RESUMEN
Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.
Asunto(s)
Anemia Aplásica , Hematología , Trasplante de Células Madre Hematopoyéticas , Pancitopenia , Adulto Joven , Humanos , Anciano , Anemia Aplásica/terapia , Inmunosupresores/uso terapéutico , Ciclosporina/uso terapéutico , Trastornos de Fallo de la Médula Ósea/tratamiento farmacológico , Donante no Emparentado , Pancitopenia/tratamiento farmacológicoRESUMEN
To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mielomonocítica Crónica , Leucemia Mielomonocítica Juvenil , Adolescente , Adulto , Anciano , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Leucemia Mielomonocítica Crónica/diagnóstico , Leucemia Mielomonocítica Crónica/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow-up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ-C30 and EQ-5D-5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85-100 g/l) with liberal thresholds (105 g/l, maintaining 110-125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention-to-treat population was 86% (95% confidence interval 75-94%) and 99% (95-100%) for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient-centred outcomes.
Asunto(s)
Transfusión de Eritrocitos , Síndromes Mielodisplásicos/terapia , Calidad de Vida/psicología , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Masculino , Pacientes AmbulatoriosRESUMEN
SF3B1, SRSF2, and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34+ cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology.
Asunto(s)
Mutación , Síndromes Mielodisplásicos/genética , Factores de Empalme de ARN/genética , Empalme del ARN , Empalmosomas/genética , Estudios de Cohortes , Reparación del ADN , Regulación de la Expresión Génica , Humanos , Síndromes Mielodisplásicos/epidemiología , Fosfoproteínas/genética , Factores de Empalme Serina-Arginina/genética , Factor de Empalme U2AF/genética , Análisis de SupervivenciaRESUMEN
Anaemia is the commonest cytopenia seen in patients with myelodysplastic syndrome (MDS), and the majority of patients will require transfusion support at some point. Blood transfusions are rich in iron, which leads to the accumulation of body iron over time. It is accepted that this ultimately causes end organ damage and may impact on both morbidity and mortality. In addition, recent data has increased our interest in the subject with regard to the potential impact on stem cell transplant outcome and an anti-leukaemic effect of iron chelation therapy. There is still debate over which patients should receive iron chelation therapy, but the emergence of new diagnostic and prognostic markers in MDS may help decision making in the clinic setting.
Asunto(s)
Terapia por Quelación/métodos , Quelantes del Hierro/uso terapéutico , Síndromes Mielodisplásicos/terapia , Medicina Basada en la Evidencia/métodos , Humanos , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Pronóstico , Reacción a la TransfusiónAsunto(s)
Síndromes Mielodisplásicos/terapia , Adulto , Anemia/complicaciones , Anemia/terapia , Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Transfusión Sanguínea/métodos , Decitabina/uso terapéutico , Manejo de la Enfermedad , Hematínicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Hemorragia/complicaciones , Hemorragia/terapia , Humanos , Quelantes del Hierro/uso terapéutico , Síndromes Mielodisplásicos/complicaciones , Neutropenia/complicaciones , Neutropenia/terapia , Trombocitopenia/complicaciones , Trombocitopenia/terapiaRESUMEN
Mutations of CSNK1A1, a gene mapping to the commonly deleted region of the 5q- syndrome, have been recently described in patients with del(5q) myelodysplastic syndromes (MDS). Haploinsufficiency of Csnk1a1 in mice has been shown to result in ß-catenin activation and expansion of haematopoietic stem cells (HSC). We have screened a large cohort of 104 del(5q) MDS patients and have identified mutations of CSNK1A1 in five cases (approximately 5%). We have shown up-regulation of ß-catenin target genes in the HSC of patients with del(5q) MDS. Our data further support a central role of CSNK1A1 in the pathogenesis of MDS with del(5q).
Asunto(s)
Transfusión Sanguínea , Deferasirox , Síndromes Mielodisplásicos , Anciano , Anciano de 80 o más Años , Deferasirox/administración & dosificación , Deferasirox/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Rabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age- and disease severity-matched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P = .009). Transplant-free survival was 52% for rATG and 76% for hATG (P = .002). On multivariate analysis, rATG (hazard ratio = 3.9, P = .003) and age more than 37 years (hazard ratio = 4.7, P = .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848.
Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Suero Antilinfocítico/uso terapéutico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Suero Antilinfocítico/efectos adversos , Linfocitos T CD4-Positivos/efectos de los fármacos , Ciclosporina/efectos adversos , Quimioterapia Combinada , Europa (Continente) , Femenino , Caballos , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Conejos , Análisis de Supervivencia , Adulto JovenRESUMEN
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.
Asunto(s)
Anemia Aplásica , Hematología , Adulto , Suero Antilinfocítico , Humanos , Recuento de Plaquetas , Estudios RetrospectivosAsunto(s)
Autoantígenos/biosíntesis , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Eritroblastos/metabolismo , Leucina/farmacología , Síndromes Mielodisplásicos , Biosíntesis de Proteínas/efectos de los fármacos , Ribonucleoproteínas/biosíntesis , Proteínas Ribosómicas/biosíntesis , Autoantígenos/genética , Células Cultivadas , Eritroblastos/patología , Femenino , Humanos , Masculino , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Biosíntesis de Proteínas/genética , Ribonucleoproteínas/genética , Proteínas Ribosómicas/genética , Antígeno SS-BRESUMEN
Interstitial deletion of chromosome 5q is the most common chromosomal abnormality in myelodysplastic syndromes. The catalogue of genes involved in the molecular pathogenesis of myelodysplastic syndromes is rapidly expanding and next-generation sequencing technology allows detection of these mutations at great depth. Here we describe the design, validation and application of a targeted next-generation sequencing approach to simultaneously screen 25 genes mutated in myeloid malignancies. We used this method alongside single nucleotide polymorphism-array technology to characterize the mutational and cytogenetic profile of 43 cases of early or advanced del(5q) myelodysplastic syndromes. A total of 29 mutations were detected in our cohort. Overall, 45% of early and 66.7% of advanced cases had at least one mutation. Genes with the highest mutation frequency among advanced cases were TP53 and ASXL1 (25% of patients each). These showed a lower mutation frequency in cases of 5q- syndrome (4.5% and 13.6%, respectively), suggesting a role in disease progression in del(5q) myelodysplastic syndromes. Fifty-two percent of mutations identified were in genes involved in epigenetic regulation (ASXL1, TET2, DNMT3A and JAK2). Six mutations had allele frequencies <20%, likely below the detection limit of traditional sequencing methods. Genomic array data showed that cases of advanced del(5q) myelodysplastic syndrome had a complex background of cytogenetic aberrations, often encompassing genes involved in myeloid disorders. Our study is the first to investigate the molecular pathogenesis of early and advanced del(5q) myelodysplastic syndromes using next-generation sequencing technology on a large panel of genes frequently mutated in myeloid malignancies, further illuminating the molecular landscape of del(5q) myelodysplastic syndromes.
Asunto(s)
Anemia Macrocítica/genética , Marcación de Gen/métodos , Mutación/genética , Síndromes Mielodisplásicos/genética , Análisis de Secuencia de ADN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Anemia Macrocítica/diagnóstico , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.
Asunto(s)
Cromosomas Humanos Par 7 , Células Germinativas , Humanos , Adulto Joven , Adulto , Dosificación de Gen , Células Madre Hematopoyéticas , MutaciónAsunto(s)
Anemia Aplásica/diagnóstico , Anemia Aplásica/terapia , Anciano , Anemia Aplásica/complicaciones , Anemia Aplásica/genética , Benzoatos/uso terapéutico , Transfusión de Componentes Sanguíneos/métodos , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/etiología , Humanos , Hidrazinas/uso terapéutico , Inmunosupresores/uso terapéutico , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/prevención & control , Embarazo , Complicaciones Hematológicas del Embarazo/terapia , Pirazoles/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
Transfusion-dependent myelodysplastic (MDS) patients are prone to iron overload. We evaluated 43 transfused MDS patients with T2* magnetic resonance imaging scans. 81% had liver and 16·8% cardiac iron overload. Liver R2* (1000/T2*), but not cardiac R2*, was correlated with number of units transfused (r=0·72, P<0·0001) and ferritin (r=0·53, P<0·0001). The area under the curve of a time-ferritin plot was found to be much greater in patients with cardiac iron loading (median 53·7x10(5) Megaunits vs. 12·2x10(5) Megaunits, P=0·002). HFE, HFE2, HAMP or SLC40A1 genotypes were not predictors of iron overload in these patients.
Asunto(s)
Sobrecarga de Hierro/etiología , Síndromes Mielodisplásicos/terapia , Miocardio/metabolismo , Reacción a la Transfusión , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Femenino , Ferritinas/sangre , Humanos , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/diagnóstico , Hígado/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.
Asunto(s)
Mutación de Línea Germinal , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Desaminasa/genética , Dineínas Axonemales/genética , Estudios de Cohortes , Humanos , Degradación de ARNm Mediada por Codón sin Sentido , Linaje , Perforina/genética , Glicoproteínas de Membrana Plaquetaria/genética , ARN Helicasas/genética , Receptores de Interleucina-17/genética , Proteínas de Transporte Vesicular/genética , Secuenciación del ExomaRESUMEN
Lymphoid enhancer-binding factor 1 (LEF1) is a neutrophilic granulopoiesis regulator whose absence is critical in congenital neutropenia. We have shown LEF1 downregulation in the CD34(+) cells of the majority of myelodysplastic syndromes (MDS) patients. LEF1 was the most significant differentially expressed gene between early and advanced MDS. Marked LEF1 downregulation was found in 27/32 patients with advanced MDS and in 6/35 patients with early MDS, and was associated with neutropenia. Downregulation of LEF1 mRNA was reflected at the protein level. Immunostaining for CD34/LEF1 may represent a marker of advanced MDS. LEF1 may play a role in the defective maturation of myeloid progenitors in MDS.