RESUMEN
INTRODUCTION: Heterozygous germline mutations of GATA2 gene (guanine-adenine-thymine-adenine binding protein 2) are hereditary mutations that can be pathogenic, sometimes occurring sporadically, responsible for a florid clinical-biological picture, sometimes serious and quickly leading to the death. CASE REPORTS: We reported two women and one man with germline mutations in the GATA2 gene. The first patient, aged 19, initially presented with monocytopenia and chronic lymphedema of the four limbs, suggestive of Emberger syndrome. The second patient, 28-years-old, presented with a disseminated atypical mycobacterium (Mycobacterium kansasii) infection, raising suspicion of an immune deficiency such as MonoMAC syndrome (deficiency syndrome of dendritic cells, monocytes, B lymphocytes and NK cells). The last patient, 30-years-old, presented with pancytopenia, leading to the diagnosis of a family form of myelodysplastic syndromes and acute myeloid leukemia characterized by a mutation of the GATA2 gene. CONCLUSIONS: Each case illustrates a typical clinical presentation of GATA2 deficiency, although the evolution of these syndromes ultimately reveals a complex, heterogeneous and intricate picture of hematological, dermatological, infectious, pulmonary, ENT or oncological symptoms. Mutations in the GATA2 gene remain a diagnostic and therapeutic challenge for the internist, and require multidisciplinary management given the florid picture that can be of interest to all specialties. The clinical spectrum of these GATA2 mutations as well as the latest management recommendations from the recent litterature and the "GATA2 club" are described in this article.
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Factor de Transcripción GATA2 , Síndromes de Inmunodeficiencia , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Femenino , Humanos , Masculino , Adenina , Factor de Transcripción GATA2/genética , Síndromes de Inmunodeficiencia/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genéticaAsunto(s)
Fibrilación Atrial/cirugía , Ablación por Catéter/efectos adversos , Fístula Esofágica/etiología , Neumotórax/etiología , Anciano , Embolia Aérea/diagnóstico , Embolia Aérea/etiología , Fístula Esofágica/diagnóstico , Resultado Fatal , Hemorragia/diagnóstico , Hemorragia/etiología , Humanos , Masculino , Enfisema Mediastínico/diagnóstico , Enfisema Mediastínico/etiología , Neumopericardio/diagnóstico , Neumopericardio/etiología , Neumotórax/diagnóstico , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/patologíaRESUMEN
Multiple myeloma (MM) is a plasma cell tumor marked by clonal evolution and preceded by a premalignant stage, which progresses via molecular pathway deregulation, including MYC activation. This activation relates to translocation or gain of the MYC locus and deregulation of upstream pathways such as IRF4, DIS3/LIN28B/let-7, or MAPK. Precision medicine is an approach to predict more accurately which treatment strategies for a particular disease will work in which groups of patients, in contrast to a "one-size-fits-all" approach. The knowledge of mechanisms responsible for MYC deregulation in MM enables identification of vulnerabilities and therapeutic targets in MYC-driven tumors. MYC can be targeted directly or indirectly, by interacting with several of its functions in cancer. Several such therapeutic strategies are evaluated in clinical trials in MM. In this review, we describe the mechanism of MYC activation in MM, the role of MYC in cancer progression, and the therapeutic options to targeting MYC.
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Mieloma Múltiple/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/fisiología , Apoptosis , Replicación del ADN , Humanos , Factores Inmunológicos/uso terapéutico , Factores Reguladores del Interferón/fisiología , Mieloma Múltiple/etiología , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas ras/fisiologíaRESUMEN
Antifungal prophylaxis (AP) has dramatically changed the epidemiology of invasive aspergillosis (IA). To better understand the differences in terms of clinical significance of IA between allogeneic stem cell transplantation (allo-SCT) recipients and patients treated for leukemia, we report a single-center study of 735 unselected consecutive patients treated between 2000 and 2004, before the era of systematic AP. Probable or confirmed IA were observed in 29 patients (2008 EORTC/MSG criteria), including 7/235 undergoing allo-SCT (5.2%), 19/380 treated for acute leukemia (5.0%), 1/116 for chronic lymphocytic leukemia (0.9%) and 2/104 for myelodysplastic syndrome (1.9%). In allo-SCT recipients, IA occurred later than in leukemia patients, after the neutropenic period. The median time between the last treatment and the diagnosis of IA was 231 days (range, 68-341) in allo-SCT recipients and 17 days (6-57) in leukemia patients (P<0.001). Importantly, the 7 cases of IA after allo- SCT occurred only in patients treated with corticosteroids for graft-versus-host disease (GVHD). Mortality directly related to IA was 24%. The 100-day, 2-year and 10-year overall survival were 42.9%, 0%, 0% in allo-SCT recipients compared to 68.1%, 18.2%, 13.6% in leukemia patients, respectively (P≥0.05). These poor outcomes were mainly attributable to non-relapse mortality (NRM). In conclusion, our data allows distinguishing 2 types of IA occurring at different time in the treatment course. In both cases, the NRM is very high and treatment remains challenging. Thus, systematic broad-spectrum AP against Aspergillus should be considered in acute leukemia patients during the neutropenic phase and in all patients undergoing allo-SCT who develop GVHD.
RESUMEN
The monitoring of the minimal residual disease by Wilms' tumor 1 expression (MRDWT1) is a standardized test, which can be used in over 80% of patients with AML. To investigate the prognostic value of MRDWT1 in patients undergoing allogeneic stem cell transplantation (allo-SCT) for AML, MRDWT1 was monitored 3 months after transplantation in 139 patients. MRDWT1 positivity did not lead to any therapeutic intervention. Median follow-up was 39.3 (6.4-99.8) months. Patients with positive MRDWT1 at 3 months experienced more often post-transplant relapse (27/30, 90%) than those with negative MRDWT1 (16/109, 14.7%) (P<0.0001). Similarly, a shorter 3-year event-free survival (EFS) was observed in MRDWT1-positive patients (10% vs 72.3% in MRDWT1-negative patients, P<0.0001). The correlation between relapse and MRDWT1 was stronger in blood than in bone marrow samples. Multivariate analysis confirmed the detrimental role of 3-month positive MRDWT1 for relapse (hazard ratio (HR): 15.42; 95% confidence interval (CI): 7.53-31.59; P<0.0001) and EFS (HR: 10.71; 95% CI: 5.41-21.21; P<0.0001). Interestingly, 3-month chimerism was less predictive of relapse than positive MRDWT1. In conclusion, our results demonstrate the usefulness of peripheral blood MRDWT1 monitoring in identifying very high-risk patients, who could benefit from an early preemptive treatment, and those who do not need such an intervention.
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Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Proteínas WT1/análisis , Médula Ósea/química , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Pronóstico , Recurrencia , Trasplante Homólogo , Resultado del Tratamiento , Proteínas WT1/sangre , Tumor de Wilms/químicaRESUMEN
Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.
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Biomarcadores de Tumor , Variaciones en el Número de Copia de ADN , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Cohortes , Resistencia a Antineoplásicos , Femenino , Dosificación de Gen , Genes p53 , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del TratamientoAsunto(s)
Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Tasa de SupervivenciaRESUMEN
The receptor-interacting protein kinase 3 (RIP3) associates with RIP1 in a necrosome complex that can induce necroptosis, apoptosis, or cell proliferation. We analyzed the expression of RIP1 and RIP3 in CD34+ leukemia cells from a cohort of patients with acute myeloid leukemia (AML) and CD34+ cells from healthy donors. RIP3 expression was significantly reduced in most AML samples, whereas the expression of RIP1 did not differ significantly. When re-expressed in the mouse DA1-3b leukemia cell line, RIP3 induced apoptosis and necroptosis in the presence of caspase inhibitors. Transfection of RIP3 in the WEHI-3b leukemia cell line or in the mouse embryonic fibroblasts also resulted in increased cell death. Surprisingly, re-expression of a RIP3 mutant with an inactive kinase domain (RIP3-kinase dead (RIP3-KD)) induced significantly more and earlier apoptosis than wild-type RIP3 (RIP3-WT), indicating that the RIP3 kinase domain is an essential regulator of apoptosis/necroptosis in leukemia cells. The induced in vivo expression of RIP3-KD but not RIP3-WT prolonged the survival of mice injected with leukemia cells. The expression of RIP3-KD induced p65/RelA nuclear factor-κB (NF-κB) subunit caspase-dependent cleavage, and a non-cleavable p65/RelA D361E mutant rescued these cells from apoptosis. p65/RelA cleavage appears to be at least partially mediated by caspase-6. These data indicate that RIP3 silencing in leukemia cells results in suppression of the complex regulation of the apoptosis/necroptosis switch and NF-κB activity.
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Caspasas/metabolismo , Leucemia Mieloide Aguda/patología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Factor de Transcripción ReIA/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Caspasa 6/metabolismo , Inhibidores de Caspasas/farmacología , Caspasas/química , Línea Celular , Femenino , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Datos de Secuencia Molecular , FN-kappa B/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Células Tumorales CultivadasRESUMEN
The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the BCR-ABL oncoprotein, which signals several downstream cell survival pathways, including phosphoinositide 3-kinase/AKT, signal transducer and activator of transcription 5 and extracellular signal-regulated kinase 1/2. In patients with CML, tyrosine kinase inhibitors (TKIs) are used to suppress the BCR-ABL tyrosine kinase, resulting in impressive response rates. However, resistance can occur, especially in acute-phase CML, through various mechanisms. Here, we show that the glucocorticoid-induced leucine zipper protein (GILZ) modulates imatinib and dasatinib resistance and suppresses tumor growth by inactivating the mammalian target of rapamycin complex-2 (mTORC2)/AKT signaling pathway. In mouse and human models, GILZ binds to mTORC2, but not to mTORC1, inhibiting phosphorylation of AKT (at Ser473) and activating FoxO3a-mediated transcription of the pro-apoptotic protein Bim; these results demonstrate that GILZ is a key inhibitor of the mTORC2 pathway. Furthermore, CD34(+) stem cells isolated from relapsing CML patients underwent apoptosis and showed inhibition of mTORC2 after incubation with glucocorticoids and imatinib. Our findings provide new mechanistic insights into the role of mTORC2 in BCR-ABL(+) cells and indicate that regulation by GILZ may influence TKI sensitivity.
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Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Benzamidas , Línea Celular Tumoral , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proteínas de la Membrana/metabolismo , Ratones , Fosforilación , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Factores de Transcripción , TransfecciónRESUMEN
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 TratamientoAsunto(s)
Isocitrato Deshidrogenasa/genética , Mutación/genética , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Proteínas de Unión al ADN/genética , Dioxigenasas , Humanos , Janus Quinasa 2/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Síndromes Mielodisplásicos/patología , Trastornos Mieloproliferativos/patología , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Human adenoviruses (HAdV) are widely used for in vitro and in vivo gene transfer. Viral hepatotropism, inflammatory responses and neutralization by pre-existing antibodies (NAbs) are obstacles for clinical applications of HAdV vectors. Although the multifactorial events leading to innate HAdV toxicity are far from being elucidated, there is a consensus that the majority of intravenously injected-HAdV vectors is sequestered by Kuppfer cells, probably independently of coagulation factors. In this study, we show that the adenoviral-associated humoral and innate cytokine immune responses are significantly reduced when HAdV-5 vector carrying human bovine chimeric fibers (HAdV-5-F2/BAdV-4) is intravenously injected into mice. Fiber pseudotyping modified its interaction with blood coagulation factors, as FIX and FX no longer mediate the infection of liver cells by HAdV-5-F2/BAdV-4. As a consequence, at early time points post-infection, several cytokines and chemokines (IFN-gamma, IL-6, IP-10, MCP-1, RANTES and MP1beta) were found to be present at lower levels in the plasma of mice that had been intravenously injected with HAdV-5-F2/BAdV-4 compared with mice injected with the parental vector HAdV-5. Moreover, genetic modification of the fiber allowed HAdV-5-F2/BAdV-4 to partially escape neutralization by NAbs.
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Adenoviridae/genética , Adenovirus Humanos/genética , Quimera , Hepatocitos/virología , Inmunidad Innata , Adenoviridae/inmunología , Adenoviridae/patogenicidad , Adenovirus Humanos/inmunología , Animales , Anticuerpos Antivirales , Factores de Coagulación Sanguínea/metabolismo , Bovinos , Línea Celular , Quimiocinas/análisis , Citocinas/análisis , Vectores Genéticos , Genoma Viral , Humanos , Inflamación/virología , Ratones , Transducción GenéticaAsunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Síndromes Mielodisplásicos/tratamiento farmacológico , Talidomida/administración & dosificación , Talidomida/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL(+) leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K+T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.
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Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Janus Quinasa 2/antagonistas & inhibidores , Mutación Missense , Comunicación Paracrina , Animales , Benzamidas , Línea Celular , Técnicas de Cocultivo , Dasatinib , Quinasas MAP Reguladas por Señal Extracelular , Mesilato de Imatinib , Interleucina-3 , Janus Quinasa 2/metabolismo , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos , Modelos Animales , Piperazinas/farmacología , Pirimidinas/farmacología , Factor de Transcripción STAT5 , Transducción de Señal , Tiazoles/farmacologíaAsunto(s)
Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/fisiología , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Leucemia Megacarioblástica Aguda/genética , Piperazinas/farmacología , Pirimidinas/farmacología , Adulto , Anciano , Benzamidas , Dasatinib , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Pirimidinas/uso terapéutico , Proteínas Recombinantes de Fusión/química , Tiazoles/uso terapéutico , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Leucemia Mieloide/tratamiento farmacológico , Premedicación , Enfermedad Aguda , Adolescente , Adulto , Amsacrina/administración & dosificación , Amsacrina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , División Celular/efectos de los fármacos , Terapia Combinada , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Leucemia Mieloide/cirugía , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Células Madre Neoplásicas/efectos de los fármacos , Modelos de Riesgos Proporcionales , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Riesgo , Terapia Recuperativa , Estimulación Química , Trasplante Homólogo , Resultado del TratamientoRESUMEN
In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBFalpha/beta genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in 17% patients. c-Kit exon 8 mutations were more frequent in inv(16) than in t(8;21) subset (20 versus 6%). Only one patient had FLT3-ITD but FLT3-D835 was as frequent as reported in AML population (7%). Ras mutations were significantly more frequent in inv(16) than in t(8;21) subset (36 versus 8%, P=0.001). RTK mutations were associated with a higher white blood cell count (WBC) (36 versus 21 G/L, P=0.05). FLT3 mutations were significantly associated with a shorter EFS and survival (P<0.0001 and P=0.0002) owing to an excess of early events. c-Kit mutations were associated with a shorter EFS and RFS (P=0.002 and P=0.003) in t(8;21) but not inv(16) patients. As previously observed, Ras mutations did not affect prognosis. Screening for RTK mutations may help to identify patients with a more adverse outcome and thus susceptible to benefit from intensified protocols or RTK inhibitors.
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Factores de Unión al Sitio Principal/genética , Leucemia Mieloide/genética , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Tirosina Quinasa 3 Similar a fms/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Preescolar , Exones , Femenino , Humanos , Lactante , Leucemia Mieloide/diagnóstico , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/ 806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26950/mm3 (7700-162000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARalpha isoform (P= 0.0003) and high WBC counts (> or = 10,000/ mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P= 0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (> or = 10,000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC > or = 10,000/mm3 at diagnosis remains to be established.