Occurrence Of Hypersensitivity Reactions Research Articles

Infliximab desensitization in patients with inflammatory bowel diseases: a safe therapeutic alternative

Background Hypersensitivity reactions (HSR) to the administration of infliximab (IFX) in Inflammatory Bowel Diseases (IBD) patients are not rare and usually lead to drug discontinuation. We report data on safety and effectiveness of desensitization to IFX in patients with previous HSR. Methods We conducted a retrospective monocentric observational study. Patients for whom a desensitization protocol to IFX was realized after a previous HSR were included. Anti-drug antibodies (ADA) and IFX trough levels at both inclusion and six months after desensitization were collected. Clinical outcomes, including recurrence of HSR were evaluated. Results From 2005 to 2020, 27 patients (Crohn’s Disease: 26 (96%) were included). Desensitization after HSR was performed after a median time of 10.4 months (2.9-33.1). Nineteen (70%) patients received immunosuppressants at time of desensitization. Eight (30%) patients presented HSR at first (n = 2), second (n = 4) or third (n = 2) IFX perfusion after desensitization. None led to intensive care unit transfer or death. Thirteen (48%) had clinical response at 6 months and 8 (29%) were still under IFX treatment two years after desensitization. IFX trough levels and ADA were available for 14 patients at time of desensitization. Most patients (12 out of 14) had ADA at a high level. At 6 months, among the 7 patients with long term response to IFX, 4 presented a decrease of ADA titers and 2 had a significant trough level of IFX. Conclusion IFX desensitization in patients with IBD is a safe therapeutic alternative and represents a potential option for patients refractory to multiple biologics. What is already known? Hypersensitivity reactions to the administration of infliximab is frequent. Occurrence of hypersensitivity reaction, either immediate or delayed, usually leads to permanent drug discontinuation. What is new here? Infliximab desensitization is well tolerated with no hypersensitivity reaction recurrence in 70% of patients. Clinical success at 6 months was of 48% and around a third of patients remained under infliximab therapy two years after desensitization. Antidrug antibodies decreased and infliximab trough levels increased in these patients showing the impact of desensitization on immunogenicity. How can this study help patient care? Infliximab desensitization represents a potential option for patients refractory to multiple biologics who presented hypersensitivity reaction to the drug.

Ranitidine and the incidence of hypersensitivity reactions to paclitaxel: A retrospective cohort study.

Paclitaxel is a commonly used chemotherapeutic agent. To minimize the risk of hypersensitivity reactions (HSRs), which occur in approximately 16–42% of patients, premedication with dexamethasone, clemastine, and ranitidine was standard of care. As of October 2019, ranitidine is no longer available. We compared the risk of HSRs to paclitaxel with and without premedication with ranitidine, hypothesizing that the incidence of HSRs to paclitaxel will be similar. In this retrospective cohort study, all first‐time paclitaxel users in the Groene Hart Hospital were included from January 2019 to August 2020. The primary outcome was the incidence of HSRs, using a Student's t‐test. One‐hundred and eight patients who were first‐time users of paclitaxel in the Groene Hart Hospital met the inclusion criteria. Most patients were treated for breast or ovarian cancer, followed by lung cancer. Analysis of all 836 paclitaxel administrations was performed. Following 349 administrations with ranitidine as premedication, eight HSRs occurred (2.3%), while following 487 administrations without ranitidine, 12 HSRs occurred (2.5%), p‐value of 0.87. An additional analysis on the occurrence of HSRs per patient was performed: 45 patients received premedication in the form of ranitidine, of which eight patients (17.8%) had a HSR. Sixty‐three patients did not receive premedication in the form of ranitidine, of whom 10 (15.8%) had a HSR, p‐value of .80. In conclusion, we found no difference in the incidence of HSRs during paclitaxel infusions between patients who received ranitidine as premedication versus those who did not.

Safety of Inulin and Sinistrin: Combining Several Sources for Pharmacovigilance Purposes.

Introduction: Inulin and its analog sinistrin are fructose polymers used in the food and pharmaceutical industries. In 2018, The French National Agency for the Safety of Medicines and Health Products (ANSM) decided to withdraw products containing sinistrin and inulin due to several reports of serious hypersensitivity reactions, including a fatal outcome. Objective: To assess the safety of inulin and sinistrin use in France. Methods: We searched multiple sources to identify adverse reactions (ARs) to inulin or sinistrin: first, classical pharmacovigilance databases including the French Pharmacovigilance (FPVD) and the WHO Database (VigiBase); second, data from a clinical trial, MultiGFR; third, data regarding current use in an hospital. All potential ARs to inulin or sinistrin were analyzed with a focus on hypersensitivity reactions and relationships to batches of sinistrin. Results: From 1991 to 2018, 134 ARs to inulin or sinistrin were registered in the FPVD or VigiBase. Sixty-three cases (47%) were classified as serious, and 129 cases (96%) were hypersensitivity reactions. We found an association between a batch of sinistrin and the occurrence of hypersensitivity reactions. During the MultiGFR clinical trial, 7 patients (7/163 participants) had an Adverse reaction; of these, 4 were hypersensitivity reactions including one case of grade 4 anaphylactic shock. In the hospital, no ARs were observed. In the literature, ARs to inulin and sinistrin are very rarely reported and mostly benign. Conclusion: Most ARs to inulin and sinistrin are hypersensitivity reactions that appear to be associated with sinistrin batches.

Retrospective cohort study of nanoparticle albumin-bound paclitaxel plus ramucirumab versus paclitaxel plus ramucirumab as second-line treatment in patients with advanced gastric cancer

BackgroundNanoparticle albumin-bound paclitaxel (nab-PTX) has shown non-inferiority to paclitaxel (PTX) as second-line therapy for advanced gastric cancer (AGC) with fewer infusion-related reactions. The efficacy and safety of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial; however, there is no randomized trial comparing this regimen with PTX plus RAM in patients with AGC. This retrospective study aimed to investigate the efficacy and safety of nab-PTX plus RAM versus PTX plus RAM in patients with AGC.MethodsThis study included patients with AGC who received nab-PTX plus RAM from September 2017 to January 2019 or PTX plus RAM from June 2015 to August 2017 as second-line chemotherapy in our hospital.ResultsA total of 113 and 138 patients who received nab-PTX plus RAM and PTX plus RAM, respectively, were analyzed. Median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]: 3.4–4.3) in the nab-PTX plus RAM group and 3.9 months (95% CI: 3.1–4.7) in the PTX plus RAM group (hazard ratio [HR]: 1.08; 95% CI: 0.83–1.40; P = 0.573). Median overall survival (OS) was 10.9 months (95% CI: 9.3–12.7) in the nab-PTX plus RAM group and 10.3 months (95% CI: 8.5–12.0) in the PTX plus RAM group (hazard ratio: 0.82; 95% CI: 0.61–1.10; P = 0.188). In patients with moderate/massive ascites, favorable outcomes for progression-free survival were observed in the nab-PTX plus RAM group compared with the PTX plus RAM group. Although anemia and fatigue (any grade) were more frequent in the nab-PTX plus RAM group, discontinuation of study treatment was not increased in the nab-PTX plus RAM group. There was no occurrence of hypersensitivity reaction in the nab-PTX plus RAM group, while two patients (1.4%) experienced grade 3 hypersensitivity reactions in the PTX plus RAM group.ConclusionsThe combination of nab-PTX plus RAM showed a similar efficacy and safety profile to PTX plus RAM as second-line treatment for patients with AGC.

Suppressive effect upon carboplatin hypersensitivity reaction via pegylated liposomal doxorubicin combination therapy.

Occurrence of hypersensitivity reaction (HSR) in patients having received multiple doses of carboplatin has been reported. Several studies demonstrated reduction of carboplatin-associated HSR with in combination with pegylated liposomal doxorubicin (PLD). The objective of this study was to determine the suppressive effect on carboplatin-induced HSR via combined treatment with PLD within clinical practice. We reviewed the medical records of women with primary or recurrent ovarian, fallopian tube, or peritoneal cancer treated with carboplatin containing regimen at our hospital between January 2009 and March 2019. We compared the incidence of carboplatin-induced HSR among patients who received more than one cycle of PLD plus carboplatin (PLD-C) therapy (i.e., PLD-C group) versus patients who never received PLD-C therapy (non-PLD-C group). A total of 414 women were included in this study (48: PLD-C group, 366: non-PLD-C group). Carboplatin-induced HSR occurred in 34 total patients (8.2%) [1/48 (2.1%) in the PLD-C group and 33/366 (9.0%) in the non-PLD-C group], with a median cycle number of carboplatin administration at onset of HSR being 9. Incidences of carboplatin-induced HSR within the PLD-C versus non-PLD-C group at the 8th, 12th, and 16th cycles of carboplatin administration were 2.2% vs 11.2%, 2.2% vs 28.6%, and 2.2% vs 39.1%, respectively [hazard ratio: 19.2 (95% confidence interval: 9.82-39.4), p < 0.0001]. Based on the data analyzed here, a suppressive effect on carboplatin-induced HSR via combination therapy with PLD was confirmed within clinical practice.

Recent updates of iodinated contrast media hypersensitivity

Previously, immediate reactions to ionic high-osmolar iodinated contrast media (ICM) were regarded as nonimmunological. How ever, despite the use of lower-osmolar ICM, ICM hypersensitivity still occurs in some patients and recent studies suggest that there would be a true allergic response, especially in more severe form. Currently, it is important to identify the sensitized ICM and avoid the agent; however, the usefulness of skin tests and challenge tests has not yet been established, since there are few large-scale studies on them. Although, skin test-negative ICM can be safely used in clinical practice, conflicting results have been reported through various studies, depending on the challenge protocols used. Therefore, standard protocols need to provided. Even if a cul prit agent is not proven by skin tests, its use should be avoided. Reuse of contrast media increases the risk of occurrence of hyper sensitivity reactions. For patients with previous hypersensitivity reactions to contrast media, premedication can help prevent recur rence, but breakthrough in hypersensitivity is not fully achieved by premedication, especially when the previous reaction was a se vere form such as anaphylaxis. Therefore, it is necessary to establish an optimal strategy to choose alternative ICM and premedica tion protocols to prevent recurrence of hypersensitivity reactions to nonionic contrast media. (Allergy Asthma Respir Dis 2020;8:107-113)

Examples of adverse effects after biological therapy.

Psoriasis is one of the most common, chronic skin diseases of as yet unexplained etiopathogenesis. In the recent years it has been proven that an immunological factor plays an important role in the dermatosis onset. This has led to introduction of biological drugs to the disease treatment regimen, which include, inter alia, adalimumab and ustekinumab. New therapy has become an alternative for patients with psoriasis resistant to standard treatment methods as well as an alternative form of treatment in case of occurrence of severe adverse drug reactions after administration of standard treatment. Despite good treatment results the administration of these drugs is associated with the occurrence of adverse reactions. This article presents cases of 4 patients who have been administered biological treatment and in whom there have been observed, inter alia, the occurrence of hypersensitivity reactions in the form of acute urticaria as well as skin lesions of erythema multiforme nature or positive antinuclear antibodies titre. The symptoms experienced by the presented patients posed no direct threat to life and the benefits of the drugs’ administration had a significant therapeutic importance.

Hypersensitivity Reactions to Iodinated Contrast Media: A Multicenter Study of 196 081 Patients.

Background Multicenter studies may be required for establishing guidelines for safe usage of iodinated contrast media (ICM). Purpose To identify the prevalence, patterns, risk factors, and preventive measures for ICM-related hypersensitivity reactions (HSRs). Materials and Methods Between March 2017 and October 2017, a total of 196 081 patients who underwent ICM administration were enrolled from seven participating institutions. The occurrence of HSRs and baseline patient information were recorded. χ2 and Student t test were performed, and logistic regression analyses were used to identify risk factors that predict occurrence and recurrence of HSR. Results Among 196 081 patients (mean age ± standard deviation, 59.1 years ± 16.0; 105 014 men and 91 067 women) who underwent ICM administration, the overall prevalence of HSRs was 0.73% (1433 of 196 081), and severe reactions occurred in 0.01% (17 of 196 081). Conditional logistic regression for patients with HSR (n = 1433) and a control group (1:1 matched group for age, sex, ICM product, and institution) demonstrated that a patient's previous individual history of an ICM-related HSR (adjusted odds ratio [OR], 198.8; P < .001), hyperthyroidism (adjusted OR, 3.6; P = .04), drug allergy (adjusted OR, 3.5; P < .001), and other allergic diseases (adjusted OR, 6.8; P < .001) and a family history of ICM-related HSRs (adjusted OR, 14.0; P = .01) were predictors of HSR occurrence. Logistic regression analysis showed that use of premedication with antihistamine (OR, 0.5; P = .01) and change in the generic profile of ICM (OR, 0.5; P < .001) were preventive against recurrent HSR. Conclusion Family history as well as previous individual history of hypersensitivity reactions (HSRs) to iodinated contrast media (ICM) were risk factors for HSR occurrence, suggesting a potential genetic predisposition. A change in the culprit ICM and premedication with antihistamine are useful for reducing the recurrence of HSRs. © RSNA, 2019 Online supplemental material is available for this article.

Long-term outcomes of enzyme replacement therapy for Taiwanese patients with Mucopolysaccharidosis I

Long-term outcomes of enzyme replacement therapy for Taiwanese patients with Mucopolysaccharidosis I

A structural in silico analysis of the immunogenicity of l-asparaginase from Escherichia coli and Erwinia carotovora

Acute lymphoblastic leukemia (ALL) is a type of cancer with a high incidence in children. The enzyme l-asparaginase (ASNase) constitutes a key element in the treatment of this disease. Four formulations of ASNase from a bacterial source are currently available. However, these formulations are characterized by their high immunogenicity, resulting in the inactivation of the drug, as well as in the occurrence of hypersensitivity reactions in a large number of patients. In this work, we performed an immunoinformatic analysis in order to clarify structural aspects of the immunogenicity of the asparaginase from Escherichia coli and Erwinia carotovora. For this purpose, we performed the prediction of immunogenic and allergenic epitopes in the structure of asparaginases by using the relative frequency of immunogenic peptides for the eight alleles most frequently distributed worldwide. This study showed that there are no significant differences in the level of immunogenicity between the two enzymes, while asparaginase from E. coli presented a higher relative frequency of allergenic epitopes. These results are consistent with previously published reports. However, from a structural point of view, to the best of our knowledge, this is the first report describing the structural determinants that contribute to the hypersensitivity response to this treatment.

Incidence of allergic reactions to Crotalidae polyvalent immune Fab

Context: The administration of Crotalidae polyvalent immune Fab (FabAV) currently requires close observation, so patients can be monitored for hypersensitivity reactions. The objective of this study was to evaluate the occurrence of hypersensitivity reactions to FabAV.Method: This was a retrospective cohort study utilizing data from a statewide poison center database in the United States. Records of all patients envenomated by a rattlesnake and treated with FabAV between January 2002 and December 2014 were evaluated. Patients with acute hypersensitivity reactions were identified, and reactions were evaluated descriptively.Results: A total of 1340 adult and pediatric patients received FabAV during the study period. Of these, 19 (1.4%) patients had a potential reaction to FabAV, with 10 requiring a reduction in infusion rate, but none requiring discontinuation of the antivenom. Reactions occurred during the loading dose (n = 10), maintenance doses (n = 4), or were delayed reactions (n = 6). Symptoms recorded included pruritus (n = 8), hives (n = 8), rash (n = 7), vomiting (n = 7), nausea (n = 6), dyspnea or wheezing (n = 4), diaphoresis (n = 3), throat irritation (n = 2), and mild hypotension (n = 2). One patient was given a concomitant administration of low dose epinephrine infusion until completion of the antivenom course. However, none of the reactions were considered to be life-threatening.Conclusion: FabAV appears to be associated with a low incidence of acute hypersensitivity reactions. Patients may not require placement in a location capable of detecting and rapidly responding to hemodynamic and/or airway issues for FabAV monitoring alone.

Impact of pelvis irradiation on toxicity of further oxaliplatin-based chemotherapy in rectal cancer.

777 Background: Radiotherapy is used in the neoadjuvant setting in majority of rectal cancer patients, while its effect on overall survival is limited mostly to patients with threatened resection margin. Preoperative pelvic irradiation might damage bone marrow. In consequence, relative dose intensity (RDI) and efficacy of further adjuvant or palliative CT might be reduced. The aim of the study was to assess whether radiation damage to the pelvic bone marrow influences the tolerance of further oxaliplatin-based CT. Methods: We have performed the cohort analysis of patients with adenocarcinoma of rectum or colon receiving FOLFOX-4 chemotherapy in adjuvant or palliative setting between 2011-2016. Oxaliplatin relative-dose intensity (RDI) within 8 weeks from the beginning of CT was calculated for each patient. The major factors, which can reduce oxaliplatin RDI, were analyzed independently (hemathological toxicity, neurological toxicity, occurrence of hypersensitivity reactions to oxaliplatin). The data regarding the first disruption of oxaliplatin dose within all planned courses of FOLFOX-4 was also collected. Results: 220 patients met eligibility criteria. 41 of them received neoadjuvant radio(chemo)therapy (study group), the remaining 179 patients were assigned to control group (n = 179). RDI did not differ significantly between irradiated and non-irradiated patients (p = 0.794). There were no statistically significant differences in observed oxaliplatin-related toxicities. The median time between the start of chemotherapy and the first disruption of oxaliplatin administration was also not statistically different between the two groups (p = 0.156). Conclusions: An impact of preoperative radio(chemo)therapy on RDI or tolerance of FOLFOX was not found in rectal cancer.

Comparison of Hypersensitivity Reactions to Carboplatin Retreatment in Gynecologic Cancer Patients between One and Two Hour Infusions: a Randomized Trial Study

Objective:To compare the incidence rate of carboplatin hypersensitivity reactions (HSRs) in gynecologic cancer patients receiving one-hour or two-hour carboplatin retreatment infusions.Setting:A Prospective Randomized Controlled Trial.Methods:Recurrent gynecologic cancer patients 25 to 80-years of age who were scheduled to receive carboplatin retreatment after previously receiving at least six cycles of carboplatin without a history of platinum allergy were invited to enroll. They were randomized to receive either a one-hour or two-hour carboplatin infusion in each cycle. The nurses recorded any occurrence of HSR. Patients who developed carboplatin HSR were discontinued from the study.Results:Forty-five patients were enrolled and randomized to receive either a one-hour carboplatin infusion arm in 69 cycles or a two-hour infusion arm in 67 cycles. Both groups were well balanced regarding median age, body mass index, type of cancer, history of drug allergy, median platinum free interval time, median total number of previous carboplatin cycles, premedication type, regimen and median total dose of carboplatin. Five (3.67%) of the 136 cycles resulted in carboplatin HSR, all of which were Grade 1. Of these, four cycles developed HSR during the one-hour infusion and only one cycle with a two-hour infusion (P=0.37). The onset of carboplatin HSR occurred within 30-105 minutes after infusion start.Conclusion:Extending the carboplatin infusion time to two hours from one hour did not significantly decrease carboplatin HSR.

Prevention of carboplatin-induced hypersensitivity reactions in women with ovarian cancer.

Background Carboplatin-based chemotherapy offers high response rates and improved overall survival for women with epithelial ovarian cancer, but its use is limited by the occurrence of hypersensitivity reactions. To evaluate the efficacy of prophylactic diphenhydramine for hypersensitivity reaction prevention, we reviewed the incidence of hypersensitivity reactions and identified patients at high risk of hypersensitivity reactions. Methods Women receiving ≥6 cycles of carboplatin-based chemotherapy for epithelial ovarian cancer were identified from our institutional database at the Princess Margaret Cancer Centre. Institutional policy was changed in 2009 to introduce diphenhydramine prophylaxis for patients receiving ≥6 cycles of carboplatin. Additional clinical data were abstracted from the patient record. Results Between 2006 and 2012, 450 women received ≥6 cycles of carboplatin-based chemotherapy for epithelial ovarian cancer. Two hundred and ninety-one women received prophylaxis with diphenhydramine. Carboplatin-induced hypersensitivity reactions occurred in 41 of 449 patients (9%). Univariable predictors of carboplatin-induced hypersensitivity reactions included administration of 8 to 10 cycles of carboplatin, history of other drug allergies and a platinum-free interval >12 months. BRCA mutational status was not predictive. In a multivariable analysis, the number of cycles of carboplatin and a platinum-free interval >12 months were independent predictors of hypersensitivity reactions. There was a trend towards diphenhydramine prophylaxis reducing the incidence of hypersensitivity reactions in women with a platinum-free interval compared to continuous delivery; this was most marked when the platinum-free interval was >12 months (n = 64) (OR: 0.2 (95% CI: 0.046-0.83), p = 0.03). Conclusions The administration of diphenhydramine to women who have a platinum-free interval may reduce the risk of hypersensitivity reaction, but prospective evaluation is required.

Histochemical Characterization of Early Response to Cochliobolus sativus Infection in Selected Barley Genotypes

Much effort is being made to breed barley with durable resistance to leaf spot blotch incited by Bipolaris sorokiniana (teleomorph: Cochliobolus sativus). We hypothesized that susceptibility and resistance traits in 11 diverse barley genotypes inoculated with a single C. sativus isolate might specify a range of distinct host cell responses. Quantitative descriptions of interaction microphenotypes exhibited by different barley genotype seedlings after infection with C. sativus are provided. Early oxidative responses occurring in epidermis and mesophyll leaf tissue were monitored by histochemical analysis of H2O2 accumulation at 8, 24, and 48 h after inoculation. Cell wall apposition (CWA) in epidermal cells and hypersensitive reaction (HR) of epidermal or mesophyll tissue were early defenses in both resistant and susceptible genotypes. There were differences in level, duration, and frequency of occurrence for CWA and HR for the different barley genotypes. Occurrence of HR in epidermal cells at post-penetration stages was indicative of compatibility. Patterns of cell responses were microphenotypically diverse between different resistant and susceptible genotypes. This suggests that timing and level of response are key features of microphenotypic diversity that distinguish different functional mechanisms of resistance and susceptibility present in barley.

Incidence, clinical features and management of hypersensitivity reactions to chemotherapeutic drugs in children with cancer

Hypersensitivity reactions (HSRs) may occur in children with cancer during the use of almost all chemotherapeutic drugs. HSRs may also produce a negative impact on treatment intensity and, as a consequence, worsen patients' outcome. The aim of this review is to summarize the incidence and the clinical features of HSRs occurring in children with cancer treated with chemotherapeutic drugs and their impact on treatment efficacy, in order to outline possible adequate prevention and management strategies. Data were collected by searching for relevant studies about incidence, clinical features and management of hypersensitivity reactions that may occur with the use of chemotherapeutic agents in children aged 0-18 years, published from January 1976 to December 2012 in the PubMed database. In children with cancer treated with chemotherapeutic drugs (especially platinum compounds, methotrexate, L-asparaginase), HSRs commonly present with mild/moderate to severe clinical patterns. Multiple factors appear to affect reaction rates, including route, rate of administration, previous exposure, drug form, presence of excipients. The occurrence of hypersensitivity to a chemotherapeutic agent can include the avoidance of re-exposure. For sensitized patients who have derived clinically meaningful benefit from a particular agent, however, continuation of treatment with the agent is desirable. Options may include attempting a trial of desensitization or treatment with a related compound. With the increasing use of cancer chemotherapy agents, hypersensitivity reactions to antineoplastic drugs are commonly encountered. Clinicians must not underestimate the potential risk and occurrence of HSRs in the pediatric population. Knowledge of the different presentations of these reactions can help to develop strategies for the prevention and the management of HSRs in order to ensure treatment outcome, to improve the quality of patient care and to reduce healthcare costs.

Development of an Enzyme-Linked Immunosorbent Assay System to Determine the Presence of Antibodies Specific for Taxane Structures

Taxanes, which are widely used in treatment of numerous cancer types, are well-known to induce hypersensitivity reactions (HSR), especially in the case of paclitaxel. Although the cause of the HSR is commonly thought to be a non-immunological direct effect of the diluent which is used to dissolve paclitaxel, some reports suggest the possibility of the presence of an immunological reaction to the common taxane structure. The aim of this study was to establish a method to determine the presence of anti-taxane antibodies in body fluids of patients who have previously received paclitaxel, in order to estimate the risk of the occurrence of HSR to other taxane compounds, such as docetaxel. To prepare an enzyme-linked immunosorbent assay (ELISA) plate for determining taxanes, 10-deacetylbaccatin III (DAB) was first succinylated by use of dimethylaminopyridine and succinic anhydride in dried pyridine. After the succinylation reaction, three different products were obtained, and these were confirmed as 7-succinoyl DAB (7-DAB), 10-succinoyl DAB (10-DAB), and 7,10-disuccinoyl DAB (7,10-DAB) by (1)H-NMR analysis. Each of these three products was conjugated with bovine serum albumin (BSA), and adsorbed on an ELISA plate. By using a commercially available anti-taxane monoclonal antibody as a model antibody, the detection limit of the anti-taxane antibodies on the 7-DAB-BSA-, 10-DAB-BSA-, and 7,10-DAB-BSA-conjugated ELISA plate was estimated as 0.3, 1 and 10 ng/ml, respectively. The ELISA system established in this study may therefore be useful for estimating the risk of HSR to taxanes in a patient prior to the use of these drugs.

Safety and Efficacy of Panitumumab Therapy After Progression With Cetuximab: Experience at Two Institutions

Cetuximab therapy has been effectively combined with cytotoxic chemotherapy in the first-, second-, and third-line treatment settings. In general, treatment with cetuximab is well tolerated, though it has been associated with the development of hypersensitivity reactions (HSRs). In the case of severe HSRs, further therapy with cetuximab is not possible. In contrast with cetuximab, HSRs have been rarely observed with panitumumab therapy. Currently, panitumumab is indicated for patients with metastatic colorectal cancer (mCRC) with progressive refractory disease, and there is recent evidence documenting its clinical efficacy with cytotoxic chemotherapy in the first-line and second-line settings. However, the safety and efficacy of panitumumab after progression with cetuximab has not been well documented. We present a retrospective review of our experience in treating 15 patients with mCRC who tolerated panitumumab with clinical benefit after failure on cetuximab therapy from November 2006 through September 2008 at the Yale Cancer Center in New Haven, CT and at the Saint Francis Cancer Treatment Center in Grand Island, NE. KRAS status was retrospectively assessed in patients with readily available tumor tissue. All 15 patients were treated with a standard dose of panitumumab 6 mg/kg intravenously every 2 weeks. No patient received premedication therapy. Of the 15 patients treated, 4 received only 2 doses of panitumumab but stopped further therapy because of deterioration in performance status. Of the 11 evaluable patients, we noted minor radiographic responses (Response Evaluation Criteria in Solid Tumors) in 3 patients and stable disease (SD) in 3 other patients after 8 weeks of therapy. Five patients had evidence for progressive disease, and further therapy was stopped. The median duration of SD was 4 months (range, 2-8 months). Among the 11 evaluable patients, 1 patient achieved > 50% reduction in carcinoembryonic antigen (CEA; 112 to 49 U/L), 3 patients had a 25% reduction (59 to 43 U/L, 84 to 61 U/L, and 67 to 42 U/L), and 1 patient had minor reduction in CEA (98 to 83 U/L). All patients tolerated panitumumab well with no occurrence of hypersensitivity reactions. Grade 3/4 toxicities were skin rash in 5 patients and asthenia in 1 patient. The other adverse events observed included grade 1-2 skin rash in 2 patients, grade 2 paronychia in 4 patients, grade 2 hypomagnesemia in 2 patients, and fatigue in 3 patients. One patient had wild-type KRAS, and this individual experienced a minor response to antibody therapy with > 50% reduction in CEA. A second patient was found to have mutant KRAS and, in terms of clinical response, this patient experienced SD for 6 months. The third patient evaluated had mutant KRAS, and this individual was unable to tolerate more than 2 doses and was therefore not evaluable for response. Panitumumab may represent an alternative treatment strategy for patients with refractory mCRC who have experienced failure with standard therapy including cetuximab-based regimens. Our relatively small clinical experience suggests that cetuximab and panitumumab may exert their antitumor activity through different mechanisms; however, further work is required to investigate this potentially interesting issue.

Paclitaxel Repackaged in an Albumin-Stabilized Nanoparticle: Handy or Just a Dandy?

Pharmaceutical excipients have a vital role in drug formulations, a role that has tended to be neglected as evidenced by the lack of regulatory procedures to assess excipient safety outside a new drug application process. In contrast to earlier views, many of the currently used excipients are not inert vehicles, but can exert a range of intrinsic adverse effects and have the potential to cause clinically significant drug interactions. One of the best-studied excipients is polyoxyethylated castor oil (Cremophor El; Basf, Ludwigshafen, Germany), which is being used as a vehicle for the solubilization of a wide variety of hydrophobic drugs, including anesthetics, photosensitizers, sedatives, immunosuppressive agents, and anticancer drugs, such as teniposide and paclitaxel. The amount of Cremophor administered with such drugs averages 5 mL (range, 1.5-10 mL), although paclitaxel is an exception as the amount is much higher per administration, about 25 mL at the recommended dose of 175 mg/m once every three weeks. For this reason, there has been a surge of interest within both industry and academia in Cremophor’s toxicological and pharmacologic profile in the context of chemotherapeutic treatment with paclitaxel. Cremophor presents a number of serious concerns when administered intravenously, including various intrinsic toxic side effects that limit the amount of paclitaxel that can be safely administered. The best known among these is an acute hypersensitivity reaction characterized by dyspnea, flushing, rash, and generalized urticaria, which effects coincide with the use of intravenous paclitaxel formulated in Cremophor. Mostly, the hypersensitivity reaction occurs within the first two courses of paclitaxel and it can be prevented by reducing the infusion rate and by the use of steroids and histamine antagonists, which are the reasons of the general belief that it resembles a nonimmunological reaction, based on degranulation of mast cells or basophils. More recently, it was postulated that complement activation is an important contributing mechanism to the hypersensitivity reactions from paclitaxel due to binding of naturally occurring anticholesterol antibodies to the hydroxyl-rich surface of Cremophor micelles. Despite extensive premedication, the overall frequency of minor reactions is still estimated as high as 44%, with major reactions, necessitating discontinuation of paclitaxel therapy, occurring in approximately 1.5% to 3% of patients. Various studies have also shown that Cremophor alters the pharmacokinetic profile of many drugs administered intravenously, including paclitaxel and agents that might be concomitantly administered, such as doxorubicin, epirubicin, and etoposide, by increasing the systemic exposure to the drug and reducing its systemic clearance. Depending on the dose and intravenous infusion rate, this phenomenon contributes to a distinct nonlinear pharmacokinetic profile of paclitaxel, which is most noticeable with 3-hour infusion regimens in the clinically relevant dose range of 100 mg/m to 225 mg/m. The phase I study reported by Nyman et al in the present issue of the Journal of Clinical Oncology on weekly administrations of a Cremophor-free, albumin-bound nanoparticle formulation of paclitaxel (ABI-007), adds to the current knowledge related to paclitaxel chemotherapy. Although hypersensitivity reactions were not expected and steroid premedication was not intended to be given, 11 patients in the study where premedicated from cycle 1 onward, thereby slightly decreasing the strength of the observation. Yet, the authors could suggest that ABI-007 can be administered as a short, 30-minute infusion on a weekly basis without steroid premedication, with no occurrence of hypersensitivity reactions and with paclitaxel delineating a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 31 NOVEMBER 1 2005

Incidence and risk factors for paclitaxel hypersensitivity during ovarian cancer chemotherapy

Hypersensitivity reaction (HSR) is still a major concern during cancer chemotherapy with paclitaxel. In the present study, we investigated retrospectively the incidence of HSRs to paclitaxel and the risk factors in 105 patients (553 courses) who received adjuvant chemotherapy (paclitaxel and carboplatin) for ovarian cancer. Moderate to severe HSRs that led to cessation or discontinuation of the chemotherapy, including respiratory distress and hypotension, were observed in 14 patients (13.3%) and 16 courses (2.9%), regardless of the use of conventional premedication with glucocorticoid, and histamine H(1) and H(2) antagonists. The incidence of HSRs to paclitaxel in patients with ovarian cancer seemed to be considerably higher than those reported by other investigators in patients with other carcinomas such as non-small-cell lung cancer and breast cancer. Four risk factors were identified: (1) history of mild dermal reactions such as facial flushing and urticaria in previous courses, (2) presence of respiratory dysfunction, (3) obesity (body mass index >25), and (4) postmenopausal at the time of ovariectomy. The incidence of hypersensitivity increased linearly as the number of risk factors increased (r=0.992, P=0.008). It is likely that disappearance of the estrous cycle facilitates the occurrence of HSRs to paclitaxel.