Drug Desensitization Research Articles

OUTCOMES OF SINGLE BAG PROTOCOLS FOR DESENSITIZATION TO ANTINEOPLASTIC AGENTS

<h3>Introduction</h3> The typical drug desensitization process includes three separate intravenous infusions with each bag containing an increasing concentration of the drug. Many biologics and chemotherapy agents may not be diluted past a specific concentration or diluted protocols are prohibitively long, making a single bag desensitization protocol useful. The aim of this case series is to describe the safety and efficacy of single bag desensitization protocols in two oncology patients. <h3>Case Description</h3> Patient A is a 55 year-old male with metastatic prostate cancer who required desensitization to Carbazitaxel following an IgE mediated reaction to another member of the taxane drug class. Patient B is a 89 year old female with metastatic squamous cell carcinoma of the tongue who required desensitization to Ceftuximab following grade 3 cyctokine release syndrome. Both patients tolerated single bag desenstization protocols in the MICU without adverse events. Both patients went on to tolerate readministration of their culprit agents in outpatient infusion centers. <h3>Discussion</h3> Developments in medical oncology are providing an increasing number of treatment modalities, making drug reactions to antineoplastic agents more common. Patients may have only one viable treatment option, necessitating desensitization following an adverse reaction. Single bag desensitization protocols may be undiluted or have a single dilution. This method should be considered as it can be well tolerated in both IgE mediated and cytokine mediated drug reactions. Single bag protocols can simplify the procedure and decrease the time required to reach the target dose, aiding transition to outpatient infusion centers thus reducing costs and increasing patient's quality of life.

Adverse Reactions to Biologic Medications Used in Allergy and Immunology Diseases.

Purpose of ReviewThe use of biologic therapies has risen exponentially over recent years, allowing for unprecedented disease control within numerous areas of Allergy/Immunology. With this expanded use, awareness and understanding of adverse reactions to biologic agents have also increased.Recent FindingsMultiple biologic adverse reaction phenotypes have been described, but significant overlap in clinical features across phenotypes exists. Given considerable phenotypic overlap, a targeted testing approach may not always be clear, and more recent classifications focus on management decision making using tools of diagnostic challenges and rapid drug desensitizations, guiding clinicians in developing a management plan when the exact underlying mechanism is not clearly known. With increased clinical experience with omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, tezepelumab, rituximab, and TNF-inhibitors, there is a growing appreciation to the spectrum and particularities of adverse reactions to these agents which are outlined in this review.SummaryOur understanding of the clinical presentation and management of adverse reactions to biologic medications encountered in Allergy/Immunology has grown. Opportunities remain to further define optimal diagnostic and management strategies for these reactions.

Pretreatment with ibrutinib facilitates rapid drug desensitization in a difficult case of brentuximab vedotin–induced anaphylaxis

Rapid drug desensitization (RDD) is a technique used to induce transient tolerance to the required medication by gradually increasing the dose of the culprit drug until the therapeutic dosage can be tolerated. RDD is mainly performed in patients who have developed IgE-mediated drug reactions and in whom alternative medicines are unavailable. The possible explanations for mast cell unresponsiveness in RDD are decreased levels of signal transduction molecules, inhibition of high-affinity IgE receptor (FCεRI) internalization, modulation of immunoreceptor tyrosine-based activation motif/ immunoreceptor tyrosine-based inhibition motif signaling pathways, and increased production of regulatory cytokines.

Editorial introductions.

Editorial introductions.

Rituximab and infliximab desensitization with anti-IgE mAb omalizumab as adjuvant therapy: a case series

Rituximab and infliximab are mAbs used in hematologic and autoimmune disease. Their use can be associated with hypersensitivity reactions (HSRs). Drug desensitization (DD) represents a therapeutic strategy to overcome HSRs.1 Although most DDs are completed successfully and safely, some can be complicated by breakthrough reactions, preventing further drug administration. We describe four patients who were treated with anti-IgE mAb omalizumab as part of DD in addition to premedication with montelukast (10 mg), famotidine (40 mg), chlorphenamine (10 mg), paracetamol (1,000 mg), and 6-methylprednisolone (40 mg), after we received approval from our ethical committee.

National Survey of United Kingdom Paediatric Allergy Services.

Comprehensive national assessments of paediatric allergy services are rarely undertaken, and have never been undertaken in the United Kingdom. A 2006 survey estimated national capacity at 30,000 adult or paediatric new allergy appointments per year and identified 58 hospital clinics offering a paediatric allergy service. The UK Paediatric Allergy Services Survey was the first comprehensive assessment of UK paediatric allergy service provision. All 450 UK hospitals responded to a survey. Paediatric allergy services are provided in 154 lead hospitals with 75 further linked hospitals. All 154 lead paediatric allergy services completed a detailed questionnaire between February 2019 and May 2020. The 154 paediatric allergy services self-define as secondary (126/154, 82%) or tertiary (28/154, 18%) level services. The annual capacity is 85,600 new and 111,400 follow-up appointments. Fifty-eight percent (85/146) of services offer ≤10 new appointments per week (no data provided from 8 services-2 no response, 6 unknown) and 50% (70/139) of the services undertaking challenges undertake ≤2 food or drug challenges per week (no data from 3 challenge services). Intramuscular adrenaline is rarely used during challenges-median annual frequency 0 in secondary services and 2 in tertiary services. Allergen-specific immunotherapy is offered in 39% (60/154) of services, with 71% (41/58) of these centres treating ≤10 patients per annum (no data from 2 immunotherapy services). The 12 largest services see 31% of all new paediatric allergy appointments, undertake 51% of new immunotherapy patient provision and 33% of food or drug challenges. Seventy percent (97/126) of secondary and all tertiary services are part of a regional paediatric allergy network. Only nine services offer immunotherapy for any food (3 for peanut), 10 drug desensitization and 18 insect venom immunotherapy. There has been a fourfold increase in paediatric allergy clinics and an approximately sevenfold increase in new patient appointment numbers in the United Kingdom over the past 15 years. Most services are small, with significant regional variation in availability of specific services such as allergen immunotherapy. Our findings emphasize the need for national standards, local networks and simulation training to ensure consistent and safe service provision.

Basophil Activation Test as a Biomarker for Taxanes Anaphylaxis.

IntroductionTaxanes are widely used chemotherapy agents, and their administration, despite premedication, is associated with hypersensitivity reactions (HR) in up to 9% of patients, 1% of which are severe. The mechanisms of these reactions are not fully understood. Finding biomarkers for early diagnosis and better understanding the underlying mechanisms of these reactions are key to defining the best treatment strategy for patients.MethodsThe purpose of this study was to evaluate the effectiveness of the basophil activation test (BAT) to diagnose patients with anaphylactic reactions to taxanes. Patients with anaphylaxis to taxane compounds (n = 15) were assessed through clinical history, skin testing (when possible), and BAT. BAT was performed immediately before rapid drug desensitization or before skin testing using anti-CD123 conjugated (APC-Biolegend), anti-HLADR conjugated (FITC-Biolegend) to gate Basophils and anti-CD63 conjugated (PE-Biolegend), and anti-CD203c conjugated (BV-Biolegend) to assess CD203c and CD63 expression on basophils under taxane stimulation. BAT was also performed in eight healthy volunteers.ResultsBAT was positive for CD203c in eight out of 15 patients and for CD63 in four out of 15 patients and in two out of eight controls. The sensitivity for CD203c was 53%, the specificity was 87%, and the area under the curve was 0.66 (p = 0.19%). For CD63, these rates were 33%, 87%, and 0.6 (p = 0.4). In a subgroup analysis of patients with positive skin tests (11 patients), CD203c was positive in six patients (sensitivity of 54.5% and specificity of 87.5%), and CD63 was positive in five patients (sensitivity of 45% and specificity of 75%).ConclusionsBAT as a diagnostic tool for immediate hypersensitivity reactions to taxanes may be relevant in patients with selected phenotypes and endotypes, especially those with severe reactions or when the diagnosis cannot be established by the skin test. Increased expression of CD203c was more frequent than of CD63 in patients with positive results, and the sensitivity of this biomarker was higher in patient sub-group with positive skin tests, i.e., patients with IgE-mediated endotypes.

Same-Day Desensitization in Patients Who Experience Their First Reaction to a Platin Agent at the Oncology Day Unit: A Pilot Study to Safely Include This Technique Within the Multidisciplinary Pathways for the Diagnosis & Management of Hypersensitivity to Platin Agents.

One of the main objectives when assessing patients who react to antineoplastics must be to ensure that they receive the required treatments without delay. From January to July 2021, at the Allergy Department at the Provincial University Consortium Hospital a pilot study was performed in which those patients suspected of having suffered a type I hypersensitivity reaction (grade 1 or 2) following Brown's anaphylaxis severity grading to a platin agent at the Provincial University Consortium oncology day unit, and once the reaction was properly treated and completely resolved, were subjected to a new procedure named as Same-Day Desensitization, which consists in the reintroduction and administration of full chemotherapy dose by allergists on the same day of the reaction by following the 1 bag/10 step protocol, looking forwards to systematize same-day reexposure using Same-Day Desensitization, doing it in the safest way possible. In total, 9 oncological patients suspected of having suffered a type I hypersensitivity reaction (grade 1 or 2) to a platin agent received total dose administration the same day of the initial reaction by following Same-Day Desensitization 1 bag/10 step protocol, without presenting further reactions. The manuscript describes a new approach in the use of Rapid Drug Desensitizations in reactive oncologic patients in treatment with platin agents, presenting the first 9 cases of oncologic patients who have been submitted to this procedure.

Outcomes of a Undiluted, One-Bag Desensitization Protocol for Chemotherapeutic Agents.

Hypersensitive reactions (HSRs) often require that the provoking medication be discontinued but chemotherapeutic drugs are often essential for the treatment of the disease. Rapid drug desensitization is a procedure that induces temporary tolerance to the drug allowing continuation of treatment in patients who have presented HSRs. Most of the desensitization protocols use 3 bags with sequential dilutions of the drug, which are infused in gradual steps. However, it has not been sufficiently investigated whether dilution is essential for successful desensitization. The objective of this study was to evaluate the efficacy and safety of a new one-bag desensitization protocol which uses a single solution of 1 mg/mL throughout the procedure allowing to reduce time and simplifying the desensitization procedure. Retrospective observational study was carried out in adult patients with HSRs to chemotherapy agents who received a new nondilution one-bag desensitization protocol between 2016 and 2021. A total of 130 desensitization procedures with an undiluted one-bag protocol were performed on 17 patients with HSRs to chemotherapy. One hundred and seven (82.3%) were for desensitization to CBDCA, 15 (11.5%) for oxaliplatin, 4 (3.1%) for paclitaxel and 4 (3.1%) for brentuximab. All of the 130 procedures were successfully accomplished, and all patients could receive their target dose. No breakthrough reactions (BTRs) occurred in 77% (100/130) of desensitizations, and only mild reactions (grade 1) with skin symptoms were observed in 23% (30/130) of desensitizations. The undiluted one-bag desensitization protocol was safe and effective and has been adopted as the standard of care at our institution in treating patients with HSRs to chemotherapeutic drugs as it requires less time and simplifies the desensitization procedure, optimizing risk management.

Findings of in vitro Analyses of Basophil Functions May Help Us Better Understand Drug Desensitization.

Drug hypersensitivity can be an important problem during pharmacological management of various diseases. Patients diagnosed as having a drug allergy usually need to avoid the offending drug, either temporarily or for life. Another way of overcoming a drug allergy is to establish desensitization using the allergen drug itself. We previously investigated in vitro desensitization of human basophils using a subthreshold dose of an IgE-crosslinking reagent. We found that basophil desensitization occurred in a dose-dependent manner over a period of one to several hours. We think that inducible basophil desensitization occurring without histamine release may explain, at least in part, the clinical features of drug desensitization in type 1 drug allergy.

Desensitization to drugs in children

Better knowledge and understanding about drug desensitization is required in the pediatric population, since there is little literature available about it and the most pediatric desensitization protocols have been adapted from adult instructions.Aiming to soften this issue and foster the future studies, this article presents a recent review about mechanisms of desensitization, diagnostic tools, and up to date management of drug hypersensitivity reactions in children. Bringing up an overview of pediatric hypersensitivity reactions to chemotherapy, biologic agents, antibiotics, nonsteroidal anti-inflammatory drugs, and vaccines.

Safety and efficacy of rapid drug desensitization in children.

Any drug taken at the recommended dosage may cause hypersensitivity reactions (DHR). Rapid drug desensitization (RDD) protocols have been developed in the case of a confirmed or highly suspected HSR to allow safe administration of the medicine when there is no alternative drug or in the presence of a less effective or more toxic alternative. The aim of this study was to evaluate the characteristics of children who underwent desensitization, the safety and efficacy of RDD in children, as well as, the characteristics and management of breakthrough reactions. This retrospective study concerned children who underwent RDD due to physician-diagnosed HSRs during or up to 48hours after the infusion of various drugs between February 2010-February 2021. Patients with a chronic disease needing chronic drug usage and acute infections seen in patients with chronic diseases were included. The results of RDD were documented. The study included 48 patients [8.1(IQR = 3.32-13.4) years, 60.4% male] with 58 HSRs of which 62.1% were classified as moderate and 5.2% as severe. Most of the patients were being treated for leukemia (41.7%), solid tumors (29.2%), and infections (6.3%). Skin tests were done for 41 out of 58 HSRs in 35 patients, and twenty of them were positive. A total of 269 RDDs were performed for 18 different drugs. Ninety percent of desensitizations were achieved with no reaction, and 3.7% and 5.6% with mild and moderate reactions, respectively. In multivariate analysis, skin test positivity was the only risk factor for breakthrough reactions (OR = 8.5, CI = 1.72-42.15, p = .009). We demonstrated the safety and efficacy of RDD in childhood, thereby offered the first line treatment options to children with chronic diseases with hypersensitivity reactions (HSRs).

Drug allergy desensitization is not a unique recipe.

Drug desensitization is the only therapeutic option for patients with drug allergies who need to receive the drugs they are allergic to, and it is especially critical in patients with an urgent need for chemotherapy, biologics, or antibiotics, where equally effective alternatives might not be available. However, drug desensitization is not a cookbook where anyone with no experience or specific training can find a general recipe. This review article will approach the singularities that make personalized and highly specialized care essential in this field. Drug desensitization needs to be personalized for each individual patient bearing in mind countless factors. Recent articles have tried to define the optimal resources and the most important factors to account for in personalization. However, drug desensitization is only a tool within the wider management pathway, and we will discuss recent findings in allergy delabelling in chemotherapy, biologics, and antibiotics. Risk-assessment, delabelling, and desensitization protocols, as a part of wider management pathways, can be adapted locally along with comprehensive and multifactorial risk-management strategies. These high-complexity and high-risk procedures, such as drug desensitization, need to be managed by expert allergists who can provide personalization, innovation, continuous improvement, research, and teaching in expert centres.

Temporal Modulation of Drug Desensitization Procedures.

Drug hypersensitivity reactions are an unavoidable clinical consequence of the presence of new therapeutic agents. These adverse reactions concern patients afflicted with infectious diseases (e.g., hypersensitivity to antibiotics), and with non-infectious chronic diseases, such as in cancers, diabetes or cystic fibrosis treatments, and may occur at the first drug administration or after repeated exposures. Here we revise recent key studies on the mechanisms underlying the desensitization protocols, and propose an additional temporal regulation layer that is based on the circadian control of the signaling pathway involved and on the modulation of the memory effects established by the desensitization procedures.

Desensitization for the prevention of drug hypersensitivity reactions.

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca2+ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal antiinflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Complete metabolic response after carboplatin desensitization in Peritoneal Carcinomatosis

High-grade serous primary peritoneal cancer is highly sensitive to platinum-based chemotherapy with response rates above 80%. Incidence of immediate hypersensitivity reactions to carboplatin is estimated to be between 15% and 20%, usually seen after a mean of 6-8 infusions, with patients developing moderate to severe reactions. A 62-year-old female patient with stage IIIC primary high-grade serous carcinoma of the peritoneum was diagnosed and chemotherapy with carboplatin and Paclitaxel was indicated by the oncology service and patient shows response. At 6 months the patient returns, a new PET/CT reports progression of the disease. Carboplatin/paclitaxel cycles are restarted and in the eight cycle of carboplatin within 40 min of administration, she presented severe anaphylaxis with skin, pulmonary, cardiac and atypical symptoms. Infusion is suspended and intramuscular epinephrine with hydrocortisone and chlorphenamine are administered resolving symptoms. Intradermal skin test with carboplatin at the concentration of 10 mg / ml (dilution 1: 100) was positive. Due to the symptoms presented and to continue the safe reintroduction to carboplatin, a 4 bag 16-step drug desensitization protocol was carried out at a total dose of 620 mg with no hypersensitivity reactions. Prolonged carboplatin use is associated with an increased incidence of carboplatin-related hypersensitivity reactions. And in patients that present hypersensitivity reactions, a safe and effective carboplatin desensitization protocol can be carried out to reach the administration of a full dose. Desensitization protocol induces tolerance to a drug temporarily and is dependent on continuous exposure.

The Role of Exosomal Non-Coding RNAs in Colorectal Cancer Drug Resistance.

Background: Colorectal cancer (CRC) is one of the most common types of cancer diagnosed worldwide with high morbidity; drug resistance is often responsible for treatment failure in CRC. Non-coding RNAs (ncRNAs) play distinct regulatory roles in tumorigenesis, cancer progression and chemoresistance. Methods: A literature search was conducted in PubMed database in order to sum up and discuss the role of exosomal ncRNAs (ex-ncRNAs) in CRC drug resistance/response and their possible mechanisms. Results: Thirty-six (36) original research articles were identified; these included exosome or extracellular vesicle (EV)-containing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and small-interfering (siRNAs). No studies were found for piwi-interacting RNAs. Conclusions: Exosomal transfer of ncRNAs has been documented as a new mechanism of CRC drug resistance. Despite being in its infancy, it has emerged as a promising field for research in order to (i) discover novel biomarkers for therapy monitoring and/or (ii) reverse drug desensitization.

Desensitization to Brentuximab Vedotin after anaphylaxis in refractory Hodgkin's lymphoma.

Brentuximab vedotin (BV) is a monoclonal antibody that targets CD30 antigen. It is indicated for the treatment of CD30 + lymphomas and classical Hodgkin lymphoma (HL), including advanced (stage III-IV) untreated disease, relapsed/refractory disease, and consolidation after autologous hematopoietic stem cell transplantation. In clinical trials the incidence of a hypersensitivity reaction is 1.2%. We present 3 cases of patients with refractory HL and anaphylaxis to the administration of BV ( Table1). Symptoms are analyzed using a grading system described by Brown (2004) and a desensitization protocol was performed with a total dose of 100 mg of BV in 4 solution bags with an initial concentration of 1:1000 of total dose for cases of severe anaphylaxis, and desensitization of 3 solution bags with baseline concentration of 1: 100 for cases of moderate anaphylaxis. Intradermal skin tests were positive. Before desensitization, premedication with methylprednisolone and chlorphenamine was administered, as well as fluid therapy with 0.9% physiological solution at 100 cc/hour at induction stage, 250 cc/hour at maintenance stage, and increased to 500 cc/hour in case of hypersensitivity reaction. Drug desensitization in 12 or 16 steps allows tolerable administration of brentuximab vedotin after moderate to severe anaphylaxis. The favorable response to treatment of these patients may indicate that desensitization is a viable strategy for patients with relapsed or refractory HL.

Use of Rapid Drug Desensitization in Delayed Hypersensitivity Reactions to Chemotherapy and Monoclonal Antibodies.

Background:Rapid drug desensitization (RDD) allows first-line therapies in patients with immediate drug hypersensitivity reactions (DHR) to chemotherapeutic drugs (ChD) and monoclonal antibodies (mAb). Desensitization in delayed drug reactions has traditionally used slow protocols extending up to several weeks; RDD protocols have been scarcely reported.Patients and Method:We retrospectively analyzed the patients referred to the Allergy Department, who had experienced a delayed DHR (> 6 h) related to a ChD or mAb and underwent an RDD protocol. The rate of successful administration of the offending drug and the presence of adverse reactions were evaluated.Results:A total of 93 RDDs were performed in 11 patients (including 6 men and 5 women, with a median age of 61 years). The primary DHR were maculopapular exanthema (MPE) (8), generalized delayed urticaria (1), MPE with pustulosis and facial edema (1), and facial edema with desquamative eczema (1). The meantime for the onset of symptoms was 3 days (range 1–16 days). RDD was performed using a protocol involving 8–13 steps, with temozolomide (25), bendamustine (4), rituximab (9), infliximab (24), gemcitabine (23), and docetaxel (8), within 4.6–6.5 h. Sixteen breakthrough reactions were reported during the RDD (17.2 %) in 5 patients; all were mild reactions including 11 delayed and 5 immediate reactions. All patients completed their treatment.Conclusions:RDD is a potentially safe and effective procedure in patients suffering from delayed reactions to ChD and mAb. It allows them to receive full treatment in a short period, thereby reducing time and hospital visits.

Converter Phenotype: A New Profile That Is Not Exclusive to Taxanes.

Introduction: Phenotype I hypersensitivity reactions are the most commonly reported drug reactions; however, precision medicine has made it possible to characterize new phenotypes. A recent communication proposed the existence of a “converter phenotype,” which would affect patients who present non-immediate hypersensitivity reactions and in subsequent exposures develop immediate hypersensitivity reactions. This study aimed to describe the clinical characteristics of converter phenotype reactions and their evolution during desensitization to chemotherapeutic drugs and monoclonal antibodies.Methods: We retrospectively reviewed our database of patients undergoing desensitization to chemotherapy or biological agents and selected those with a converter phenotype. Demographic and clinical characteristics of the patients, the results of skin tests, tryptase and IL-6 levels, and desensitization outcomes were assessed.Results: Of 116 patients evaluated, 12 (10.3%) were identified as having a converter phenotype. The median interval between drug exposure and reaction was 90.6 h (range 8-288 h). After the conversion, phenotype I was the most frequent (58.3%), followed by cytokine release reactions (33.3%). Fifty-one desensitizations were undertaken and all treatments completed, with 10 (19.6%) breakthrough reactions. No new changes in the phenotype were detected.Conclusions: The symptoms of non-immediate drug hypersensitivity reactions may indicate the need for an early allergological evaluation to assess the risk of future immediate drug reactions. Clinical characteristics, skin test results, and biomarkers can help predict responses to rapid drug desensitization, guiding clinicians on how to optimize therapy delivery while maintaining patient safety.