collected to determine the baseline characteristics, disease factors, detailed AE occurrence as well as outcomes in this cohort. Results: The analysis included 68 cHL patients who received immunotherapy. The cohort had a mean age of 62.2 years (SD=15.9) and a median age of 66 years (IQR 54-72). The majority of the patients were male (97%) and White (80%) and only 6% of patients had a history of autoimmune disease. The distribution of patients across stages was as follows: Stage 1 (5%), Stage 2 (15%), Stage 3 (40%), and Stage 4 (40%). Additionally, 20% of patients underwent autologous stem cell transplantation (ASCT), with 10% receiving immunotherapy before transplantation and the remaining 10% receiving it post-transplant. In our cohort, 31% had documented adverse effects related to immunotherapy. The most common adverse events observed were hematological/cytopenias (8%), dermatologic/rash (6%), endocrine-related (6%), pneumonitis (5%), hepatitis (2%), myocarditis (2%), and other adverse events (8%). Discontinuation of therapy due to irAEs occurred in 12% of patients. These findings align with prior literature, which has consistently reported thyroid gland dysfunction (such as hypothyroidism and thyroiditis) and rash as the most frequently observed immune-related adverse events [2]. The most common management of irAEs were holding therapy followed by use of corticosteroids. Kaplan-Meier survival analysis revealed a median overall survival of 55.4 months (IQR=37.2-59.2), with a median follow-up time of 36.4 months (IQR=21.6 -58.6). Conclusion: This study, utilizing the VA database, provides a distinctive and valuable perspective on irAEs associated with immunotherapy in cHL patients. By leveraging a comprehensive database on a large scale, this study significantly enhances our comprehension of immunotherapy in the context of cHL, thereby offering crucial guidance for treatment decisions concerning relapsed/refractory Hodgkin lymphoma patients. The findings of this study strongly indicate the sustained benefits of immune checkpoint inhibitors (ICI) in this population, emphasizing the importance of close patient monitoring to detect and manage immune-related adverse events at an early stage, thereby preventing life-threatening complications.

Survival Among Veterans Receiving Steroids for Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy

Systemic steroids are commonly used to manage immune-related adverse events (irAEs), but it remains unclear whether they may undermine immune checkpoint inhibitor (ICI) therapy outcomes. Few studies have assessed the impact of steroid timing and its association with continuation or cessation of ICI therapy. To characterize how systemic steroids and steroid timing for irAEs are associated with survival in patients receiving ICI therapy. This multicenter retrospective cohort study encompassed veterans receiving ICI for cancer between January 1, 2010, and December 31, 2021. Data analysis was conducted September 8, 2023. Identifiable primary diagnosis of cancer. Patients were categorized into 3 cohorts: those receiving no steroids, systemic steroids for irAEs, and steroids for non-irAE-associated reasons. All eligible patients received 1 or more doses of an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab). Eligible patients in the steroid group received at least 1 dose (intravenous, intramuscular, or oral) of dexamethasone, hydrocortisone, methylprednisolone, prednisone, or prednisolone. Steroid use at baseline for palliation or infusion prophylaxis or delivered as a single dose was deemed to be non-irAE associated. All other patterns of steroid use were assumed to be for irAEs. The primary outcome was overall survival, with a 5-year follow-up after ICI initiation. Kaplan-Meier survival analyses were performed with pairwise log-rank tests to determine significance. Risk was modeled with Cox proportional hazard regression. The cohort consisted of 20 163 veterans receiving ICI therapy including 12 221 patients (mean [SD] age, 69.5 [8.0] years; 11 830 male patients [96.8%]; 9394 White patients [76.9%]) who received systemic steroids during ICI treatment and 7942 patients (mean [SD] age, 70.3 [8.5] years; 7747 male patients [97.5%]; 6085 White patients [76.6%]) who did not. Patients with an irAE diagnosis had significantly improved overall survival (OS) compared with those without (median [IQR] OS, 17.4 [6.6 to 48.5] months vs 10.5 [3.5 to 36.8] months; adjusted hazard ratio, 0.84; 95% CI, 0.81-0.84; P < .001). For patients with irAEs, systemic steroids for irAEs were associated with significantly improved survival compared with those who received steroids for non-irAE-related reasons or no steroid treatment (median [IQR] OS, 21.3 [9.3 to 58.2] months vs 13.6 [5.5 to 33.7] months vs 15.8 [4.9 to not reached] months; P <.001). However, among those who received steroids for irAEs, early steroid use (<2 months after ICI initiation) was associated with reduced relative survival benefit vs later steroid use, regardless of ICI continuation or cessation following steroid initiation (median [IQR] OS after ICI cessation 4.4 [1.9 to 19.5] months vs 16.0 [8.0 to 42.2] months; median [IQR] OS after ICI continuation, 16.0 [7.1 to not reached] months vs 29.2 [16.5 to 53.5] months; P <.001). This study suggests that steroids for irAE management may not abrogate irAE-associated survival benefits. However, early steroid administration within 2 months of ICI initiation is associated with shorter survival despite continuation of ICI therapy.

Infliximab for Treatment of Immune Adverse Events and Its Impact on Tumor Response.

Background: Immune-related adverse events (irAEs) challenge the use of immune checkpoint inhibitors (ICIs). We performed a retrospective study to evaluate response to infliximab for immune-related adverse event management, and infliximab's effect on progression-free survival (PFS) and overall survival (OS) with a focus on melanoma and genitourinary cancers. Methods: We retrospectively reviewed records of all cancer patients exposed to infliximab after immune checkpoint inhibitor (ICI) treatment from 2004 to 2021 at the MD Anderson Cancer Center. Survival was assessed utilizing the Kaplan-Meier method. Univariate and multivariate logistic regression was utilized to evaluate predictors of infliximab response, OS, and PFS. Results: We identified 185 cancer patients (93 melanoma and 37 genitourinary cancers) treated with ICI and who received infliximab to treat irAEs. Within 3 months of treatment initiation, 71% of the patients responded to infliximab, 27% had no response, and 2% had unknown response. Among different irAEs, colitis was associated with increased response to infliximab at 3 months, irrespective of the type of malignancy. We evaluated best tumor response before and after infliximab in the entire cohort and again in the melanoma and genitourinary (GU); the findings were similar in the melanoma cohort and the entire cohort, where best tumor response before and after infliximab was not significantly different. In the melanoma cohort, acute kidney injury (AKI) was associated with increased risk of death, p = 0.0109, and having response to infliximab was associated with decreased risk of death, p = 0.0383. Interestingly in GU cancer patients, myositis was associated with increased risk of death, p = 0.0041, and having a response to infliximab was marginally associated with decreased risk of death, p = 0.0992. As regards PFS, in a multivariate Cox regression model, having a history of cardiovascular disease remained significantly associated with shorter PFS in the melanoma cohort. For patients with GU cancers, response to infliximab was associated with longer PFS. Conclusions: Our study is among the largest retrospective analyses of infliximab use for irAE management. Patients with colitis were the best responders to infliximab. AKI before initiation of infliximab in the melanoma subcohort and myositis in GU subcohort are associated with higher risk of death. Our results indicate no association between infliximab and cancer progression with the exception of genitourinary cancers.

Immune-Related Adverse Events in Patients with Lung Cancer.

Immune checkpoint inhibitors (ICI) have been widely adopted for the treatment of lung cancer since receiving first U.S Food and Drug Administration (FDA) approval in 2015. However, along with their use, the occurrence of immune-related adverse events (irAEs) has presented a challenge for both patients and oncology providers. In this manuscript, we reviewed the clinical trials that led to the approval of ICI by the FDA for the treatment of lung cancer between 2015 and 2023 to establish the frequency of irAEs in this patient population. Among the adverse events associated with ICI, we focused on the most common and relevant ones, including hypothyroidism, pneumonitis, diarrhea/colitis, skin rash, and hepatitis. We thoroughly examined the available literature, including society guidelines concerning these complications, to discuss various aspects such as their pathophysiology, epidemiology, diagnostic process, grading system, and clinical management. Additionally, we explored the association between irAEs and disease response. The management of irAEs is a crucial aspect of oncologic care, particularly due to their potential to cause severe and life-threatening clinical manifestations. We present each pertinent aspect in a concise and organized manner to provide guidance and assistance to oncology providers managing these patients in both outpatient and inpatient settings.