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1.
J Clin Lab Anal ; 36(2): e24221, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34979042

RESUMEN

OBJECTIVES: Platelet (PLT) recovery after chemotherapy is associated with the prognosis of patients with acute myeloid leukaemia (AML). This study aimed to explore the prognostic significance of early high PLT values in patients with de novo non-M3 AML who achieved first complete remission (CR). METHODS: A total of 206 patients with de novo non-M3 AML were analysed in this retrospective study. A receiver operating characteristic (ROC) curve was used to determine the optimal PLT cut-off. The overall survival (OS) and relapse-free survival (RFS) were assessed using Kaplan-Meier and Cox regression analyses. RESULTS: 312×109 /L was confined as the cut-off of the PLT count. The estimated 3-year OS of patients with high PLT was higher than that of their counterparts (72.3% vs. 34.6%, p = 0.001). In subgroup analysis, patients with high PLT had better OS in the favourable- and intermediate-risk (non-adverse-risk) AML (p = 0.001). The estimated 3-year RFS for the high and low PLT groups was 75.1% and 45.7% respectively (p = 0.078). Multivariate analyses revealed that high PLT count was an independent favourable variable for OS (HR = 0.264, p < 0.001) and RFS (HR = 0.375, p = 0.011) in the non-adverse-risk group. CONCLUSION: Our results showed that early high PLT count recovery at first CR in non-adverse-risk AML patients is a positive prognostic marker for survival outcomes.


Asunto(s)
Quimioterapia de Inducción , Leucemia Mieloide/sangre , Recuento de Plaquetas , Adolescente , Adulto , Anciano , Niño , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Inducción de Remisión , Estudios Retrospectivos
2.
Medicine (Baltimore) ; 100(35): e26959, 2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34477125

RESUMEN

ABSTRACT: The purpose of this study was to evaluate the correlation of long non-coding RNA maternally expressed gene 3 (Lnc-MEG3) with disease features, treatment response, and survival in pediatric acute myeloid leukemia (AML) patients.Among 92 de novo pediatric AML patients (before treatment and after 1 course of induction) and 40 controls, bone marrow mononuclear cells were obtained. Then, Lnc-MEG3 expression was determined by reverse transcription quantitative polymerase chain reaction. After 1 course of standard induction therapy of pediatric AML patients, complete remission (CR) was assessed. Furthermore, event-free survival (EFS) and overall survival (OS) were determined according to follow-up data.Lnc-MEG3 was reduced in pediatric AML patients compared with controls. In pediatric AML patients, Lnc-MEG3 was correlated with French-American-Britain subtypes and lower Chinese Medical Association risk stratification, while it was not associated with cytogenetic features, FLT3-ITD mutation, CEBPA mutation, NPM1 mutation, WT1 mutation, or National Comprehensive Cancer Network risk stratification. After 1 course of treatment, Lnc-MEG3 exhibited an up-regulation trend. Furthermore, Lnc-MEG3 was of no difference before treatment between patients with and without CR, while elevated Lnc-MEG3 and change of Lnc-MEG3 after 1 course of treatment were associated with increased CR rate. Additionally, increased Lnc-MEG3 expression before treatment was associated with longer EFS but not OS, while enhanced Lnc-MEG3 expression after 1 course of treatment was correlated with both prolonged EFS and OS.Lnc-MEG3 may have clinical significance as a biomarker for assisting with disease management, treatment optimization, and prognosis improvement in pediatric AML patients.


Asunto(s)
Biomarcadores de Tumor/análisis , Leucemia Mieloide/genética , Leucemia Mieloide/mortalidad , ARN Largo no Codificante/análisis , Niño , Preescolar , Femenino , Humanos , Leucemia Mieloide/complicaciones , Masculino , Nucleofosmina , Pronóstico , Inducción de Remisión
3.
Curr Hematol Malig Rep ; 16(3): 286-303, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33945086

RESUMEN

PURPOSE OF REVIEW: Monocytosis is a distinct but non-specific manifestation of various physiologic and pathologic conditions. Among hematopoietic stem cell neoplasms, depending on the criteria used for disease classification, monocytosis may be a consistent and integral component of diseases such as chronic myelomonocytic leukemia or acute myeloid leukemia with monocytic differentiation, or it may represent an inconsistent finding that often provides a clue to the underlying genetic changes driving the neoplasm. The purpose of this review is to provide the readers with a laboratory-based approach to neoplastic monocytosis. RECENT FINDINGS: In-depth elucidation of the genomic landscape of myeloid neoplasms within the past few years has broadened our understanding of monocytosis and its implications for diagnosis and prognosis. Genetic findings also shed light on potential disease response - or lack thereof - to various therapeutic agents used in the setting of myeloid neoplasms. In this review, we provide our approach to diagnose neoplastic monocytosis in the context of case-based studies while incorporating the most recent literature on this topic.


Asunto(s)
Leucemia Mieloide/diagnóstico , Leucemia Mielomonocítica Crónica/diagnóstico , Factores de Edad , Biomarcadores , Médula Ósea/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Manejo de la Enfermedad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Leucemia Mieloide/etiología , Leucemia Mieloide/mortalidad , Leucemia Mielomonocítica Crónica/etiología , Leucemia Mielomonocítica Crónica/mortalidad , Monocitos/metabolismo , Monocitos/patología
4.
Curr Hematol Malig Rep ; 16(3): 276-285, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33890194

RESUMEN

PURPOSE OF REVIEW: In this review, we provide a comprehensive and contemporary understanding of malignant monocytosis and provide a framework by which the appropriate diagnosis with malignant monocytosis can be rendered. RECENT FINDINGS: Increasing data support the use of molecular data to refine the diagnostic approach to persistent monocytosis. The absence of a TET2, SRSF2, or ASXL1 mutation has ≥ 90% negative predictive value for a diagnosis of CMML. These data may also reliably differentiate chronic myelomonocytic leukemia, the malignancy that is most associated with mature monocytosis, from several other diseases that can be associated with typically a lesser degree of monocytosis. These include acute myelomonocytic leukemia, acute myeloid leukemia with monocytic differentiation, myelodysplastic syndromes, and myeloproliferative neoplasms driven by BCR-ABL1, PDGFRA, PDGFRB, or FGFR1 rearrangements or PCM1-JAK2 fusions among other rarer aberrations. The combination of monocyte partitioning with molecular data in patients with persistent monocytosis may increase the predictive power for the ultimate development of CMM but has not been prospectively validated. Many conditions, both benign and malignant, can be associated with an increase in mature circulating monocytes. After reasonably excluding a secondary or reactive monocytosis, there should be a concern for and investigation of malignant monocytosis, which includes hematopathologic review of blood and marrow tissues, flow cytometric analysis, and cytogenetic and molecular studies to arrive at an appropriate diagnosis.


Asunto(s)
Susceptibilidad a Enfermedades , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/etiología , Monocitos/metabolismo , Monocitos/patología , Edad de Inicio , Algoritmos , Animales , Biomarcadores de Tumor , Biopsia , Médula Ósea/patología , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Regulación Leucémica de la Expresión Génica , Humanos , Inmunohistoquímica , Leucemia Mieloide/mortalidad , Leucemia Mieloide/terapia , Neoplasias Primarias Secundarias/etiología
5.
Blood ; 136(14): 1670-1684, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32492700

RESUMEN

Additional sex combs-like 1 (ASXL1), an epigenetic modulator, is frequently mutated in myeloid neoplasms. Recent analyses of mutant ASXL1 conditional knockin (ASXL1-MT-KI) mice suggested that ASXL1-MT alone is insufficient for myeloid transformation. In our previous study, we used retrovirus-mediated insertional mutagenesis, which exhibited the susceptibility of ASXL1-MT-KI hematopoietic cells to transform into myeloid leukemia cells. In this screening, we identified the hematopoietically expressed homeobox (HHEX) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between ASXL1-MT and HHEX in myeloid leukemogenesis. Expression of HHEX enhanced proliferation of ASXL1-MT-expressing HSPCs by inhibiting apoptosis and blocking differentiation, whereas it showed only modest effect in normal HSPCs. Moreover, ASXL1-MT and HHEX accelerated the development of RUNX1-ETO9a and FLT3-ITD leukemia. Conversely, HHEX depletion profoundly attenuated the colony-forming activity and leukemogenicity of ASXL1-MT-expressing leukemia cells. Mechanistically, we identified MYB and ETV5 as downstream targets for ASXL1-MT and HHEX by using transcriptome and chromatin immunoprecipitation-next-generation sequencing analyses. Moreover, we found that expression of ASXL1-MT enhanced the binding of HHEX to the promoter loci of MYB or ETV5 via reducing H2AK119ub. Depletion of MYB or ETV5 induced apoptosis or differentiation in ASXL1-MT-expressing leukemia cells, respectively. In addition, ectopic expression of MYB or ETV5 reversed the reduced colony-forming activity of HHEX-depleted ASXL1-MT-expressing leukemia cells. These findings indicate that the HHEX-MYB/ETV5 axis promotes myeloid transformation in ASXL1-mutated preleukemia cells.


Asunto(s)
Transformación Celular Neoplásica/genética , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Mutación , Células Mieloides/metabolismo , Proteínas Represoras/genética , Factores de Transcripción/genética , Animales , Apoptosis/genética , Biomarcadores de Tumor , Biopsia , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Ciclo Celular/genética , Diferenciación Celular/genética , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Ensayo de Unidades Formadoras de Colonias , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Estudios de Asociación Genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Inmunofenotipificación , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/mortalidad , Leucemia Mieloide/patología , Ratones , Células Mieloides/patología , Pronóstico , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo
6.
Int J Hematol ; 111(2): 247-255, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31701479

RESUMEN

Although the combination of fludarabine and high-dose melphalan (FLU/MEL) has been widely used in allogeneic stem cell transplantation, high-dose MEL causes life-threatening adverse events, especially in elderly patients. To reduce the toxicity of MEL without losing its antileukemic effect, we formulated a regimen comprising FLU (125 mg/m2), MEL (100 mg/m2), and a non-myeloablative busulfan dosage [4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. We retrospectively analyzed 32 patients with myeloid malignancies who received FLU/MEL/BU at our institute. Median age was 59 years and the median observation period after allo-SCT was 8.2 years. The disease status of most of the patients (97%) at transplantation was controlled. The rate of neutrophil engraftment was 93.3%. The 5-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) were 68.5%, 62.1%, 22.0%, and 15.9%, respectively, in all patients. Notably, the outcome of FLU/MEL/iv BU was excellent, with the 5-year OS and DFS being 75.6% and 70.8%, respectively, accompanied by a reduced 5-year NRM and RR of 19.3% and 9.8%, respectively. In conclusion, FLU/MEL/BU, particularly FLU/MEL/iv BU, has curative potential for controlled myeloid malignancies.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Busulfano/administración & dosificación , Leucemia Mieloide/tratamiento farmacológico , Melfalán/administración & dosificación , Vidarabina/análogos & derivados , Busulfano/efectos adversos , Humanos , Leucemia Mieloide/mortalidad , Melfalán/efectos adversos , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/efectos adversos
7.
Blood ; 135(4): 261-268, 2020 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-31697811

RESUMEN

Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer-associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73 to 94 years, all with >20 years' follow-up. We sequenced DNA from peripheral blood with a customized 21-gene panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in 2 twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins was found for any specific gene, subgroup, or CHIP mutations overall, and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases, the affected twin died first (P = .72). Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.


Asunto(s)
Hematopoyesis , Leucemia Mieloide/genética , Gemelos/genética , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Enfermedades en Gemelos/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidad , Humanos , Leucemia Mieloide/mortalidad , Masculino , Mutación , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética
8.
Transfus Clin Biol ; 26(4): 217-223, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31420221

RESUMEN

OBJECTIVES: Myelodysplastic syndrome (MDS) is a highly mortal disease in which anemia is unresponsive to treatment. In this study, the effect of basal ferritin values on prognosis and survival was investigated in MDS patients without history of transfusion. METHODS: Data were retrospectively analyzed for 62 MDS cases. The cases were divided into two groups according to ferritin values. RESULTS: The mean survival time was 61.1±4.8 months. During the follow-up period, 34 (54.8%) patients deceased. Median ferritin level was 358ng/mL. The serum ferritin (SF) level associated with mortality was determined as 400ng/mL (ROC area for SF was 0.731 with a cutoff value of 400; sensitivity and specificity were 70.7% and 68.2%, respectively) (P=0.002). There were 29 (46.8%) patients with serum ferritin levels of ≥400ng/mL. Patients with serum ferritin levels≥400ng/mL had low survival rates. Ferritin≥400ng/mL was associated with six times increased mortality (P=0.001). CONCLUSION: Although the acceptable ferritin level at the start of chelation therapy is 1000ng/mL, the fact that 400ng/mL value is associated with survival in our study suggests that it may be useful to start chelation therapy in the early period. Further case studies on the subject are required.


Asunto(s)
Ferritinas/sangre , Síndromes Mielodisplásicos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Linaje de la Célula , Progresión de la Enfermedad , Eritrocitos Anormales/ultraestructura , Femenino , Fibrosis , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Estudios Retrospectivos , Sensibilidad y Especificidad , Análisis de Supervivencia
9.
Cancer ; 125(21): 3845-3852, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31299106

RESUMEN

BACKGROUND: Older adults with acute myeloid leukemia (AML) are often assumed to have poor outcomes after admission to the intensive care unit (ICU). However, little is known about ICU utilization and post-ICU outcomes in this population. METHODS: The authors conducted a retrospective analysis for 330 patients who were 60 years old or older and were diagnosed with AML between 2005 and 2013 at 2 hospitals in Boston.They used descriptive statistics to examine the proportion of patients admitted to the ICU as well as their mortality and functional recovery. They used logistic regression to identify risk factors for in-hospital mortality. RESULTS: Ninety-six patients (29%) were admitted to the ICU, primarily because of respiratory failure (39%), septic shock (28%), and neurological compromise (9%). The proportions of patients who survived to hospital discharge, 90 days, and 1 year were 47% (45 of 96), 35% (34 of 96), and 30% (29 of 96), respectively. At 90 days, 76% of the patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and 86% were in complete remission (CR) and/or continued to receive AML-directed therapy. In a multivariate analysis, a poorer baseline ECOG PS score (odds ratio, 2.76; P = .013) and the need for 2 or more life-sustaining therapies (ie, vasopressors, invasive ventilation, and/or renal replacement therapy; odds ratio, 12.4; P < .001) were associated with increased odds of in-hospital mortality. CONCLUSIONS: Although almost one-third of older patients with AML are admitted to an ICU, nearly half survive to hospital discharge with good functional outcomes. The baseline performance status and the need for 2 or more life-sustaining therapies predict hospital mortality. These data support the judicious use of ICU resources for older patients with AML.


Asunto(s)
Mortalidad Hospitalaria/tendencias , Hospitalización/estadística & datos numéricos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Leucemia Mieloide/terapia , Enfermedad Aguda , Anciano , Boston , Femenino , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Pronóstico , Estudios Retrospectivos
11.
Leukemia ; 33(12): 2842-2853, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31089247

RESUMEN

Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.


Asunto(s)
Leucemia Mieloide/etiología , Mutación , Síndromes Mielodisplásicos/genética , Neoplasias Primarias Secundarias/etiología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Biomarcadores , Biopsia , Aberraciones Cromosómicas , Análisis Citogenético , Diagnóstico Diferencial , Femenino , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Tasa de Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/mortalidad , Pronóstico , Adulto Joven
12.
N Engl J Med ; 380(17): 1628-1637, 2019 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-31018069

RESUMEN

BACKGROUND: Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin. METHODS: In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 µg or 12 µg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response. RESULTS: Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 µg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups. CONCLUSIONS: In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).


Asunto(s)
Antineoplásicos/administración & dosificación , Células Dendríticas , Leucemia Mieloide/tratamiento farmacológico , Proteínas Recombinantes de Fusión/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Síndrome de Fuga Capilar/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/efectos adversos , Adulto Joven
13.
Lifetime Data Anal ; 25(1): 168-188, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29374789

RESUMEN

The aim of this study is to provide an analysis of gap event times under the illness-death model, where some subjects experience "illness" before "death" and others experience only "death." Which event is more likely to occur first and how the duration of the "illness" influences the "death" event are of interest. Because the occurrence of the second event is subject to dependent censoring, it can lead to bias in the estimation of model parameters. In this work, we generalize the semiparametric mixture models for competing risks data to accommodate the subsequent event and use a copula function to model the dependent structure between the successive events. Under the proposed method, the survival function of the censoring time does not need to be estimated when developing the inference procedure. We incorporate the cause-specific hazard functions with the counting process approach and derive a consistent estimation using the nonparametric maximum likelihood method. Simulations are conducted to demonstrate the performance of the proposed analysis, and its application in a clinical study on chronic myeloid leukemia is reported to illustrate its utility.


Asunto(s)
Simulación por Computador , Leucemia Mieloide/mortalidad , Análisis de Regresión , Análisis de Supervivencia , Causas de Muerte , Exactitud de los Datos , Análisis de Datos , Progresión de la Enfermedad , Humanos , Leucemia Mieloide/fisiopatología , Funciones de Verosimilitud , Modelos Estadísticos , Factores de Tiempo
14.
Int J Hematol ; 109(2): 197-205, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30448938

RESUMEN

A conditioning regimen with fludarabine and myeloablative dose of busulfan (FLU/BU4) has been commonly used in allogeneic hematopoietic cell transplantation (allo-HCT). However, there are two major problems with this regimen: insufficient anti-leukemic effect, especially in advanced cases, and slow time to complete donor-type chimerism, especially T-cell chimerism. To overcome these issues, we designed a combination regimen with FLU (150 mg/m2), intravenous BU (12.8 mg/kg), and melphalan (100 mg/m2) (FLU/BU4/MEL) and conducted retrospective analyses of treatment outcomes at our institute. Forty-two patients with myeloid malignancies received allogeneic bone-marrow transplantation or peripheral blood stem-cell transplantation (allo-BMT/PBSCT) with FLU/BU4/MEL regimen. The median age of patients was 46.5 years (20-63 years). Thirteen patients (31%) did not achieve complete hematological remission at transplantation. All patients examined achieved complete whole and T-cell chimerism within 1 month after allo-HCT. The 4-year overall survival and disease-free survival rates were 66.0% [95% confidence interval (CI) 49.4-78.3%] and 59.5% (95% CI 43.2-72.6%) in all patients, and 49.4% (95% CI 19.7-73.6%) and 38.5% (95% CI 14.1-62.8%) in patients who were not in remission. In conclusion, FLU/BU4/MEL showed curative potential, even in patients with advanced myeloid malignancies, accompanied by achievement of rapid complete chimerism after allo-BMT/PBSCT.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide/terapia , Melfalán/administración & dosificación , Sarcoma Mieloide/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Trasplante de Médula Ósea/métodos , Busulfano/uso terapéutico , Quimerismo/efectos de los fármacos , Femenino , Humanos , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Trasplante de Células Madre de Sangre Periférica/métodos , Estudios Retrospectivos , Sarcoma Mieloide/mortalidad , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Adulto Joven
15.
Cancer Genomics Proteomics ; 16(1): 91-98, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30587503

RESUMEN

BACKGROUND: Mutations in splicing factor 3b subunit 1 (SF3B1) have been reported to be associated with a favorable prognosis, while the prognostic impact of tet methylcytosine dioxygenase 2 (TET2) mutations is still controversial. The clinical significance of combined SF3B1 and TET2 mutation is even more uncertain. In this study, the clinical consequences of concurrent double SF3B1/TET2 mutation were compared with isolated SF3B1 or TET2 mutation. MATERIALS AND METHODS: The demographics, diagnosis, cytogenetic abnormalities, and overall survival time of 130 patients with isolated SF3B1 (n=48) or TET2 mutation (n=54), or double SF3B1/TET2 mutation (n=28) were compared by next-generation sequencing. RESULTS: Patients with double mutation were found to be significantly older than patients with isolated TET2 mutation. Patients with double mutation or isolated SF3B1 mutation were less likely to be diagnosed with acute myeloid leukemia than patients with isolated TET2 mutation. Patients with myelodysplasia had a higher percentage of double or isolated SF3B1 mutation, while patients with myeloproliferative neoplasms had a higher percentage of isolated TET2 mutation. Patients with double mutation more frequently had increased ring sideroblasts similarly to patients with isolated SF3B1 mutation. The percentage of patients with normal cytogenetics or good cytogenetic abnormalities was significantly higher in patients with double mutation than those with isolated mutation. Finally, in patients with myelodysplasia and normal cytogenetics, the median survival time in those with double mutation was significantly longer than in those with isolated SF3B1 mutation, even though the overall survival curve was not statistically significant. CONCLUSION: TET2 mutation appeared not to have additional effects when combined with SF3B1, and patients with double mutation appeared to have at least as, good as or even better prognosis than patients with isolated mutation.


Asunto(s)
Biomarcadores de Tumor , Proteínas de Unión al ADN/genética , Mutación , Neoplasias/genética , Neoplasias/mortalidad , Fosfoproteínas/genética , Proteínas Proto-Oncogénicas/genética , Factores de Empalme de ARN/genética , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Dioxigenasas , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide/genética , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Pronóstico
16.
Am J Hematol ; 93(11): 1337-1346, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30105844

RESUMEN

The work-up of patients with hypereosinophilia (HE) is complex. Following the recently revised World Health Organization criteria, we retrospectively reviewed 125 patients who were referred to us to exclude a neoplastic cause of HE (2003-2016). The clinical laboratory work-up confirmed secondary HE in 25 (20%) patients; myeloid/lymphoid neoplasms with rearrangements of PDGFRA (n = 9) or PDGFRB (n = 2) (9%); HE associated with a well-defined myeloid neoplasm in 8 (6%); and abnormal bone marrow and/or molecular genetic abnormalities consistent with chronic eosinophilic leukemia (CEL), not otherwise specified (NOS) in 21 (17%) patients. For the remaining 60 (48%) patients, a specific diagnosis was not identified, and 56 patients had HE related findings consistent with idiopathic hypereosinophilic syndrome (HES), while 4 patients who were asymptomatic. With a median follow up of 35.3 months (range, <1-104), patients with CEL, not otherwise specified (NOS) had a median OS of 26.1 months, significantly inferior to patients with idiopathic HES (not reached, P < .01). Thus, our experience in a single tertiary cancer center shows that the work-up of HE following WHO recommendations requires a multimodality-based approach; and a correct diagnosis determines risk stratification and proper patient management. However, the causes of HE remain unknown in approximately half of referred patients, indicating the need for further studies.


Asunto(s)
Síndrome Hipereosinofílico/diagnóstico , Leucemia Mieloide/diagnóstico , Leucemia/diagnóstico , Adulto , Terapia Combinada , Manejo de la Enfermedad , Humanos , Síndrome Hipereosinofílico/complicaciones , Síndrome Hipereosinofílico/etiología , Síndrome Hipereosinofílico/mortalidad , Leucemia/mortalidad , Leucemia Mieloide/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Tasa de Supervivencia
17.
Nat Commun ; 9(1): 2733, 2018 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-30013160

RESUMEN

ASXL1 mutations occur frequently in myeloid neoplasms and are associated with poor prognosis. However, the mechanisms by which mutant ASXL1 induces leukaemogenesis remain unclear. In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis. BAP1 expression results in increased monoubiquitination of ASXL1-MT, which in turn increases the catalytic function of BAP1. This hyperactive ASXL1-MT/BAP1 complex promotes aberrant myeloid differentiation of haematopoietic progenitor cells and accelerates RUNX1-ETO-driven leukaemogenesis. Mechanistically, this complex induces upregulation of posterior HOXA genes and IRF8 through removal of H2AK119 ubiquitination. Importantly, BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity of ASXL1-MT-expressing myeloid leukemia cells. Furthermore, BAP1 is also required for the growth of MLL-fusion leukemia cells with posterior HOXA gene dysregulation. These data indicate that BAP1, which has long been considered a tumor suppressor, in fact plays tumor-promoting roles in myeloid neoplasms.


Asunto(s)
Carcinogénesis/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide/genética , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Animales , Médula Ósea/metabolismo , Médula Ósea/patología , Trasplante de Médula Ósea , Sistemas CRISPR-Cas , Carcinogénesis/metabolismo , Carcinogénesis/patología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Edición Génica , Células HEK293 , Células HeLa , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Leucemia Mieloide/metabolismo , Leucemia Mieloide/mortalidad , Leucemia Mieloide/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinación , Irradiación Corporal Total
19.
Curr Med Res Opin ; 34(5): 757-763, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-28027687

RESUMEN

BACKGROUND: ASXL1 gene mutations include nonsense, missense, and frameshift mutations. Although their clinical significance is still debated, they may play an important role in the pathogenesis of several hematologic malignancies. METHODS: Herein, we offer a comprehensive review on ASXL1 mutations, and link them with survival and clinical outcomes in patients with various myeloid neoplasms. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2016. FINDINGS: In acute myeloid leukemia (AML), ASXL1 mutations tend to correlate with older age and male gender, and affect predominantly patients with secondary AML. De novo AML patients with ASXL1 mutations had significantly lower complete remission rates after standard high-dose chemotherapy and shorter survival. In chronic myelomonocytic leukemia and low- or intermediate-risk myelodysplastic syndromes, frameshift and nonsense mutations correlated with shorter survival and a higher risk of leukemic transformation. Overall survival was also shorter in primary myelofibrosis in the presence of ASXL1 mutations. CONCLUSIONS: Further research on the role of ASXL1 mutations and therapeutic implications in neoplastic myeloid disorders is stringently needed. Given the relatively high prevalence of ASXL1 mutations, larger studies involving patients affected by these mutations will be feasible in the near future.


Asunto(s)
Proteínas Represoras/genética , Anciano , Femenino , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/mortalidad , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología
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