Does Rapid Drug Desensitization to Chemotherapy Affect Survival Outcomes?

BACKGROUND AND OBJECTIVE: Hypersensitivity reactions to oxaliplatin may affect prognosis by jeopardizing the timely completion of scheduled treatment sessions or by forcing reactive patients into unexpected changes in therapy. Rapid drug desensitization (RDD) enables these patients to receive their first-choice treatments safely. However, the possible effects of RDD on the efficacy of oxaliplatin have never been studied. Objective: The objective of this study was to evaluate the effect of RDD on survival rates in oxaliplatin-hypersensitive patients. METHODS: We performed a 7-year retrospective study to compare survival between oxaliplatin-hypersensitive cases (patients receiving oxaliplatin by RDD) and nonallergic controls (patients receiving standard oxaliplatin infusions). The primary endpoint of this study was overall survival (OS) in cases and controls (Kaplan-Meier method with log-rank test comparisons). RESULTS: OS was 23.7 months (95%CI, 15.3-30.9) for the 67 cases who underwent 337 RDDs, while for controls (n=143), OS was 34.5 months (95%CI, 21.7-55.5). There were no significant differences between the groups (HR, 1.42; 95%CI, 0.93-2.17; P =.104). CONCLUSIONS: Survival outcomes of oxaliplatin-hypersensitive patients who received oxaliplatin via RDD did not differ significantly from those of control patients who received oxaliplatin via standard administration. Receiving oxaliplatin by means of RDD might be an effective therapeutic alternative for oxaliplatin-hypersensitive patients.

Delving into cornerstones of hypersensitivity to antineoplastic and biological agents: value of diagnostic tools prior to desensitization.

BACKGROUND: Evidence regarding drug provocation test (DPT) with antineoplastic and biological agents is scarce. Our aim was to assess the usefulness of including DPT as a paramount gold standard diagnostic tool (prior to desensitization). METHODS: Prospective, observational, longitudinal study with patients who, during a 3-year period, were referred to the Desensitization Program at Ramon y Cajal University Hospital. Patients underwent a structured diagnostic protocol by means of anamnesis, skin tests (ST), risk assessment, and DPT. Oxaliplatin-specific IgE was determined in oxaliplatin-reactive patients (who underwent DPT regardless of oxaliplatin-specific IgE results). Univariate analysis and multivariate analysis were used to identify predictors of the final diagnosis among several variables. RESULTS: A total of 186 patients were assessed. A total of 104 (56%) patients underwent DPT. Sixty-four percent of all DPTs were negative (i.e., hypersensitivity was excluded). Sensitivity for oxaliplatin-specific IgE (0.35 UI/l cutoff point) was 34%, specificity 90.3%, negative predictive value 45.9%, positive predictive value 85%, negative likelihood ratio 0.7, and positive likelihood ratio 3.5. CONCLUSIONS: These are the first reported data based on more than 100 DPTs with antineoplastic and biological agents (paclitaxel, oxaliplatin, rituximab, infliximab, irinotecan, and other drugs). Implementation of DPT in diagnostic protocols helps exclude hypersensitivity (in 36% of all referred patients), and avoids unnecessary desensitizations in nonhypersensitive patients (30-56% of patients, depending on culprit-drug). Drug provocation test is vital to validate diagnostic tools; consequently, quality data are shown on oxaliplatin-specific IgE and oxaliplatin-ST in the largest series of oxaliplatin-reactive patients reported to date (74 oxaliplatin-reactive patients). Identifying phenotypes and predictors of a diagnosis of hypersensitivity may be helpful for tailored plans.

Hypersensitivity and desensitization to antineoplastic agents: outcomes of 189 procedures with a new short protocol and novel diagnostic tools assessment.

BACKGROUND: Desensitization to antineoplastic agents is becoming a standard of care. Efforts to establish and improve these techniques are being made at many institutions. Our aims are to evaluate a new rapid desensitization protocol designed to be shorter (approximately 4 h) and safer (reducing hazardous drugs exposure risks) and to assess the oxaliplatin-specific immunoglobulin E (IgE) as a novel diagnostic tool. METHODS: Prospective, observational, longitudinal study with patients who, for a 1-year period, suffered reactions to antineoplastic agents and were referred to the Desensitization Program at Ramon y Cajal University Hospital (RCUH). Patients were included or excluded as desensitization candidates after anamnesis, skin testing, risk assessment, and graded challenge. Specific IgE was determined in oxaliplatin-reactive patients. Candidate patients were desensitized using the new RCUH rapid desensitization protocol. RESULTS: Of 189 intravenous rapid desensitizations, 188 were successfully accomplished in the 23 patients who met inclusion criteria for desensitization (of 58 referred patients). No breakthrough reactions occurred in 94% of desensitizations, and most breakthrough reactions were mild. In 10 oxaliplatin-reactive patients, 38 desensitizations were successfully accomplished. Sensitivity for oxaliplatin-specific IgE was 38% (0.35UI/l cutoff point) and 54% (0.10UI/l cutoff point); specificity was 100% for both cutoff points. CONCLUSIONS: In the hands of a Desensitization Program, managed by drug desensitization experts, this new protocol has proven an effective therapeutic tool for hypersensitivity to several antineoplastic agents (oxaliplatin, carboplatin, paclitaxel, docetaxel, cyclophosphamide, and rituximab); moreover, it improves safety handling of hazardous drugs. We report the first large series of oxaliplatin desensitizations. Oxaliplatin-specific IgE determination could be helpful.

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

BACKGROUND: For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. METHODS: This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. RESULTS: Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. CONCLUSION: Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies.

Does rapid drug desensitization to chemotherapy affect survival outcomes?

BACKGROUND: Hypersensitivity reactions to oxaliplatin may affect prognosis by jeopardizing the timely completion of scheduled treatment sessions or by forcing reactive patients into unexpected changes in therapy. Rapid drug desensitization (RDD) enables these patients to receive their first-choice treatments safely. However, the possible effects of RDD on the efficacy of oxaliplatin have never been studied. OBJECTIVE: The objective of this study was to evaluate the effect of RDD on survival rates in oxaliplatin-hypersensitive patients. METHODS: We performed a 7-year retrospective study to compare survival between oxaliplatin-hypersensitive cases (patients receiving oxaliplatin by RDD) and nonallergic controls (patients receiving standard oxaliplatin infusions). The primary endpoint of this study was overall survival (OS) in cases and controls (Kaplan-Meier method with log-rank test comparisons). RESULTS: OS was 23.7 months (95%CI, 15.3-30.9) for the 67 cases who underwent 337 RDDs, while for controls (n=143), OS was 34.5 months (95%CI, 21.7-55.5). There were no significant differences between the groups (HR, 1.42; 95%CI, 0.93-2.17; P =.104). CONCLUSIONS: Survival outcomes of oxaliplatin-hypersensitive patients who received oxaliplatin via RDD did not differ significantly from those of control patients who received oxaliplatin via standard administration. Receiving oxaliplatin by means of RDD might be an effective therapeutic alternative for oxaliplatin-hypersensitive patients

ANTECEDENTES: Las reacciones de hipersensibilidad al oxaliplatino podrían afectar al pronóstico vital cuando fuerzan a los pacientes a cambiar de tratamiento o cuando impiden que lo finalicen. La desensibilización rápida medicamentosa permite que estos pacientes reciban sus tratamientos de primera elección. Sin embargo, no existen datos sobre si la desensibilización rápida medicamentosa podría tener algún efecto sobre la eficacia del oxaliplatino. OBJETIVO: El objetivo de este estudio es evaluar los efectos que la desensibilización rápida medicamentosa al oxalipatlino pudiera tener sobre la eficacia del tratamiento en los pacientes alérgicos al oxaliplatino sometidos a desensibilización. MÉTODOS: Estudio retrospectivo comparando datos de supervivencia, durante un periodo de 7 años, de pacientes alérgicos al oxaliplatino (recibiendo oxaliplatino mediante desensibilización rápida medicamentosa) y controles no alérgicos (recibiendo administraciones estándar de oxaliplatino). La supervivencia global se seleccionó como el criterio de valoración de la eficacia principal y se analizó con el estimador Kaplan-Meier utilizando comparaciones mediante la prueba de log-ran. RESULTADOS: La supervivencia global de los 67 casos fue de 23,7 meses (IC95%, 15,3-30,9), que se sometieron a 337 desensibilizaciones rápidas medicamentosas. Para los 143 controles la supervivencia global fue 34,5 meses (IC95%, 21,7-55,5). No se encontraron diferencias significativamente estadísticas entre ambos grupos (HR, 1,42; IC95%, 0,93-2,17;P=0,104). CONCLUSIONES: Los resultados de supervivencia de los pacientes sometidos a desensibilización no fueron significativamente distintos a los de los controles que recibieron oxaliplatino de forma estándar. La desensibilización se presenta como una alternativa para recibir oxaliplatino de forma eficaz en pacientes alérgicos

The cost of asthma treatment in Spain and rationalizing the expense.

According to Weiss et al. [12], the main providers of asthma care in the United States in 1992 were general and family medicine + internal medicine (46%), pediatrics (19%), allergy (25%), pulmonary medicine (5%), and others (5%). In an overall climate of a shift of referral from primary care to the specialties, specialists will have to provide evidence that their intervention in the control of patients provides truly better clinical and economical outcomes than that of general practitioners. In order to support this hypothesis, we estimated: (1) the development of the costs of medication for asthma in a population of 40 million people (Spain) and (2) the correlation between these costs and the intervention of a specialized attendance. In Spain the annual costs incurring from allergic diseases are estimated to be approximately 1,500 million Euros and, the cost due to asthma alone is about 900-1,200 million Euros. There are two main ways to explain the size of these figures. First, the prevalence of allergic diseases is rising year by year. Second, the relevance of allergology in the control of asthma is often greatly reduced. This has resulted in a reduction in the etiological diagnosis and treatment with specific immunotherapy (SIT). However, SIT is the only specific causal treatment of allergic asthma that is able to modify the natural history of disease or disease progression. So, it is possible to hypothesize that this reduction in a proper etiological diagnosis and treatment could be a cause (among others) of increasing costs.

Patient satisfaction and allergen immunotherapy.

Although health-related quality of life and patient satisfaction are shifting doctors' attention to the patient, the scant number of publications on quality of life questionnaires and allergen immunotherapy contrasts with the quickly growing number of those dealing with this topic and pharmacotherapy. We delivered an original, self-administered patient satisfaction questionnaire to 95 patients (age = 17.7 +/- 7.9 years) suffering from allergic rhinoconjunctivitis (45%) and/or asthma (55%), who had been receiving allergen immunotherapy for more than 1 year (22.2 +/- 10.5 months). The anonymous, voluntary questionnaire was filled in at home; although only 32% were returned, we found no significant differences relating to age, sex, asthma, allergen sensitization or allergen immunotherapy regimen between the source sample and those who replied. Patient expectations, which were scored on a scale of 1 to 10 points, were rather poor, in sharp contrast with patient perception score after treatment (5.4 +/- 1.8 vs. 8.0 +/- 2.0, p < 0.0001). Perception scores did not differ between patients receiving seasonal or perennial allergen immunotherapy, nor did they depend on the duration of treatment. In addition, patient age, sex, diagnosis or sensitization did not appear to influence perceptions. In conclusion, our data suggest that when a voluntary, anonymous questionnaire is used, patients express a poor opinion of allergen immunotherapy, in contrast with high satisfaction after treatment, provided that allergen immunotherapy lasts long enough.

Chemotherapy in mastocytosis: administration issues, hypersensitivity, and rapid drug desensitization

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Sublingual immunotherapy with a standardized cat dander extract: evaluation of efficacy in a double blind placebo controlled study.

BACKGROUND: Little information is available on the clinical efficacy of sublingual immunotherapy (SLIT) using extracts derived from mammalian epithelia. OBJECTIVES: To assess clinical efficacy of cat SLIT based on natural exposure challenge test (NCT). MATERIAL AND METHODS: Fifty cat allergic patients with rhinoconjunctivitis with or without asthma were included in a randomized double blind placebo controlled clinical trial of cat SLIT during 1 year. Twenty-five patients received active treatment and 25 placebo. Sublingual immunotherapy efficacy was assessed by natural exposure challenge to a cat in a cat-room and by skin tests. Airborne Fel d 1 levels, symptom scores and peak expiratory flow (PEF) values were monitored. RESULTS: Thirty-three (66%) out of 50 patients completed the treatment. Fel d 1 content of the maximum concentration was 0.51 microg per ml. During the build up phase, the accumulated dose was 1.7 mug of Fel d 1 and during the entire length of the study was 17.1. No adverse reports were reported. The active group showed a marked reduction (62%) in symptoms during the NCT (P < 0.001) with no changes in placebo group. Active group also showed a reduced PEF response to cat exposure (P < 0.05), and an improvement in skin test reactivity to a standardized cat extract (P < 0.05), without significant changes in placebo group. Mean Fel d 1 exposure during the NCT was 6.2 +/- 2.21 ng/m(3). CONCLUSIONS: The results suggest that the cat SLIT used in this study was able to improve cat allergy based on natural exposure challenge.

Immunotherapy with depigmented glutaraldehyde-polymerized extracts: changes in quality of life.

BACKGROUND: Immunotherapy (IT) with modified allergens reduces allergic rhinitis (AR) symptoms and medications requirements. Improvement of quality of life (QOL) is a key point in the treatment of AR. The aim of this study was to provide evidence of changes related to the patient's QOL (well-being) induced by a modified (depigmented glutaraldehyde-polymerized) therapeutic vaccine and of its safety. MATERIAL AND METHODS: Fifty-three patients with a well-documented clinical history of seasonal AR sensitized to Dactylis glomerata and Olea europaea pollens were included in a randomized clinical trial. Twenty-five patients (Group-A) received a mixture of D. glomerata and O. europaea pollen extracts and 28 patients received placebo (group-C). Any adverse event was recorded and graded in accordance with EAACI guidelines. RQLQ was recorded before the treatment (pollen season 2000) and after 1 year of treatment (pollen season 2001). Dose-response skin prick test with each allergen extract was conducted at baseline and at the end of the study. RESULTS: Each patient received 17 injections during this period. All patients completed the trial and no systemic adverse reactions were recorded. Symptom scores (P<0.001) and medication requirements (P<0.001) were significantly reduced in the IT group during the pollen season. This patient group also experienced greater and statistically significant improvement in overall RQLQ score and in five of the seven domains, all of them surpassing the threshold of 'minimal important difference' of 0.5 points. CONCLUSIONS: Results of this study provided evidence that IT with depigmented, glutaraldehyde-modified allergen extracts was well-tolerated and added beneficial effects to AR treatment in pollen allergic patients eliciting an improvement in QOL enough to justify a change in the patient's treatment.

Immunotherapy in bronchial asthma.

The incidence and prevalence of allergic diseases are constantly increasing in our times. The only etiologic treatments currently available are allergen avoidance and immunotherapy. Many scientific data demonstrate that immunotherapy with allergens is an effective and safe treatment for allergic rhinitis and asthma in adequately selected patients and that it reduces treatment costs for the patients in the long run. Other promising aspects of immunotherapy are its capacity to produce prolonged clinical remissions over time, that it is the only treatment capable of stopping the natural development of the respiratory allergic disease, and the possibility that immunotherapy could avoid evolution to asthma in a significant percent of patients with rhinitis.

Specific IgE antibody response to human insulin in diabetic subjects.

Treatment with heterologous insulin preparations induce insulin antibody formation in most of the patients. A hundred of diabetic individuals in treatment with human insulin (HI) for at least 6 months at the time of the study and without any clinical immunological reaction, were selected in order to study the development of specific IgE antibodies against HI by in vivo and in vitro methods. Serologic specific IgE antibodies to HI were measured by RAST (Pharmacia) and 5 RAST-positive subjects were found. The specificity of these results were confirmed in 4 of the 5 subjects by RAST-inhibition. Thus, the prevalence of specific serologic IgE to HI in our study was 4% (1.1%-9.9%, p < 0.05). Only two of the RAST-positive subjects had cutaneous reactivity to HI by intradermal technique and one of the RAST-negative subjects presented also insulin skin reactivity. HI skin reactivity was found in 3% (0.6%-8.5%, p < 0.05) of the 100 diabetic subjects. These results differ from others obtained with heterologous insulins.

Immunotherapy safety: a prospective multi-centric monitoring study of biologically standardized therapeutic vaccines for allergic diseases.

BACKGROUND: The fear of side-effects has led to strict regulations preventing a more widespread use of specific immunotherapy (SIT) in some countries, in spite of the low risk of systemic reactions (SRs) reported in well-controlled studies. The goal of the study was to carry out a prospective and multi-centric trial to evaluate the safety, risk factors and compliance degree of commercially available SIT. MATERIALS AND METHODS: The study was carried out in 14 allergy departments from Spain. Four-hundred and eighty-eight patients with rhinitis and/or asthma were submitted to treatment with biologically standardized allergen extracts commercially available. They were administered following the European Academy of Allergy and Clinical Immunology guidelines. RESULTS: Four hundred and twenty-three patients (86.7%) completed the treatment and remained under control at the end of the trial. Out of 17,526 administered doses, 17,368 doses (99.1%) were not associated with a reaction. Eighteen patients (3.7%) experienced 53 (0.3% of the doses) SRs. All immediate SRs were mild or moderate and responded well to ordinary treatment measures. There were no fatal reactions, anaphylactic shock or life-threatening reactions. A higher ratio of SRs was found among asthmatic and dust mite allergic patients, although multi-variable logistic analysis did not demonstrate any risk factor associated with SRs. There was also a subgroup of patients at risk for recurrent reactions, and therefore 40% of SRs had been avoided if the maximal number of SRs had been previously limited to only three SRs. CONCLUSIONS: This multi-centric study showed that SIT was a safe treatment with a very good compliance. Future guidelines of SIT should limit the maximal number of SRs.