RESUMEN
We evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) with induction failure. Between 1993 and 2009, 3324 patients with newly diagnosed AML were enrolled in 5 prospective treatment trials of the German-Austrian AML Study Group. After first induction therapy with idarubicin, cytarabine and etoposide (ICE), 845 patients had refractory disease. In addition, 180 patients, although responding to first induction, relapsed after second induction therapy. Of the 1025 patients with induction failure, 875 (median age 55 years) received intensive salvage therapy: 7+3-based (n=59), high-dose cytarabine combined with mitoxantrone (HAM; n=150), with all-trans retinoic acid (A; A-HAM) (n=247), with gemtuzumab ozogamicin and A (GO; GO-A-HAM) (n=140), other intensive regimens (n=165), experimental treatment (n=27) and direct allo-HCT (n=87). In patients receiving intensive salvage chemotherapy (n=761), response (complete remission/complete remission with incomplete hematological recovery (CR/CRi)) was associated with GO-A-HAM treatment (odds ratio (OR), 1.93; P=0.002), high-risk cytogenetics (OR, 0.62; P=0.006) and age (OR for a 10-year difference, 0.75; P<0.0001). Better survival probabilities were seen in an extended Cox regression model with time-dependent covariables in patients responding to salvage therapy (P<0.0001) and having the possibility to perform an allo-HCT (P<0.0001). FLT3 internal tandem duplication, mutated IDH1 and adverse cytogenetics were unfavorable factors for survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Terapia Recuperativa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.
Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Línea Celular Tumoral , Metilación de ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glutaratos/metabolismo , Código de Histonas/efectos de los fármacos , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Metilación/efectos de los fármacos , Ratones , Terapia Molecular Dirigida , Mutación , Mutación Missense , Células Mieloides/efectos de los fármacos , Mielopoyesis/efectos de los fármacos , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/enzimología , Mutación Puntual , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Ensayo de Tumor de Célula Madre , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
As knowledge of molecular and cellular mechanisms of development and aging is elucidated, the need to understand the relationships among tissues, organ systems, health habits, nutrition, physical activity, and environmental factors on successful aging becomes more explicit. Progress in our understanding of how the immune system functions and responds with other factors, such as aging and nutrition, is spawning significant inroads to achieving a successful old age.