Infusion Hypersensitivity Reactions Research Articles

Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas

BackgroundSEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater...

Incidence and associated factors of cetuximab-induced hypersensitivity infusion reactions in 1392 cancer patients treated in four French areas: a possible association with Lyme disease?

Background:Previous studies have observed an increased incidence of Cetuximab-induced hypersensitivity infusion reactions (CI-IRs) in the southeastern states of the USA. Tick’s bites were suspected of generating cross-reactions between cetuximab and alpha-gal. This study aims was to describe the incidence and associated risk factors of CI-IRs, in the French areas chosen according to their Lyme disease incidence.Patients and methods:A retrospective chart review was conducted on patients that received cetuximab infusion from January 2010 to June 2019 in 4 French areas with different Lyme disease incidence rates.Results:Of 1392 patients, 117 (8.4%) experienced a CI-IR, including 68 severe (grade 3 or 4) reactions (4.9%). This CI-IR incidence was significantly higher in the Lyme disease high-risk area than in the other areas (13.2% versus 7.1%, 8.1% and 6.4%; P = 0.016). Sex (P = 0.53), premedication (P = 0.91), primary cancer location (P = 0.46) and chemotherapy regimen type (P = 0.78) had no impact on CI-IR incidence in the overall population. In the head and neck squamous cell carcinoma (HNSCC) patient subgroup, CI-IRs were significantly more frequent in the high-risk area (16.4% versus 6.7%, 7.1% and 7.0%; P = 0.0015).Conclusion:This study suggests that patients treated in the French area with the highest incidence of Lyme disease are at a higher risk of CI-IRs.

Safety of Therapy with Tocilizumab and Other Interleukin Inhibitors

Monoclonal antibodies directed against interleukin and interleukin receptors have been successfully used for the treatment of rheumatic diseases since 2001, and since 2020 they have been used as part of complex therapy for patients with severe COVID-19. This raises the question of safety of these products, especially when used for new indications. The aim of the study was to analyse data on potential adverse reactions to tocilizumab and other interleukin inhibitors in order to increase the safety of pharmacotherapy of systemic connective tissue diseases, as well as of severe COVID-19. Literature data suggest that the most frequent adverse reactions to tocilizumab and other interleukin inhibitors are infections, hypercholesterolemia, leukopenia, neutropenia, thrombocytopenia, and increased liver enzyme activity. Hypersensitivity and acute infusion reactions, manifested as pseudoallergic reactions, also pose serious health risks and can even be fatal. However, the identification of undesirable reactions to interleukin inhibitors is challenging, due to their prolonged intake and long intervals between injections. Besides, they are often used in combination with other medicines, such as methotrexate or glucocorticosteroids, which complicates establishment of a reliable correlation between an adverse reaction and a particular medicine. At present, the safety of tocilizumab and other interleukin inhibitors for the treatment of severe COVID-19 has not been studied properly and needs further research with an increased number of participants and a careful analysis of the risk/benefit ratio of these medicines when used for COVID-19 treatment.

Optimizing chair time in infusion centers using intravenous cetirizine premedication for the prevention of hypersensitivity infusion reactions.

e13508 Background: Oncology infusion centers are increasingly focused on improving operational efficiencies and patient satisfaction, while maintaining quality care. One key component is optimizing chair time, which has been especially important for patient safety during the COVID-19 pandemic to reduce risk of transmission. Many infusions require antihistamine premedication to reduce the risk of hypersensitivity infusion reactions (IRs). The two IV options are IV diphenhydramine and IV cetirizine, which have a quicker onset than oral options and can be administered IV push. In treating acute urticaria, IV cetirizine was shown to be comparable to IV diphenhydramine, with fewer side effects, and it may be effective for preventing IRs with improved chair time. Methods: A randomized, double-blind phase 2 study evaluating premedication with single dose IV cetirizine 10 mg versus IV diphenhydramine 50 mg was conducted in 34 patients receiving paclitaxel, rituximab, its biosimilar or obinutuzumab (first cycle, retreatment after 6 months or with persistent IRs). The primary objective was the incidence of IRs after premedication. Secondary endpoints included sedation due to antihistamines and time to readiness for discharge. Sedation was reported by patients on a scale of 0-4 (0 = none to 4 = extremely severe). No formal statistical analyses were planned given the exploratory nature of the study. Results: Adults primarily with cancer (n = 31 [91%]) were enrolled during the COVID-19 pandemic, from March 25 to November 23, 2020. The median age was 65 and 67 years in the IV cetirizine and diphenhydramine groups, respectively. The number of patients with IRs was 2/17 (11.8%) with IV cetirizine versus 3/17 (17.6%) with IV diphenhydramine. The mean sedation score in the IV cetirizine group compared to the IV diphenhydramine group was lower at all time points, including at discharge (0.1 vs 0.4, respectively). Mean time to discharge was 24 minutes less with IV cetirizine (4.3 hours [1.5]) versus IV diphenhydramine (4.7 hours [1.2]). This difference was greater (30 minutes less) in those ≥65 years of age (4.4 [1.3] vs 4.9 [1.0] hours). Regardless of whether patients received paclitaxel (n = 9) or an anti-CD20 (n = 25), patients had less chair time when premedicated with IV cetirizine. There were fewer treatment-related adverse events (AEs) with IV cetirizine (2 events) than with IV diphenhydramine (4 events). Conclusions: This was the first randomized, controlled trial evaluating IV antihistamine premedication for IRs and chair time. It was shown that IV cetirizine can prevent IRs, with less sedation, fewer related AEs and reduced chair time compared to IV diphenhydramine. This improves infusion center operations and patient experience. Clinical trial information: NCT04189588.

Comparison of subsequent infusion hypersensitivity reactions to paclitaxel using two different infusion strategies.

The purpose of this study was to compare the incidence of rescue medication utilization with up to 3 subsequent doses of paclitaxel in patients who underwent an infusion rate escalation versus those who continued on the standard infusion rate after experiencing an initial paclitaxel infusion hypersensitivity reaction (HSR) requiring rescue medications. A retrospective, single-center review was conducted on patients who experienced a paclitaxel infusion HSR requiring rescue medications to their first or second lifetime dose of paclitaxel. A total of 99 patients were included for analysis, and from this group, 22 patients were continued on the standard infusion rate, while 77 patients were changed to an infusion rate escalation. The rate of subsequent rescue medication utilization was 5% in patients who were continued at the standard infusion rate versus 23% in patients who were changed to an infusion rate escalation (p = 0.064). The incidence of subsequent rescue medication utilization was unrelated to disease stage (p = 0.39), the paclitaxel dosing regimen (p = 0.99), or a diagnosis of asthma (p = 0.99). This single-center, retrospective study suggests that while not statistically significant, there was a potentially clinically meaningful increase in the rate of subsequent rescue medication utilization in patients who were changed to an infusion rate escalation compared to those who continued on the same standard infusion rate after experiencing an initial HSR to paclitaxel.

Complement Activation: A Potential Threat on the Safety of Poly(ethylene glycol)-Coated Nanomedicines

In this issue of ACS Nano, Chen et al. provide in vitro and in vivo evidence for monoclonal anti-poly(ethylene glycol) (anti-PEG) antibody-triggered, complement terminal complex-mediated damage to PEGylated liposomal doxorubicin, entailing the release of the encapsulated drug from the vesicles. These results reveal a new dimension of the potential damage of anti-PEG antibody-mediated complement activation on PEGylated nanomedicines in addition to previous observations on infusion hypersensitivity reactions and the accelerated blood clearance effect. The possibility of a destructive attack of the complement system on the liposome drug carrier may have safety implications in patients displaying high levels of preformed anti-PEG antibodies. In this Perspective, we summarize the experimental and clinical data highlighting the relationships among the above adverse immune phenomena and the options available for reducing the risk of immune damage caused by PEGylated nanomedicines.

Incidence of infusion hypersensitivity reaction after withholding dexamethasone premedication in early breast cancer patients not experiencing two previous cycles of infusion hypersensitivity reaction for weekly paclitaxel chemotherapy.

Premedication with dexamethasone is an essential part of the prevention of hypersensitivity reaction (HSR) associated with taxane administration. However, the possibility of stopping dexamethasone premedication has been investigated in previous studies to reduce the steroid's adverse events; however, either the result or the particular protocol was limited. Thus, our study aimed to evaluate the incidence of HSR after dexamethasone premedication discontinuation after lack of HSR in two previous weekly paclitaxel infusions. Early breast cancer patients who received adjuvant weekly paclitaxel in a retrospective cohort from January 2012 through February 2016 at the King Chulalongkorn Memorial Hospital were reviewed. All patients received a standard premedication protocol prior to the first and second paclitaxel infusion. Dexamethasone was omitted in later cycles in all patients who did not undergo infusion HSR. Patients who developed HSR during the first or second cycles of paclitaxel infusion were excluded. The incidence of HSR during the later cycle of paclitaxel administration and factors associated with this adverse reaction were collected. Eighty-one of 85 patients who did not undergo infusion HSR after 2cycles of weekly paclitaxel administration were retrospectively reviewed. The median age was 51years (range 27-74years). Only 16% of the patients had a BMI greater than 30kg/m2, 57.8% were premenopausal, 67.9% had no comorbidity, none had a history of allergy or asthma, 65.4% received weekly paclitaxel as a single agent, and 34.6% received weekly paclitaxel in combination with trastuzumab. Five of 81 patients reported grade I-II HSR (6.25%), which occurred mostly during the first 6cycles (60%). Temporary discontinuation of paclitaxel infusion was observed in all HSR patients. No differences regarding age, BMI, menopausal status, and underlying disease between the HSR and no HSR groups were identified. Concerning the safety profile, peripheral neuropathy (gr I 60%, gr II 13.5%, and gr III 2.4%), myalgia (43.4%), and edema (10.5%) were commonly reported, whereas dyspepsia (5.3%) and insomnia (14.5%) were rarely described in withholding patients. Withholding dexamethasone premedication in non-experiencing HSR patients after two previous cycles of weekly paclitaxel administration was safe and did not impact the higher incidence of HSR. A discontinuing dexamethasone protocol should be recommended generally in these patients, especially those with a high risk for steroid-induced side effects.

First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers

Background:YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects.Methods:This FIH study was designed to determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) to assess the tolerance, pharmacokinetics (PK) and pharmacodynamics profiles of YS110 and preliminary efficacy. YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours.Results:Thirty-three patients (22 mesothelioma) received a median of 3 (range 1–30) YS110 infusions across six dose levels (0.1–6 mg kg-1). MTD was not reached and two dose-limiting toxicities (infusion hypersensitivity reactions) led to the institution of a systemic premedication. Low-grade asthenia (30.3%), hypersensitivity (27.3%), nausea (15.2%), flushing (15.2%), chills (12.1%) and pyrexia (12.1%) were reported as ADRs. Pharmacokinetic parameters (AUC and Cmax) increased in proportion with the dose. sCD26/DPPIV assays indicated CD26 modulation. Prolonged stable diseases were observed in 13 out of 26 evaluable patients.Conclusions:YS110 is well tolerated up to 6 mg kg-1 Q1W, which has been defined as the RP2D, with encouraging prolonged disease stabilisations observed in a number of patients with advanced/refractory mesothelioma.

Feasibility of withholding dexamethasone premedication in patients not experiencing two previous cycles of weekly paclitaxel related infusion hypersensitivity reaction.

e21634Background: Premedication with dexamethasone is an essential part in prevention of hypersensitivity reaction associated with taxane administration. However, the possibility of stopping dexame...

Complement activation-related pseudoallergy: insights into a stress reaction to nanomedicines in blood

The term “nanomedicine” is somewhat of a paradox. Although “nano” implies something very small, nanomedicines tend to be much larger than most medicines traditionally used in pharmacotherapy. The consequence of their larger size is that they are often mistaken by the immune system as pathogenic virus, an error that often sets off a defense reaction to eliminate the benevolent “intruder”. This unwarranted defense reaction may result not only in the loss of the medicine’s beneficial effect, but also in adverse effects on the patient. The immune reaction against intravenously applied nanomedicines may involve a rapid inflammatory-like hypersensitivity reaction, also known as infusion reaction, and/or a slow specific response manifested in antibody formation against the drug. The latter “immunogenicity” may prevent the drug from carrying out its specific and reproducible therapeutic mission, transforming it into a vaccine. Thus, immunogenicity of nanomedicines and biologicals with formation of anti-drug antibodies represents a major problem in modern pharmacotherapy. Accordingly, the phenomenon has attracted significant attention in the fields of experimental and clinical immunology and pharmacology. In contrast, the issue of infusion hypersensitivity reactions has received much less attention to date. One possible explanation for the difference is that immunogenicity prohibits the use of nanomedicines, while acute hypersensitivity reactions are in most cases preventable and manageable, their risk is accepted by the patient and the physician. Nevertheless, a small fraction of infusion reactions are not preventable, nor manageable, and cause life threatening or even fatal reactions. Due to this, hypersensitivity reactions represent a significant safety concern, for which testing in preclinical drug development is listed among the most recent regulatory recommendations. It has been increasingly recognized over the past 20 years that a major cause of acute infusion reactions to liposomeand micelle-based nanomedicines is their ability to activate the complement (C) system, which is the humoral arm of nonspecific immunity. This phenomenon was named C activation-related pseudoallergy or CARPA, a term that highlights the mechanism of the reaction. CARPA has been the subject of numerous studies and reviews to date, evolving into the broader claim that it is a manifestation of the commonly known “stress” phenomenon, wherein the body responds to external and internal noxious effects with a standard pattern of physiological changes. In the case of CARPA the noxious agents are nanoparticulate drugs mimicking viruses, the reaction proceeds via the anaphylatoxin-mast cell/macrophage axis rather than the hypothalamo-pituitary-adrenal one, and the effectors are allergy mediators rather than steroid hormones. As a reflection of growing awareness towards CARPA, the current and the 2015 July issue of the European Journal of Nanomedicine presents a series of reviews and research papers on CARPA, providing an unprecedented spectrum of old and new information on the subject. The topics addressed in the two issues include a historic account of how the concept developed from a problem in liposome research to the daring claim that CARPA is a universal stress reaction that may afflict most or all animals that have C in their blood; the types of reactogenic drugs and drug carrier nanosystems; the symptoms and mechanism of CARPA; the role of PIM cells; in vitro tests and animal models, especially pigs and rodents; prediction of CARPA in patients and approaches to prevention, as well as various other aspects of C activation and function. The guest editors of this two-part series strongly hope that the compilation of papers on CARPA in these freely accessible issues of the European Journal of Nanomedicine will significantly contribute to greater understanding of this relatively neglected subject and to its further research.

Stopping paclitaxel premedication after two doses in patients not experiencing a previous infusion hypersensitivity reaction.

Paclitaxel-based chemotherapy continues to be an integral component of breast cancer treatment. Prolonged use of paclitaxel may result in repeated doses of premedications that can have unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose of paclitaxel are infrequent and not well characterized. We previously published the results of a small, prospective pilot trial demonstrating the safety and feasibility of discontinuing premedications in patients who received the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction. In this study, we aimed to retrospectively characterize the incidence of rescue medication using this abbreviated premedication regimen in our institution following the publication of the pilot study. Patients with stages I-IV breast cancer who received paclitaxel from January 2011 through June 2013 were screened for eligibility. Patients who did not experience an infusion hypersensitivity reaction with their first or second dose of paclitaxel and discontinued paclitaxel premedication for subsequent doses were included in this analysis. The primary endpoint was to estimate the incidence of rescue medication use for the treatment of paclitaxel infusion hypersensitivity during doses three to six of paclitaxel in the study population. In total, 449 patients received paclitaxel-based chemotherapy for the treatment of breast cancer during the interval time period. After receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction, 234 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. These patients tolerated future paclitaxel doses without severe or life-threatening complications related to infusion hypersensitivity. The majority of patients did not have any symptoms of an infusion reaction, with only two of these patients requiring rescue medication to treat an infusion hypersensitivity reaction with subsequent paclitaxel doses (0.85; 95% confidence interval (CI), 0.10-3.05%). Discontinuation of paclitaxel premedications in breast cancer patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel is not associated with increased rate of rescue medication use for infusion hypersensitivity.

Efficacy and Safety of a Single Dose of Dexamethasone Pre Docetaxel Treatment: the Auckland Experience

ABSTRACT Aim: Auckland City Hospital implemented a change to single intravenous (IV) pre-medication (pre-med) 20mg dose of dexamethasone pre-docetaxel treatment, because of patient (pt) reports of un-wanted side effects of insomnia, reflux-oesophagitis, weight gain with multi-dose regimens, and treatment delays to missed oral pre-med doses of dexamethasone. The new pre-med regimen was based on data by Choudham, J Oncol Pharm Practice, 2011. Methods: An audit tool was developed and data were collected prospectively to identify the impact of symptoms and overall safety in pts receiving this regimen. All pts received outpatient treatment at 3 week intervals. 610 cycles of docetaxel were administered to 160 pts with breast, lung, prostate, head & neck cancer who received the following regimens; FEC-D, TC, TH, TCH, Docetaxel, Docetaxel/Carboplatin±trastuzumab, and TPF. Demographics; 126 female and 34 male, median age 53 years (range 28-78). 134 pts commenced treatment with single pre-med dose of dexamethasone (SD). Multi-day (MD) group comprised various IV/PO dexamethasone regimens ranging from day -1 to day 4 (n = 26). The MD group included prostate pts who received IV 20mg dexamethasone plus prednisone 5mg PO BD continuously. Oedema at/before cycle 3 in SD and MD groups were compared. Results: Infusion hypersensitivity reactions (HSR) occurred in 17 cycles (3%) and in 13 patients (8%). 1 pt experienced a severe reaction, leading to treatment discontinuation. Docetaxel was successfully re-administrated after corticosteroids and anti-histamine in all 16 mild/moderate HSR. No HSR occurred after cycle 4. Only 1 pt experienced a weight gain of >10%. Oedema Cycle 3 Nausea & vomiting Cycle 1 Hand/foot syndrome (HFS) Cycle 1 SD 11% 32% 29% MD 12% 35% 11% Conclusions: Single dose dexamethasone is an acceptable first-line pre-med for docetaxel, with the option of adding in additional doses as required. Rates of oedema, N&V and weight gain were comparable to MD regimens. Infusion HSR rate is low and acceptable. Anecdotally it results in less insomnia and reflux-oesophagitis, though a formal comparison would be required to demonstrate this conclusively with validated tools. HFS appears to be more common. Disclosure: All authors have declared no conflicts of interest.

Management of Hypersensitivity Reactions to Carboplatin and Paclitaxel in an Outpatient Oncology Infusion Center: A 5-Year Review

A high incidence of hypersensitivity reactions (HSR) to carboplatin and Taxol is limiting the use of carboplatin and Taxol. We conducted a 5-year study of all patients with HSR to carboplatin or Taxol to better understand the nature of infusion HSR and success or failure of management plans after the initial HSR. We performed a retrospective chart review of all safety reports from the Massachusetts General Hospital outpatient chemotherapy infusion center between January 2006 and February 2011. All the patients with HSRs to carboplatin or Taxol were identified and included in the final analysis. We reviewed patient characteristics, clinical symptoms, timing, and treatment of the initial HSR, and determined if the patient was rechallenged despite an initial HSR. We identified 152 patients with HSR to carboplatin (n= 45) or Taxol (n= 107). Carboplatin HSR was less severe than Taxol HSR. When comparing the 2 groups, the patients with carboplatin HSRs more commonly described itchy palms and feet, generalized itch, and general urticaria and/or erythema, whereas patients with Taxol HSR more commonly described facial flushing, back pain, and chest or throat tightness (all P < .05). Among 40 patients with mild-to-moderate carboplatin HSRs, only 7 were rechallenged, and 100% tolerated rechallenge without desensitization. None of the patients with severe carboplatin HSRs (n= 5) were rechallenged. Most patients (75%) with Taxol HSRs were rechallenged, and 91% tolerated rechallenge without desensitization; the patients with a severe HSR to Taxol were less likely to be rechallenged. The clinical symptoms and timing of carboplatin HSR are distinct from Taxol HSR. Most patients with carboplatin HSR were not rechallenged, whereas most patients with Taxol HSR were successfully rechallenged.

Cetuximab hypersensitivity infusion reactions: Incidence and risk factors

Cetuximab is a chimeric mouse-human (30:70) IgG1 monoclonal antibody that competitively inhibits the binding of epidermal growth factor. Cetuximab is generally well tolerated; however, hypersensitivity infusion reactions have been reported. The incidence at the University of Oklahoma was currently unknown, though anecdotally high. The purpose of this study was to determine the incidence of severe HIRs and secondarily to determine risk factors for cetuximab-induced hypersensitivity infusion reactions. A retrospective chart review was conducted and included all patients that received cetuximab from 2005 to 2010 at the outpatient clinics of the Oklahoma University Health Sciences Center. A total of 153 patients were included in the analysis. The overall incidence proportion of severe hypersensitivity infusion reactions was 12.4%. Male patients had an increased incidence of severe hypersensitivity infusion reactions compared to female patients (20.6% vs. 5%, p = 0.0036). Current smokers had an increased incidence of severe hypersensitivity infusion reactions of 23.6% when compared to never smokers or former smokers, p = 0.0012. Cervical cancer had a significantly decreased risk of severe hypersensitivity infusion reactions when compared to other tumor types (5.3% vs. 16.7%, p = 0.0387). Multivariate analysis identified risk factors associated with severe HIRs to be: male gender, RR = 3.9, p = 0.01 and current smokers, RR = 3.98, p = 0.0048. Patients at the University of Oklahoma had an increased incidence of severe hypersensitivity infusion reactions when compared to the national average. Male patients and current smokers were found to be at increased risk for severe hypersensitivity infusion reactions in our study. Further investigation is warranted.

Feasibility of stopping paclitaxel premedication after two doses in patients not experiencing a previous infusion hypersensitivity reaction

PurposePaclitaxel-based chemotherapy continues to be an integral component in the treatment of many solid tumors. Prolonged use of paclitaxel may result in repeated doses of premedications and potential unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose are infrequent and not well characterized. We hypothesized that patients whose paclitaxel premedications were discontinued after two doses were unlikely to experience infusion hypersensitivity reactions with subsequent paclitaxel doses.MethodsPatients receiving paclitaxel-based chemotherapy who did not experience an infusion hypersensitivity reaction with their first or second dose had their paclitaxel premedications discontinued. The primary endpoint was to estimate the incidence of rescue medication for the treatment of paclitaxel infusion hypersensitivity during doses 3 to 6 for patients whose paclitaxel premedications had been discontinued.ResultsAfter receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction (any grade), 55 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. None of these patients required rescue medication to treat an infusion hypersensitivity reaction with subsequent doses.ConclusionsIn patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel, discontinuation of paclitaxel premedications may be considered an option without an increased risk of infusion hypersensitivity requiring rescue medication.

Incidence and risk factors of cetuximab-induced hypersensitivity infusion reactions (HIRs).

e19531 Background: The reported national incidence of grade 3/4 hypersensitivity infusion reactions (HIRs) with cetuximab is approximately 3%. The purpose of this study is to estimate the incidence of HIRs at the University of Oklahoma and to identify risk factors for developing HIRs. Methods: This is a retrospective chart review of patients who received cetuximab at the University of Oklahoma from July 2005 to August 2010. The incidence proportion of HIRs in this population was calculated. A reverse step-wise poisson regression analysis was performed on all factors with a bivariate analysis alpha value ≤0.2 and any logical interaction term. The outcome variable for all analyses was either HIR or severe HIR (defined as reaction grade 3 or 4 per CTCAE v.4.03). An alpha value of 0.05 was considered significant. Results: In the specified time period, 153 patients were identified that received cetuximab. Head and neck (50.33%) and cervical cancer (37.25%) were the most common malignancies. Other malignancies included non-small cell lung cancer, colorectal cancer, and ovarian cancer. The overall incidence proportion of severe HIRs was 12.42%. The incidence of severe HIRs in patients with head and neck cancer was 18.18% and the incidence in patients with cervical cancer was 5.26%. The incidence of HIRs in patients with cervical cancer was significantly less than all other malignancies combined (p = 0.0387). According to poisson regression, the risk factors most strongly associated with HIRs included current smoking (RR = 3.6, p=0.0093) and receiving cetuximab as a single agent (RR = 3.2, p=0.0391), after adjusting for cancer type. Conclusions: Regionally, there is an increased incidence of severe HIRs as compared to the national average. Interestingly, the incidence of cervical cancer was significantly lower than head and neck cancer and other malignancies in patients receiving cetuximab. To our knowledge, the incidence of HIRs in patients with cervical cancer has not been reported. Additional risk factors associated with higher incidence of HIRs included current smokers and use of single agent cetuximab. Further investigation is warranted to better predict who is a risk for cetuximab-induced hypersensitivity reactions.

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant &gt; Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&amp;N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&amp;N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&amp;N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

Antitumor necrosis factor therapy for inflammatory bowel disease: A review of agents, pharmacology, clinical results, and safety

Tumor necrosis factor-α (TNFα), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFα activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient to justify recent U.S. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis (RA). Similarly, preliminary controlled trials have suggested efficacy for CDP571 in active CD and RA. Larger controlled trials have demonstrated efficacy for etanercept in RA patients who have failed disease modifying antirheumatic drug (DMARD) therapy leading to FDA approval for RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin's lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti-TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents.

Acute reactions to chemotherapy agents

Acute reactions occur infrequently with chemotherapy agents. However, selected drugs have been known to be associated with severe hypersensitivity reactions, infusion reactions and other acute adverse events. The British Columbia Cancer Agency recently updated the list of selected drugs associated with hypersensitivity reactions and the minimum time that immediate physician coverage is needed.

逐に開始されたモノクローナル抗体による治療 クローン病における抗ＴＮＦ‐α療法

Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP 571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFalpha activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient to justify recent U. S. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis(RA). Similarly, preliminary controlled trials have suggested efficacy for CDP 571 in active CD. And etanercept is effective in patients with active CD similar to RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin's lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti-TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents.