Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Azacitidina/uso terapéutico , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Estudios RetrospectivosAsunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/análogos & derivados , Azacitidina/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Adulto , Anciano , Metilación de ADN/efectos de los fármacos , Decitabina , Femenino , Humanos , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Enfermedades Mielodisplásicas-Mieloproliferativas/tratamiento farmacológico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
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 JovenRESUMEN
Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Estudios de Validación como AsuntoRESUMEN
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.
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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
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.
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Proteínas Portadoras/genética , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Proteínas Nucleares/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Codón sin Sentido , Femenino , Mutación del Sistema de Lectura , Pruebas Genéticas , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Análisis Multivariante , Pronóstico , Factores de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
Myelodysplastic syndromes (MDS) are clonal diseases of the elderly characterized by chronic cytopenias, dysplasia and a variable risk of progression to acute myeloid leukemia (AML). Aberrant methylation of tumor-suppressor gene promoters has been established for many years and recently tracked to the most immature cells of MDS, suggesting that these alterations are drivers of MDS pathogenesis. In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation and in covalent histone modifications have been reported in myeloid malignancies, including MDS. Whole-genome epigenetic profiles of MDS are also emerging. In parallel with these advances in the molecular pathogenesis of MDS, clinical trials have established hypomethylating agents (HMAs) as the mainstay of therapy in the advanced forms of the disease. In this review, we summarize the current understanding of the molecular machinery involved in epigenetic regulation, discuss how epigenetic alterations arise in MDS and contribute to its pathogenesis and then discuss the mode of action of HMAs in MDS.
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Epigénesis Genética , Síndromes Mielodisplásicos/genética , Metilación de ADN , Histonas/metabolismo , HumanosAsunto(s)
Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/mortalidad , Mutación , Receptores del Factor Estimulante de Colonias/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mapeo Físico de Cromosoma , Polimorfismo de Nucleótido Simple , PronósticoRESUMEN
Chronic myelomonocytic leukemia (CMML) shares with other myeloid diseases a number of somatic gene mutations. These mutations can now be integrated within the framework of evolution theory to address the mechanisms of the disease. Several evidences indicate that the disease emerges in adult hematopoietic stem cells (HSC) through the age-dependent accumulation of DNA damage, leading stochastically to a driver mutation that confers a competitive advantage to the cell. A mutation in TET2 gene could be one of these driver mutations provoking the emergence of clonality. After a long latency, secondary lesions, such as mutations in the SRSF2 gene, contribute to progression to full-blown malignancy, with abnormal differentiation. Additional mutations accumulate and branching arising mostly through mitotic recombination generates clonal heterogeneity. Modifications in the microenvironment probably affect this clonal dynamics, whereas epigenetic alterations, such as hypermethylation of the TIF1γ gene promoter, may generate phenotypic diversification of otherwise clonal populations. The preserved although deregulated myeloid differentiation that characterizes CMML, with granulomonocyte expansion and various cytopenias, may depend on early clonal dominance in the hematopietic cell hierarchy. Progression to acute myeloid leukemia observed in 25-30% of the patients may arise from the massive expansion of a clone with novel genetic lesions, providing a high fitness to previously minor subclones when in chronic phase of the disease. This review discusses the various models of disease emergence and progression and how this recent knowledge could drive rational therapeutic strategies.
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Evolución Clonal/fisiología , Epigénesis Genética/fisiología , Regulación Leucémica de la Expresión Génica/fisiología , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Humanos , Leucemia Mielomonocítica Crónica/fisiopatología , Mutación/fisiologíaRESUMEN
A large proportion of lower-risk myelodysplastic syndromes (MDS) respond to erythropoiesis-stimulating agents (ESA), but most responses are transient. We updated a previously reported cohort of lower-risk MDS patients treated with ESA and analyzed outcomes after ESA failure. In 120 patients with primary resistance and 66 patients with relapse after an initial response to ESA, the 5-year cumulative incidence of acute myeloid leukemia (AML) after failure was 18.9% and 11.6%, respectively (P=0.20). Median overall survival (OS) after failure was 40.1 and 44.9 months (P=0.35), respectively. We further categorized patients as 'early failures' (including resistance and relapse after <6 months of response), or 'later failures' (that is, relapse after ≥6 months). The 5-year cumulative incidence of AML and median OS after failure in early and later failure were 21.6% and 9% (P=0.02) and 36.7 and 54.3 months (P=0.02), respectively. Early failure to ESA and a baseline diagnosis of refractory anemia with excess blasts (RAEB)-1 were independent prognostic factors for AML progression and, along with trisomy 8, for shorter OS. Median OS from treatment onset was 40, 90.7 and 65.8 months in early failure, later failure and no relapse, respectively (P=0.001). Lower-risk MDS with early failure to ESA have a relatively unfavorable outcome, and should be offered alternative treatments.
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Anemia/complicaciones , Cromosomas Humanos Par 5 , Hematínicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Femenino , Humanos , Masculino , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genética , Recurrencia , Resultado del TratamientoRESUMEN
We studied a retrospective cohort of 282 higher-risk MDS treated with azacitidine, including 32 patients who concomitantly received an ESA for a median of 5.8 months after azacitidine onset. Forty-four percent of ESA and 29% of no-ESA patients reached HI-E (p=0.07); 48% and 20% achieved transfusion independence (p=0.01). Median OS was 19.6 months in the ESA and 11.9 months in the no-ESA groups (p=0.04). Addition of an ESA significantly improved OS (p=0.03) independently of azacitidine schedule and duration, and of our proposed azacitidine risk score (Blood 2011;117:403-11). Adding an ESA to azacitidine in higher-risk MDS should be studied prospectively.
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Antimetabolitos Antineoplásicos/administración & dosificación , Azacitidina/administración & dosificación , Hematínicos/administración & dosificación , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20-30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P=0.03, P=0.047 and P=0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P=0.007). Mutated TET2 (P=0.04) and favorable cytogenetic risk (intermediate risk: P=0.04, poor risk: P=0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas/genética , Anciano , Anciano de 80 o más Años , Metilación de ADN/efectos de los fármacos , ADN de Neoplasias/genética , Proteínas de Unión al ADN/fisiología , Dioxigenasas , Supervivencia sin Enfermedad , Femenino , Hemoglobinas/análisis , Humanos , Estimación de Kaplan-Meier , Cariotipificación , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/fisiología , Proteínas Proto-Oncogénicas/fisiología , Análisis de Secuencia de ADN , Resultado del TratamientoAsunto(s)
Antimetabolitos/uso terapéutico , Azacitidina/uso terapéutico , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 7/genética , Monosomía , Síndromes Mielodisplásicos/genética , Deleción Cromosómica , Ensayos de Uso Compasivo , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Cariotipificación , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-beta and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500 U/l or other cytopenia(s) (absolute neutrophilic count <1.0 G/l or platelets <50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500 U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-beta-ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.
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Eritropoyetina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Tretinoina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutropenia/tratamiento farmacológico , Neutrófilos , Recuento de Plaquetas , Proteínas Recombinantes , Trombocitopenia/tratamiento farmacológico , Resultado del Tratamiento , Adulto JovenRESUMEN
Myelodysplastic syndromes (MDS) remain challenging to both clinicians and biologists. This year's edition of the Annual Meeting of the American Society of Hematology has provided several breakthroughs in the biology and therapeutics of MDS, such as uncovering of the molecular genetics of the 5q- syndrome and clear evidence of a survival advantage with a hypomethylating agent in high-risk MDS. We summarize those advances and delineate some perspectives for these diseases.