ABSTRACT
Immune checkpoint inhibitors (ICI) represent a breakthrough in cancer therapy. They are effective in various tumor entities and can be used in more and more treatment settings. This leads to an increase in the number and complexity of cases with immune-related adverse events (irAE). The most common irAE are cutaneous, gastrointestinal and endocrine side effects, whereas less common irAE include pneumonitis, nephritis, myocarditis or neurological reactions. IrAE can usually be successfully treated, mainly with corticosteroids or other immunosuppressants, but they can also result in long-term sequelae or death. The optimal management of patients with steroid-refractory or steroid-dependent side effects still remains unclear. Broad awareness of these irAE across specialties is therefore of crucial importance to ensure early diagnosis and to improve irAE management.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Humans , Immune Checkpoint Inhibitors/adverse effects , Neoplasms/drug therapy , Neoplasms/immunology , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/therapyABSTRACT
Immune checkpoint inhibitors (ICIs) have emerged as crucial therapeutic agents for various malignancies by activating the host immune system against tumor cells. However, many different types of skin adverse reactions may occur during its use, including eruption, pruritus, blistering, hypopigmentation, alopecia, and even severe cases, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). These cutaneous immune-related adverse events (cirAEs) had a high incidence, which seriously affected patients' quality of life and antitumor treatment decisions. Some severe cutaneous adverse reactions (SCARs) even endanger patients' lives. Therefore, the Chinese Society of Dermatology, the Chinese Dermatologist Association of the Chinese Medical Doctor Association, the Dermatology Division of the Chinese Geriatrics Society, and other relevant experts jointly discussed and formulated the 'Chinese Expert Consensus on the Diagnosis and Treatment of Immune Checkpoint Inhibitor-Related Cutaneous Adverse Reactions'. This consensus covers the name, epidemiology, pathogenesis, clinical features, classification and grading of cirAEs, principles of management and the re-initiation of ICIs. It aims to provide a more scientific and authoritative reference for the diagnosis and treatment of cirAEs in China in the future.
Subject(s)
Consensus , Immune Checkpoint Inhibitors , Humans , Immune Checkpoint Inhibitors/adverse effects , China , Stevens-Johnson Syndrome/therapy , Stevens-Johnson Syndrome/diagnosis , Stevens-Johnson Syndrome/etiology , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/therapy , Quality of Life , Skin/pathology , Neoplasms/drug therapy , Drug Eruptions/diagnosis , Drug Eruptions/therapy , Drug Eruptions/etiologyABSTRACT
OBJECTIVES: The use of immune checkpoint inhibitors (ICIs) as anticancer therapy across a variety of malignancies has led to durable efficacy in a subset of patients. However, associated side effects denoted immune-related adverse events (irAEs) have emerged and can result in substantial morbidity and mortality. Particularly early in the experience of using these agents, a lack of standardized education regarding irAEs among patients and clinical providers may have contributed to poor outcomes. Optimal management of these emerging toxicities depends on a coordinated institutional approach. We hypothesized that centralized educational programs and electronic health record (EHR)-based interventions, targeted both toward ICI-treated patients as well as patient-interfacing providers, would improve patient outcomes. METHODS: We created a multidisciplinary team of clinicians and associated staff to direct a coordinated approach to the education and management of patients receiving ICIs across our institution. A 3-tiered approach was designed: patient-centered, internally centered, and externally centered. Multimedia educational products were produced for patients to improve knowledge and awareness of ICIs and associated irAEs. An EHR-based banner was deployed to improve identification of patients receiving ICIs across disciplines. Tailored educational seminars were provided to clinicians who interact with ICI-treated patients at all levels. Educational seminars were also offered to local physicians and institutions. We assessed patient uptake of educational products and surrogate patient outcomes to measure the potential impact of our interventions. RESULTS: Fox Chase Cancer Center (FCCC)-specific ICI identification cards were created and distributed to patients. By the end of the investigational period, 98.6% of ICI-treated patients reported receiving a card. An ICI-focused on-line portal was created accessible only to ICI-treated patients, with 9.4% of these patients accessing the portal in the first 6 months without marketing promotion. Deidentified surrogate clinical endpoints of corticosteroid use, direct referral unit (DRU) visits, and hospital admissions all improved during the study period. CONCLUSIONS: Institutionally directed educational initiatives are feasible at a free-standing academic cancer center and may lead to improved outcomes in patients developing irAEs from ICIs. More granular patient-specific data and studies at other types of institutions are necessary to determine the applicability of similar approaches on a broader scale.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Male , Female , Patient Education as Topic , Drug-Related Side Effects and Adverse Reactions/therapy , Drug-Related Side Effects and Adverse Reactions/etiology , Middle Aged , Electronic Health Records , Patient Care Team , AgedABSTRACT
Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/therapy , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Drug-Related Side Effects and Adverse Reactions/therapy , Texas , Immunotherapy/methods , Immunotherapy/adverse effectsABSTRACT
BACKGROUND: Immunotherapy has reshaped the prognoses for many cancers and is increasingly used in both metastatic and adjuvant settings. There is a high prevalence of immunotherapy side effects, or immune-related adverse events (irAEs), which can affect any organ. Some irAEs can cause permanent or prolonged morbidity and, in rare cases, may be fatal. irAEs can present with mild, non-specific symptoms, resulting in delays to identification and management. OBJECTIVE: We aim to provide a general overview of immunotherapy and irAEs, highlighting common clinical scenarios and general principles of management. DISCUSSION: Cancer immunotherapy toxicity is an important clinical problem that is increasingly relevant to general practice, where patients with adverse events may first present. Early diagnosis and timely intervention are important in limiting the severity and morbidity of these toxicities. The management of irAEs should follow treatment guidelines, in consultation with patients' treating oncology teams.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , General Practice , Neoplasms , Humans , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/therapy , Immunotherapy/adverse effects , Immunotherapy/methods , Neoplasms/drug therapyABSTRACT
Parkinson's disease (PD) is a neurodegenerative disease with a heavy burden on patients, families, and society. Deep brain stimulation (DBS) can improve the symptoms of PD patients for whom medication is insufficient. However, current open-loop uninterrupted conventional DBS (cDBS) has inherent limitations, such as adverse effects, rapid battery consumption, and a need for frequent parameter adjustment. To overcome these shortcomings, adaptive DBS (aDBS) was proposed to provide responsive optimized stimulation for PD. This topic has attracted scientific interest, and a growing body of preclinical and clinical evidence has shown its benefits. However, both achievements and challenges have emerged in this novel field. To date, only limited reviews comprehensively analyzed the full framework and procedures for aDBS implementation. Herein, we review current preclinical and clinical data on aDBS for PD to discuss the full procedures for its achievement and to provide future perspectives on this treatment.
Subject(s)
Deep Brain Stimulation , Drug-Related Side Effects and Adverse Reactions , Neurodegenerative Diseases , Parkinson Disease , Humans , Parkinson Disease/therapy , Parkinson Disease/diagnosis , Deep Brain Stimulation/methods , Drug-Related Side Effects and Adverse Reactions/therapyABSTRACT
Extravasation is the leakage of intravenous solutions into surrounding tissues, which can be influenced by drug properties, infusion techniques, and patient-related risk factors. Although peripheral administration of vesicants may increase the risk of extravasation injuries, the time and resources required for central venous catheter placement may delay administration of time-sensitive therapies. Recent literature gathered from the growing use of peripheral vasopressors and hypertonic sodium suggests low risk of harm for initiating these emergent therapies peripherally, which may prevent delays and improve patient outcomes. Physiochemical causes of tissue injury include vasoconstriction, pH-mediated, osmolar-mediated, and cytotoxic mechanisms of extravasation injuries. Acidic agents, such as promethazine, amiodarone, and vancomycin, may cause edema, sloughing, and necrosis secondary to cellular desiccation. Alternatively, basic agents, such as phenytoin and acyclovir, may be more caustic due to deeper tissue penetration of the dissociated hydroxide ions. Osmotically active agents cause cellular damage as a result of osmotic shifts across cellular membranes in addition to agent-specific toxicities, such as calcium-induced vasoconstriction and calcifications or arginine-induced leakage of potassium causing apoptosis. A new category has been proposed to identify absorption-refractory mechanisms of injury in which agents such as propofol and lipids may persist in the extravasated space and cause necrosis or compartment syndrome. Pharmacological antidotes may be useful in select extravasations but requires prompt recognition and frequently complex administration strategies. Historically, intradermal phentolamine has been the preferred agent for vasopressor extravasations, but frequent supply shortages have led to the emergence of terbutaline, a ß2 -agonist, as an acceptable alternative treatment option. For hyperosmolar and pH-related mechanisms of injuries, hyaluronidase is most commonly used to facilitate absorption and dispersion of injected agents. However, extravasation management is largely supportive and requires a protocolized multidisciplinary approach for early detection, treatment, and timely surgical referral when required to minimize adverse events.
Subject(s)
Extravasation of Diagnostic and Therapeutic Materials , Saline Solution, Hypertonic , Vasoconstrictor Agents , Vasoconstrictor Agents/administration & dosage , Vasoconstrictor Agents/adverse effects , Vasoconstrictor Agents/therapeutic use , Saline Solution, Hypertonic/administration & dosage , Saline Solution, Hypertonic/adverse effects , Extravasation of Diagnostic and Therapeutic Materials/epidemiology , Extravasation of Diagnostic and Therapeutic Materials/prevention & control , Extravasation of Diagnostic and Therapeutic Materials/therapy , Risk Factors , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/therapy , Vasoconstriction , HumansABSTRACT
AIM: Unexplained infertility is a major burden for couples who want to have children. Lymphocyte immunotherapy (LIT) could be a therapeutic help for these couples. Although LIT has been carried out for decades, the data on the success of therapy are still controversial and there is hardly information on possible adverse drug reactions. METHODS: In this study, we used a questionnaire to determine the frequency of local and systemic adverse drug reactions in our patients who were treated with LIT between 2017 and 2020 (n = 302). In addition, we asked about pregnancies and/or live births after LIT in a 2-year follow-up (n = 140). RESULTS: Most of the patients reported the occurrence of mild local adverse drug reactions in a period of less than 4 weeks: Over 75% reported moderate erythema, itching or swelling, over 10% erythema, itching or swelling as more pronounced adverse drug reaction. Blistering was specified in 10% of the cases. Serious adverse drug reactions or adverse events were not described. In the follow-up, 69% of our patients stated a pregnancy after LIT, and 50% a life birth. CONCLUSIONS: Overall, LIT represents a well-tolerated therapy for couples with unexplained infertility, however, more evidence is needed on the benefits.
Subject(s)
Drug-Related Side Effects and Adverse Reactions , Infertility , Child , Drug-Related Side Effects and Adverse Reactions/therapy , Female , Humans , Immunotherapy/adverse effects , Infertility/therapy , Live Birth , Lymphocytes , Pregnancy , Pregnancy Rate , Pruritus , Retrospective StudiesABSTRACT
Immune-oncologic (IO) therapy has revolutionized the treatment and management of oncologic disease. Immunotherapy functions by enhancing the host immune-systems ability to endogenously clear malignant cells, however, this activation can also lead to immune-mediated damage to healthy native tissues. These side effects are known as immune-related adverse events or irAEs and can even present with phenotypes similar to autoimmune diseases. IrAEs are the major consequence of checkpoint inhibitors and can have a significant impact on a patient's cancer treatment and long-term quality of life. The management of these irAEs follows a similar approach to autoimmune diseases. More specifically, the management is akin to that of autoimmune disease exacerbations. While there is an array of immune-suppressing agents that can be used, steroids, immunomodulators and IO discontinuation are cornerstones of irAE management. The exact approach and dosing are based on the severity and subtype of irAE presented. Within recent years, there has been a push to better prevent and manage irAEs when they arise. There has been an additional effort to increase the number of steroid-sparing agents available for irAE treatment given the consequences of long-term steroid therapy as well as patient contraindications to steroids. The goals of this review are to summarize irAE management, highlight significant advances made in recent years and emphasize the future directions that will optimize the use of IO therapy in oncology.
Subject(s)
Autoimmune Diseases , Drug-Related Side Effects and Adverse Reactions , Neoplasms , Autoimmune Diseases/etiology , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/therapy , Humans , Immunotherapy/adverse effects , Neoplasms/drug therapy , Quality of LifeABSTRACT
OBJECTIVE: To design a physician and patient derived tool, the Adverse Event Unit (AEU), akin to currency (e.g. U.S. Dollar), to improve AE burden measurement independent of any particular disease or medication class. PATIENTS/METHODS: A Research Electronic Data Capture (REDCap) online survey was administered to United States physicians with board certification or board eligibility in general neurology, subspecialty neurology, primary care internal medicine or family medicine, subspecialty internal medicine, general pediatrics, and subspecialty pediatrics. Physicians assigned value to 73 AE categories chosen from the Common Terminology Criteria of Adverse Events (CTCAE) relevant to neurologic disorder treatments. An online forced choice survey was administered to non-physician, potential patients, through Amazon Mechanical Turk (MTurK) to weight the severity of the same AE categories. Physician and non-physician data was combined to assign value to the AEU. Surveys completed between 1/2017 and 3/2019. RESULTS: 363 physicians rated the 73 AE categories derived from CTCAE. 660 non-physicians completed forced choice experiments comparing AEs. The AEU provides 0-10, weighted values for the AE categories studied that differ from the ordinal 1-4 CTCAE scale. For example, CTCAE severe diabetes (category 4) is assigned an AEU score of 9. Although non-physician input changed physician assigned AEU values, there was general agreement among physicians and non-physicians about severity of AEs. CONCLUSION: The AEU has promise to be a useful, practical tool to add precision to AE burden measurement in the clinic and in comparative efficacy research with neurology patients. AEU utility will be assessed in planned comparative efficacy clinical trials.
Subject(s)
Adverse Drug Reaction Reporting Systems/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/pathology , Drugs, Investigational/adverse effects , Nervous System Diseases/drug therapy , Patient Reported Outcome Measures , Physicians/statistics & numerical data , Adult , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/therapy , Female , Humans , Male , Middle Aged , Nervous System Diseases/pathology , Surveys and QuestionnairesABSTRACT
Aim: To understand the preferences of US patients and oncologists for PARP inhibitors as second-line maintenance (2LM) for epithelial ovarian cancer. Methods: A discrete choice experiment was conducted to assess the preferences of treatment attributes. Results: The most valued attributes were risk of grade 3/4 adverse events (AEs; patients, n = 204) and progression-free survival (PFS; oncologists, n = 151). To accept a 37% increased risk of grade 3/4 AEs, PFS would need to increase by 27.9 months (patients) and 6.3 months (oncologists). The least valued attributes were dosing form/frequency (patients) and grade 3/4 anemia risk (oncologists). Conclusion: Patients' and oncologists' willingness to make benefit-risk trade-offs in the 2LM setting suggests that the PFS gains observed in selected studies of poly (ADP-ribose) polymerase inhibitors in BRCA-mutated disease are worth the toxicity risk.
Plain language summary Maintenance therapy is a treatment option intended to keep ovarian cancer from coming back or getting worse for as long as possible after responding to chemotherapy. PARP inhibitors are a new type of maintenance therapy for ovarian cancer. This study aimed to understand the patients' and physicians' preferences for the benefits and risks associated with different PARP inhibitors used as maintenance therapy for ovarian cancer. Participants were asked to compare various treatment options based on their different safety profiles, effectiveness and form of medication (e.g., three capsules by mouth once a day versus two tablets by mouth twice a day), and then choose the treatment they most preferred. Through this exercise, the treatment features that mattered most to patients and physicians were identified. The most important treatment feature for patients was decreasing the chance of experiencing a serious side effect that requires medical intervention or hospitalization. In contrast, physicians valued lengthening the time that a cancer remains stable and does not worsen. To accept a 37% higher chance of experiencing a side effect that requires medical intervention or hospitalization, patients expect their cancer to remain stable and not worsen for an additional 28 months. This was a large difference from the 6 months that the physicians would consider as acceptable. The least important treatment features for patients are the amount of pills required per dose, the form of the given medication (e.g., tablet vs capsule) and the schedule of taking the treatment. On the other hand, physicians were least concerned about lowering the risk of experiencing low blood counts that, requiring medical intervention.
Subject(s)
Carcinoma, Ovarian Epithelial/drug therapy , Oncologists/statistics & numerical data , Ovarian Neoplasms/drug therapy , Patient Preference/statistics & numerical data , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Adult , Aged , Cost-Benefit Analysis , Decision Making , Drug-Related Side Effects and Adverse Reactions/therapy , Female , Humans , Maintenance Chemotherapy , Middle Aged , Progression-Free Survival , United States/epidemiology , Young AdultABSTRACT
OBJECTIVES: Myelofibrosis is a rare bone marrow disorder associated with a high symptom burden, poor prognosis, and shortened survival. While allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis, the only approved and reimbursed pharmacotherapy for non-HSCT candidates in Belgium is ruxolitinib. METHODS: These updated recommendations are based on a consensus reached during two meetings and provide guidance for ruxolitinib administration in myelofibrosis patients considering the particularities of Belgian reimbursement criteria. RESULTS AND DISCUSSION: In Belgium, ruxolitinib is indicated and reimbursed for transplant-ineligible myelofibrosis patients from intermediate-2- and high-risk groups and from the intermediate-1-risk group with splenomegaly. Our recommendation is to also make ruxolitinib available in the pre-transplant setting for myelofibrosis patients with splenomegaly or heavy symptom burden. Before ruxolitinib initiation, complete blood cell counts are recommended, and the decision on the optimal dosage should be based on platelet count and clinical parameters. In anemic patients, we recommend starting doses of ruxolitinib of 10â mg twice daily for 12 weeks and we propose the use of erythropoiesis-stimulating agents in patients with endogenous erythropoietin levels ≤500 mU/mL. Increased vigilance for opportunistic infections and second primary malignancies is needed in ruxolitinib-treated myelofibrosis patients. Ruxolitinib treatment should be continued as long as there is clinical benefit (reduced splenomegaly or symptoms), and we recommend progressive dose tapering when stopping ruxolitinib. CONCLUSION: Based on new data and clinical experience, the panel of experts discussed ruxolitinib treatment in Belgian myelofibrosis patients with a focus on dose optimization/monitoring, adverse events, and interruption/rechallenge management.
Subject(s)
Janus Kinase Inhibitors/therapeutic use , Molecular Targeted Therapy , Nitriles/therapeutic use , Primary Myelofibrosis/drug therapy , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Biomarkers , Clinical Decision-Making , Combined Modality Therapy/methods , Disease Management , Disease Susceptibility , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Molecular Targeted Therapy/methods , Nitriles/administration & dosage , Nitriles/adverse effects , Platelet Count , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/etiology , Prognosis , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Treatment OutcomeABSTRACT
Lenvatinib is an oral multikinase inhibitor approved for use as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, like other agents in this drug class, lenvatinib is associated with clinically important adverse events (AEs) that could adversely affect patient outcomes. Hypertension, diarrhea, decreased appetite/weight, hand-foot skin reaction, and proteinuria are among the most common AEs associated with lenvatinib therapy. This article provides strategies for the effective management of lenvatinib-associated AEs based on the expert opinion of authors and currently available literature. Due to the high risk of AEs in patients receiving lenvatinib, prophylactic measures and regular monitoring for AEs are recommended. Lenvatinib dose interruption, adjustment, or discontinuation of treatment may be required for patients who develop AEs. For grade 1 or 2 AEs, dose interruption is generally not required. For persistent or intolerable grade 2 or 3 AEs, lenvatinib treatment should be interrupted until symptoms improve/resolve to grade 0-1 or baseline levels. Thereafter, treatment should be resumed at the same or a lower dose. Disease progression may occur in patients who do not initially respond to treatment or receive a suboptimal lenvatinib dose following dose reduction, resulting in lack of efficacy. Therefore, to derive maximum treatment benefit and ensure long-term disease control, lenvatinib should be maintained at the highest possible dose when managing AEs. To conclude, lenvatinib-associated AEs can be managed with prophylactic measures, regular monitoring and symptomatic management, which can ensure continued treatment and maximum survival benefit in patients with advanced HCC receiving first-line lenvatinib therapy.
Subject(s)
Carcinoma, Hepatocellular , Drug-Related Side Effects and Adverse Reactions , Liver Neoplasms , Phenylurea Compounds , Quinolines , Carcinoma, Hepatocellular/drug therapy , Consensus , Drug-Related Side Effects and Adverse Reactions/therapy , Humans , Liver Neoplasms/drug therapy , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , Quinolines/adverse effectsSubject(s)
Drug-Related Side Effects and Adverse Reactions/etiology , Hepatic Veno-Occlusive Disease/etiology , Adolescent , Child , Disease Management , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/therapy , Female , Hepatic Veno-Occlusive Disease/diagnosis , Hepatic Veno-Occlusive Disease/therapy , Humans , Male , Qatar/epidemiology , Radiotherapy/adverse effects , Treatment OutcomeABSTRACT
Acute anaphylaxis to small molecule drugs is largely considered to be antibody-mediated with immunogloblin E (IgE) and mast cell activation being key. More recently, a role for drug-reactive immunoglobulin G (IgG) with neutrophil activation has also been suggested, at least in reactions to neuromuscular blocking agents (NMBAs). However, the mast cell receptor MRGPRX2 has also been highlighted as a possible triggering mechanism in acute anaphylaxis to many clinically used drugs. Significantly, MRGPRX2 activation is not dependent upon the presence of drug-recognising antibody. Given the reasonable assumption that MRGPRX2 is expressed in all individuals, the corollary of this is that in theory, anybody could respond detrimentally to triggering drugs (recently suggested to be around 20% of a drug-like compound library). But this clearly is not the case, as the incidence of acute drug-induced anaphylaxis is very low. In this mini-review we consider antibody-dependent and -independent mechanisms of mast cell activation by small molecule drugs with a focus on the MRGPRX2 pathway. Moreover, as a juxtaposition to these adverse drug actions, we consider how increased understanding of the role of MRGPRX2 in anaphylaxis is important for future drug development and can complement exploration of this receptor as a drug target in broader clinical settings.
Subject(s)
Anaphylaxis/immunology , Nerve Tissue Proteins/immunology , Receptors, G-Protein-Coupled/immunology , Receptors, Neuropeptide/immunology , Anaphylaxis/etiology , Anaphylaxis/therapy , Drug Hypersensitivity/etiology , Drug Hypersensitivity/immunology , Drug Hypersensitivity/therapy , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/immunology , Drug-Related Side Effects and Adverse Reactions/therapy , Gene Expression , Humans , Mast Cell Activation Disorders/etiology , Mast Cell Activation Disorders/immunology , Mast Cell Activation Disorders/therapy , Mast Cells/drug effects , Mast Cells/immunology , Models, Immunological , Nerve Tissue Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, Neuropeptide/geneticsABSTRACT
PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS: A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS: The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell-associated neurotoxicity syndrome should be managed with corticosteroids and supportive care.Additional information is available at www.asco.org/supportive-care-guidelines.
Subject(s)
Cytokine Release Syndrome/therapy , Drug-Related Side Effects and Adverse Reactions/therapy , Immunotherapy, Adoptive/adverse effects , Neoplasms/therapy , Practice Guidelines as Topic/standards , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/pathology , Disease Management , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/pathology , Humans , Neoplasms/immunology , Neoplasms/pathology , PrognosisABSTRACT
BACKGROUND/AIM: Recently, the number of patients with cancer receiving outpatient chemotherapy using oral anticancer drugs has increased, but the currently available outpatient cancer chemotherapy is not safer than that available before. The present study aimed to identify risk factors associated with unplanned acute care (UAC) requiring outpatient chemotherapy-related consultation and hospitalisation. PATIENTS AND METHODS: We conducted a case- control study among 1,674 patients who received oral anticancer drug treatment either alone or in combination with injectable anticancer drugs at National Cancer Center Hospital East, Japan, between December 1, 2014, and November 30, 2015. RESULTS: Body mass index (BMI) was identified as a risk factor for UAC during chemotherapy. Patients with a BMI of <18.5 kg/m2, classified as underweight according to the World Health Organization classification of nutritional status, had a significantly higher risk of UAC. CONCLUSION: A low BMI immediately before the occurrence of chemotherapy-related UAC is a risk factor for adverse effects; therefore, underweight patients need more careful monitoring and supportive care.
Subject(s)
Ambulatory Care , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug-Related Side Effects and Adverse Reactions/therapy , Neoplasms/drug therapy , Administration, Oral , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Body Mass Index , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/etiology , Female , Humans , Injections , Male , Middle Aged , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. METHODS: ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736. FINDINGS: 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death). INTERPRETATION: Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. FUNDING: Janssen Research & Development.
Subject(s)
Abiraterone Acetate/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prednisone/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Thiohydantoins/therapeutic use , Aged , Androgen Receptor Antagonists/therapeutic use , Double-Blind Method , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/therapy , Humans , Male , Neoplasm Metastasis , Progression-Free Survival , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Steroid Synthesis Inhibitors/therapeutic use , Survival RateABSTRACT
SARS CoV-2 virus has infected more than 200 million people worldwide and more than 4.4 million in Indonesia. The vaccination program has become one of the solutions launched by many countries globally, including Indonesia, to reduce the transmission rate of COVID-19. Various vaccination platforms are produced, such as inactivated, viral vector, mRNA, and protein subunit. The vaccination booster program with mRNA platform (Moderna) was launched by the Indonesian government to give better protection for health care workers, particularly from delta variant. In this case report, we discuss one of the typical side effects of Moderna vaccine, which is referred to as the COVID arm.