RESUMEN
Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.
Asunto(s)
Mielofibrosis Primaria , Humanos , Nitrilos , Mielofibrosis Primaria/inducido químicamente , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , Pronóstico , Pirazoles/efectos adversos , Pirimidinas , Estudios RetrospectivosAsunto(s)
Vacunas contra la COVID-19/efectos adversos , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/inmunología , Vacunas contra la COVID-19/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/patología , RecurrenciaAsunto(s)
Inhibidores de las Cinasas Janus/efectos adversos , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/etiología , Mielofibrosis Primaria/complicaciones , Pirazoles/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Duración de la Terapia , Femenino , Humanos , Italia/epidemiología , Inhibidores de las Cinasas Janus/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Tasa de Mutación , Neoplasias Primarias Secundarias/epidemiología , Nitrilos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/etiología , Pirazoles/uso terapéutico , Pirimidinas , Adulto JovenRESUMEN
α-Bisabolol (BSB) is a plant-derived sesquiterpene alcohol able to trigger regulated cell death in transformed cells, while deprived of the general toxicity in several mouse models. Here, we investigated the involvement of lysosomal and mitochondrial compartments in the cytotoxic effects of BSB, with a specific focus on the BH3-only activator protein BID. We found that BSB particularly accumulated in cancer cell lines, displaying a higher amount of lipid rafts as compared to normal blood cells. By means of western blotting and microscopy techniques, we documented rapid BSB-induced BID translocation to lysosomes and mitochondria, both of them becoming dysfunctional. Lysosomal membranes were permeabilized, thus blocking the cytoprotective autophagic flux and provoking cathepsin B leakage into the cytosol. Multiple flow cytometry-based experiments demonstrated the loss of mitochondrial membrane potential due to pore formation across the lipid bilayer. These parallel events converged on neoplastic cell death, an outcome significantly prevented by BID knockdown. Therefore, BSB promoted BID redistribution to the cell death executioner organelles, which in turn activated anti-autophagic and proapoptotic mechanisms. This is an example of how xenohormesis can be exploited to modulate basic cellular programs in cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Lisosomas/metabolismo , Mitocondrias/metabolismo , Sesquiterpenos Monocíclicos/farmacología , Autofagia/efectos de los fármacos , Bencimidazoles/farmacología , Carbocianinas/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular , Gangliósido G(M1)/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Lisosomas/efectos de los fármacos , Microdominios de Membrana/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Mitocondrias/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacosAsunto(s)
Agranulocitosis , Fibrilación Atrial , Dabigatrán , Estudios de Seguimiento , Humanos , RivaroxabánRESUMEN
A rapid restoration of hemostasis should be regarded as a primary goal for management of critical bleeding, which often represents a life-threatening condition. Among the various therapeutic strategies available in this clinical setting, we aim to summarize in this narrative review the current status on the use of recombinant-activated factor VII and prothrombin complex concentrates. The safety and effectiveness of these hemostatic agents in reversal of the anticoagulant effects of vitamin K antagonists will be also explored. In addition, their role in the management of acute bleeding associated with the newer direct oral anticoagulants dabigatran, rivaroxaban, and apixaban will be analyzed in a dedicated section.
Asunto(s)
Factor VIIa/uso terapéutico , Hemorragia/tratamiento farmacológico , Hemostasis , Hemostáticos/uso terapéutico , Administración Oral , Animales , Anticoagulantes/uso terapéutico , Factores de Coagulación Sanguínea/uso terapéutico , Humanos , Protrombina/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Vitamina K/antagonistas & inhibidoresRESUMEN
Recombinant activated factor VII (rFVIIa) was initially developed to treat bleeding episodes in patients with congenital hemophilia and inhibitors. Due to the initial success in this clinical setting, its use has been extended to other coagulopathies characterized by impaired thrombin generation, i.e. acquired hemophilia, inherited factor VII deficiency and Glanzmann's thrombasthenia, for which it is currently licensed. Extensive research in the last decade has increased our knowledge of the mechanisms utilized by rFVIIa to restore normal hemostasis. This paper reviews current understanding of the mechanisms of action of rFVIIa before summarizing the clinical experience, in terms of safety and efficacy, to date in its licensed indications.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Deficiencia del Factor VII/tratamiento farmacológico , Factor VIIa/farmacología , Hemofilia A/tratamiento farmacológico , Trombastenia/tratamiento farmacológico , Ensayos Clínicos como Asunto , Hemostáticos/farmacología , Humanos , Proteínas Recombinantes/farmacologíaRESUMEN
ABO blood group antigens are complex carbohydrate molecules expressed on the surface of red blood cells and a variety of human cells and tissues. It is well known that ABO blood type exerts a profound influence on hemostasis, being a major determinant of von Willebrand factor (VWF), and consequently factor VIII, plasma levels. In this review, we will focus on the molecular mechanisms underlying the interaction between ABO blood group and VWF in normal and pathological conditions.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/fisiología , Factor de von Willebrand/fisiología , Proteínas ADAM/sangre , Proteína ADAMTS13 , Glicosilación , Hemostasis/fisiología , Humanos , Fenotipo , Enfermedades de von Willebrand/sangre , Factor de von Willebrand/químicaAsunto(s)
Sistema del Grupo Sanguíneo ABO/sangre , Fibrilación Atrial , Enfermedad Arterial Periférica , Trombosis , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/sangre , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/epidemiología , Enfermedad Arterial Periférica/etiología , Estudios Retrospectivos , Trombosis/sangre , Trombosis/epidemiología , Trombosis/etiologíaRESUMEN
Bendamustine proved to be effective for the treatment of chronic lymphocytic leukemia (CLL). However, the relationship between its activity with clinico-biological prognosticators has been addressed only in few studies. We retrospectively evaluated the efficacy of bendamustine, in a real-life contest, on 142 patients, median age 70 years, median number of previous regimens 2 (0-8, 13% previously untreated). Bendamustine was administered for a median number of 4 cycles, in 84% of cases with rituximab. Overall (ORR) and complete response (CRR) rates were 68 and 16.5%, respectively. Multivariate analysis demonstrated a relationship between ORR and number of prior treatments (OR 0.25, 95% CI 0.08-0.71; P = 0.009), del(17p) (OR 0.10, 95% CI 0.03-0.32; P < 0.001) and concomitant rituximab (OR 4.37, 95% CI 1.12-17.04; P = 0.033). The estimated 1- and 2-years overall survival (OS) and progression free survival (PFS) rates were 76, 61, 51, and 26%, respectively. Previous sensitivity to fludarabine (HR 0.36, 95% CI 0.16-0.82), response to bendamustine (HR 0.21, 95% CI 0.10-0.45), and del(17p) (HR 2.18, 95% CI 1.002-4.74) had a prognostic significance in multivariate analysis for PFS, while the number of previous therapies (HR 3.48, 95% CI 1.29-9.38; P = 0.014), concomitant use of rituximab (HR 0.32, 95% CI 0.11-0.93) and response to bendamustine (HR 0.22, 95% CI 0.07-0.66) were significant for OS. Side effects included grade 3-4 neutropenia, infections, thrombocytopenia and anemia which occurred in 40, 14, 14, and 10% of patients, respectively. These results confirm the activity and safety of bendamustine and rituximab combination even in patients with unfavorable clinical and biological features excluding del(17p).
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Clorhidrato de Bendamustina , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/fisiopatología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Compuestos de Mostaza Nitrogenada/administración & dosificación , Compuestos de Mostaza Nitrogenada/efectos adversos , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Rituximab , Análisis de SupervivenciaRESUMEN
Hemophilia B is a recessive X-linked bleeding disorder characterized by deficiency of the coagulation factor IX (FIX). In hemophilia B patients the severity of the bleeding phenotype is related to the degree of the FIX defect. Hemophilia B treatment has improved greatly in the last 20 years with the introduction first of plasma-derived and then of recombinant FIX concentrates. Replacement therapy may be administered through on-demand or prophylaxis regimens, but the latter treatment modality has been shown to be superior in prevention of hemophilic arthropathy and in improvement of patients' quality of life. The purpose of this narrative review is to summarize the current knowledge on treatment strategies for hemophilia B, focusing on recombinant FIX products either clinically used or in development. There is only one rFIX product that is licensed to treat hemophilia B patients; from the analysis of the literature data presented in this review, the authors conclude that this rFIX product has demonstrated an excellent safety profile and excellent clinical efficacy for halting and preventing bleeds in hemophilia B patients. While prophylaxis has emerged as the best therapeutic strategy for such patients because of its ability to prevent hemophilic arthropathy and to improve patients' quality of life, the pharmacokinetically tailored dosing of rFIX is another key point when planning hemophilia B treatment, as it allows optimization of the factor concentrate usage. Further clinical studies are needed to better assess the safety and efficacy (ie, the incidence of adverse reactions and inhibitor development) of newer rFIX products.