GEDEFO-SEFH management of antineoplastic extravasations survey results.

INTRODUCTION: Extravasation is a potentially severe complication of intravenous administration of antineoplastic drugs. The limited data makes it difficult to develop an optimal management scheme. The objective of this study is to describe the clinical practice in the extravasation management of antineoplastic agents in Spanish centers. METHODS: An online survey was distributed to oncology pharmacists using the email distribution list of the Spanish Society of Hospital Pharmacists. Respondents were surveyed on the standard operational protocol (SOP) of extravasation, tissue damage risk classification, and specific measures of extravasation management. RESULTS: A total of 68 surveys were completed. A specific extravasation SOP was available in 82.4% centers. The pharmacist participates in the authorship (100%) and actively collaborates in extravasation management (76.5%). A tissue damage risk classification based on the three categories was mostly adopted (48.2%) and 73.2% applied specific criteria based on concentration and/or extravasated volume. Extravasation management was mainly performed with the application of physical measures and/or antidotes (91.2%). High variability in the choices of pharmacological and/or physical measures recommended is outstanding. CONCLUSION: The results of this study highlight the involvement of Spanish pharmacists in extravasation management, the application of physical measures and/or pharmacological measures as the method of choice in extravasation management, as well as the existing discrepancies in tissue damage risk classification and management recommendations.

N-Acetylcistein for thrombotic thrombocytopenic purpura: an observational case series study.

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. N-Acetylcysteine (NAC) rapidly degrades ultra-large von Willebrand factor multimers by disrupting the disulfide bonds. We report a series of twelve consecutive patients diagnosed with acquired TTP successfully treated with high-dose NAC (150 mg/kg/day) in combination with plasma exchange and steroids. Eight patients also received rituximab. Two patients presented refractory TTP. All patients achieved a quick clinical response in a median time of 5.5 days after starting NAC and are alive after a median follow-up of 29 months. The treatment was feasible and well tolerated. These data provide further evidence of the potential benefit and safety of adding NAC to the standard of care.

Drug-drug interactions in patients undergoing hematopoietic stem cell transplantation: systematic review.

OBJECTIVE: The present paper provides a systematic review aimed at identifying studies on pharmacological interactions in patients  undergoing hematopoietic stem cell transplantation. Secondary objectives  include a characterization of the prevalence of such interactions and an  investigation of their specific characteristics. METHOD: A search was performed of the terms "drug-drug interaction", "drug interaction", "stem cell transplant", "transplantation  conditioning", and "conditioning regimen" in the PubMed database, and of  the terms "drug interaction", "stem cell transplantation", and  "transplantation conditioning" in the Embase database. Only results  directly related to the objective of the review were selected. Studies in  humans published between January 2000 and November 2020, written in  English or Spanish, were prioritized. RESULTS: The review identified two groups of studies: epidemiological studies and studies analyzing interactions between specific drugs. The 10 epidemiological studies selected, which showed a prevalence of interactions between 60 and 100%, mainly used the Micromedex®  database, focused on pharmacokinetic interactions involving azole  antifungals.Results were highly heterogeneous. Of the 52 drug interaction studies reviewed, the majority were pharmacokinetic and focused primarily on the interactions of azole antifungals with calcineurin inhibitors. Some  studies described the possible relationship between the interactions and  specific adverse reactions or deaths from adverse events. CONCLUSIONS: The prevalence of drug-drug interactions in patients  undergoing hematopoietic stem cell transplantation is high, with  heterogeneous results both in terms of prevalence and of the profile of the interactions resulting from the use of disparate study designs and  databases. The most common factor associated with drug-drug  interactions was the number of drugs administered. Studies evaluating  drug-drug interactions are mostly pharmacokinetic and focus mainly on  azole antifungals and calcineurin inhibitors. It would be important to unify  the criteria followed in epidemiological studies to obtain results that may  help establish risk reduction strategies and conduct a more in-depth  investigation into the pharmacodynamic mechanisms involved and into the interactions between other drugs frequently used in patients undergoing  transplantation, including those recently introduced in our therapeutic  arsenal.

Objetivo: El objetivo principal de este trabajo es identificar, mediante revisión bibliográfica sistemática, los estudios sobre  interacciones farmacológicas en pacientes sometidos a trasplante de  progenitores hematopoyéticos. Los objetivos secundarios son describir la  prevalencia de dichas interacciones y extraer información de interacciones  fármaco-fármaco concretas.Método: Búsquedas en PubMed con los términos "drug-drug interaction", "drug interaction", "stem cell transplant", "transplantation  conditioning" y "conditioning regimen" y en Embase "drug interaction",  "stem cell transplantation" y "transplantation conditioning", seleccionando  aquellos resultados relacionados directamente con el objetivo de la  revisión. Se priorizaron estudios en humanos, en idiomas inglés y español, entre enero de 2000 y noviembre de 2020.Resultados: La revisión identificó dos grupos de estudios  epidemiológicos y de análisis de interacciones entre fármacos concretos).  Los 10 estudios epidemiológicos mostraron una prevalencia de  interacciones entre el 60% y el 100%, la base de datos más utilizada fue  Micromedex®, el mecanismo farmacocinético y los fármacos más  implicados fueron los antifúngicos azólicos, con resultados muy  heterogéneos. Los 52 estudios de interacciones entre fármacos fueron casi todos farmacocinéticos y se centraron fundamentalmente en las  interacciones de antifúngicos azólicos e inhibidores de la calcineurina. Algunos estudios describieron la posible relación entre interacciones y  reacciones adversas concretas o muertes por efectos adversos.Conclusiones: La prevalencia de interacciones en pacientes sometidos a  trasplante de progenitores hematopoyéticos es elevada, siendo los  esultados heterogéneos, tanto en prevalencia como en el perfil de las  interacciones. En ello repercuten las diferencias en los diseños de los  estudios y en las bases de datos utilizadas. Entre los factores relacionados  con el riesgo de que se produzcan interacciones farmacológicas destaca el  elevado número de fármacos administrados. Los estudios que evalúan las  interacciones fármaco-fármaco son casi todos farmacocinéticos y se  centran mayoritariamente en antifúngicos azólicos e inhibidores de la  calcineurina. Sería importante unificar los criterios de los estudios  epidemiológicos para obtener resultados que ayuden a establecer  estrategias de reducción de riesgo, investigar en mayor profundidad las  interacciones de mecanismo farmacodinámico, las interacciones entre  otros fármacos de uso frecuente en el trasplante y en aquellos de  introducción reciente en el arsenal terapéutico.

Predictive biomarkers of response to immune checkpoint inhibitors.

OBJECTIVE: The present paper provides a literature review aimed at  identifying the tumor-dependent factors capable of influencing a  subject's response to immune checkpoint inhibitors, with a special  emphasis on those that may act as predictive biomarkers. METHOD: A search was performed of the terms biomarkers, PD-1, PD- L1, CTLA-4, and checkpoint inhibitors in the title and the abstract of the  records in the PubMed database. Articles including relevant information  on the tumor-dependent factors capable of influencing a subject's  response of immune checkpoint inhibitors were selected. Priority was  given to studies in humans (clinical trials and reviews) published  between January 2015 and June 2019, in English and Spanish. Results: The literature review exposed the complex relationship that xists between the immune system and tumors. It also revealed that the factors capable of influencing a subject's response to immune  checkpoint inhibitors are multiple, heterogeneous and ill understood,  which makes it difficult to obtain simple and/or universal predictive  biomarkers. CONCLUSIONS: The only biomarkers currently used in clinical practice include the expression of the programmed cell death ligand-1  and microsatellite instability/ deficient DNA mismatch repair, but their  usefulness is limited. Tumor mutational burden and gene signatures  associated to IFN-γ could become useful biomarkers once determination techniques and cutoff points are systematized.

Objetivo: El objetivo del presente trabajo es identificar mediante  revisión bibliográfica los factores dependientes del tumor que  condicionan la respuesta a los inhibidores de los puntos de control  inmunitario, incidiendo especialmente en aquellos que se postulan como posibles biomarcadores predictivos.Método: Búsquedas en Pubmed con los términos biomarkers, PD-1,  PD­L1, CTLA-4, checkpoint inhibitors, en el título o el abstract,  seleccionando aquellos que incluyeran información relevante sobre  factores tumorales que condicionan la respuesta a los inhibidores de los  puntos de control inmunitario. Se priorizaron estudios en humanos  (ensayos clínicos y revisiones) publicados entre enero de 2015 y junio  de 2019, en idiomas inglés y español.Resultados: La revisión pone de manifiesto las complejas relaciones entre sistema inmunitario y tumor, con factores que influyen  en la respuesta a los inhibidores de los puntos de control inmunitario  variados, y aun poco conocidos, lo cual dificulta la obtención de  biomarcadores predictivos sencillos y/o universales.Conclusiones: Actualmente los únicos biomarcadores utilizados en práctica clínica, en algunos escenarios, son la expresión del ligando  del receptor de muerte celular programada-1 y la inestabilidad de  microsatélites/deficiencias en las enzimas de reparación de los  apareamientos erróneos durante la replicación del ácido  desoxirribonucleico, aunque su utilidad es limitada. La carga mutacional  y las firmas génicas asociadas a interferón gamma se postulan como  biomarcadores útiles, una vez sistematizadas las técnicas de  determinación y los puntos de corte.

Observational study of drug-drug interactions in oncological inpatients.

OBJECTIVE: To determine the prevalence of potential clinically relevant drug- drug interactions in adult oncological inpatients, as well as to describe the most  frequent interactions. A standard database was used. METHOD: An observational, transversal, and descriptive study including patients  admitted to the Oncology Service of a reference hospital. All prescriptions were  collected twice a week during a month. They were analysed using Lexicomp®  database, recording all interactions classified with a level of risk: C, D or X. RESULTS: A total of 1 850 drug-drug interactions were detected in 218  treatments. The prevalence of treatments with at least one clinically relevant  interaction was 95%, being 94.5% for those at level C and 26.1% for levels D  and X. The drugs most commonly involved in the interactions detected were  opioid analgesics, antipsychotics (butyrophenones), benzodiazepines,  pyrazolones, glucocorticoids and heparins, whereas interactions with  antineoplastics were minimal, highlighting those related to paclitaxel and  between metamizole and various antineoplastics. CONCLUSIONS: The prevalence of clinically relevant drug-drug interactions rate  was very high, highlighting the high risk percentage of them related to level of  risk X. Due to the frequency of onset and potential severity, highlighted the  concomitant use of central nervous system depressants drugs with risk of  respiratory depression, the risk of onset of anticholinergic symptoms when  combining morphine or haloperidol with butylscopolamine, ipratropium bromide  or dexchlorpheniramine and the multiple interactions involving metamizole.

Objetivo: Determinar la prevalencia de potenciales interacciones clínicamente relevantes en pacientes oncológicos adultos ingresados, mediante una base de datos de uso habitual, así como describir las interacciones más frecuentes.Método: Estudio observacional, transversal, descriptivo, que incluye pacientes ingresados a cargo del Servicio de Oncología de un hospital de referencia. Se recopilaron todas las prescripciones dos veces por semana durante un periodo de un mes. Se analizaron mediante la base de datos Lexicomp®, registrando todas las interacciones clasificadas con un nivel de riesgo C, D o X.Resultados: Se detectaron un total de 1.850 interacciones farmacológicas en  218 tratamientos. La prevalencia de tratamientos con al menos una interacción  clínicamente relevante fue de un 95%, siendo del 94,5% para las de nivel C y  del 26,1% para los niveles D y X. Los analgésicos opioides, antipsicóticos  (butirofenonas), benzodiacepinas, pirazolonas, glucocorticoides y heparinas  fueron los fármacos más comúnmente involucrados en las interacciones  detectadas, mientras que las interacciones con antineoplásicos fueron mínimas,  destacando las relacionadas con paclitaxel y entre metamizol y diversos  antineoplásicos.Conclusiones: La prevalencia de tratamientos con interacciones farmacológicas clínicamente relevantes fue muy elevada, destacando el elevado  porcentaje de riesgo X. Por la frecuencia de aparición y potencial gravedad  destacan el uso concomitante de fármacos depresores del sistema nervioso  central con riesgo de depresión respiratoria, el riesgo de aparición de síntomas  anticolinérgicos cuando se combinan morfina o haloperidol con  butilescopolamina, bromuro de ipratropio o dexclorfeniramina, así como las  múltiples interacciones que implican al metamizol.

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological adult patients.

OBJECTIVE: To assess the toxicity of a standardized triple intrathecal chemotherapy in onco- hematological adult patients and to establish risk factors of toxicity. METHOD: Observational and prospective study of standardized triple intrathecal chemotherapy administrations in onco-hematologic adult patients for 18 months. RESULTS: There were some adverse events in 39.3% of the 56 administrations registered. 96.7% of the events were grade 1-2 and only 1 event was grade 3. The lower age of the patient and the greater difference between the administered drug volume and cerebrospinal fluid removed volume were shown as risk factors for toxicity. CONCLUSIONS: The administration of standardized triple intrathecal chemotherapy was related to a low frequency of toxicity and most of adverse events were mild-moderate. The detection of adverse effects was significantly greater in young adults and in those administrations where the difference between cerebrospinal fluid remove volume and the administered drug was greater.

Objetivo: Evaluar la toxicidad asociada a la administración de quimioterapia triple intratecal estandarizada en pacientes onco-hematológicos adultos e identificar los factores de riesgo asociados.Método: Estudio observacional y prospectivo de las administraciones de quimioterapia triple intratecal estandarizada administradas a pacientes onco-hematológicos adultos durante 18 meses.Resultados: Se registró algún evento adverso en el 39,3% de las 56 administraciones registradas. El 96,7% de los eventos fueron grado 1-2 y solo 1 evento fue grado 3. La menor edad del paciente y la mayor diferencia entre el volumen administrado y el líquido cefalorraquídeo extraído se mostraron como factores de riesgo de toxicidad.Conclusiones: La administración de quimioterapia triple intratecal estandarizada estuvo relacionada con una baja frecuencia de toxicidad y la mayoría de los eventos adversos fueron de gravedad leve-moderada. La detección de efectos adversos fue significativamente mayor en adultos jóvenes y en aquellas administraciones en las que la diferencia entre el volumen de líquido cefalorraquídeo extraído y de fármaco administrado fue mayor.

Practical aspects of the use of intrathecal chemotherapy.

INTRODUCTION: Intrathecal chemotherapy is frequently used in clinical practice for treatment and prevention of neoplastic meningitis. Despite its widespread use, there is little information about practical aspects such as the volume of drug to be administered or its preparation and administration. OBJECTIVE: To conduct a literature review about practical aspects of the use of intrathecal chemotherapy. MATERIALS: Search in PubMed/ Medline using the terms "chemotherapy AND intrathecal", analysis of secondary and tertiary information sources. RESULTS: The most widely used drugs in intrathecal therapy are methotrexate and cytarabine, at variable doses. One of the aspects with higher variability among different studies is their potential combination with a glucocorticoid, the specific corticoid selected and its dose. The efficacy and toxicity of the different combinations have not been compared. Regarding preparation, it is worth highlighting the recommendation to adjust pH and osmolarity to the physiological range, with the aim of improving tolerability. The volume of administration can influence distribution, and recommendated range is between 5 and 12 mL. Overall, it is recommended to extract a similar volume of cerebrospinal fluid before administration. The position of the patient during and after administration can have an impact on distribution and toxicity; lateral decubitus or sitting position is recommended in the first case, and prone and/ or supine position in the second one. Most publications don't explain how the treatment has been prepared or administered, and the lack of standardization could affect results. CONCLUSIONS: There is a great variability in practice when using intrathecal chemotherapy, despite being an effective therapy, accepted by all international groups. This uncertainty is not li mited to the drugs and doses administered, but it also includes the manner of preparation and the administration technique. The heterogeneity in clinical practice can influence the efficacy and toxicity of this therapy.

Introducción: La quimioterapia intratecal es utilizada frecuentemente, en la practica clinica, para el tratamiento y prevencion de la meningitis neoplasica. A pesar de su uso extendido, existe poca informacion acerca de aspectos practicos tales como el volumen de farmaco a administrar o la forma de preparacion y administracion. Objetivo: Realizar una revision de la literatura acerca de aspectos practicos de la utilizacion de la quimioterapia intratecal. MATERIAL: Busqueda en PubMed/Medline utilizando los terminos "chemotherapy AND intrathecal", analisis de fuentes de informacion secundarias y terciarias. Resultados: Los farmacos mas utilizados en terapia intratecal son metotrexato y citarabina, con dosis variables. La asociacion o no con un glucocorticoide, el corticoide concreto seleccionado y su dosis es uno de los aspectos con mayor variabilidad entre distintos estudios. No se han comparado la eficacia y toxicidad de las distintas combinaciones. En la preparacion destaca la recomendacion de ajustar pH y osmolaridad al rango fisiologico, con el objetivo de mejorar la tolerancia. El volumen de administracion puede influir en la distribucion, oscilando las recomendaciones entre 5-12 mL. En general, se aconseja extraer previamente un volumen de liquido cefalorraquideo similar. La posicion del paciente durante y tras la administracion puede influir en la distribucion y la toxicidad; se recomienda el decubito lateral o la sedestacion, en el primer caso, y el decubito prono y/o supino, en el segundo. La mayoria de las publicaciones no indican como se ha preparado o administrado el tratamiento, y la falta de estandarizacion podria afectar a los resultados. Conclusiones: Existe gran variabilidad en la practica a la hora de utilizar la quimioterapia intratecal, a pesar de ser una terapia efectiva asumida por todos los grupos internacionales. La incertidumbre no se limita a los farmacos y dosis administradas, sino que se extiende a la forma de preparacion de las mezclas y la tecnica de administracion. La heterogeneidad en la practica clinica puede influir en la efectividad y toxicidad de esta terapia.

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological pediatric patients.

Background The administration of triple intrathecal therapy with methotrexate, cytarabine and a corticosteroid for the prophylaxis and treatment of neoplastic cell infiltration in the central nervous system in hematological malignancies is a widespread practice. There is limited information available about its toxicity profile. Several factors related to intrathecal preparation can affect toxicity. Thus, it was decided to standardize intrathecal chemotherapy, trying to obtain the best toxicity profile. Objective To assess the toxicity of a standardized triple intrathecal chemotherapy in oncohematological pediatric patients and to establish risk factors of toxicity. Setting Oncohematological pediatric unit from a tertiary hospital in Spain. Methods Prospective, descriptive and observational study in which all the administrations of standardized triple intrathecal chemotherapy in pediatric patients were registered. Main outcome measure Toxicity of the intrathecal therapy was recorded and possible risk factors were assessed. Results A total of 269 administrations of triple intrathecal chemotherapy were registered in 41 patients (mean age = 6.6 ± 3.9 years). In 16.7% of the procedures, an adverse event was reported (total number of adverse events = 61). 47.5% were grade 1, 47.5% grade 2 and 4.9% grade 3. The administration of intrathecal chemotherapy inpatient and patient age ≥3 years were risk factors of toxicity in the multivariate analysis. Conclusions The administration of standardized triple intrathecal chemotherapy is related to a low frequency of toxicity and most of the adverse events registered were mild/moderate. The detection of adverse effects was significantly greater in children with age greater than or equal to three years and in hospitalized patients.

Stability of four standardized preparations of methotrexate, cytarabine, and hydrocortisone for intrathecal use.

INTRODUCTION: Intrathecal administration of methotrexate, cytarabine, and hydrocortisone is commonly used to treat and prevent central nervous system involvement in leukemias and lymphomas. The use of intrathecal solutions with pH and osmolarity values close to physiologic range of CSF (pH 7.31-7.37, osmolarity 281-306 mOsm/kg) and standardization of the methotrexate, cytarabine, and hydrocortisone doses in children and adults based on age is highly recommended. Stability studies of standardized intrathecal mixtures under these conditions have not yet been published. OBJECTIVE: The purpose of this study was to evaluate the physical and chemical stabilities of four standardized mixtures of methotrexate, cytarabine, and hydrocortisone stored at 2-8℃ and 25℃ up to 7 days after preparation. METHODS: Four different standardized intrathecal mixtures were prepared and stored at 2-8℃ and 25℃ and protected from light. Triplicate samples were taken at different times and precipitation, appearance, color, pH, and osmolarity were analyzed. Methotrexate, cytarabine, and hydrocortisone concentrations were measured using a modified high-performance liquid chromatography method. RESULTS: No variation greater than 10% of the initial concentration of methotrexate, cytarabine, and hydrocortisone was observed in any of the four standardized mixtures for the 7 days of study when stored at 2-8℃ and 25℃ and protected from light. The osmolarity of the four preparations was within the physiologic range of CSF for 7 days at both 2-8℃ and 25℃. The pH values close to the physiologic range of CSF were stable for 48 h at 25℃ and for 120 h at 2-8℃. CONCLUSIONS: Triple intrathecal standardized preparations of methotrexate, cytarabine, and hydrocortisone sodium phosphate are physically and chemically stable at 25℃ for 48 h and at 2-8℃ for 5 days.

Clonazepam for seizure prophylaxis in adult patients treated with high dose busulfan.

BACKGROUND: Due to their favorable toxicity profile and lack of interactions, benzodiazepines have been proposed as prophylaxis of busulfan induced seizures. Although they are broadly used in pediatric patients, the experience in adults is limited. OBJECTIVE: To describe the effectivity for seizure prophylaxis of the fixed 1 mg every 8 h (q8h) i.v. clonazepam dosing in adult patients receiving high dose i.v busulfan, as part of the hematopoietic progenitors transplant conditioning regimen. METHODS: Retrospective, observational study, from January 2008 to June 2012. Patients over 15 years old that had received high dose busulfan and prophylaxis with 1 mg q8h i.v. clonazepam from 12 h before the first dose of busulfan to 24 h after the last one were selected. The primary endpoint was the occurrence of seizures until 72 h after finishing conditioning. RESULTS: Thirty-three patients, 13 female and 20 male, median age 48, were included. Autologous transplant was performed in 17 patients and allogeneic in 16. Busulfan dose was 3.2 mg/kg every 24 h with a variable duration of 2-4 days. No seizures were recorded. CONCLUSION: The 1 mg q8h i.v. clonazepam fixed schedule is easily administered and is effective for the prevention of high dose busulfan induced seizures in adult patients.