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  • Medicine  (8)
  • XA 33000  (8)
  • 1
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2159-2159
    Abstract: Targeted therapy with the Bcr-Abl tyrosine kinase inhibitor Imatinib Mesylate can induce high response rates in chronic myelogenous leukemia (CML) patients. However, evidences that discontinuation of imatinib mesylate inevitably exerts rapid loss of response and some patients with imatinib mesylate monotherapy virtually occur potential relapse suggest that the modification of treatment strategy is critical. We have previously demonstrated that the combination of trisenox (arsenic trioxide) with the tyrosine kinase inhibitor imatinib mesylate or genistein appears to induce markedly more cell apoptosis than imatinib mesylate alone through downregulating Bcl-XL and Bcr-Abl in Bcr-Abl gene transfected HL-60 cells. We here report the preliminary results of a pilot study comparing imatinib mesylate plus trisenox with imatinib mesylate alone for frontline treatment of CML patients. Up to date 56 patients were enrolled in this clinical trail. All patients (required to be 18 years or older with Bcr-Abl positive CML in chronic phase within three month of diagnosis) were divided into two groups, i.e., monotherapy group and combined therapy group. 42 patients entering monotherapy received imatinib mesylate 400mg daily and 14 patients entering combined therapy imatinib mesylate 400mg daily plus trisenox 10mg daily for one week and then twice a week. We compared treatment results of both groups including complete hematologic response(CHR), major/complete cytogenetic response(MCR/CCR),--defined as 1–35% Ph+ and 0% Ph+ metaphases respectively and major/complete molecular response(MMR/CMR),--defined as ≥ 3 log reduction and negative expression in Bcr-Abl transcript numbers assayed by RQ-PCR respectively. The median follow-up for patients in both groups lasted 36 months. In the combined therapy group, the median age of patients is 42 years old (range, 22–61), the CHR, MCR, CCR, MMR and CMR is 92.8%, 64.3%, 42.9%, 35.7% and 21.4%, respectively. While in the imatinib mesylate monotherapy group, the median age of patients is 46 years old (range, 23–65), the CHR, MCR, CCR, MMR and CMR is 85.7%, 59.5%, 40.5%, 33.3% and 19%, respectively. Although combination therapy of imatinib with trisenox is not significantly superior to imatinib mesylate monotherapy in efficacy, no resistance case happens in the combination therapy group, in the imatinib mesylate monotherapy group, imatinib resistance occurs in 4 patients. In addition, the safety and tolerability of a combination of imatinib mesylate and trisenox is good. This result indicates that the combination of imatinib and trisenox to treat chronic myeloid leukemia may be promising in avoiding the occur of imatinib resistance.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 2
    Online Resource
    Online Resource
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 4449-4449
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4449-4449
    Abstract: We aimed to evaluate the effects of arsenic trioxide (ATO, Trisenox) on STI571 (Gleevec, imatinib mesylate)-induced apoptosis of a chronic myelogenous leukemia (CML) cell line, K562 cells. Cell prolifration and colony-forming assays were performed to determine the cytotoxicity of ATO alone and in combination with STI571. Apoptosis was analyzed by morphological changes, apoptosis rate and cell cycles. An Elisa assay was used to detect the levels of cytosolic cytochrome c (cyt c) and caspase-3 in K562 cells exposed to ATO and STI571 at graded concentrations. Semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to assay the transcriptional levels of Bcl-XL and Bcr-Abl genes in K562 cells. Results showed that both the colony-forming assay and cell proliferation assay demonstrated additive to synergistic effects of ATO on STI571-induced apoptosis in K562 cells, a Bcr-Abl positive cell line. Caspase-3 was activated during apoptosis and there was an increase in cytosolic accumulation of cytochrome c. Treatment of K562 cells with STI571 alone led to down-regulation of transcriptional levels of Bcl-XL at 12 hours and Bcr-Abl at 96 hours after drug administration. Treatment with ATO alone only led to reduce the mRNA levels of Bcl-XL, but not Bcr-Abl. Combined treatment with ATO and STI571 down regulated the transcripts of Bcl-XL at 12 hours and Bcr-Abl 72 hours after drug administration. We conclude that ATO enhanced cytotoxic and proapoptotic actions of STI571 could be mediated by the down-regulation of Bcr-Abl and Bcl-XL genes in K562 cells. Therefore ATO in combination with STI571 could be a promising therapy for CML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    Online Resource
    Online Resource
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 5230-5230
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 5230-5230
    Abstract: The classic Bcr-Abl negative myeloproliferative disorders (MPDs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF). They are considered clonal stem cell disorders. Recently two acquired somatic mutations JAK2V617F and MPLW515L/K have been identified to play an important role in pathogenisis of MPDs. JAK2V617F was detected in almost all PV and nearly 50% in ET and IMF, and the MPLW515L/K mutation occured in only 1% and 4% in ET and IMF respectively. However it is interesting that there are some patients with slightly increased blood cells did not meet the criteria of PV and ET clinically. These early prefibrotic stages of MPDs are overlooked by both the Polycythemia Vera Study Group (PVSG) and the 2001 WHO criteria for the diagnosis of PV, ET and IMF. In order to investigate the prevalence of JAK2V617F and MPLW515L/K mutation in patients with early MPDs without a secondary cause, genomic DNA from bone marrow or blood mononuclear cells of 30 patients with early MPDs was screened by allele specific polymerase chain reaction (AS-PCR) for JAK2V617F and MPLW515L/K mutations and the history of thrombosis was assessed retrospectively by using patient files. Results showed that 14 out of 30 patients (46.7%) were positive for the JAK2V617F mutation, and none of them had the MPLW515L/K. Of the 14 patients with JAK2V617F mutation, a history of thrombosis was comfirmed in 5 patients(35.7%), while none of 16 patients with WT JAK2 had the thrombosis history. The average age of patients with the JAK2V617F mutation exceeded the patients with wild type JAK2(P & lt;0.05), whereas there is no statistical significance on sexual Athe counts of white cell and the occurance of complications (thrombosis) between the patients with and without the JAK2V617F mutation. All the patients have been followed up since onset and 22 patients have available results. Among them, 12 patients with the burden of JAK2V617F turned out to be MPDs, however only 1 out of 10 patients without this mutation also evolved to MPDs. Our results suggest that JAK2V617F mutation can occur in a certain percentage of these early stage of MPDs patients and has help to diagnose early MPDs. Because these patients might have a high rate of complications, proper treatment of the MPD including aspirin and/or cytoreductive therapy is recommended in latent MPDs patients associated with the JAK2V617F mutation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 5255-5255
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 5255-5255
    Abstract: Essential thrombocytosis (ET) is a subtype of Bcr-Abl negative the chronic myeloproliferative disorders and the mutated JAK2V617F has been identified and correlated with ET. The aim of this study was to analyze the mutational status and quantitative expression of JAK2V617F mRNA transcripts in cohort of 98 Chinese patients with ET and to determine the disease features. The cohort consisted of 46 men and 52 women with median age at diagnosis was 50 years (range 17–87), granulocyte cDNA was enriched from blood samples obtained at the time of clinical assessment. A quantitative JAK2V617F measurements were made using amplification-refractory mutation sequencing polymerase chain reaction (ARMS-PCR) and capillary electrophoresis assay. Fifty-nine(60.2%) patients harboring the JAK2 V617F mutation were found, including 17 homozygous and 42 heterozygous changes. The quantitative assay by capillary electrophoresis showed that the mutated mRNA ratio was (89.9±6.7)% in the JAK2V617F homozygote and was (57.1±6.7)% in the JAK2V617F heterozygote patients, the difference was significant(P & lt;0.005). JAK2V617F-positive ET patients were older than patients without the mutation (55 versus 38 years, p & lt;0.001), and the patients whose age ≥ 60 years showed significantly higher JAK2 mutated RNA levels as compared to patients whose age ≤60 years(68.2% versus 80.2%, P =0.0056). Males and females had similar JAK2V617F prevalence (63.0% versus 57.7%) and frequency of homozygosity (17.4% versus 17.3%). As compared to heterozygous ET patients, higher leukocyte count was observed in homozygous ET patients (27.9×109/L versus 15.2×109/L, P©‚0.05), JAK2V617F-positive patients also had a higher median white cell count than wild-type patients (19.4×109/L versus 9.7×109/L, P©‚0.05), but there were no significant differences in hemoglobin concentration or platelet count. During follow-up, 30 patients suffered from documented thrombotic events, with 24 having JAK2V617F mutations. The rate of thrombotic complications in JAK2V617F-positive and homozygous patients was higher than in JAK2 wild-type and heterozygous patients, respectively. (52.2% versus 17.6%, 75% versus 32.8%, respectively ). Compared with patients without thrombotic events, there were higher levels of mutated JAK2 mRNA in patients with thrombotic events(76.9% versus 58.4%, P©‚0.05), thrombotic events were also significantly correlated with leukocytosis and older age. Our results suggest that there are different clinical features between JAK2V617F-positive and JAK2V617F-negative, homozygote and heterozygote, higher and lower levels of mutated JAK2 mRNA, and correlated with leukocytosis and thrombosis. Therefore, detection of the JAK2V617F mutational status and mutated JAK2 mRNA can help not only identify the disease state and progression, but also affect the management of ET patients.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4536-4536
    Abstract: Abstract 4536 Objective To evaluate the safety profile and efficacy of umbilical cord-derived mesenchymal stem cell infusion in patients with steroid-resistant, severe, acute graft-versus-host disease (aGVHD). Methods A total of 19 patients with steroid-resistant severe aGVHD received mesenchymal stem cell infusion treatment. We analyzed the treatment response, transplantation-related mortality, events associated with infusion and relapse rate. Results Two patients with grade II, 5 patients with grade III and 12 patients with grade ‡W aGVHD received a total of 58 infusions of mesenchymal stem cell. The mean total dose of mesenchymal stem cell was 2.13×106 (range 0.6–7.2×106) cells per kg bodyweight. 7 patients received one infusion, 2 patients received two infusions, and 10 patients received three or more infusions. 11 patients had a complete response and 4 had a partial response and 4 had no response. No patients had side-effects during or immediately after infusions of mesenchymal stem cell and no ectopic tissue was detected to date. 11 patients survived and 8 died, 4 for aGVHD, 1 for infection and 2 for aGVHD with concomitant infection and 1 for underlying leukemia relapse. The cell viability of freshly prepared mesenchymal stem cell is 93% (92%-95%) by trypan blue staining. The cell viability of controlled-rate freezed and thawed cells mesenchymal stem cell is 72% (70%-74%). Conclusion Infusion of umbilical cord-derived mesenchymal stem cell expanded in vitro is an effective therapy for patients with steroid-resistant, severe aGVHD without negative impact on relapse. Freshly prepared mesenchymal stem cells are superior to freezed and thawed cells in terms of cell viability. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4721-4721
    Abstract: Abstract 4721 Objective Nestin was detected in some tumor cells and nestin expression was positive relative with malignancy of glioma, angioma and melanoma. Nestin maybe was considered as marker of tumor malignancy and cell proliferation. There was no report about nestin expression in acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL). Herein, we describe the clinicopathological and immunohistochemical features of 48 patients with acute leukemia, introducing nestin as an additional marker that identifies these tumors .Meanwhile, Nestin and ki67 antigen expression were done to identify the relation of nestin and cell proliferation in AML, and the correlation between histoscore of nestin expression on leukemic blasts and patients' complete remission rate (CR) and overall survival (OS) was analyzed in AML. Methods Nestin and ki67 antigen expression in a series of 37 AML samples, 11 ALL samples, 2 multiple myeloma samples (MM) and 2 chronically myeloid leukemia samples (CML) were done with immunohistochemistry. Histoscore of nestin expression on leukemic blasts with AML and ALL was done and analyzed with independent t-test. The correlation of histoscore of nestin expression with patients' CR rate in AML was analyzed by the method of chi-square test. Patients' OS analysis was determined by the method of Kaplan and Meier, with log-rank analysis to estimate statistical significance in AML. P values of 〈 0.05 were considered significant. Results Among 37 cases with AML, Nestin expression was observed in most leukemic blasts, and matural granulocytic cell also expressed nestin in 30 cases .The ratio of tumor cell expressing nestin and total tumor cells was over fifty percents in AML in 14 patients. The ratio of tumor cell expressing nestin and total tumor cells was over ten percents in AML in 7 patients. The ratio of tumor cell expressing nestin and total tumor cells was less ten percents in AML in 9 patients. Nestin expression was not observed in 8 patients. Where ki67 expressed in AML, nestin expressed intensely in 7 cases with AML. But other cases did not express ki67. However, histoscore of nestin expression on leukemic blasts in AML was not correlated with patients' CR (p=0.701) and OS (p=0.245). Nestin immune-reactivity in ALL mainly focused on matural granulocytic cells, matural lymphocytic cells and tumor cells did not express nestin. Compared with AML, there was significant statistical significance (p=0.007). Conclusions These findings constitute the first conclusive evidence that stem cell marker nestin expression in leukemic blasts with AML, CML, MM, but nestin did not express in leukemic blasts with ALL. Nestin may be a useful immunohistochemical marker for identifying AML and ALL. Nestin expression was not correlated with cell proliferation, patients' CR and OS in AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 5031-5031
    Abstract: The salvage therapy in patients with relapsed/refractory acute myeloid leukemia still poses a highly unmet clinical need. Given the established activity and toxicity profiles of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) in patients with untreated acute myeloid leukemia (AML), we explored the therapeutic effects of dose adjusted DAC in patients with relapsed / refractory AML, and compared treatment outcome with the conventional FLAG regimen. Patients and Methods 27 patients with relapsed/refractory AML were included in this analysis. Twelve patients were treated with DAC 20 mg/m2 per day as 1-hour intravenous infusion for consecutive five days, with additional  1-3 doses of DAC added based on response and tolerability (Table 1). Another group of 15 patients received a course of FLAG regimen as controls. Results Although the overall response rates (ORR) were similar in DAC group (5/12) and FLAG group (9/15)£¨41.7 % versus 60 %, P=0.449£©, the complete remission (CR) rate plus CRi was lower in DAC group (2/12) than in FLAG group(10/15)£¨16.7 %versus 66.7 %, P=0.047£©. Induction mortality was 0 (0% at 8 weeks) and toxicities were manageable in both groups. Toxicities were predominantly hematologic. The most common drug-related adverse events (AEs£© were grade 4 myelosuppression which were comparable for DAC and FLAG., DAC group hadfewer infections£¨DAC, 6/12£»FLAG£€n=14/15, P=0.024£©. The 2-year survival rate was similar in the two groups: 25.0% in the DAC versus 26.7% in the FLAG group£¨P=0.574£©, while median survival times of the two groups were 4 and 12 months, respectively. Conclusion Dose-adjusted DAC achieved similar overall response rate with lower infection risk compared to FLAG regimen in patients with relapsed / refractory AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    Online Resource
    Online Resource
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 5533-5533
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 5533-5533
    Abstract: Purpose: Allogeneic stem cell transplantation (alloSCT) has significantly improved the prognosis of patients with Int/High risk myelodysplastic syndrome (MDS). However, it is associated with severe graft-versus-host disease (GVHD), and the lack of available human leukocyte antigen (HLA)-matched donors remains a major obstacle.In the present study, we explored the clinical value and feasibility of HLA-mismatched or HLA-matched hematopoietic stem cell infusion combined with chemotherapy (micro-transplantation) as a new therapy to improve the prognosis of MDS patients. Methods: 6 patients diagnosed with Int/High myelodysplastic syndrome between May 15 2014 and May 5 2015 who received micro-transplantation were enrolled in our study. Their diagnoses were defined by the FAB and WHO criteria, including 1 patient with RARS, 2 with RCMD, 1 with RAEB-1, 1 with RAEB-2 and 1 with CMML. Among them, one patient with RCMD was diagnosed as secondary MDS who received radiotherapy with lung cancer. According to IPSS, 2 patients with Int-1 risk group, 1 patients with In-2, and 3 patients with high risk group. 4/6 presented with complex karyotype, 3/6 with P53 mutation and 1/6 with mutation of ASXL1 and DNMT3. Before receiving micro-transplantation, the treatment of 4 patients were unsuccessful: one patient with RARS who received supportive therapy and vitamin B6 for 18 month was still dependent on RBC transfusion, with hemoglobin between 39g/l and 50g/l, and his iron overloading was severe; one patients with RCMD who received decitabine therapy and acquired hematopoietic improvement; one patient with CMML received induction chemotherapy of CAG and did not present with PR or hematologic improvement; one patient with RAEB-2 achieved CR after the first cycle of decitabine therapy (20mg/m2*5d) and relapsed after the next three courses. Before the micro-transplantion, remission induction chemotherapy consisted of intra- venous infusion of decitabine (25mg/m2) for 4 days (-9,-8,-7,-6), cytarabine (235mg/m2) for 3 days (-5, -4, -3). For one patients with RAEB-2, we increased the dose of cytarabine to 1g/m2, q12h for 3 days (-5, -4, -3). Among the 3 patients with high risk IPSS scores, 2 patients who presented with P53 mutation additionally received another Idarubicin (10mg) or VP-16 (100mg). Results: The median number of donor peripheral blood mononuclear cells was 4.26*10E8/kg (range:2.55-6.18), and the median number of CD34+ cells was 1.275*10E8/kg (range:0.85-1.6). The median time of patients with NE ≥0.5×109/L was 13 ( range:10-18) days, and median time of Plt≥20×109/L was 13 ( range:11-16) days. After miro-transplantation, bone marrow test indicated that all the six patients received CR, and their karyotype and molecular mutation became negative. Peripheral blood routine test suggested the significant hematopoietic improvement, and the STR was between 1.3% and 7.8%. No patients presented with acute GVHD, and all the six patients were alive until now, with median follow-up time after micro-transplantation was 6 months (2-14month). Conclusion: In present study, micro-transplantation therapy achieved a promising outcome in patients with Int /High risk MDS, all patients achieved hematopoietic improvement and no patients died for severe infection or GVHD. For MDS patients, those with older age, without HLA-matched donor, or with poor performance status who can not tolerated the blative or reduced intensity conditioning, micro-transplantation may be a new choice. Considering the small number of patients and different conditioning therapy we used before micro-transplantation in our study, further study may been needed to verify our findings. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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    detail.hit.zdb_id: 80069-7
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