RESUMEN
In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age ≥65 years predicted venous thrombosis in polycythemia vera (PV). In the current study, we sought to validate the above findings and identify additional predictors of arterial versus venous thrombosis. At a median follow up of 109 months, thrombosis after diagnosis occurred in 128 (22%) patients; 82 (14%) arterial and 57 (10%) venous events. On multivariate analysis, prior arterial events (<0.0001), hyperlipidemia (p = 0.03), and hypertension (p = 0.02) predicted subsequent arterial events. In comparison, prior venous events (p = 0.05), leukocytosis ≥11 × 109/L (p = 0.002), and major hemorrhage (p = 0.02) were predictors of subsequent venous events. Salient associations with arterial thrombosis included age ≥ 60 years, hypertension, diabetes, hyperlipidemia and normal karyotype whereas age ≤ 60 years, females, palpable splenomegaly and history of major hemorrhage were associated with venous thrombosis. TET2 or ASXL1 mutations did not impact arterial nor venous thrombosis. In conclusion, we identify distinct associations for arterial versus venous thrombosis in PV and confirm that a prior arterial or venous thrombotic event is the most reliable predictor of subsequent events.
Asunto(s)
Policitemia Vera/complicaciones , Trombosis/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Trombosis/epidemiología , Adulto JovenAsunto(s)
Calreticulina/genética , Hematopoyesis Extramedular , Leucocitosis/complicaciones , Mielofibrosis Primaria/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Frecuencia de los Genes , Hematopoyesis Extramedular/genética , Humanos , Leucocitosis/epidemiología , Leucocitosis/genética , Leucocitosis/patología , Masculino , Persona de Mediana Edad , Mutación , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Estudios Retrospectivos , Adulto JovenAsunto(s)
Síndrome Hipereosinofílico/clasificación , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenAsunto(s)
Anemia/etiología , Estudios de Asociación Genética , Mutación , Proteínas Nucleares/genética , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/genética , Ribonucleoproteínas/genética , Anemia/diagnóstico , Humanos , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , Pronóstico , Factor de Empalme U2AFAsunto(s)
Anemia Refractaria/complicaciones , Anemia Refractaria/tratamiento farmacológico , Anemia Sideroblástica/complicaciones , Anemia Sideroblástica/tratamiento farmacológico , Indoles/uso terapéutico , Niacinamida/análogos & derivados , Trombocitosis/complicaciones , Anemia Refractaria/diagnóstico , Anemia Refractaria/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Terapia Combinada , Humanos , Niacinamida/uso terapéutico , Oligonucleótidos , Trombocitosis/diagnósticoRESUMEN
Mutations involving epigenetic regulators (TET2~60% and ASXL1~40%) and splicing components (SRSF2~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had >3 mutations. In a univariate analysis, the presence of ASXL1 mutations (P=0.02) and the absence of TET2 mutations (P=0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P=0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (P=0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n=56), ASXL1mut/TET2wt (n=31), ASXL1mut/TET2mut (n=50) and ASXL1wt/TET2mut (n=38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P=0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P=0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.
Asunto(s)
Proteínas de Unión al ADN/genética , Epistasis Genética , Estudios de Asociación Genética , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dioxigenasas , Femenino , Regulación Leucémica de la Expresión Génica , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Since its reclassification as a distinct disease entity, clinical research efforts have attempted to establish baseline characteristics and prognostic scoring systems for chronic myelomonocytic leukemia (CMML). Although existing data for baseline characteristics and CMML prognostication have been robustly developed and externally validated, these results have been limited by the small size of single-institution cohorts. We developed an international CMML data set that included 1832 cases across eight centers to establish the frequency of key clinical characteristics. Of note, we found that the majority of CMML patients were classified as World Health Organization CMML-1 and that a 7.5% bone marrow blast cut-point may discriminate prognosis with higher resolution in comparison with the existing 10%. We additionally interrogated existing CMML prognostic models and found that they are all valid and have comparable performance but are vulnerable to upstaging. Using random forest survival analysis for variable discovery, we demonstrated that the prognostic power of clinical variables alone is limited. Last, we confirmed the independent prognostic relevance of ASXL1 gene mutations and identified the novel adverse prognostic impact imparted by CBL mutations. Our data suggest that combinations of clinical and molecular information may be required to improve the accuracy of current CMML prognostication.
Asunto(s)
Leucemia Mielomonocítica Crónica/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Conjuntos de Datos como Asunto , Árboles de Decisión , Femenino , Predisposición Genética a la Enfermedad , Humanos , Cooperación Internacional , Estimación de Kaplan-Meier , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Curva ROC , Adulto JovenAsunto(s)
Médula Ósea/patología , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Mastocitos/patología , Mastocitosis Sistémica/patología , Médula Ósea/metabolismo , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Inmunofenotipificación , Mastocitos/metabolismo , Mastocitosis Sistémica/metabolismo , Células Tumorales CultivadasRESUMEN
In patients with chronic myelomonocytic leukemia (CMML), age>65 years is an adverse prognostic factor. Our objective in the current study was to examine risk factors for survival and treatment outcome in 261 'young' adults with CMML, as defined by age ⩽65 years. In multivariable analysis, lower HB (P=0.01), higher circulating blast % (P=0.002), ASXL1 (P=0.0007) and SRSF2 mutations (P=0.008) and Mayo-French cytogenetic stratification (P=0.04) negatively impacted survival. Similarly, leukemia-free survival was independently affected by higher circulating blast % (P<0.0001), higher bone marrow blast % (P=0.0007) and the presence of circulating immature myeloid cells (P=0.0002). Seventy-five (29%) patients received hypomethylating agents (HMA), with the median number of cycles being 5, and the median duration of therapy being 5 months. The over-all response rate was 40% for azacitidine and 30% for decitabine. Fifty-three (24%) patients underwent an allogeneic hematopoietic stem cell transplant (AHSCT), with a response rate of 56% and a non-relapse mortality of 19%. Survival in young adults with CMML, although higher than in older patients, is poor and even worse in the presence of ASXL1 and SRSF2 mutations. Treatment outcome was more impressive with AHSCT than with HMA and neither was influenced by ASXL1/SRSF2 mutations or karyotype.
Asunto(s)
Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/genética , Proteínas Nucleares/genética , Pronóstico , Ribonucleoproteínas/genética , Adulto , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mielomonocítica Crónica/epidemiología , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Mutación , Factores de Empalme Serina-Arginina , Resultado del Tratamiento , Adulto JovenRESUMEN
Although KITD816V occurs universally in adult systemic mastocytosis (SM), the clinical heterogeneity of SM suggests presence of additional phenotype-patterning mutations. Because up to 25% of SM patients have KITD816V-positive eosinophilia, we undertook whole-exome sequencing in a patient with aggressive SM with eosinophilia to identify novel genetic alterations. We conducted sequencing of purified eosinophils (clone/tumor sample), with T-lymphocytes as the matched control/non-tumor sample. In addition to KITD816V, we identified a somatic missense mutation in ethanolamine kinase 1 (ETNK1N244S) that was not present in 50 healthy controls. Targeted resequencing of 290 patients showed ETNK1 mutations to be distributed as follows: (i) SM (n=82; 6% mutated); (ii) chronic myelomonocytic leukemia (CMML; n=29; 14% mutated); (iii) idiopathic hypereosinophilia (n=137; <1% mutated); (iv) primary myelofibrosis (n=32; 0% mutated); and (v) others (n=10; 0% mutated). Of the 82 SM cases, 25 had significant eosinophilia; of these 20% carried ETNK1 mutations. The ten mutations (N244S=6, N244T=1, N244K=1, G245A=2) targeted two contiguous amino acids in the ETNK1 kinase domain, and are predicted to be functionally disruptive. In summary, we identified novel somatic missense ETNK1 mutations that were most frequent in SM with eosinophilia and CMML; this suggests a potential pathogenetic role for dysregulated cytidine diphosphate-ethanolamine pathway metabolites in these diseases.
Asunto(s)
Eosinofilia/genética , Leucemia Mielomonocítica Crónica/genética , Mastocitosis Sistémica/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto , Anciano , Anciano de 80 o más Años , Eosinofilia/complicaciones , Eosinofilia/patología , Exoma/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielomonocítica Crónica/complicaciones , Leucemia Mielomonocítica Crónica/patología , Masculino , Mastocitosis Sistémica/complicaciones , Mastocitosis Sistémica/patología , Persona de Mediana Edad , MutaciónAsunto(s)
Benzamidas/uso terapéutico , Calreticulina/genética , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Expresión Génica , Marcadores Genéticos , Humanos , Janus Quinasa 1/genética , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Mutación , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/patología , Pronóstico , Receptores de Trombopoyetina/genética , Análisis de SupervivenciaRESUMEN
The impact of calreticulin (CALR) mutations on long-term survival in essential thrombocythemia (ET) was examined in 299 patients whose diagnosis predated 2006. Mutational frequencies were 53% for Janus kinase 2 (JAK2), 32% for CALR and 3% for MPL; the remaining 12% were 'triple-negative'. We confirmed the association of mutant CALR (vs JAK2V617F) with younger age (P=0.002), male sex (P=0.01), higher platelet count (0.0004), lower hemoglobin (P<0.0001), lower leukocyte count (0.02) and lower incidence of recurrent thrombosis (0.04). Triple-negative patients were also younger than their JAK2-mutated counterparts (P=0.003) and displayed lower hemoglobin (P=0.003), lower leukocyte count (<0.0001) and lower thrombotic events (P=0.02). Median follow-up time was 12.7 years and 47% of the patients were followed until death. Survival was the longest for triple-negative and shortest for MPL-mutated patients. Median survival was 19 years for JAK2 and 20 years for CALR-mutated cases (P=0.32); the corresponding figures for patients of age ⩽65 years were 26 and 32 years (P=0.56). The two mutational categories were also similar for leukemic (P=0.28) and fibrotic (P=0.28) progression rates. The current study is uniquely characterized by its very long follow-up period and provides accurate estimates of long-term survival in ET and complements current information on mutation-specific phenotype and prognosis.
Asunto(s)
Calreticulina/genética , Mutación , Trombocitemia Esencial/genética , Trombocitemia Esencial/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Pronóstico , Receptores de Trombopoyetina/genética , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/diagnóstico , Adulto JovenRESUMEN
In a cohort of 466 patients, we sought to clarify the prognostic relevance of ASXL1 and SETBP1 mutations, among others, in World Health Organization-defined chronic myelomonocytic leukemia (CMML) and its added value to the Mayo prognostic model. In univariate analysis, survival was adversely affected by ASXL1 (nonsense and frameshift) but not SETBP1 mutations. In multivariable analysis, ASXL1 mutations, absolute monocyte count >10 × 10(9)/l, hemoglobin <10 g/dl, platelets <100 × 10(9)/l and circulating immature myeloid cells were independently predictive of shortened survival: hazard ratio (95% confidence interval (CI)) values were 1.5 (1.1-2.0), 2.2 (1.6-3.1), 2.0 (1.6-2.6), 1.5 (1.2-1.9) and 2.0 (1.4-2.7), respectively. A regression coefficient-based prognostic model based on these five risk factors delineated high (≥3 risk factors; HR 6.2, 95% CI 3.7-10.4) intermediate-2 (2 risk factors; HR 3.4, 95% CI 2.0-5.6) intermediate-1 (one risk factor; HR 1.9, 95% CI 1.1-3.3) and low (no risk factors) risk categories with median survivals of 16, 31, 59 and 97 months, respectively. Neither ASXL1 nor SETBP1 mutations predicted leukemic transformation. The current study confirms the independent prognostic value of nonsense/frameshift ASXL1 mutations in CMML and signifies its added value to the Mayo prognostic model, as had been shown previously in the French consortium model.