RESUMEN
Little evidence exists regarding the prognostic impact of the major BCR-ABL gene variants (e13a2 and e14a2) in chronic myeloid leukemia (CML) patients diagnosed and treated in the developing Asian countries. In this study, 139 Thai CML patients were followed for a median period of 3 years (range 18-43 months). Clinical presentations of both BCR-ABL gene variant groups (73% e14a2+ and 27% e13a2+) were similar, although e14a2+ patients tended to be older (42 vs. 37 years) and had higher white blood cell counts than e13a2+ patients. The majority of patients in both groups presented with Sokal stage 2-3 (score >0.8) and were categorized as Hasford's intermediate- to high-risk groups (score >780). All patients received oral chemotherapy and 13% underwent allogeneic stem cell transplantation. None received oral tyrosine kinase inhibitors. In the conventional chemotherapy group, the overall survival (OS) rate was slightly better in e14a2+ than in e13a2+ patients (p = n.s.). The median survival in e14a2+ and e13a2+ patients who did not receive stem cell transplantation was 49 and 33 months, respectively (p = n.s.). The type of blastic crisis in e14a2+ and e13a2+ patients was similar, being predominantly myeloid. In conclusion, CML patients in Thailand, despite being much younger, had a comparable OS with those in the Western countries, with no different OS between e14a2+ and e13a2+ patients. Future studies should focus on the impact of novel oral BCR-ABL tyrosine kinase inhibitors on the outcome of Thai CML patients with different BCR-ABL gene variants.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Genes abl , Variación Genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Trasplante de Células Madre , Tailandia , Trasplante HomólogoRESUMEN
Xenograft models of chronic phase human chronic myeloid leukemia (CML) have been difficult to develop because of the persistence of normal hematopoietic stem cells in most chronic phase CML patients and the lack of methods to selectively isolate the rarer CML stem cells. To circumvent this problem, we first identified nine patients' samples in which the long-term culture-initiating cells were predominantly leukemic and then transplanted cells from these samples into sublethally irradiated NOD/SCID and NOD/SCID-beta2microglobulin-/- mice. This resulted in the consistent and durable (>5 months) repopulation of both host genotypes with similar numbers of BCR-ABL+/Ph+ cells. The regenerated leukemic cells included an initial, transient population derived from CD34+CD38+ cells as well as more sustained populations derived from CD34+CD38- progenitors, indicative of a hierarchy of transplantable leukemic cells. Analysis of the phenotypes produced revealed a reduced output of B-lineage cells, enhanced myelopoiesis with excessive production of erythroid and megakaropoietic cells and the generation of primitive (CD34+) leukemic cells displaying an autocrine IL-3 and G-CSF phenotype, all characteristics of primary CML cells. These findings demonstrate the validity of this xenograft model of chronic phase human CML, which should enable future investigation of disease pathogenesis and new approaches to therapy.
Asunto(s)
Modelos Animales de Enfermedad , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/patología , Leucemia Experimental/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/trasplante , Animales , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Interleucina-3/genética , Interleucina-3/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Fenotipo , Quimera por Radiación , Factores de Tiempo , Trasplante Heterólogo/métodosRESUMEN
Very limited data exists in Thailand regarding the frequency of BCR-ABL leukemic gene and its prognostic implication in Thai CML patients. The objective of this study was to develop a rapid molecular assay for the detection of the two most commonly reported variants of BCR-ABL fusion gene, B2A2 and B3A2 in CML patients. Bone marrow or peripheral blood were used for RNA extraction and reverse-transcribed to cDNA for PCR amplification. 92 per cent of CML patients (91/99) were positive for BCR-ABL gene (61% B3A2 and 31% B2A2). 8/99 CML patients were BCR-ABL-negative. B3A2 and B2A2-positive patients did not have any different clinical and hematological features at presentation although B3A2 patients tended to be slightly older and had higher platelet counts. 71/71 non-CML including other MPD and leukemia cases were all negative for BCR-ABL gene. In conclusion, a rapid RT-PCR assay has now been developed for the detection of this hallmark gene in CML patients. It should be of great value in the differential diagnosis of CML from other diseases. Long-term follow-ups of CML patients with different variants are needed to determine the prognostic importance of each gene variant.
Asunto(s)
Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Médula Ósea/patología , Proteínas de Fusión bcr-abl/análisis , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Adulto , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Diagnóstico Diferencial , Femenino , Proteínas de Fusión bcr-abl/sangre , Humanos , Masculino , Pronóstico , Reproducibilidad de los Resultados , TailandiaRESUMEN
Stem cell transplantation (SCT) has become the therapy of choice for many hematologic and immunologic disorders. At present, only 25% of patients have suitable HLA-identical donors. In an attempt to increase the donor pool for SCT in Thailand and Southeast Asia, we developed a program whereby parents and mismatched siblings can be used as donors. In this preliminary study, after granulocyte-colony-stimulating factor (G-CSF) was given to adult donors, peripheral blood stem cells (PBSC) were collected and CD34+ cells purified using a CliniMACS immunomagnetic device (Miltenyi Biotec, Germany). In seven experiments, purified CD34+ cells could be obtained from G-CSF-stimulated PBSC in large numbers (1.71 +/- 0.19 x 10(8)), with high purity (93 +/- 2.4%) and excellent recovery (64.28% - 85.62%). Immune reactive T and NK cells were adequately depleted to less than 0.2%. The purification procedure can be completed within 3 hours. In conclusion, a clinical stem cell purification program using this novel device is now established in Thailand and for the first time in Southeast Asia. This should allow further development of advanced SCT therapy including haploidentical and mismatched CD34+ SCT for patients' lacking HLA-identical donors in this region.
Asunto(s)
Donantes de Sangre , Trasplante de Células Madre Hematopoyéticas/métodos , Adulto , Antígenos CD34/análisis , Recuento de Células Sanguíneas , Citometría de Flujo , Enfermedad Injerto contra Huésped/prevención & control , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/inmunología , Humanos , Separación Inmunomagnética , Leucaféresis , Depleción Linfocítica , Núcleo Familiar , Padres , TailandiaRESUMEN
Aplastic anemia has been reported to occur after viral hepatitis of unknown etiology. Recently, TT virus (TTV), a novel DNA virus, was identified in a Japanese patient with posttransfusion non-A-E hepatitis. The prevalence of TTV infection was investigated among blood donors and patients with aplastic anemia in Thailand. Of 99 blood samples from blood donors, 37 tested positive for TTV DNA via semi-nested polymerase chain reaction (PCR) using TTV-specific primers. Seventeen percent of samples from blood donors younger than 20 were positive for TTV DNA, whereas 48% from donors older than 20 were positive. The high prevalence of TTV infection in Thailand is comparable to that reported in China (28%), Mongolia (43%), and Egypt (29%). Forty-two percent of newly diagnosed aplastic anemia patients tested also had TTV DNA in blood. The detection rate of TTV DNA in aplastic anemia patients does not differ significantly from rates in normal blood donors. Our present data thus argue against the role of this novel hepatitis-associated virus in the pathogenesis of aplastic anemia in Thailand. However, larger epidemiological studies may be needed to further evaluate their association.