Biomarkers for gastrointestinal adverse events related to thiopurine therapy
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ABSTRACT:
SUBMITTER: Zudeh G
PROVIDER: S-EPMC8517779 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Drug-related adverse events (AEs) are reported to be common amongst patients receiving outpatient parenteral antimicrobial therapy (OPAT). However, comparative data regarding intravenous (iv) catheter-related AEs are lacking. OBJECTIVES:To compare drug- and iv catheter-related AEs from a large UK OPAT centre. PATIENTS AND METHODS:We reviewed 544 OPAT episodes [median (IQR) age: 57 (39-71) years, 60% male, 13% with diabetes] with a median (IQR) duration of 7 (2-18) days. Clinically significant drug- and iv catheter-related AEs were calculated as a percentage of OPAT episodes with an AE and also as AEs per 1000 iv drug/catheter days. RESULTS:Drug-related AEs complicated 13 (2.4%) OPAT episodes at 1.7 (95% CI 0.9-2.9) per 1000 drug days. Catheter-related AEs occurred more frequently, complicating 32 (5.9%) episodes at 5.7 (95% CI 4.2-7.9) per 1000 iv catheter days (χ2 test for difference in AE rate: P < 0.001). Non-radiologically guided midline catheters were associated with the most frequent AEs (n = 23) at 15.6 (95% CI 10.3-23.4) per 1000 iv catheter days compared with other types of iv catheters (HR 8.4, 95% CI 2.4-51.9, P < 0.004), and self-administration was associated with a higher rate of catheter-related AEs at 12.0 (95% CI 6.0-23.9) per 1000 iv catheter days (HR 4.15, 95% CI 1.7-9.1, P = 0.007). CONCLUSIONS:Clinically significant iv catheter-related AEs occurred more frequently than drug-related AEs, especially when using non-radiologically guided midline catheters. Regular review of the need for iv therapy and switching to oral antimicrobials when appropriate is likely to minimize OPAT-related AEs.
| S-EPMC6376853 | biostudies-other
Project description: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.
| S-EPMC10854719 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFα and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFα and one or two ICIs.Case presentationsFive patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.ConclusionsConcurrent treatment with anti-TNFα and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.
| S-EPMC6704680 | biostudies-literature
Project description:BackgroundIn the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity.AimsWe assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival.MethodsWe performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient.ResultsOf 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase.ConclusionsApproximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.
| S-EPMC8741678 | biostudies-literature
Project description:Immune checkpoint inhibitors are becoming a cornerstone of cancer immunotherapy as a result of their clinical success in relieving immune suppression and driving durable antitumor T cell responses in certain subsets of patients. Unfortunately, checkpoint inhibition is also associated with treatment-related toxicities that result in a myriad of side effects, ranging from mild and manageable to severe and debilitating. In this issue of the JCI, Das and colleagues report an association between early therapy-induced changes in circulating B cells and an increased risk of high-grade immune-related adverse events (IRAEs) in patients treated with checkpoint inhibitors that target cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and programmed cell death protein 1 (PD1). These findings identify potential predictive biomarkers for high-grade IRAEs that may be leveraged to improve patient monitoring and may prompt new treatment strategies to prevent IRAEs.
| S-EPMC5785256 | biostudies-literature
Project description:BackgroundGastrointestinal cancers constitute a major burden of global cancer mortalities. In recent years, the advent of immune checkpoint inhibitors has greatly improved the survival of patients with advanced gastrointestinal cancers, while predictive biomarkers of treatment efficacy and toxicities are still unmet demands.MethodsIn our retrospective study, patients with advanced gastrointestinal cancers who received single or double immune checkpoint inhibitors in the Department of Gastrointestinal Oncology in Peking University Cancer Hospital between July 2016 and February 2022 were enrolled. Records of clinicopathological information, survival parameters, safety data, and baseline and posttreatment peripheral blood constituents were retrieved. Cox regression analysis and logistic regression analysis were performed to identify the predictive factors of treatment outcomes and immune-related adverse events.ResultsWe demonstrated that early treatment lines, the presence of immune-related adverse events, and a lower C2 neutrophil-to-lymphocyte ratio were independent factors predicting a superior objective response rate and progression-free survival in patients treated with immunotherapy. Lower ECOG PS, higher baseline albumin, and lower C2 neutrophil-to-lymphocyte ratios were independent risk factors for the onset of immune-related adverse events. Patients who succumbed to immune-related adverse events during immunotherapy presented better survival.ConclusionOur results indicate that peripheral blood markers have potential for predicting treatment outcomes and immune-related adverse events in patients with advanced gastrointestinal cancer. Prospective validations are warranted.
| S-EPMC9367581 | biostudies-literature
Project description:The enthusiasm for immune checkpoint inhibitors (ICIs), an efficient tumor treatment model different from traditional treatment, is based on their unprecedented antitumor effect, but the occurrence of immune-related adverse events (irAEs) is an obstacle to the prospect of ICI treatment. IrAEs are a discrete toxicity caused by the nonspecific activation of the immune system and can affect almost all tissues and organs. Currently, research on biomarkers mainly focuses on the gastrointestinal tract, endocrine system, skin and lung. Several potential hypotheses concentrate on the overactivation of the immune system, excessive release of inflammatory cytokines, elevated levels of pre-existing autoantibodies, and presence of common antigens between tumors and normal tissues. This review lists the current biomarkers that might predict irAEs and their possible mechanisms for both nonspecific and organ-specific biomarkers. However, the prediction of irAEs remains a major clinical challenge to screen and identify patients who are susceptible to irAEs and likely to benefit from ICIs.
| S-EPMC7734811 | biostudies-literature
Project description:BackgroundTreatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for the treatment of advanced melanoma, is associated with some immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or GI irAE) and skin rash, which are managed by treatment guidelines. Nevertheless, predictive biomarkers that can help identify patients more likely to develop these irAEs could enhance the management of these toxicities.MethodsTo identify candidate predictive biomarkers associated with GI irAEs, gene expression profiling was performed on whole blood samples from 162 advanced melanoma patients at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and CA184007). Overall, 49 patients developed Grade 2 or higher (grade 2+) GI irAEs during the course of treatment. A repeated measures analysis of variance (ANOVA) was used to evaluate the differences in mean expression levels between the GI irAE and No-GI irAE groups of patients at the three time points.ResultsIn baseline samples, 27 probe sets showed differential mean expression (? 1.5 fold, P ? 0.05) between the GI irAE and No-GI irAE groups. Most of these probe sets belonged to three functional categories: immune system, cell cycle, and intracellular trafficking. Changes in gene expression over time were also characterized. In the GI irAE group, 58 and 247 probe sets had a ? 1.5 fold change in expression from baseline to 3 and 11 weeks after first ipilimumab dose, respectively. In particular, on-treatment expression increases of CD177 and CEACAM1, two neutrophil-activation markers, were closely associated with GI irAEs, suggesting a possible role of neutrophils in ipilimumab-associated GI irAEs. In addition, the expression of several immunoglobulin genes increased over time, with greater increases in patients with grade 2+ GI irAEs.ConclusionsGene expression profiling of peripheral blood, sampled before or early in the course of treatment with ipilimumab, resulted in the identification of a set of potential biomarkers that were associated with occurrence of GI irAEs. However, because of the low sensitivity of these biomarkers, they cannot be used alone to predict which patients will develop GI irAEs. Further investigation of these biomarkers in a larger patient cohort is warranted.
| S-EPMC3637501 | biostudies-literature
Project description:The main aim of this study was to examine the differences between triple therapy (T: SSZ and HCQ added to MTX) and etanercept (E) added to MTX with regard to the infectious and gastrointestinal (GI) adverse events (AEs) reported in The Rheumatoid Arthritis Comparison of Active Therapies Trial.The patients were 353 RA MTX incomplete responders who were randomized to T (n = 178) or E (n = 175). Of these, 88 patients were switched to the alternative treatment from the initial treatment (E or T) at 24 weeks per protocol. Infectious and GI serious AEs (SAEs) and non-serious AEs (NAEs) were reported during 48 and 4 weeks after the intervention period. Generalized linear models were used to estimate the incidence rate ratios (IRRs) of AEs between the two therapies.Patients on E therapy were more likely to have infectious NAEs (IRR = 1.56, 95% CI: 1.11, 2.19). There was a greater number of infectious SAEs that occurred when patients received E than T therapy [12 E (6.9%) vs 4 T (2.2%), P = 0.19]. Pneumonia was the most common infectious SAE for both treatments [6 E (3.4%) and 2 T (1.1%)]. Conversely, patients who were on E were less likely to have GI NAEs than those on T therapy (IRR = 0.62, 95% CI: 0.40, 0.94). The most common GI SAE reported was GI haemorrhage, which occurred among three patients on E (1.7%).This study provides evidence of different likelihoods of infectious and GI AEs associated with two common, equally effective treatments for RA patients who have had incomplete responses to MTX.ClinicalTrials.gov, http://clinicaltrials.gov , NCT00405275.
| S-EPMC5850115 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) have substantially improved the prognosis of patients with different types of cancer. Through blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), negative feedback mechanisms of the immune system are inhibited, potentially resulting in very durable anti-tumor responses. Despite their promise, ICIs can also elicit auto-immune toxicities. These immune-related adverse events (irAEs) can be severe and sometimes even fatal. Therefore, being able to predict severe irAEs in patients would be of added value in clinical decision making. A search was performed using "adverse events", "immune checkpoint inhibitor", "biomarker", and synonyms in PubMed, yielding 3580 search results. After screening title and abstract on the relevance to the review question, statistical significance of reported potential biomarkers, and evaluation of the remaining full papers, 35 articles were included. Five additional reports were obtained by means of citations and by using the similar article function on PubMed. The current knowledge is presented in comprehensive tables summarizing blood-based, immunogenetic and microbial biomarkers predicting irAEs prior to and during ICI therapy. Until now, no single biomarker has proven to be sufficiently predictive for irAE development. Recommendations for further research on this topic are presented.
| S-EPMC7905347 | biostudies-literature