RESUMEN
On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single-arm, multicenter Study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% [95% confidence interval (CI), 35.1-53.2], with complete responses in 12%. Median response duration was 7.6 months (95% CI, 6.3-not estimable). Grade 3-4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Carcinoma de Células Transicionales/tratamiento farmacológico , Aprobación de Drogas , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/secundario , Esquema de Medicación , Humanos , Infusiones Intravenosas , Estudios Multicéntricos como Asunto , Estadificación de Neoplasias , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudencia , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/patologíaAsunto(s)
Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Hipertiroidismo , Hipotiroidismo , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Hipertiroidismo/inducido químicamente , Hipertiroidismo/epidemiología , Hipertiroidismo/terapia , Hipotiroidismo/inducido químicamente , Hipotiroidismo/epidemiología , Hipotiroidismo/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéuticoAsunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Inhibidores de Proteasoma/efectos adversos , Microangiopatías Trombóticas , United States Food and Drug Administration , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/epidemiología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/epidemiología , Inhibidores de Proteasoma/uso terapéutico , Microangiopatías Trombóticas/inducido químicamente , Microangiopatías Trombóticas/epidemiología , Estados Unidos/epidemiologíaRESUMEN
The U.S. Food and Drug Administration (FDA) has approved several vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, including lenvatinib, for thyroid and renal malignancies. Inhibition of the VEGFR signaling pathway impairs angiogenesis and can disrupt wound healing. The objective of this work was to evaluate wound healing complications as a potential safety risk for patients treated with lenvatinib. We searched the FDA Adverse Event Reporting System (FAERS) database for postmarketing reports of wound healing complications with lenvatinib between 13 February 2015 (FDA approval date) and 15 February 2017. The search identified nine FAERS cases of lenvatinib-associated wound healing complications that were not previously reported in the medical literature. Seven cases involved postoperative wound healing complications, such as impaired healing or wound dehiscence. In our case series, the reported time to identification of delayed wound healing from tissue injury or surgery varied over a wide range (4-58 days). The time of initial lenvatinib exposure relative to the tissue injury was also highly varied in our series, which may have influenced the development and detection of impaired healing. FAERS case-level evidence suggests that lenvatinib may have contributed to wound healing complications based on temporality and biologic plausibility. Healthcare professionals should be aware of this safety risk to facilitate prompt recognition and risk mitigation.
Asunto(s)
Farmacovigilancia , Compuestos de Fenilurea/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Cicatrización de Heridas/efectos de los fármacos , Adulto , Anciano , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Estados Unidos , United States Food and Drug Administration , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
BACKGROUND: Gonorrhea is the second most commonly reported notifiable condition in the United States. Infrequently, Neisseria gonorrhoeae can cause disseminated gonococcal infection (DGI). Eculizumab, a monoclonal antibody, inhibits terminal complement activation, which impairs the ability of the immune system to respond effectively to Neisseria infections. This series describes cases of N. gonorrhoeae infection among patients receiving eculizumab. METHODS: Pre- and postmarketing safety reports of N. gonorrhoeae infection in patients receiving eculizumab worldwide were obtained from US Food and Drug Administration safety databases and the medical literature, including reports from the start of pivotal clinical trials in 2004 through 31 December 2017. Included patients had at least 1 eculizumab dose within the 3 months prior to N. gonorrhoeae infection. RESULTS: Nine cases of N. gonorrhoeae infection were identified; 8 were classified as disseminated (89%). Of the disseminated cases, 8 patients required hospitalization, 7 had positive blood cultures, and 2 required vasopressor support. One patient required mechanical ventilation. Neisseria gonorrhoeae may have contributed to complications prior to death in 1 patient; however, the fatality was attributed to underlying disease per the reporter. CONCLUSIONS: Patients receiving eculizumab may be at higher risk for DGI than the general population. Prescribers are encouraged to educate patients receiving eculizumab on their risk for serious gonococcal infections and perform screening for sexually transmitted diseases (STDs) per the Centers for Disease Control and Prevention STD treatment guidelines or in suspected cases. If antimicrobial prophylaxis is used during eculizumab therapy, prescribers should consider trends in gonococcal antimicrobial susceptibility due to emerging resistance concerns.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Infecciones por Neisseriaceae , Adolescente , Adulto , Inactivadores del Complemento/efectos adversos , Femenino , Gonorrea/diagnóstico , Gonorrea/etiología , Humanos , Huésped Inmunocomprometido , Infecciones por Neisseriaceae/diagnóstico , Infecciones por Neisseriaceae/etiología , Adulto JovenRESUMEN
BACKGROUND: Non-meningococcal, non-gonococcal Neisseria spp. are typically commensal and rarely cause invasive disease. Eculizumab is a terminal complement inhibitor that increases susceptibility to meningococcal disease, but data on disease caused by typically-commensal Neisseria spp. are lacking. This series describes postmarketing reports of typically-commensal Neisseria spp. disease in patients receiving eculizumab. METHODS: We searched the FDA Adverse Event Reporting System (FAERS) and medical literature for reports of commensal Neisseria spp. disease in patients receiving eculizumab, from eculizumab U.S. approval (2007) through January 31, 2018. RESULTS: We identified seven FAERS reports (including one case also reported in the literature) of non-meningococcal, non-gonococcal Neisseria disease, including N. sicca (mucosa)/subflava (nâ¯=â¯2), N. cinerea (nâ¯=â¯2), N. sicca (mucosa) (nâ¯=â¯1), N. mucosa (nâ¯=â¯1, with concurrent alpha-hemolytic Streptococcus bacteremia), and N. flavescens (subflava) (nâ¯=â¯1). Four cases had sources of patient immunosuppression in addition to eculizumab. Three patients had sepsis (nâ¯=â¯2) or septic shock (nâ¯=â¯1). Five patients were bacteremic. All patients were hospitalized; the infections resolved with antibiotics. CONCLUSIONS: Our search identified seven cases of disease from typically commensal Neisseria spp. in eculizumab recipients. These findings suggest that any Neisseria spp. identified from a normally sterile site in an eculizumab recipient could represent true infection warranting prompt treatment.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Bacteriemia/inducido químicamente , Infecciones Meningocócicas/inducido químicamente , Infecciones Meningocócicas/microbiología , Neisseria/efectos de los fármacos , Adolescente , Adulto , Bacteriemia/microbiología , Niño , Preescolar , Femenino , Humanos , Masculino , Infecciones Meningocócicas/diagnóstico , Neisseria/patogenicidad , SimbiosisAsunto(s)
Pneumocystis carinii , Neumonía por Pneumocystis/inducido químicamente , Neumonía por Pneumocystis/tratamiento farmacológico , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperidinas , Neumonía por Pneumocystis/mortalidad , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificaciónRESUMEN
Central nervous system hemorrhages are an uncommon but severe complication of hemophilia, occurring in only 2-8% of children with hemophilia. Less than 10% of these CNS hemorrhages are intraspinal. The authors report on their care of an infant with hemophilia A who presented with irritability, meningismus, and decreased spontaneous movement. These symptoms prompted imaging studies, which revealed a spinal epidural hematoma (SEH) extending from C-1 through the cauda equina. The boy was treated with factor replacement and close monitoring. Repeat radiographic imaging 14 days later demonstrated complete resolution, and the patient had returned to his normal baseline status. A literature review in the modern treatment era revealed 24 cases of SEH in children with hemophilia. Of these 24 cases, 11 underwent laminectomy and 13 received conservative treatment. All conservatively treated patients, 5 of whom had presented with weakness, experienced a full recovery. Of the 11 laminectomy patients, 10 presented with weakness and all but 3 experienced full neurological improvement. These 3 patients were notable for having previously undiagnosed hemophilia. An increased index of suspicion facilitates the essential management features of prompt diagnosis and correction of coagulopathies in children who present with SEHs. The authors apply a multidisciplinary approach involving a pediatric hematologist, neurosurgeon, and pediatric intensive care unit to ensure timely correction of the coagulation disorder, maintenance of adequate factor levels, and close hemodynamic and neurological monitoring. Observation with aggressive correction of coagulopathy is a reasonable treatment choice for hemophilic patients presenting with SEH and a stable neurological examination.
Asunto(s)
Antiinflamatorios/uso terapéutico , Conducta Cooperativa , Dexametasona/uso terapéutico , Factor VIII/uso terapéutico , Hematoma Espinal Epidural/diagnóstico , Hematoma Espinal Epidural/terapia , Hemofilia A/complicaciones , Comunicación Interdisciplinaria , Grupo de Atención al Paciente , Compresión de la Médula Espinal/terapia , Terapia Combinada , Esquema de Medicación , Factor VIII/metabolismo , Estudios de Seguimiento , Hematoma Espinal Epidural/sangre , Hemofilia A/sangre , Humanos , Lactante , Infusiones Intravenosas , Imagen por Resonancia Magnética , Masculino , Examen Neurológico , Compresión de la Médula Espinal/sangre , Compresión de la Médula Espinal/diagnóstico , Tomografía Computarizada por Rayos XAsunto(s)
Inhibidores de Factor de Coagulación Sanguínea/sangre , Factor VIIa/uso terapéutico , Defectos del Tabique Interventricular/tratamiento farmacológico , Hemofilia A/tratamiento farmacológico , Inhibidores de Factor de Coagulación Sanguínea/biosíntesis , Ensayo de Actividad Hemolítica de Complemento , Defectos del Tabique Interventricular/sangre , Defectos del Tabique Interventricular/complicaciones , Hemofilia A/sangre , Hemofilia A/complicaciones , Humanos , Lactante , MasculinoRESUMEN
Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are disorders with an overlapping spectrum of congenital anomalies. Mutations in the RAS-MAPK pathway have recently been reported in both of these syndromes, with HRAS mutations characteristic for CS and BRAF and MEK1/2 mutations for CFC. We report on a 3-year-old boy who underwent a cardiac transplant at age 8 months for hypertrophic cardiomyopathy; he was subsequently suspected to have CS. At age 35 months he presented with an intra-cardiac mass that was diagnosed as metastatic hepatoblastoma. Although hepatoblastoma is not known to have an increased frequency in immunocompromised patients, questions were raised as whether the post-transplant immuno-suppressive therapy played a role in tumor development. The patient died shortly thereafter and his post-mortem DNA analysis revealed a MEK1 mutation (Y130C) previously reported in CFC. While CS is associated with increased cancer risk, only a single case of leukemia has been reported in a patient with CFC, making this the first case of a solid tumor reported in a patient with CFC.