Rate Of Hypersensitivity Reactions Research Articles

Paclitaxel hypersensitivity reaction (HSR) rate: Titrated versus non-titrated infusions among gynecologic oncology patients.

e23240 Background: Paclitaxel is a common chemotherapeutic agent used for treatment of various cancers, and is associated with hypersensitivity reactions (HSR). An HSR is mostly likely to occur during first or second infusions. Prior studies have suggested that performing Paclitaxel infusions without titration may be safe for the majority of patients, but increase in number of HSRs. At our institution, Paclitaxel infusions without titration was implemented around April 2023. Our aim was to evaluate the rate of HSR in Paclitaxel infusions without titration among gynecologic patients. Methods: This was a retrospective review of hypersensitivity reactions in patients receiving Paclitaxel at the titrated rate versus the full rate from May 2022 through November 2023. Patients had newly diagnosed gynecologic cancers (ovarian, uterine, cervical), who presented for their first or second Paclitaxel infusions. Patients previously treated with Paclitaxel for any reason were excluded. Results: 145 patients were included in this study, each with one (4%) or two (96%) infusions, for a total of 281 infusion visits. There were 176 infusions with Paclitaxel dose titration (62.6%), and 105 infusions at full rate (37.4%). HSRs occurred in 19% of the full rate Paclitaxel infusions and in 11.9% of titrated Paclitaxel infusions (OR 1.74 [95% CI 0.89 – 3.38]; p = 0.10). When stratifying by first or second infusion, the HSR rate increased significantly for full rate second infusion to 22.4%, compared to 8.3% for titrated infusions (OR 3.18 [95% CI 1.14 – 8.86]; p = 0.026). Grade 3 or greater infusion reactions occurred in 45% of full rate infusion and in 14.2% of titrated infusion reactions (OR 4.91 [95% CI 1.08 – 22.14]; p = 0.0038). There was no difference in timing of hypersensitivity reactions in relation to initiation of Paclitaxel infusion. Conclusions: Overall, the HSR rate was higher with full rate first infusions, and significantly increased during the second infusion with full rate Paclitaxel. Additionally, Grade 3 infusion reactions were more likely to be seen with full rate infusions. There is significant variability in Paclitaxel infusion; further studies to determine optimal infusion rates are warranted.

Rates of paclitaxel hypersensitivity reactions using a modified Markman’s infusion protocol as primary prophylaxis

PurposeMarkman’s desensitisation protocol allows successful retreatment of patients who have had significant paclitaxel hypersensitivity reactions. We aimed to reduce the risk and severity of paclitaxel hypersensitivity reactions by introducing this protocol as primary prophylaxis.MethodsWe evaluated all patients with a gynaecological malignancy receiving paclitaxel before (December 2018 to September 2019) and after (October 2019 to July 2020) the implementation of a modified Markman’s desensitisation protocol. The pre-implementation group received paclitaxel over a gradually up-titrated rate from 60 to 180 ml/h. The post-implementation group received paclitaxel via 3 fixed-dose infusion bags in the first 2 cycles. Rates and severity of paclitaxel hypersensitivity reactions were compared.ResultsA total of 426 paclitaxel infusions were administered to 78 patients. The median age was 64 years (range 34–81), and the most common diagnosis was ovarian, fallopian tube and primary peritoneal cancer (67%, n = 52/78). Paclitaxel hypersensitivity reaction rates were similar in the pre-implementation (8%, n = 16/195) and post-implementation groups (9%, n = 20/231; p = 0.87). Most paclitaxel hypersensitivity reactions occurred within 30 min (pre- vs. post-implementation, 88% [n = 14/16] vs. 75% [n = 15/20]; p = 0.45) and were grade 2 in severity (pre- vs. post-implementation, 81% [n = 13/16] vs. 75% [n = 15/20]; p = 0.37). There was one grade 3 paclitaxel hypersensitivity reaction in the pre-implementation group. All patients were successfully rechallenged in the post-implementation group compared to 81% (n = 13/16) in the pre-implementation group (p = 0.43).ConclusionThe modified Markman’s desensitisation protocol as primary prophylaxis did not reduce the rate or severity of paclitaxel hypersensitivity reactions, although all patients could be successfully rechallenged.

Beta-lactam antibiotics administration among adult inpatients with a beta-lactam allergy label: incidence, predictors, and outcomes.

A beta-lactam antibiotics (BLA) allergy label is common, resulting in disadvantageous outcomes due to the usage of second-line antimicrobial agents. Noncontrolled case-series analyses report low rates of hypersensitivity reactions, following intentional/non-intentional BLA challenges among labeled inpatients. The study aims were to explore predictors and outcomes associated with hypersensitivity reactions following BLA challenge among BLA-allergic labeled inpatients. Retrospective cohort study (2019-2020) of adult (≥18 years) inpatients (Shamir Medical Center, Israel), labeled as allergic to ≥1 BLA, who received ≥1 dose/s of BLA during their stay. Independent predictors to develop allergic reactions and the independent associations of allergic reactions with clinical outcomes were queried by logistic and Cox regressions. Of 9,670 inpatients (14,088 hospitalizations), 3,570 (37%) were labeled as allergic to ≥1 BLA. Of those, 1,171 (33%) patients received ≥1 BLA. The majority were women (67%), and the mean age was 69.3 ± 19.4 years. Only 30 patients (2.6%) developed a reaction, all mild. Independent predictors to develop an allergic reaction were documented reactions in the past, atopic background, antihistamines administration prior to the BLA challenge, and high risk for cross-reactivity, based on the BLA side chains, between the labeled and the challenged agents. Reaction upon the BLA challenge was not independently associated with any worse outcome. Despite the commonality of allergy labeling, and the commonality of BLA administration to labeled inpatients, hypersensitivity reactions were mild and rare. Interventional stewardship strategies for active BLA de-labeling among low-risk patients should be promoted, to improve patients' and institutional health and fiscal outcomes.

Desensitization in patients with hypersensitivity to platinum and taxane in gynecological cancers.

Exposure to paclitaxel and carboplatin has the risk of developing hypersensitivity reactions (HSRs), which could necessitate using less effective treatments to avoid anaphylaxis. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen; therefore, this study investigated rates and benefits of successful desensitization in patients with gynecologic cancers (GC). We collected data from 241 patients with GC who had at least one cycle of platinum or taxane chemotherapy. The rate of HSRs and successful desensitization were evaluated, and an outcome analysis was conducted. The rate of HSRs to platinum and taxane was 6.39% and 13.07%, respectively. We observed a 100% success rate of desensitization in our cohort. Patients with HSR were significantly younger (57.1 vs. 64.9 years, p = 0.030) in the taxane cohort. Importantly, the overall survival (OS) of patients with platinum and taxane HSRs who underwent desensitization was comparable to that of patients with no HSRs (platinum vs. controls; median OS 60.36 vs. 60.39 months, p = 0.31; taxane vs. controls; OS 80.29 vs. 60.00 months, p = 0.59). Thus, we show that desensitization for platinum and taxane HSRs is safe and effective, resulting in an outcome that is well comparable to patients without HSR. Based on these observations, desensitization procedures might be considered as standard of care before switching to less effective treatment for patients with GC.

Immunogenicity of Recombinant Erwinia asparaginase (JZP458) for Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL)

Introduction: L-asparaginase is important in multi-agent treatment regimens for pediatric and adult patients (pts) with ALL/LBL. However, hypersensitivity reactions (HSRs) to E. coli-derived asparaginases (ASP) often lead to treatment delay or discontinuation. JZP458, a recombinant Erwinia ASP derived from a Pseudomonas fluorescens expression platform, is indicated as part of multi-agent chemotherapy regimens for ALL/LBL in adult and pediatric pts ≥1 month old who developed HSRs to E. coli-derived ASP. Here we report the immunogenicity profile of JZP458 based on study AALL1931. Methods: AALL1931 was an open-label, 2-part, multicenter, phase 2/3 trial conducted with the Children's Oncology Group to investigate efficacy, safety, and pharmacokinetics (PK) of JZP458 in ALL/LBL (NCT04145531). Eligible pediatric and adult pts with ALL/LBL who developed HSRs (grade ≥3 allergic reaction or silent inactivation) to E. coli-derived ASP received JZP458 as part of their multi-agent treatment regimen. Each dose of E. coli-derived pegaspargase was substituted with 6 doses of JZP458 either intramuscularly (IM, Part A) or intravenously (IV, Part B) on Mon/Wed/Fri over 2 weeks, defined as 1 course. Efficacy endpoints were the proportion of pts maintaining therapeutic nadir serum ASP activity (SAA) ≥0.1 IU/mL at the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) time point during course 1. Other endpoints included safety and tolerability, PK, and antidrug antibody (ADA) formation. Immunogenicity samples were collected prior to dose 1 in each course, prior to dose 6 in course 1, and at end-of-study safety follow-up visit (30±3 days after last dose). For pts experiencing HSRs, additional samples were tested for ADAs. A multi-tiered approach was used to measure ADAs and neutralizing antibodies (NAbs) to evaluate immunogenicity of JZP458. First, samples were screened for ADAs that bind JZP458. Samples with potentially ADA-positive (+) results were retested for binding specificity confirmation. Samples confirmed as ADA+ were tested further for NAbs. For pts with ADA+ samples obtained prior to study end, follow-up ADA samples up to approximately 6 months after the last dose of the last course were collected. The ADA assay was a validated binding assay based on an electro-chemiluminescence immunosorbent assay technique and the NAb assay was a validated enzymatic activity assay. Results: The median (range) age of pts was 10 (1-25) years. Analysis of pts receiving IM JZP458 (n=167) showed that 82 (49%) pts had confirmed ADA toward JZP458; of these, 7 (4%) were ADA+ at pre-dose 1. Twenty-two pts (15% of 146 pts with samples) remained ADA+ at the end of study. Overall, 18 (11%) pts developed treatment-related HSRs after receiving IM JZP458. Among ADA+ pts (n=82), 11 (13%) experienced treatment-related HSR and 4 (5%) developed positive NAbs. Of ADA-negative (-) pts, 7/85 (8%) experienced treatment-related HSRs. Among pts receiving IV JZP458 (n=61), 34 (56%) had confirmed ADA toward JZP458; of these, 1 (2%) was ADA+ at pre-dose 1. Seventeen pts (34% of 50 pts with samples) remained ADA+ at the end of study. Overall, 16 (26%) pts developed treatment-related HSRs after receiving IV JZP458. Among ADA+ pts (n=34), 12 (35%) experienced treatment-related HSRs and 2 (6%) developed positive NAbs. Of ADA- pts, 4/27 (15%) experienced treatment-related HSRs. Anti-JZP458 antibody status was evaluated as a potential covariate for PK of IM or IV JZP458 within the population PK analysis and it was not found to be a significant covariate. SAA levels were similar between ADA+ and ADA- pts. Overall treatment-related adverse events (TRAEs) in ADA+ and ADA- pts were similar and consistent with the most common TRAEs expected with ASP-containing chemotherapy for ALL (Table). TRAEs led to JZP458 discontinuation for 14 pts with ADA+ status in Part A (8%) and 13 in Part B (21%). Conclusions: The majority of pts who developed ADAs did not develop HSRs or NAbs. The overall rate of HSRs was similar to literature-reported rates for ASP and appeared to be higher with IV vs IM JZP458. ADA status did not appear to impact PK and other AEs for JZP458. Based on these results, no specific immunological concerns were identified with JZP458 beyond known immunogenicity risks associated with ASP and no specific clinical decisions are recommended based on immunogenicity testing.

Standardized Titration Protocol Reduces the Incidence of Paclitaxel Infusion-Related Hypersensitivity Reactions.

Infusion-related hypersensitivity reactions with paclitaxel are common despite the use of dexamethasone and diphenhydramine premedications. Paclitaxel titration protocols that may reduce reactions are empirically derived from clinical observations, and there are no phase III trials that confirm superiority of any management recommendations. The purpose of this study was to compare the frequency and severity of hypersensitivity reactions associated with a recently initiated standardized paclitaxel titration protocol verses standard-of-care (SOC) infusion protocols. This was a retrospective review of hypersensitivity reactions in patients receiving paclitaxel infusions at five ambulatory infusion centers using a standardized titration protocol (February 2021 to April 2021) versus SOC paclitaxel (November 2018 to December 2019). Patients were age 18 years or older and presented for their first or second infusions. The primary study measure was the rate of hypersensitivity reactions. Secondary evaluations included the timing of the reaction after the start of the infusion, use of premedications, and severity of reactions. A total of 451 patients were included in this study. Eighty-four (18.6%) patients were identified in the titration protocol group and 367 (81.4%) patients in the SOC group. Hypersensitivity reactions occurred in 4.8% of the titration group and 18.3% of the SOC group (odds ratio [OR], 0.224; 95% CI, 0.09 to 0.74; P = .002). Grade 3 or greater infusion reactions were 0% in the titration group versus 18% in the SOC group (OR, 0.28; P < .008). Reactions occurred later with the titration protocol, compared with the SOC paclitaxel infusion. Finally, no differences were observed in the use of appropriate premedications. A standardized paclitaxel titration protocol was associated with a significant reduction in the rate of infusion-related hypersensitivity reactions in patients receiving their first and second infusions. A prospective randomized trial is needed to validate these observations.

O03 Penicillin and cephalosporin cross-reactivity: a single-centre UK study

Abstract Background Penicillin allergy (PenA) labels limit antimicrobial options, and concerns about cross-reactivity between penicillin and cephalosporins can further restrict prescribing. Alternative therapies are associated with reduced efficacy, poorer safety profiles and increased healthcare costs. Emerging literature suggests the incidence of cross-reactivity between penicillins and cephalosporins may be lower than historically reported rates of 2–10%. Furthermore, there is a lack of real-time data evaluating the percentage of patients with PenA who tolerate a cephalosporin. Objectives To determine the percentage of patients with a PenA label who tolerated cephalosporins in a secondary care setting. Methods Patients prescribed a cephalosporin from 01 January 2016 to 31 December 2020 at Leeds Teaching Hospitals NHS Trust (LTHT) were identified using the inpatient electronic prescribing system. 1613 with a PenA label were extracted for analysis. The team reviewed and clarified whether each patient (i) had a PenA label that was a potential hypersensitivity reaction, intolerance, or unknown/undocumented label and (ii) tolerated a cephalosporin. Tolerance was defined as receiving ≥1 dose without adverse effects or subsequent cephalosporin allergy label. We recorded if allergy or intolerance was a documented reason for stopping the cephalosporin. Results There were 1279 patients with a PenA label that received a cephalosporin. 555 (43%) had documentation in-keeping with a potential IgE-mediated allergic reaction to penicillins, 177 (14%) were deemed to have an intolerance and 547 (43%) had an unknown or undocumented label. 1263 (98.7%) patients tolerated a cephalosporin. Six (0.5%) patients stopped due to intolerance. One patient asked to stop therapy due to ‘changes’ in the skin. Nine (0.7%) patients developed possible allergic symptoms to cephalosporin; 4 patients developed a rash, 2 patients developed facial or lip swelling (without airway compromise), 1 patient developed hypotension, 1 patient developed difficulty breathing and 1 patient developed chest pain, breathlessness and itching. Of the 9 patients that had reactions; 5 had documented PenA labels that were classified as potential hypersensitivity reactions. Four patients had unknown or undocumented reactions to penicillins. Eight patients received a 2nd-generation cephalosporin (cefuroxime) and 1 received a 3rd generation (cefotaxime). Conclusions The rate of potential hypersensitivity reaction following administration of a cephalosporin in patients with any PenA label at LTHT was 0.7%. The incidence of cephalosporin allergy is estimated to be 1–3% of the general population (with/without PenA label). We conclude that, for patients with a history of unverified, non-anaphylactic PenA label, any cephalosporin could be administered without an increased risk of hypersensitivity reaction.

A Three-Step Taxane Titration Protocol Decreases Hypersensitivity Reactions During First and Second Exposures.

Patients receiving taxanes are at risk for developing hypersensitivity reactions (HSRs) primarily during first and second lifetime exposures. Immediate HSRs require emergency care and can interfere with the continuation of preferred treatment. Although different approaches to slow titration have been used successfully for desensitization after HSR occurrence, there are no standardized recommendations for taxane titration to prevent HSRs. To determine if a gradual, three-step infusion rate titration decreases the rate and severity of immediate HSRs during first and second lifetime exposures to paclitaxel and docetaxel. We used a prospective, interventional design with historical comparisons to evaluate a sample of 222 first and second lifetime exposure paclitaxel and docetaxel infusions. The intervention was a three-step infusion rate titration provided at the initiation of first and second lifetime exposures. Ninety-nine titrated infusions were compared with 123 historical records of nontitrated infusions. Compared with the nontitrated group (n = 123), the titrated group (n = 99) had significantly less HSRs (19% v 7%; P = .017). No significant difference in HSR severity was found between groups (P = 1.00). However, four nontitrated patients received epinephrine, and one required transfer to the emergency department (ED) because of reaction severity. In contrast, no titrated patients received epinephrine or required transfer to the ED. In the nontitrated group, seven patients did not complete their infusions versus one patient in the titrated group. A standardized, three-step infusion rate titration prevented HSR occurrence. Significant issues affecting practice feasibility and sustainability were addressed.

Impact of institutional interventions on the rate of paclitaxel hypersensitivity reactions.

Paclitaxel is associated with hypersensitivity reactions (HSRs). Intravenous premedication regimens have been devised to decrease the incidence and severity of HSRs. At our institution oral histamine 1 receptor antagonists (H1RA) and histamine 2 receptor antagonists (H2RA) were adopted as standard. Standardizations were implemented for consistent premedication use in all disease states. The purpose of this retrospective study was to compare the incidence and severity of HSRs before and after standardization. Patients who received paclitaxel from 20 April 2018 to 8 December 2020 having an HSR were included in analysis. An infusion was flagged for review if a rescue medication was administered after the start of the paclitaxel infusion. The incidences of all HSR prior to and post-standardization were compared. A subgroup analysis of patients receiving paclitaxel for the first and second time was performed. There were 3499infusions in the pre-standardization group and 1159infusions in the post-standardization group. After review, 100 HSRs pre-standardization and 38 HSRs post-standardization were confirmed reactions. The rate of overall HSRs was 2.9% in the pre-standardization group and 3.3% in the post-standardization group (p = 0.48). HSRs, during the first and second doses of paclitaxel, occurred in 10.2% of the pre-standardization and 8.5% of the post-standardization group (p = 0.55). This retrospective interventional study demonstrated that same-day intravenous dexamethasone, oral H1RA, and oral H2RA are safe premedication regimens for paclitaxel. No change in the severity of reactions was seen. Overall, better adherence to premedication administration was seen post-standardization.

Adjuvant trastuzumab and vinorelbine for early-stage HER2+ breast cancer.

The single-arm phase II APT trial established trastuzumab and paclitaxel (TH) as the standard adjuvant regimen for small human epidermal growth factor receptor 2 (HER2+) tumors. However, paclitaxel causes alopecia and has high rates of neuropathy and hypersensitivity reactions. In patients with metastatic HER2+ breast cancer (BC), the combination of trastuzumab and vinorelbine (TV) is effective and well tolerated. There is a need for alternative non-anthracycline/taxane-based regimens for patients with HER2+ early-stage BC, especially for those with contraindications or who wish to avoid side effects of taxane-based regimens. Here we describe our institutional experience with adjuvant TV for patients with early-stage HER2+ BC. Clinicopathological characteristics, treatment details, and outcomes of patients with localized HER2+ BC treated with adjuvant TV from 2007 to 2021 at a large academic medical institution were collected. Study endpoints included invasive disease-free survival (IDFS), overall survival (OS), and safety/tolerability. IDFS and OS were measured from start date of TV treatment to date of event/last follow-up and date of death/last follow-up, respectively. A total of 30 patients were treated with TV. All patients received trastuzumab at standard dosing and vinorelbine at a starting dose of 25 mg/m2 either on days 1/8 or on days 1/8/21 (weekly) of a 21-day cycle with four planned cycles. Median age at diagnosis was 59 years (range: 36-81). 90.3% of patients had anatomic pathologic stage IA BC and 9.7% stage IIA BC. Of the 30 patients, 24 of them opted to pursue TV due to concerns related to alopecia, neuropathy, and other toxicities, and 6 switched from treatment with TH to TV due to toxicities. Eight patients experienced neutropenia with no cases of febrile neutropenia. No patients experienced alopecia or long-term neuropathy. With a median follow-up of 68 months (5.7 years), the 5-year IDFS rate was 90.9%, with one local and one distant recurrence. The 5-year OS was 100%. Trastuzumab in combination with vinorelbine in the adjuvant, early-stage setting for low-risk HER2+ BC demonstrated clinical efficacy and appeared to be well tolerated. TV warrants further evaluation as an alternative regimen to TH for patients with early-stage HER2+ BC.

Universal Premedication for Pegylated (PEG)-Asparaginase Treatment in Children with Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LLy) Has No Impact on Frequency of Hypersensitivity Reactions

Asparaginase is an established and critical chemotherapeutic agent in the treatment of Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LLy). Currently, pegylated asparaginase (PEG-Asp), an E. coli derived enzyme, is the first-line asparaginase preparation used in most contemporary ALL therapy protocols. Hypersensitivity reactions are one of the main toxicities of PEG-Asp therapy occurring in up to 30% of patients (1) and is one of most common reasons for discontinuation of PEG-Asp requiring substitution. Infusion reactions are also seen in patients receiving intravenous (IV) PEG-Asp, but are clinically difficult to differentiate from hypersensitivity reactions, which are associated with neutralizing anti-asparaginase antibody-production. Reactions lead to a switch to more costly and more frequent treatment with Erwinia Asparaginase, an immunologically distinct formulation. Pre-medication with H1/H2 blockers has been shown to reduce the incidence of infusion reactions (2). This has led to adoption of premedication with H1/H2 blockers, including at our centre. However, the data remain mixed, with some data supporting and some disputing this claim (3-4). There also remain concerns regarding premedication masking of milder reactions due to neutralizing antibodies and as such we have implemented serum asparaginase activity (SAA) monitoring along with premedication. This study aimed to assess the impact of pre-medication with H2 blockers and diphenhydramine for PEG-Asparaginase treatment as well as to create a cost analysis to determine the cost-savings effects of universal premedication. To achieve this, we performed a retrospective chart review at the McMaster Children's Hospital comparing rates of hypersensitivity reactions in pediatric leukemia and lymphoma patients prior to universal pre-medication (PM-) from 2016-2018 and after implementation (PM+) from 2019-2021 at our centre. We also assessed the cost-saving effects of universal premedication at our centre. We reviewed a total of 107 charts of pediatric patients with ALL & LLy cared for at our centre over the period of 2016 - 2021. Our results demonstrate that there was no significant difference in reactions between PM- and PM+ patients across all risk stratifications (p = 0.25, CI -0.25, +0.07). There was no difference in median CTCAE grade reactions. There was a total of 2 patients that were diagnosed as a silent inactivation utilizing SAA monitoring. These findings suggest that universal premedication had no impact on the rate of hypersensitivity reactions or CTCAE grade of reaction in patients receiving PEG-Asparaginase, but SAA monitoring has proven effective in diagnosing silent inactivation that may have otherwise been missed. In determining the costs of universal pre-medication per patient, the cost at our centre ranged from $10.88 - $85.14 depending on ALL risk stratification as well as weight-based doses. This does not include the costs for administering the IV medications, nursing costs, time added to care, and hospital waste including vials and syringes. There was no statistically significant difference in number of Erwinia doses administered between groups. Our limitations include the retrospective nature of the study and small sample size. In conclusion, our data suggest that universal premedication did not impact the number and grade of hypersensitivity reactions to PEG-Asp, nor the number of Erwinia doses needed to be substituted. Larger studies are recommended to confirm our findings. We recommend continued SAA monitoring for patients receiving PEG-Asparaginase to identify patients with silent inactivation of asparaginase. References 1) Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010 Oct;32(7):554-63 2) Kurtzberg, J., et al (1993). Antibodies to asparaginase alter pharmacokinetics and decrease enzyme activity in patients on asparaginase therapy. In Proc Am Assoc Cancer Res (Vol. 34, p. 304). 3) Menig, S., et al. (2016). The Impact of PEG-Aspargase Premedication on Hypersensitivity Reaction in Pediatric Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LLy) Patients. Poster Presentation. 4) Young, D., et al. Universal premedication for asparaginase-based therapy should be standard of care. ASPHO Conference Presentation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Premedication and Therapeutic Drug Monitoring (TDM) for Pegaspargase: A Prospective Multicenter Multi-Ethnic Study of Pediatric and Adolescent Patients

Background: Pegaspargase (PEG) is integral in the treatment of patients with acute lymphoblastic leukemia/lymphoma (ALL/LBL). However, full exposure to all doses of PEG can be limited by hypersensitivity reactions (HSR), which necessitate a switch to alternative asparaginase formulations. Previous studies in the pediatric population evaluating the use of premedication with antihistamines (H1 and H2) to decrease the incidence of HSR have largely been retrospective and showed mixed results. We conducted the first prospective, multicenter study to evaluate the efficacy of premedicating pediatric and adolescent patients receiving PEG with H1 and H2 blockers to decrease the rate of HSR. We report on our interim analysis with a special focus on ethnic disparities in asparaginase activity and HSR. Methods: We enrolled patients with ALL/LBL treated according to a Children's Oncology Group protocol at six centers across the US. Starting with the first dose of PEG in consolidation and subsequently, patients received an H1 blocker (diphenhydramine) and an H2 blocker (ranitidine, famotidine or cimetidine) 30-60 minutes prior to every dose of PEG, which was infused over 60-120 minutes. TDM was performed at 7-10 and 14-17 days post each PEG infusion. Therapeutic asparaginase activity was defined as ≥ 0.1 IU/mL (≥100 IU/L ) at 7-10 days post infusion and greater than the lower level of quantification at 14-17 days. We observed for silent inactivation (subtherapeutic levels without symptoms) and accelerated clearance (levels below quantification at 14-17 days without symptoms). Ethnicity differences were assessed using Chi-square and independent t-tests, increased odds of HSR by GLM procedure, and average asparaginase activity across treatments using GEE analyses. Results: We report on the 74 patients enrolled from 10/2019 to 7/2021 who completed all PEG therapy at the time of analysis. The median age at diagnosis was 7.7 years [range 1.3-19.8], 63.5% were male, 90.5% had B-ALL, 35.1% were NCI High Risk (HR) at diagnosis, and 8.1% had Down Syndrome (Table 1). A majority self-identified as Hispanic ethnicity (56.8%). We noted a disparity in obesity/overweight status by ethnicity. Overall, 50.0% of Hispanics were obese (31.0%) or overweight (19.0%) compared to 12.6% of non-Hispanics (6.3% obese and 6.3% overweight), p=.007. The average body mass index (BMI, kg/m2) in Hispanic compared to non-Hispanic patients was 20.7 (SD=6.5) vs. 16.9 (SD=2.7), p=.001. A total of 157 infusions of PEG was administered to 74 patients. The average dose of PEG was 2780 IU with an average time of infusion of 128 minutes in those without HSR. The incidence of HSR for Hispanic patients was 31% compared to 18.8% for non-Hispanics, although this was non-significant (p=0.234). In 19 patients who experienced HSR, 84% were Grade 3 and one was a Grade 4. Most HSR occurred during consolidation (79.9%). Silent inactivation occurred in 3 patients (4%) and one patient experienced delayed clearance. The average asparaginase activity level at 7-10 and 14-17 days was 1.03 IU/mL (SD=0.35) and 0.71 IU/mL (SD=0.30), respectively. There was no significance in asparaginase activity levels between Hispanics and non-Hispanics (p>.05). Overall, 81% of all patients achieved a (-) minimal residual disease (MRD) at the end of induction with no difference in Hispanic (83.3%) versus non-Hispanics (78.1%). In an adjusted analysis to evaluate potential determinants of HSR, we noted that NCI HR at diagnosis (p=0.019) was associated with increased incidence of HSR, while obesity, sex and ethnicity were not (Table 2). Interestingly, age >8 years was associated with higher odds of HSR unadjusted for NCI HR (OR=3.83, p=.016). Conclusion: We found that the two factors which increase the odds of HSR are age > 8 years and NCI high risk at diagnosis. We will be able to confirm the efficacy of premedication with a larger cohort upon the completion of all patients enrolled. Both silent inactivation and delayed clearance was infrequent. Although the standard therapeutic asparaginase activity is widely accepted to be ≥ 0.1 IU/mL, we observed supratherapeutic levels at 1 and 2 weeks post PEG at 1.03 IU/mL and 0.71, respectively. We are currently performing additional analysis to evaluate PEG related toxicity in various ethnic groups, determining the single nucleotide polymorphisms (SNPs) involved in HSR and toxicity, and creating a dose model based on pharmacokinetic analysis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reducing paclitaxel hypersensitivity reactions in gynecologic oncology patients (521)

Reducing paclitaxel hypersensitivity reactions in gynecologic oncology patients (521)

Adjuvant trastuzumab and vinorelbine (TV) for early-stage HER2+ breast cancer.

e12521 Background: The anti-HER2 antibody trastuzumab has vastly improved outcomes for women with early stage and advanced HER2+ breast cancer (BC) when used in combination with chemotherapy. Anthracycline and taxane-based regimens have historically made up the chemotherapy backbone for patients with localized HER2+ BC, though recent evidence suggests anthracyclines can be safely omitted. The single arm phase II APT trial established trastuzumab and paclitaxel as the standard adjuvant regimen for small HER2+ tumors. However, paclitaxel requires weekly treatment, causes alopecia, and has high rates of neuropathy and hypersensitivity reactions. In patients with metastatic HER2+ BC, the combination of trastuzumab and vinorelbine (TV) is effective and well tolerated. There is a need for alternative regimens for patients with HER2+ early-stage BC, especially for those with contraindications to anthracycline and taxane-based regimens. We conducted a retrospective study of patients with early stage HER2+ BC treated with adjuvant TV to evaluate a non-anthracycline/taxane-based, alopecia-sparing regimen. Methods: Clinicopathological characteristics, treatment details, and outcomes of patients with localized HER2+ BC treated with adjuvant TV for from 2007 to 2021 at a large academic medical institution were collected. Study endpoints included invasive disease-free survival (IDFS), overall survival (OS), and safety/tolerability. IDFS and OS were measured from start date of TV treatment to date of event or last follow-up, respectively. 5-year survival rates were generated in GraphPad Prism. Results: A total of 25 patients were treated with TV. All patients received trastuzumab at standard dosing and vinorelbine at a starting dose of 25 mg/m2 on days 1/8 of a 21-day cycle with 4 planned cycles. Median age at diagnosis was 61 years (range: 36-81). 88% of patients had anatomic pathologic Stage IA BC and 12% Stage IIA BC. Of the 25 patients, 24 of them opted to pursue TV due to concerns over alopecia, neuropathy, and other toxicities while 1 patient had received prior adriamycin and therefore opted for TV. With a median follow-up time of 68 months (5.7 years), the 5-year rate of survival from invasive disease was 90.9%, with 1 local and 1 distant recurrence. The 5-year overall survival was 100%. 76% of patients completed 4 cycles of TV without dose holds or delays and 92% completed 4 cycles without dose reductions. 2 patients required hospitalization during treatment with TV due to toxicity (diarrhea attributed to V, rigors/fever attributed to T). No patients experienced alopecia or long-term neuropathy. Conclusions: Trastuzumab in combination with vinorelbine in the adjuvant, early-stage setting for HER2+ BC is effective and well-tolerated and warrants further exploration as an alternative to taxane-based regimen.

Pharmacological and clinical monitoring in children with acute lymphoblastic leukemia treated with a biogeneric PEG-l-asparaginase product.

l-Asparaginase (ASP) plays a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Currently, different ASP products are available in the market, including both native and pegylated drugs. Several biogeneric Escherichia coli ASP (GEN-ASP) products have been developed in response to shortages and expensiveness of the native E. coli ASP innovator compounds, but some concerns have been raised about their quality. Recently, a number of generic pegylated ASP products (GEN-PEG-ASP) have been marketed to substitute for the innovator product (PEG-ASP). Clinical courses and serum asparaginase activity (SAA) levels were monitored in 12 children with ALL, who were treated in our institution with two doses of a GEN-PEG-ASP product, given IV at 2500IU/m2 during the remission induction phase. Results were compared with those obtained in a reference cohort of 35 patients treated in our institution, who received the innovator PEG-ASP product at same dosage and within the same chemotherapy background. Compared to the reference cohort treated with PEG-ASP, SAA levels were significantly lower in the 12 patients receiving GEN-PEG-ASP (p<.0001); a higher proportion of ASP-associated hypersensitivity reactions (2/12 vs. 0/35; p=.061) and silent inactivation (3/12 vs. 0/35; p=.014) were observed in comparison with the reference cohort. Our results highlighted different pharmacological profiles and different rates of hypersensitivity reactions and silent inactivation in the GEN-PEG-ASP cohort compared to those treated with the innovator product. Our findings suggest that a rigorous clinical attention and a thorough pharmacological monitoring are advisable in patients treated with GEN-PEG-ASP products.

Histamine-2 (H2 ) antagonists can be safely removed from standard paclitaxel premedication regimens.

AimsThe aim of this study is to investigate the rates of hypersensitivity reactions (HSRs) in patients receiving paclitaxel chemotherapy, with and without a histamine‐2 (H2) antagonists.MethodThis prospective, multi‐centre, cohort study compared patients receiving paclitaxel treated with premedication regimens containing chlorphenamine, dexamethasone and an H2 antagonist vs patients treated without an H2 antagonist. Rates of HSRs were described and logistic multivariable regression was used to investigate any associations with H2 antagonist treatment, adjusting for confounding variables.ResultsA total of 1043 individuals were included in the study; of these, 638 (61%) patients received an H2 antagonist and 405 (49%) were not given an H2 antagonist. Incidence of HSR in the cohort treated with H2 antagonists was 11.31% (n = 70) vs 9.86% (n = 41) in the cohort without. There was no statistically significant difference between the rates of HSR observed in those receiving and not receiving an H2 antagonist (odds ratio 1.04, 95% CI 0.65, 1.66, P = .9).ConclusionsResults presented within the study are consistent with other recently published evidence to suggest that H2 antagonists do not confer any advantage as part of premedication regimens in reducing the incidence of HSR in patients treated with paclitaxel.

Allergic-like Hypersensitivity Reactions to Gadolinium-based Contrast Agents: An 8-year Cohort Study of 154 539 Patients.

Background With the widespread use of gadolinium-based contrast agents (GBCAs), the incidence of allergic-like hypersensitivity reactions (HSRs) to GBCAs is increasing. Research on the incidence and risk factors for HSRs to GBCAs is needed for their safe use. Purpose To determine the incidence of acute and delayed reactions to GBCAs and to discuss the risk factors and strategies for the prevention of HSRs to GBCAs. Materials and Methods All cases of HSRs to contrast media that occurred at the Seoul National University Hospital from July 1, 2012, to June 30, 2020, were assessed. Information including age, sex, GBCA type, onset, and severity of HSRs was retrospectively analyzed. Results Among the 331070 cases of GBCA exposure in 154539 patients, 1304 cases of HSRs (0.4%) were reported. Acute HSRs accounted for 1178 cases (0.4%), while 126 cases (0.04%) were delayed HSRs. While both premedication (odds ratio [OR] = 0.7, P = .041) and changing the type of GBCA (OR = 0.2, P < .001) showed preventative effects in patients with a history of acute HSRs, only premedication (OR = 0.2, P = .016) significantly reduced the incidence of HSRs in patients with a history of delayed reactions. The risk of an HSR to GBCA was higher in those with a history of an HSR to iodinated contrast media (OR = 4.6, P < .001). Conclusion The rate of hypersensitivity reactions (HSRs) to gadolinium-based contrast agents (GBCAs) was 0.4%. The absence of premedication, repeated exposures to the culprit GBCA, and a history of HSRs to iodinated contrast media and GBCAs were risk factors for HSRs to GBCAs. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kallmes and McDonald in this issue.

A Pilot Study of Omalizumab to Treat Oxaliplatin-Induced Hypersensitivity Reaction.

Oxaliplatin hypersensitivity reactions (HSRs) are immunoglobulin E (IgE)-mediated and prevent maximum benefit from this drug. This study was designed to determine whether oxaliplatin HSRs could be prevented or reduced with omalizumab (Xolair), an anti-IgE antibody. This was a single-arm prospective pilot study. Patients receiving oxaliplatin-based chemotherapy for gastrointestinal cancers who were experiencing grade 1/2 HSRs were eligible. Patients received omalizumab 300 mg subcutaneously every 2 weeks, alternating with oxaliplatin-based chemotherapy. Nine patients enrolled. The primary end point was reduction of repeat HSR over the next 2 cycles. The sample size of 12 patients would achieve 79% power to detect a decrease from HSR rate of 70% (the null hypothesis) to 35% using a 1-sided binomial test. The study would be considered positive if fewer than 6 HSR events over 2 cycles occurred on omalizumab. Nine patients received 58 cycles of omalizumab. The mean number of treatments was 6 (range, 1-12). Eight of 9 patients (88%) completed 2 or more cycles and 7 (78%) completed 4 or more cycles; the overall rate of HSR was 12%. Five of 7 evaluable patients had stable disease, including 1 with near partial response. Omalizumab reduces or abrogates oxaliplatin HSRs and allows months of additional therapy with apparent clinical benefit.

MRNA COVID-19 vaccine safety in patients with previous immediate hypersensitivity to pegaspargase

mRNA COVID-19 vaccine safety in patients with previous immediate hypersensitivity to pegaspargase

Improving management of hypersensitivity reactions: A BC Cancer-Victoria quality improvement initiative.

230 Background: Hypersensitivity reactions (HSR) are a documented, predictable side effect of multiple chemotherapy agents. Reactions negatively affect the patient experience, increase the amount of chair time, nursing and physician resources, may result in the omission of a potentially effective cancer management tool from a patient’s treatment plan and could potentially result in death. BC Cancer is a Health Care Organization with 6 cancer centres across British Columbia, Canada. Guideline(GL)s have been developed at BC Cancer to support clinicians to manage reactions acutely and reduce the risk of reactions with subsequent cycles. A recent audit identified that the GLs were not always being followed at the Victoria Centre. Our goal was to encourage physician and nursing staff to follow GLs, which we hypothesized would result in decreased rates of HSR. Methods: Our aim was to decrease HSR to &lt; 5% of doses delivered within 1 year at BC Cancer-Victoria. We engaged stakeholders (nursing, physicians, pharmacy, clerical staff and administration). Our change ideas improved adherence to GLs by focusing on: physician attendance and documentation, written orders for rescue medication, and rate of infusion of the chemotherapy drug rechallenge. Our interventions included: two physician-education sessions, one nursing education session, daily huddles, pre-printed order development for management of the reaction (PPOA) and prophylaxis for subsequent cycles (PPOB), and a modified clinic flow. All interventions were introduced and underwent modifications through PDSA cycles. Our family of measures were: Outcome: number of reactions, percent of reactions per dose given. Process: percent of PPO use per reaction, physician attendance and notes dictated per reaction. Balancing: physician and nursing satisfaction. We analyzed the data using quality improvement run charts and control charts. Results: After the start of our initiative, our total number of reactions displayed special cause variation, and a shift in the baseline from a mean of 11.27 HSR per month to 7.526. This change was reflected in the percentage of reactions per doses given which fell from 3.1% to 1.9%. Average percentage of dictated notes per reaction increased from 55% to 64%. Physician attendance per reaction also showed special cause variation with the average increasing from 57% to 90%. PPOA and PPOB use both increased over time. Nursing and Physician satisfaction data will also be presented. Conclusions: Our successful initiative has resulted in HSR management which more closely reflects GLs, including increased physician attendance and notes, and clear consistent written orders detailed on PPO A and B. This has led to decreased HSRs at our site, resulting in decreased resource use and increased patient safety and quality. This has provincial implications as there is the potential to spread this initiative to other BC Cancer sites.