Azacitidine ; analogs & derivatives ; therapeutic use ; Humans ; Myelodysplastic Syndromes ; drug therapy

OBJECTIVETo investigate the effect of all transretinoicacid(ATRA) combined with decitabine (5-Aza-2'-deoxycytidine;DAC) on DNA methylation and gene expression of p16INK4a (p16) and retinoic acid receptor β (RARβ), and to explore their combined anti neoplastic effect on U937 cells and newly diagnose delder acute myeloid leukemia(AML) patients.

METHODSThe expression levels of p16 and RARβ were determined by qRT-PCR and Western blot. Methylation-specific PCR was used to analyze their methylation status. WST-1 and flow cytometry were performed to detect growth inhibition, differentiation, apoptosis and cell cycle of U937 cells respectively.

RESULTSThe expression p16 and RARβ was down-regulated by promoter hypermethylation in newly diagnose delder AML patients and U937 cells. Combination treatment of ATRA and DAC induced DNA hypomethylation as well as gene expression of p16 and RARβ, which contributed to the growth inhibition, differentiation, apoptosis and cell cycle arrest of U937 cells. In addition for elder AML patients intolerable to standard chemotherapy, the combination regimen of ATRA and DAC showed antineoplastic activity accompamied by up-regulation of p16 and RARβ expression and decrease of bone marrow blast, moreover the parients showed good tolerence to the reginen.

CONCLUSIONThe regimen of ATRA combined with DAC as the combination therapeutic strategy for inducing differentiation and demethylation possesses the anti-AML potency, and contributes to optimizing the therapeutic strategy for elder AML patients and promoting the clinical prognosis.

Azacitidine ; analogs & derivatives ; Decitabine ; Humans ; Leukemia, Myeloid, Acute ; Tretinoin ; U937 Cells

Myelodysplastic syndrome (MDS) is a clonal marrow stem cell disorder, characterized by ineffective haemopoiesis leading to blood cytopenias. As a disease of grey zone, along with the development of research, the exploration on its pathogenesis have been shifted from molecular genetics and the feature of immunophenotype to the epigenetic and micro environment. But at present, the pathogenesis of MDS is still not clear, the research of the molecular genetics and immunophenotype can not meet the needs of experimental and clinical application any longer. The hematopoietic stem cells, cytokines, epigenetic studies, however, have made a lot of achievements. Targeted medicine such as azacitidine and decitabine had promising response in treating MDS patients. In this article the abnormality of stromal cells, cytokines and epigenetic changes in hematopoietic microenvironment of MDS are reviewed in order to optimize the monitoring MDS progress and guide its clinical medication strategy.
Azacitidine ; analogs & derivatives ; Bone Marrow ; Cytokines ; Hematopoietic Stem Cells ; Humans ; Immunophenotyping ; Myelodysplastic Syndromes ; Stromal Cells

Azacitidine ; analogs & derivatives ; therapeutic use ; Clinical Trials, Phase III as Topic ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; Multicenter Studies as Topic

OBJECTIVETo evaluate the efficacy of decitabine (DAC) bridging therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic syndrome (MDS).

METHODSThe clinical characteristics and curative effect of MDS patients who received allo-HSCT from 2010 July to 2013 December were retrospectively analyzed. Of them, 25 MDS patients who received decitabine bridging allo-HSCT were randomly selected (referred to as the bridging group),while at the same time another 33 MDS patients who did not receive decitabine for allo-HSCT in MDS were also randomly selected as control group. The effect of decitabine bridging allo-HSCT on the patients' survival and occurrence of graft versus host disease (GVHD) was analyzed.

RESULTSWith decitabine bridge therapy, 64.0% patients (16/25) achieved marrow complete remission before allo-HSCT, while the control group was only 15.1% (5/33, P<0.05). Decitabine bridging group of early transplant-related mortality was lower than that of the control group (4.0% vs 18.2%), but the difference was not statistically significant (P=0.106). Up to follow-up deadline, the mortality of decitabine bridging group was 12.0%, while that of the control group was 30.3% (P<0.05). The 2-year OS of decitabine bridging group was 83.0%, while that of the control group was 59.0% (P<0.05). Of the 14 patients in decitabine bridging group with aGVHD, 7 was grade IaGVHD, 3 grade II and 4 grade III. Of the 16 patients in control group with aGVHD, 7 was grade IaGVHD, 8 grade II and 1 grade III.

CONCLUSIONDecitabine bridging therapy followed by allo-HSCT in the treatment of MDS is safe and effective.

Azacitidine ; analogs & derivatives ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Myelodysplastic Syndromes ; Retrospective Studies ; Transplantation, Homologous

Aged ; Antimetabolites, Antineoplastic ; therapeutic use ; Azacitidine ; analogs & derivatives ; therapeutic use ; Female ; Humans ; Leukemia, Myelomonocytic, Chronic ; drug therapy

Findings in epigenetic changes in meylodysplastic syndromes (MDS) and the development of demethylating drugs provide a new approach to the treatment of MDS. We used standard-dose decitabine for treatment of MDS in an elderly patient with an International Prostate Symptom Score (IPSS) of moderate risk group 2, and achieved a complete response in the first course. We report our experience with this case and review the relevant literatures.
Azacitidine ; analogs & derivatives ; therapeutic use ; DNA Modification Methylases ; antagonists & inhibitors ; Female ; Humans ; Middle Aged ; Myelodysplastic Syndromes ; drug therapy

OBJECTIVETo investigate the safety and efficacy of decitabine combined with CAG regimen in the treat-ment of newly diagnosed elderly patients with acute myeloid leukemia(AML).

METHODSFourty-nine patients with newly diagnosed acute myeloid leukemia (except M3) who were admitted to our hospital were selected. All the patients were older than 50 years old, and allogeneic hematopoietic stem cell transplantation could not be performed for various reasons. Decitabine-based chemotherapy regimens were used during induction therapy including single decitabine therapy(DAC), decitabine combined with CAG regimen(DAC-CAG) and decitabine combined with HAAG regimen(DAC-HAAG). Most of patients continued to use the original treatment after complete remission, while others were given the standard "3+7" regimen chemotherapy. A total of 2-4 courses of treatment was conducted in the majority of patients.

RESULTSAll of the 49 patients completed the induction therapy, in which 26 cases achieved complete remission(CR), 7 cases achieved partial remission(PR) and no response(NR) existed in 16 cases. The complete remission and the overall response rate(ORR) were 53% and 67% respectively. The overall response rate of DAC group, DAC-CAG group and DAC-HAAG group were 17%, 77% and 63% respectively. 14 patients were infected and 1 patients died of pulmonary infection during the induction therapy. The median number of suspended red blood cells and platelet infused were 9 units and 69 units respectively. Neutrophil recovery time was 15.1 days while the platelet recovery time was 20.1 days during the induction therapy. The mean follow-up time was 21 months. Overall survival(OS) was 75% at 6 months, 30% at 1 year, and 26% at 2 year, while disease-free survival(DFS) was 83% at 3 months, 54% at 1 year, and 47% at 2 year. The induction therapy could reach CR that was an independent prognostic factor, however, the initial white blood cell count, platelet count, age, chemotherapy regimen, prognostic stratification and whether complical by pnenmonia during chemotherapy were not independent prognostic factors.

CONCLUSIONThe induction efficacy of decitabine combined with chemotherapy is superior to that of decitabine alone. The outcome of induction chemotherapy is an independent prognostic factor, however, the high white blood cell count, poor karyotype, complications and AML with myelodysplasia-related changes do not affect long-term survival. DAC-CAG regimen is effective and have relatively few adverse reactions in AML. It is suitable for the patients who are ineligible for conventional chemotherapy.

Aged ; Antineoplastic Combined Chemotherapy Protocols ; Azacitidine ; analogs & derivatives ; Cytarabine ; Decitabine ; Humans ; Induction Chemotherapy ; Leukemia, Myeloid, Acute ; Middle Aged ; Remission Induction ; Treatment Outcome

OBJECTIVETo evaluate the clinical efficacy and safety of decitabine and cyclosporine for treatment of low-risk and intermediate-risk-1 myelodysplastic syndrome (MDS) patients.

METHODSThe clinical data of 27 cases of low risk and intermediate-risk-1 MDS during the past 3 years in Tongji hospital were analyzed retrospectively. These MDS patients were divided into 2 groups: decitabine group (11 cases) and cyclosporine group (16 cases). The MDS patients in the 2 groups were treated with ultra low dose of decitabine and cyclosporine A; the curetive efficacy and adverse reactions were evaluated.

RESULTSIn the 11 patients with low-risk and intermediate-risk-1 MDS treated with 2 courses of ultra-low-dose decitabine, 4 cases (36.4%) achieved a hematological improvement, 7 cases (63.6%) showed ineffective, including non-remission in 6 cases (54.5 %) and death in 1 patient (9.1%), total effective rate were 36.4%; 3 cases died within the first year and the overall survival (OS) rate was 72.7%. The causes of death mainly were severe myelosuppression and the associated infection and bleeding. In the 16 patients with low-risk and intermediate-risk-1 MDS treated with cyclosporine (CsA), 10 cases (62.5%) achieved a hematological improvement, 6 cases (37.5%) showed ineffective, the total efficiency of 62.5%; no patients died within 1 year, the 1-year OS was 100%. Changes in neutrophils, hemoglobin and platelet were not significantly different between the two group.

CONCLUSIONThe clinical efficacy of decitabine on low-risk and intermediate-risk-1 MDS has not confirmed to be superior to cyclosporine (P = 0.252). However, the side effects of serious infection and myelosuppression were more severe in decitabine group than that in the cyclosporine group. Moreover, the 1-year overall survival rate in decitabine group is much lower than that in the cyclosporine group (P = 0.027). In regard to the small number of cases and short follow-up time in our this study, the more patients and longer follow-up time are needed to study.

Azacitidine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Cyclosporine ; administration & dosage ; therapeutic use ; Humans ; Myelodysplastic Syndromes ; drug therapy ; Pancytopenia ; Retrospective Studies ; Survival Rate ; Treatment Outcome

OBJECTIVETo detect p15(INK4B) methylation levels and the kinetics of the methylation status before and after decitabine to explore its influences on prognosis and response to decitabine in myelodysplastic syndromes (MDS) patients.

METHODSWe examined 261 MDS patients (143 male and 118 female) with the median age of 52 years (32-78). Of them, 172 cases were low-risk group (low-risk 104 cases, intermediate-1 68 cases), 89 cases high-risk group (intermediate-2 52 cases, high risk 37 cases). Collections of bone marrow mononuclear cells of MDS patients and extracted the genomic DNA, the methylation status of p15(INK4B) was detected by methylation-specific PCR (MSP) method. Survival analysis was conducted according to the level of p15(INK4B) methylation in the cohort of patients. The kinetics of the methylation levels of p15(INK4B) in 58 MDS patients before and after 2 courses of decitabine have been assessed with the method of MSP.

RESULTSThe methylation level of p15(INK4B) in low-risk group patients was significantly lower than that in high-risk group (117.22 vs 157.63, P<0.05 ). The expected 2-year survival rate of p15(INK4B) methylation positive patients was lower than that of negative ones (91.8% vs 69.8%, P<0.05); the expected 2-year survival rate of p15(INK4B) methylation positive patients was shorter than that of negative ones in low-risk group（78.2% vs 92.0%, P<0.05）, meanwhile there was no significant difference in terms of expected 2-year survival rate and median expected survival between p15(INK4B) methylation positive and negative patients in high-risk group [35.6% vs 38.5%, (17.0±9.3) month vs (18.0±5.7) month, P>0.05]. Multivariate analysis showed p15(INK4B) methylation degree was an independent prognostic factor for overall survival. No statistical difference of overall response (OR) rates were found between p15(INK4B) methylation positive patients and negative patients before decitabine（65.9% vs 76.5%, P>0.05）, and complete remission (CR) rates between these two groups also showed no statistical difference（22.0% vs 29.4%, P>0.05）. p15(INK4B) methylation levels had no obvious change before and after treatment in decitabine responders（P>0.05）.

CONCLUSIONThe survival of newly diagnosed MDS patients with positive p15(INK4B) methylation was comparatively shorter, but p15(INK4B) methylation had no influence on response to decitabine.

Adult ; Aged ; Azacitidine ; analogs & derivatives ; Cyclin-Dependent Kinase Inhibitor p15 ; genetics ; DNA Methylation ; Female ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes ; drug therapy ; genetics ; Prognosis ; Survival Rate ; Treatment Outcome