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ABSTRACT: Patients with acute myeloid leukemia (AML) who experience relapse following allogeneic hematopoietic cell transplantation (alloHCT) face unfavorable outcomes regardless of the chosen relapse treatment. Early detection of relapse at the molecular level by measurable residual disease (MRD) assessment enables timely intervention, which may prevent hematological recurrence of the disease. It remains unclear whether molecular MRD assessment can detect MRD before impending relapse and, if so, how long in advance. This study elucidates the molecular architecture and kinetics preceding AML relapse by using error-corrected next-generation sequencing (NGS) in 74 patients with AML relapsing after alloHCT, evaluating 140 samples from peripheral blood collected 0.6 to 14 months before relapse. At least 1 MRD marker became detectable in 10%, 38%, and 64% of patients at 6, 3, and 1 month before relapse, respectively. By translating these proportions into monitoring intervals, 38% of relapses would have been detected through MRD monitoring every 3 months, whereas 64% of relapses would have been detected with monthly intervals. The relapse kinetics after alloHCT are influenced by the functional class of mutations and their stability during molecular progression. Notably, mutations in epigenetic modifier genes exhibited a higher prevalence of MRD positivity and greater stability before relapse, whereas mutations in signaling genes demonstrated a shorter lead time to relapse. Both DTA (DNMT3A, TET2, and ASXL1) and non-DTA mutations displayed similar relapse kinetics during the follow-up period after alloHCT. Our study sets a framework for MRD monitoring after alloHCT by NGS, supporting monthly monitoring from peripheral blood using all variants that are known from diagnosis.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Neoplasia Residual , Trasplante Homólogo , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Femenino , Neoplasia Residual/diagnóstico , Adulto , Anciano , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento , Recurrencia , Adulto Joven , AdolescenteRESUMEN
Treatment options for relapsed and refractory acute myeloid leukemia patients (R/R AML) are limited. This retrospective cohort study compares safety and efficacy of fludarabine, cytarabine, and idarubicin (FLA-IDA) without or with venetoclax (FLAVIDA) in patients with R/R AML. Thirty-seven and 81 patients received one course FLA-IDA with or without a 7-day course of venetoclax, respectively. The overall response rate (ORR) was significantly higher in FLAVIDA compared to FLAIDA- treated patients (78% vs. 47%; P=0.001), while measurable residual disease was negative at a similar proportion in responding patients (50% vs. 57%), respectively. Eighty-one percent and 79% of patients proceeded to allogeneic hematopoietic cell transplantation or donor lymphocyte infusion after FLAVIDA and FLA-IDA, respectively. Event-free and overall survival were similar in FLAVIDA- and FLA-IDA-treated patients. Refractory patients could be salvaged more successfully after FLA-IDA compared to FLAVIDA pretreatment. Neutrophil and platelet recovery times were similar in the venetoclax and the control group. In conclusion, short-term venetoclax in combination with FLA-IDA represents an effective treatment regimen in R/R AML identifying chemosensitive patients rapidly and inducing measurable residual disease-negative remission in a high proportion of R/R AML patients.
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Idarrubicina , Leucemia Mieloide Aguda , Humanos , Idarrubicina/uso terapéutico , Citarabina , Estudios Retrospectivos , Factor Estimulante de Colonias de Granulocitos , Leucemia Mieloide Aguda/tratamiento farmacológico , Vidarabina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Donor lymphocyte infusions (DLIs) can directly target leukemic cells through a graft-versus-leukemia effect and play a key role in the prevention and management of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Predictors of response to DLIs are not well established. We evaluated measurable residual disease (MRD) before, 30 and 90 days after DLI treatment as biomarkers of response. MRD was assessed by next-generation sequencing in 76 DLI-treated acute myeloid leukemia patients. MRD status before DLI treatment was independently prognostic for event-free survival (EFS, p < 0.001) and overall survival (OS, p < 0.001). Within 90 days of DLI treatment, 73% of MRD+ patients converted to MRD- and 32% of patients without remission achieved remission. MRD status 90 days after DLI treatment was independently prognostic for the cumulative incidence of relapse (CIR, p = 0.011) and relapse-free survival (RFS, p = 0.001), but not for OS. To evaluate the role of DLI treatment in MRD- patients, 23 MRD- patients who received DLIs were compared with a control cohort of 68 MRD- patients not receiving DLIs. RFS (p = 0.23) and OS (p = 0.48) were similar between the two cohorts. In conclusion, MRD is prognostic before (EFS, OS) and after (CIR, RFS) DLI treatment and may help in the selection of patients who benefit most from DLIs.
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Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Pronóstico , RecurrenciaRESUMEN
Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML) is widely applicable and prognostic prior to allogeneic hematopoietic cell transplantation (alloHCT). We evaluated the prognostic role of clonal hematopoiesis-associated DNMT3A, TET2, and ASXL1 (DTA) and non-DTA mutations for MRD monitoring post-alloHCT to refine MRD marker selection. Of 154 patients with AML, 138 (90%) had at least one mutation at diagnosis, which were retrospectively monitored by amplicon-based error-corrected NGS on day 90 and/or day 180 post-alloHCT. MRD was detected in 34 patients on day 90 and/or day 180 (25%). The rate of MRD positivity was similar when DTA and non-DTA mutations were considered separately (17.6% vs 19.8%). DTA mutations had no prognostic impact on cumulative incidence of relapse, relapse-free survival, or overall survival in our study and were removed from further analysis. In the remaining 131 patients with at least 1 non-DTA mutation, clinical and transplantation-associated characteristics were similarly distributed between MRD-positive and MRD-negative patients. In multivariate analysis, MRD positivity was an independent adverse predictor of cumulative incidence of relapse, relapse-free survival, and overall survival but not of nonrelapse mortality. The prognostic effect was independent of different cutoffs (above limit of detection, 0.1% and 1% variant allele frequency). MRD log-reduction between diagnosis and post-alloHCT assessment had no prognostic value. MRD status post-alloHCT had the strongest impact in patients who were MRD positive prior to alloHCT. In conclusion, non-DTA mutations are prognostic NGS-MRD markers post-alloHCT, whereas the prognostic role of DTA mutations in the posttransplant setting remains open.
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Leucemia Mieloide Aguda , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Neoplasia Residual , Estudios RetrospectivosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia/tratamiento farmacológico , Terapia Recuperativa , Enfermedad Aguda , Adolescente , Adulto , Anciano , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Citarabina/administración & dosificación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Sulfonamidas/administración & dosificación , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Molecular measurable residual disease (MRD) assessment is not established in approximately 60% of acute myeloid leukemia (AML) patients because of the lack of suitable markers for quantitative real-time polymerase chain reaction. To overcome this limitation, we established an error-corrected next-generation sequencing (NGS) MRD approach that can be applied to any somatic gene mutation. The clinical significance of this approach was evaluated in 116 AML patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) in complete morphologic remission (CR). Targeted resequencing at the time of diagnosis identified a suitable mutation in 93% of the patients, covering 24 different genes. MRD was measured in CR samples from peripheral blood or bone marrow before alloHCT and identified 12 patients with persistence of an ancestral clone (variant allele frequency [VAF] >5%). The remaining 96 patients formed the final cohort of which 45% were MRD+ (median VAF, 0.33%; range, 0.016%-4.91%). In competing risk analysis, cumulative incidence of relapse (CIR) was higher in MRD+ than in MRD- patients (hazard ratio [HR], 5.58; P < .001; 5-year CIR, 66% vs 17%), whereas nonrelapse mortality was not significantly different (HR, 0.60; P = .47). In multivariate analysis, MRD positivity was an independent negative predictor of CIR (HR, 5.68; P < .001), in addition to FLT3-ITD and NPM1 mutation status at the time of diagnosis, and of overall survival (HR, 3.0; P = .004), in addition to conditioning regimen and TP53 and KRAS mutation status. In conclusion, NGS-based MRD is widely applicable to AML patients, is highly predictive of relapse and survival, and may help refine transplantation and posttransplantation management in AML patients.
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Biomarcadores de Tumor/genética , Trasplante de Células Madre Hematopoyéticas/mortalidad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia Mieloide Aguda/diagnóstico , Mutación , Recurrencia Local de Neoplasia/diagnóstico , Neoplasia Residual/diagnóstico , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/terapia , Neoplasia Residual/genética , Neoplasia Residual/mortalidad , Neoplasia Residual/terapia , Nucleofosmina , Pronóstico , Inducción de Remisión , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
We integrated molecular data with available prognostic factors in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) from MDS to evaluate their impact on prognosis. Three hundred four patients were sequenced for mutations in 54 genes. We used a Cox multivariate model and competing risk analysis with internal and cross validation to identify factors prognostic of overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). In multivariate analysis, mutated NRAS, U2AF1, IDH2, and TP53 and/or a complex karyotype were significant prognostic markers for OS besides age above 60 years, remission status, IPSS-R cytogenetic risk, HCT-CI > 2 and female donor sex. Mutated NRAS, IDH1, EZH2, and TP53 and/or a complex karyotype were genetic aberrations with prognostic impact on CIR. No molecular markers were associated with the risk of NRM. The inclusion of molecular information results in better risk prediction models for OS and CIR when assessed by the Akaike information criterion. Internal cross validation confirmed the robustness of our comprehensive risk model. In summary, we propose to combine molecular, cytogenetic, and patient- and transplantation-associated risk factors into a comprehensive risk model to provide personalized predictions of outcome after alloHCT.
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Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide/genética , Mutación , Síndromes Mielodisplásicos/genética , Neoplasias Primarias Secundarias/genética , Enfermedad Aguda , Adulto , Anciano , Algoritmos , Femenino , Humanos , Leucemia Mieloide/terapia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Síndromes Mielodisplásicos/terapia , Neoplasias Primarias Secundarias/terapia , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Medicina de Precisión , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Análisis de Secuencia de ADN , Análisis de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Mutations in the cohesin complex are novel, genetic lesions in acute myeloid leukemia (AML) that are not well characterized. In this study, we analyzed the frequency, clinical, and prognostic implications of mutations in STAG1, STAG2, SMC1A, SMC3, and RAD21, all members of the cohesin complex, in a cohort of 389 uniformly treated AML patients by next generation sequencing. We identified a total of 23 patients (5.9%) with somatic mutations in 1 of the cohesin genes. All gene mutations were mutually exclusive, and STAG1 (1.8%), STAG2 (1.3%), and SMC3 (1.3%) were most frequently mutated. Patients with any cohesin complex mutation had lower BAALC expression levels. We found a strong association between mutations affecting the cohesin complex and NPM1. Mutated allele frequencies were similar between NPM1 and cohesin gene mutations. Overall survival (OS), relapse-free survival (RFS), and complete remission rates (CR) were not influenced by the presence of cohesin mutations (OS: hazard ratio [HR] 0.98; 95% confidence interval [CI], 0.56-1.72 [P = .94]; RFS: HR 0.7; 95% CI, 0.36-1.38 [P = .3]; CR: mutated 83% vs wild-type 76% [P = .45]). The cohesin complex presents a novel pathway affected by recurrent mutations in AML. This study is registered at www.clinicaltrials.gov as #NCT00209833.
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Antígenos Nucleares/genética , Biomarcadores de Tumor/genética , Proteínas de Ciclo Celular/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteínas Cromosómicas no Histona/genética , Leucemia Mieloide Aguda/mortalidad , Proteínas Nucleares/genética , Fosfoproteínas/genética , Adolescente , Adulto , Estudios de Casos y Controles , Análisis Citogenético , Proteínas de Unión al ADN , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/metabolismo , Estadificación de Neoplasias , Nucleofosmina , Reacción en Cadena de la Polimerasa , Pronóstico , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenRESUMEN
Mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are frequently found in glioma, acute myeloid leukemia (AML), melanoma, thyroid cancer, and chondrosarcoma patients. Mutant IDH produces 2-hydroxyglutarate (2HG), which induces histone- and DNA-hypermethylation through inhibition of epigenetic regulators. We investigated the role of mutant IDH1 using the mouse transplantation assay. Mutant IDH1 alone did not transform hematopoietic cells during 5 months of observation. However, mutant IDH1 greatly accelerated onset of myeloproliferative disease-like myeloid leukemia in mice in cooperation with HoxA9 with a mean latency of 83 days compared with cells expressing HoxA9 and wild-type IDH1 or a control vector (167 and 210 days, respectively, P = .001). Mutant IDH1 accelerated cell-cycle transition through repression of cyclin-dependent kinase inhibitors Cdkn2a and Cdkn2b, and activated mitogen-activated protein kinase signaling. By computational screening, we identified an inhibitor of mutant IDH1, which inhibited mutant IDH1 cells and lowered 2HG levels in vitro, and efficiently blocked colony formation of AML cells from IDH1-mutated patients but not of normal CD34(+) bone marrow cells. These data demonstrate that mutant IDH1 has oncogenic activity in vivo and suggest that it is a promising therapeutic target in human AML cells.
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Regulación Leucémica de la Expresión Génica , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutación , Adolescente , Adulto , Animales , Antígenos CD34/metabolismo , Apoptosis , Trasplante de Médula Ósea , Ciclo Celular , Femenino , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Adulto JovenRESUMEN
Overexpression of MN1, ERG, BAALC, and EVI1 (MEBE) genes in cytogenetically normal acute myeloid leukemia (AML) patients is associated with poor prognosis, but their prognostic effect in patients with myelodysplastic syndromes (MDS) has not been studied systematically. Expression data of the four genes from 140 MDS patients were combined in an additive score, which was validated in an independent patient cohort of 110 MDS patients. A high MEBE score, defined as high expression of at least two of the four genes, predicted a significantly shorter overall survival (OS) (HR 2.29, 95 % CI 1.3-4.09, P= .005) and time to AML progression (HR 4.83, 95 % CI 2.01-11.57, P< .001) compared to a low MEBE score in multivariate analysis independent of karyotype, percentage of bone marrow blasts, transfusion dependence, ASXL1, and IDH1 mutation status. In a validation cohort of 110 MDS patients, a high MEBE score predicted shorter OS (HR 1.77; 95 % CI 1.04-3.0, P= .034) and time to AML progression (HR 3.0, 95 % CI 1.17-7.65, P= .022). A high MEBE expression score is an unfavorable prognostic marker in MDS and is associated with an increased risk for progression to AML. Expression of the MEBE genes is regulated by FLI1 and c-MYC, which are potential upstream targets of the MEBE signature.
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Proteínas de Unión al ADN/genética , Síndromes Mielodisplásicos/diagnóstico , Proteínas de Neoplasias/genética , Proto-Oncogenes/genética , Transactivadores/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Estudios de Cohortes , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/mortalidad , Proteínas de Neoplasias/metabolismo , Valor Predictivo de las Pruebas , Preleucemia/diagnóstico , Preleucemia/genética , Preleucemia/metabolismo , Pronóstico , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Regulador Transcripcional ERG , Proteínas Supresoras de Tumor/metabolismo , Estudios de Validación como AsuntoRESUMEN
Mutations in genes of the splicing machinery have been described recently in myelodysplastic syndromes (MDS). In the present study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as described previously, SF3B1, in the context of other molecular markers, including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1, and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P < .001) and IDH1 (P = .013) mutations, whereas U2AF1 mutations were associated with ASXL1 (P = .005) and DNMT3A (P = .004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for overall survival (hazard ratio = 2.3; 95% confidence interval, 1.28-4.13; P = .017) and acute myeloid leukemia progression (hazard ratio = 2.83; 95% confidence interval, 1.31-6.12; P = .008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.
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Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Proteínas Nucleares/genética , Ribonucleoproteínas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Ensayos Clínicos como Asunto , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Mutación/fisiología , Síndromes Mielodisplásicos/epidemiología , Nucleofosmina , Valor Predictivo de las Pruebas , Pronóstico , Factores de Empalme Serina-Arginina , Factor de Empalme U2AF , Adulto JovenRESUMEN
PURPOSE: To study the incidence and prognostic impact of mutations in Additional sex comb-like 1 (ASXL1) in a large cohort of patients with myelodysplastic syndrome (MDS). PATIENTS, MATERIALS, AND METHODS: Overall, 193 patients with MDS and 65 healthy volunteers were examined for ASXL1 mutations by direct sequencing and for expression levels of ASXL1. The prognostic impact of ASXL1 mutation and expression levels was evaluated in the context of other clinical and molecular prognostic markers. RESULTS: Mutations in ASXL1 occurred with a frequency of 20.7% in MDS (n = 40 of 193) with 70% (n = 28) of mutations being frameshift mutations and 30% (n = 12) being heterozygous point mutations leading to translational changes. ASXL1 mutations were correlated with an intermediate-risk karyotype (P = .002) but not with other clinical parameters. The presence of ASXL1 mutations was associated with a shorter overall survival for frameshift and point mutations combined (hazard ratio [HR], 1.744; 95% CI, 1.08 to 2.82; P = .024) and for frameshift mutations only (HR, 2.06; 95% CI, 1.21 to 3.50; P = .008). ASXL1 frameshift mutations were associated with a reduced time to progression of acute myeloid leukemia (AML; HR 2.35; 95% CI, 1.17 to 4.74; P = .017). In multivariate analysis, when considering karyotype, transfusion dependence, and IDH1 mutation status, ASXL1 frameshift mutations remained an independent prognostic marker in MDS (overall survival: HR, 1.85; 95% CI, 1.03 to 3.34; P = .040; time to AML progression: HR, 2.39; 95% CI, 1.12 to 5.09; P = .024). CONCLUSION: These results suggest that ASXL1 mutations are frequent molecular aberrations in MDS that predict an adverse prognostic outcome. Screening of patients for ASXL1 mutations might be useful for clinical risk stratification and treatment decisions in the future.
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Mutación del Sistema de Lectura , Síndromes Mielodisplásicos/genética , Mutación Puntual , Proteínas Represoras/análisis , Adulto , Anciano , Anciano de 80 o más Años , Suero Antilinfocítico , Biomarcadores , Ensayos Clínicos como Asunto/estadística & datos numéricos , Metilación de ADN , Análisis Mutacional de ADN , Progresión de la Enfermedad , Exones/genética , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Genes MHC Clase II , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Pronóstico , Modelos de Riesgos Proporcionales , ARN Mensajero/biosíntesis , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , RiesgoRESUMEN
BACKGROUND: Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders with a high propensity to transform into acute myeloid leukemia. Heterozygous missense mutations in IDH1 at position R132 and in IDH2 at positions R140 and R172 have recently been reported in acute myeloid leukemia. However, little is known about the incidence and prognostic impact of IDH1 and IDH2 mutations in myelodysplastic syndromes. DESIGN AND METHODS: We examined 193 patients with myelodysplastic syndromes and 53 patients with acute myeloid leukemia arising from myelodysplastic syndromes for mutations in IDH1 (R132), IDH2 (R172 and R140), and NPM1 by direct sequencing. RESULTS: We found that mutations in IDH1 occurred with a frequency of 3.6% in myelodysplastic syndromes (7 mutations in 193 patients) and 7.5% in acute myeloid leukemia following myelodysplastic syndromes (4 mutations in 53 patients). Three mutations in codon R140 of IDH2 and one mutation in codon R172 were found in patients with acute myeloid leukemia following myelodysplastic syndromes (7.5%). No IDH2 R140 or R172 mutations were identified in patients with myelodysplastic syndromes. The presence of IDH1 mutations was associated with a shorter overall survival (HR 3.20; 95% CI 1.47-6.99) and a higher rate of transformation into acute myeloid leukemia (67% versus 28%, P=0.04). In multivariate analysis when considering karyotype, transfusion dependence and International Prognostic Scoring System score, IDH1 mutations remained an independent prognostic marker in myelodysplastic syndromes (HR 3.57; 95% CI 1.59-8.02; P=0.002). CONCLUSIONS: These results suggest that IDH1 mutations are recurrent molecular aberrations in patients with myelodysplastic syndromes, and may become useful as a poor risk marker in these patients. These findings await validation in prospective trials.