Asunto(s)
Virus BK , Encéfalo/metabolismo , Encefalitis Viral , Riñón/metabolismo , Linfoma Folicular , Infecciones por Polyomavirus , Trasplante de Células Madre , Infecciones Tumorales por Virus , Aloinjertos , Encéfalo/virología , Encefalitis Viral/sangre , Encefalitis Viral/etiología , Resultado Fatal , Humanos , Riñón/virología , Linfoma Folicular/sangre , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/etiología , Infecciones Tumorales por Virus/sangre , Infecciones Tumorales por Virus/etiologíaRESUMEN
The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
Asunto(s)
Células Clonales/patología , Síndromes Mielodisplásicos/patología , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Metilación de ADN/genética , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/genética , Transducción de Señal/genética , Empalmosomas/genéticaRESUMEN
Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.
Asunto(s)
Nucleótidos de Adenina/administración & dosificación , Arabinonucleósidos/administración & dosificación , Busulfano/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante , Adulto , Anciano , Aloinjertos , Clofarabina , Supervivencia sin Enfermedad , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n=180) and validation sets (n=88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P<0.0001) and donor genotypes of IL6 (rs1800797; P=6.2 × 10(-4)) and IFNG (rs2069727; P=4.4 × 10(-4)) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n=74) vs high risk (scores 1-3; n=106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P<0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P=0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.