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  • American Society of Hematology  (18)
  • 1
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3373-3373
    Abstract: Abstract 3373 Poster Board III-261 Purpose Several gene mutations had been found to have clinical implications in patients with acute myeloid leukemia (AML), especially in those with normal karyotype. However, the role of such gene mutations for AML patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) was unclear and inconclusive. We retrospectively evaluated the prognostic impact of 8 gene mutations in adult AML patients undergoing allo-HSCT. Materials & Methods From 1995 to 2007, a total of 463 consecutive adult patients with de novo non-M3 AML had comprehensive gene mutation analyses at the National Taiwan University Hospital. Three hundred and twenty five patients who received conventional induction chemotherapy were enrolled in this study. Those who received only low dose chemotherapy or palliative treatment were excluded. The genetic alterations analyzed included NPM1, FLT3/ITD, FLT3/TKD, CEBPA, AML1/RUNX1, RAS, MLL/PTD, and WT1. The clinical implication of these genetic alterations in the patients receiving allo-HSCT was analyzed, and the result was compared with that in patients without allo-HSCT. Results The clinical characteristics in the patients receiving allo-HSCT (n=100) and those without (n=225) were similar with the exception of age, being younger in the former group (35.4 years vs. 49.5 years p 〈 0.001). In univariate analysis, older age (Age 〉 45 years), higher initial WBC count (WBC 〉 50K/μL), elevated LDH level, unfavorable karyotype, FLT3/ITD, mutations of AML1/RUNX1 were significantly associated with poorer overall survival (OS) in patients not receiving allo-HSCT; While NPM1mut/FLT3ITDneg and CEBPA mutations served as significantly good prognostic indicators. In multivariate analysis, age, WBC count, karyotype, FLT3/ITD, AML1/RUNX1, CEBPA and NPM1mut/FLT3ITDneg remained to be independent prognostic factors in non-allo-HSCT patients. However, in patients receiving allo-HSCT, only unfavorable karyotype and disease status (refractory or remission) at the time of transplantation were associated with poorer OS both in univariate and multivariate analyses. The similar prognostic impact of FLT3/ITD, CEBPA, AML1/RUNX1 and NPM1 on OS was not seen in patients receiving allo-HSCT. Furthermore, in contrast to its poor prognostic impact in non-allo-HSCT patients, mutation of AML1/RUNX1 was a significant good prognostic factor for relapse free survival (p=0.046), although not for OS, in allo-HSCT group. Conclusion FLT3/ITD, mutations of AML1/RUNX1, CEBPA and NPM1 have great prognostic implication for OS in AML patients not receiving allo-HSCT. However, their impact on OS is ameliorated in patients receiving allo-HSCT. The results need to be confirmed by further studies on more patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
    In: Blood, American Society of Hematology, Vol. 114, No. 26 ( 2009-12-17), p. 5352-5361
    Abstract: Somatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 3
    In: Blood, American Society of Hematology, Vol. 115, No. 25 ( 2010-06-24), p. 5222-5231
    Abstract: The impact of WT1 mutations in acute myeloid leukemia (AML) is not completely settled. We aimed to determine the clinical implication of WT1 mutation in 470 de novo non-M3 AML patients and its stability during the clinical course. WT1 mutations were identified in 6.8% of total patients and 8.3% of younger patients with normal karyotype (CN-AML). The WT1 mutation was closely associated with younger age (P 〈 .001), French-American-British M6 subtype (P = .006), and t(7;11)(p15;p15) (P = .003). Multivariate analysis demonstrated that the WT1 mutation was an independent poor prognostic factor for overall survival and relapse-free survival among total patients and the CN-AML group. A scoring system incorporating WT1 mutation, NPM1/FLT3-ITD, CEBPA mutations, and age into survival analysis proved to be very useful to stratify CN-AML patients into different prognostic groups (P 〈 .001). Sequential analyses were performed on 133 patients. WT1 mutations disappeared at complete remission in all WT1-mutated patients studied. At relapse, 3 of the 16 WT1-mutated patients who had paired samples lost the mutation and 2 acquired additional mutations, whereas 3 of 110 WT1-wild patients acquired novel mutations. In conclusion, WT1 mutations are correlated with poor prognosis in AML patients. The mutation status may be changed in some patients during AML progression.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 4
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5800-5800
    Abstract: Introduction: Acute lymphoblastic leukemias (ALLs) harboring t(9;22)(Ph+-ALL) are very high risk (VHR) ALL displaying poor clinical outcome irrespective of intensive chemotherapies plus tyrosine kinase inhibitor (TKI) treatment. HQ17(3)[10'(Z),13'(E),15'(E)-heptadecatrienyl hydroquinone] isolated from sap of the lacquer tree showed rapid (within 24hrs) and potent cytotoxic effect at micromolar concentration on several ALL cell lines, including Imatinib-refractory Ph+-ALL SUP-B15 cells, but spared normal PB leukocytes, and showed nontoxic in experimental rats after 28-day injection. Therefore HQ17(3) presents as a potential anti-leukemic agents and provide a platform for exploring anti-leukemic adjuvants. Our previous study showed HQ17(3)-induced rapid cell demise, characterized by oxidative stress, mitochondrial membrane potential disturbance, loss of membrane integrity, and nuclear DNA fragmentation. HQ17(3)-induced cell death is a caspase-independent program, and is different from the RIP1-mediated controlled necroptosis since both pan-caspase inhibitor and RIP-1 inhihitor failed to protect SUP-B15 cells from death. The ER stress markers (chaperon Grp78 and phosphorylated-eIF2α) were up-regulated as early as 5hrs after HQ17(3) treatment. Here we aim to illustrate the characters of the HQ17(3)-induced non-classical death on Ph+-SUP-B15 cells, focus on ER stress-associated mitochondrial Ca2+ homeostasis. Methods: Cell death and changes of mitochondria in response to HQ17(3) w/wo inhibitors were analyzed. Cells were stained by Annexin V/PI and analyzed by flow cytometry for cell death. Mitochondria mass, mitochondrial Ca2+ accumulation was detected by fluorescent Mitotracker Green and Rhod-2 probes, respectively. Mitochondrial superoxide was measured by Mitosox stain. Western blot analysis was used to analyze MFN1/2, OPA1 (mitochondrial markers). Nuclear accumulation of apoptosis inducing factor (AIF), co-localization of mitochondrial COX-IV and LC3-II (mitophagy) were revealed by immunofluorescence stain and confocal microscopy. Results: We showed mitochondrial Ca2+ accumulation at the early time when ER stress occurred (Fig 1), accompanied by mitochondrial superoxide elevation, followed by loss of mitochondrial membrane potential (MMP) and nuclear translocation of apoptosis-inducing factor (AIF). HQ17(3) treatment lead to decreased mitochondrial proteins MFN1/2 and OPA1, while Mitotracker Green stain showed significant loss of mitochondrial mass preceded cell death, indicating damaged mitochondria underwent fission followed by mitophagy. Immunofluorescence stain showed evidence of mitophagy (COX IV and LC3B co-localization). Calpain-1 inhibitor PD150606 blocked AIF nuclear translocation but only slightly reduced the HQ17(3)-induced cell death (Fig 2). Further, Ca2+ chelator Bapta-AM prevented mitochondrial superoxide production, MMP loss, mitophagy (Fig 3), and rescued cell death (Fig 1) more effectively. Conclusion: In Ph+-ALL SUP-B15 cells, HQ17(3) induce ER stress by yet-defined mechanism, this mobilizes Ca2+ to mitochondria and acts in multi-facet: a) results in AIF cleavage and translocation to mediate nuclear chromatin fragmentation, b) Ca2+-overload leads to oxidative stress and perturbs mitochondria integrity, c) damaged mitochondria trigger extensive mitophagy and cell death ensues. Therefore, agents that help elicit similar intricate effector network associated with ER/mitochondria stress will have potential to be adjuvants in aiding control of the Ph+ VHR-ALL cells refractory to conventional chemotherapies and TKI regime. 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: 2018
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  • 5
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 409-409
    Abstract: Abstract 409 Background: DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. Materials and Methods: Mutation analysis of DNMT3A exons 2–23 was performed by polymerase chain reaction and direct sequencing in 506 de novo AML patients. Their interaction with clinical parameters, chromosomal abnormalities and genetic mutations were analysed. Results: DNMT3A mutations were identified in 14% of total patients and 22.9% of patients with normal karyotype (CN-AML). 30 different kinds of DNMT3A mutations were identified in 70 patients. Twelve were missense mutations, eight were nonsense mutations, nine were frame-shift mutations and one, in-frame mutation. The most common mutation was R882H (26 patients), followed by R882C (15 patients), R882S (3 patients), R736H (3 patients) and R320X (2 patients). DNMT3A mutations were closely associated with older age, higher white blood cell (WBC) and platelet counts at diagnosis, FAB M4/M5 subtype, intermediate-risk and normal cytogenetics. Among the 70 patients with DNMT3A mutations, 68 (97.1%) showed additional molecular abnormalities at diagnosis. The most common associated molecular event was NPM1 mutation (38 cases), followed by FLT3-ITD (30 cases), IDH2 mutation (16 cases) and FLT3-TKD (9 cases). Patients with DNMT3A mutations had significantly higher incidences of NPM1 mutation, FLT3-ITD, IDH2 and PTPN11 mutations than those with DNMT3A-wild type (54.3% vs. 15.3%, P 〈 0.0001; 42.9% vs. 19.3%, P 〈 0.0001; 22.9% vs. 9.1%, P=0.0016; and 10% vs. 3.5%; P=0.007, respectively). On the contrary, CEBPA was rarely seen in patients with DNMT3A mutations (4.3% vs. 14.7%, P=0.0134). Totally, 40 patients (58.8%) had concurrent both Class I and Class II or NPM1 mutations at diagnosis. With a median follow-up of 55 months (ranges, 1.0 to 160), patients with DNMT3A mutation had significantly poorer overall survival (OS) and relapse-free survival (RFS) than those without DNMT3A mutation (median, 14.5 months vs. 38 months, P =0.013, and medium, 7.5 months vs. 15 months, P=0.012, respectively). In the subgroup of 130 younger patients (less than 60 years) with CN-AML, the differences between patients with and without DNMT3A mutation in OS (median, 15.5 months vs. not reached, P= 0.018) and RFS (median, 6 months vs. 21 months, P=0.004) were still significant. Multivariate analysis demonstrated that DNMT3A mutation was an independent poor prognostic factor for OS and RFS among total patients (HR 2.218, 95% CI 1.333–3.692, P=0.002 and HR 2.898, 95% CI 1.673–5.022, P 〈 0.001, respectively) and CN-AML group (HR 2.303, 95% CI 1.088–4.876, P=0.029 and HR 3.496, 95% CI 1.773–6.896, P 〈 0.001, respectively). Further, a scoring system incorporating DNMT3A mutation and eight other prognostic factors, including age, WBC count, cytogenetics, and gene mutations (NPM1/FLT3-ITD, CEBPA, AML1/RUNX1, WT1, and IDH2 mutations), into survival analysis was proved to be very useful to stratify AML patients into different prognostic groups (P 〈 0.001). DNMT3A mutations were serially studied in 316 samples from 138 patients, including 35 patients with distinct DNMT3A mutations and 103 patients without mutation at diagnosis. Among the 34 patients with DNMT3A mutations who had ever obtained a CR and had available samples for study, 29 lost the original mutation at remission status, but five retained it; all these five patients relapsed finally within a median of 3.5 months and died of disease progression, suggesting presence of leukemic cells. In the 13 patients who had available samples for serial study at relapse, all patients regained the original mutations, including mutant clone was found by TA cloning in one patient. Among the 103 patients who had no DNMT3A mutation at diagnosis, none acquired DNMT3A mutation at relapse, while karyotypic evolution was noted at relapse in 39% of them. Conclusion: DNMT3A mutations are associated with distinct clinical and biological features and poor prognosis in de novo AML patients. Furthermore, the mutation may be a potential biomarker for monitoring of minimal residual disease. 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
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  • 6
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1564-1564
    Abstract: Abstract 1564 Poster Board I-587 Somatic mutation of AML1/RUNX1 (RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 individuals (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male gender, older age, lower LDH value, FAB M0/M1 subtypes and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19 and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD (P=0.0061), but negatively associated with CEBPA (P=0.0057) and NPM1 mutations (P=0.0001). AML patients with RUNX1 mutations had a significantly lower complete remission rate, shorter disease-free and overall survival than those without the mutation (P=0.0087, P 〈 0.0001 and P=0.012, respectively). Subgroup analysis of patients with normal karyotype showed that RUNX1-mutation was also closely associated with worse OS and DFS (P= 0.001 and P=0.001, respectively). Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival (hazard ratio 1.874, 95% CI, 1.101- 3.189, P=0.021). Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidences that RUNX1 mutations are associated with distinct biological and clinical characteristics and poor prognosis in patients with de novo 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
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  • 7
    In: Blood, American Society of Hematology, Vol. 119, No. 2 ( 2012-01-12), p. 559-568
    Abstract: DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P 〈 .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 8
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4138-4138
    Abstract: The development of acute myeloid leukemia (AML) is a multistep process. Gilliland and colleagues proposed a two hit theory of leukemogenesis that requires collaboration of at least two classes of gene mutations. The Class I gene mutations activate the signal transduction pathway and confer proliferation and survival advantage to hematopoietic cells. The Class II gene mutations affect transcriptional activators or coactivators and serve to impair cell differentiation. In this study, comprehensive analyses of a panel of gene mutations, their interactions and associations with antigen expression of leukemia cells were performed in 324 patients with primary AML, including 275 adults and 49 children(≤18years). The gene mutations included FLT3/ ITD (78 cases, 24.1%), FLT/ TKD (24 cases, 7.4%), NPM(63 cases, 19.4%), CEBPA(45 cases, 13.9%), NRAS (39 cases, 12%), AML1 (31 cases, 9.6%), PTPN11 (14 cases, 4.3%), MLL/PTD(13 cases, 4%), KIT(10 cases, 3.1%), KRAS (8 cases, 2.5%), and JAK2 (3 cases, 0.9%). In addition, 33 patients had t(8;21), 24 had t(15;17), 9 had inv(16) and 13 had 11q23 translocations. Totally, the Class I gene mutations were detected in 155 patients (47.8%), and Class II gene mutations, in 228 patients (70.4%). Most Class II mutation was associated with a distinct immunophenotype of leukemic cells, such as CEBPA mutation: HLADR(+)CD7(+)CD15(+)CD19(−)CD34(+) (p 〈 0.05), NPM mutation: HLADR(−)CD19(−)CD34(−)CD33(+)(p 〈 0.05), AML1 mutation: HLADR(+)(p 〈 0.05), MLL/PTD: CD7(−)(p 〈 0.05), AML1/ETO: HLADR(+)CD7(−)CD19(+)CD33(−)CD34(+)CD56(+)(p 〈 0.05), PML/RARA: HLADR(−)CD2(+)CD7(−)CD11b(−)CD34(−)(p 〈 0.05), CBFB/MYH11: CD11b(+)CD14(+), and translocation 11q23: CD19(+)CD33(−)CD34(−) (p 〈 0.05). The interactions between Class I and Class II mutations are shown in table 1. Among Class I mutations, FLT3/ ITD could interact with each subtype of Class II gene mutations, but were particularly associated with NPM mutations (p 〈 0.001) and MLL/PTD (p=0.001). FLT3/ TKD was closely related to NPM mutations (p=0.03). Most KIT mutation were detected in the core binding factor leukemia (p 〈 0.001). PTPN11 mutations were more frequently detected in patients with NPM mutations than in others (p=0.035). Few patients with complex cytogenetics revealed mutations of the gene panel studied (Table 1), suggesting that leukemogenesis in these patients was through mechanism other than the known Class I and Class II mutations. In this study, the cooperative gene alterations of the NUP98/HOXA9 fusion gene were demonstrated (Table1) which, to the best of our knowledge, have not been reported before. In conclusion, the development of AML requires multistep genetic changes. Most Class II mutation is closely associated with a distinct pattern of antigen expression of leukemic cells. Exploring the interactions of gene mutations may help us more understand the pathogenesis of leukemia and benefit further therapeutic strategy. Table I. Interaction of Class I and Class II gene mutations
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 9
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1495-1495
    Abstract: Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by increasing immature progenitors in the bone marrow and peripheral blood. Prior reports suggested a relationship between surface antigens expression and prognosis of AML. However, there were some debates in subsequent studies. In this study, we performed cluster analysis of the immunophenotype expression profile in AML patients with NPM1 gene mutation, and correlated the result with clinical characteristics, other gene mutations and prognosis. Patients and Methods A total of 534 patients diagnosed as having AML at the National Taiwan University Hospital from 1987 to 2007 were recruited in this study. A panel of monoclonal antibodies was used to characterize the phenotypes of the leukemic cells. Expression of surface antigens on the leukemic cells was shown by an indirect immunoalkaline phosphatase method before 1998 and by flow cytometry thereafter. Cytogenetic study was done on bone marrow cells after 1–3 days of unstimulated culture. Analysis of gene mutation of NPM1, FLT3, CEBPA, MLL/ITD, AML1, JAK2, PTPN11, WT1, NRAS and KRAS were performed by polymerase chain reaction and direct sequencing. Abnormal sequencing results were confirmed by at least two repeated analyses. Comparisons were made with the ANOVA and the Chi-square test. Hierarchical cluster analysis was performed with agglomeration schedule, and cluster distance measured with Binary Square Euclidean distance. Dendrogram was plotted with average linkage method. Survival curves were plotted by the Kaplan-Meier method; differences between curves were analyzed by the log-rank test. All statistical analyses were performed by use of SPSS 13.0 for Windows (SPSS, Chicago, IL). Values of P & lt; 0.05 were considered significant. Result: Clinical characteristics of patients with NPM1 gene mutation. There were 309 men and 225 women. 51 were children less than 18 years and 483 were adults. NPM1 gene mutations were detected in 106 (19.8%) of the total AML patients and 37% of those with a normal karyotype, similar to our previous report (Cancer Res. 2006). Most patients with NPM1 mutation were HLADR(−)CD33(+) CD34(−) (p & lt;0.001). The patients with NPM1 mutations were older than the others (56 vs 47 years, p & lt;0.001). Hierarchical cluster analysis of immunophenotypes in patients with NPM1 gene mutations. The cluster analysis was performed based on the expression profile of eight surface markers (HLADR, CD34, CD13, CD33, CD7, CD14, CD15, CD56). The clustering result was displayed by the Treeview dendrogram. The rows represented individual cases and the columns were the results of expression of individual surface markers. The blue color indicates positive expression and yellow color, negative. A total of 89 patients with NPM1 mutation and complete immunophenotype data were enrolled to the hierarchical cluster analysis. The clustering analysis divided the patients with NPM1 mutations into two groups, designated as cluster groups I (n=73, green) and II (n=16, red), based on the expression profiles of immunophenotype (Figure 1). Most patients in group I showed CD34(−)/CD7(−) but with variable expression of other antigens, while most group II patients showed HLA DR(+)/CD34(+)/CD7(+). With a median follow-up time of 56 months, groups II patients showed significantly shorter relapse free survival (RFS, median: 4 vs 22 months, p=0.005) and overall survival (OS, median: 8 vs 94 months, p=0.05) than group I patients. There was no association of immunophenotypic cluster with any other gene mutation, such as FLT3, CEBPA, MLL, AML1, JAK2, PTPN11, WT1, NRAS or KRAS. Multivariate analysis of variables including clinico-laboratory data (age, sex, WBC, Hb, PLT, LDH) and gene mutations revealed that immunophenotype cluster was an independent prognostic factor (RFS, p=0.002; OS, p=0.024) in AML patients with NPM1 mutation. For more practical use, we compared the outcome of patients with positivity for all HLADR, CD34 and CD7, with that of other patients; it was also shown that the former groups had significantly poor prognosis than the latter one (RFS, p=0.0005, OS, p=0.01). Conclusion: Hierarchical cluster analysis of the immunophenotype profile of patients with NPM1 gene mutation could reveal two distinct groups with different prognosis. The immunophenotypic cluster with HLADR(+) CD34(+) CD7(+) predicts poor prognosis in AML patients with NPM1 mutation, independently from other gene mutations and clinico-laboratory variables. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 10
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 5171-5171
    Abstract: Abstract 5171 Although thrombotic complications are common in myeloproliferative neoplasms (MPN), the pertinent risk factors are not well characterized. This study aims to explore the general characteristics of MPN patients, focusing on risk factors for developing thrombotic complications. Thrombotic events were defined as relevant to the MPN if they occurred after the diagnosis of MPN or around the time of diagnosis. Results Totally 361 patients were collected, including 135 (37%) cases of polycythemia vera (PV), 167 (46%) cases of essential thrombocythemia (ET) and 59 (16%) cases of primary myelofibrosis (PMF). The positive rates of JAK2V617F mutation were 90%, 65%, and 75% for PV, ET and PMF, respectively (PV vs. ET, p 〈 0.001). PV was associated with higher incidence of transformation to myelofibrosis compared with ET (9% vs. 3%, p=0.027) and also higher level of white blood cell count (WBC) (mean 15018/ul, 95% confidence interval (CI):13655–16381/ul; PV vs. ET, p=0.005; PV vs. PMF, p=0.001 ), higher bone marrow cellularity (bone marrow cellularity more than 60%: PV,89%; ET,70%; PV vs. ET, p=0.026; PMF,76%), and more frequent hypertension (PV, 50%; ET, 43%; PMF 19%; PV vs PMF, p 〈 0.001; ET vs. PMF, p=0.001). ET was associated lower incidence of coagulopathy with prolonged INR in prothrombin time (ET, 19%; PV, 36%; PV vs. ET, p=0.001; PMF, 44%; ET vs. PMF, p=0.001). PMF was associated with higher incidence of leukemia transformation(PMF,15%; PV,3.7%; ET, 2.4%; PV vs. PMF, p=0.012; ET vs. PMF, p=0.001), higher incidence of coagulopathy with prolonged aPTT (PMF,51%; PV,37%;ET, 30%; ET vs. PMF, p=0.012), increased reticulin fiber(moderate increased reticulin fiber: MF,92%; PV,44%; PV vs. PMF, p 〈 0.001; ET, 48%;ET vs. PMF,p 〈 0.001) and splenomegaly (mean 17.3cm, 95% CI:15.8–18.4cm, p 〈 0.001). Venous thromboembolism occurred in 6.4% of these MPN patients with incidence of 7.4%, 6.6% and 3.4% in patients of PV, ET and PMF, respectively. Arterial thrombosis developed in 20% of these MPN patients with incidence of 28%, 17%, and 10% in patients of PV, ET and PMF, respectively. (Table1) Majority of venous thromboembolism presented as deep vein thrombosis (DVT) /pulmonary embolism (PE) and portal or splenic vein thrombosis with an incidence of 1.7/1.1% and 2.2%, respectively. The most common arterial thrombotic events was ischemic stroke, followed in order by ischemic heart disease, peripheral artery occlusive disease (PAOD), and ischemic bowel disease with an incidence of 14%, 9%, 3.0% and 1.1%, respectively. (Table1) The probability of thrombosis-free survival in these 361 patients was 85%, 78% and 70% at 1, 3 and 10 year, respectively (Figure 1). In terms of arterial and venous thromembolism altogether, univariate risk factor analysis revealed several risk factors including a positive JAK2V617F, diagnosis of PV, WBC more than 16000/ul, hemoglobin level higher than 16 mg/dl, albumin level less than 4.0 g/dl, LDH higher than 250U/L, congestive heart failure(CHF),hypertension(HTN) and diabetes mellitus. With multivariate analysis, however, only WBC more than 16000/ul (Odds ratio: 3.556,95% CI:1.287–9.822,p=0.014) remained as the most significant risk factors for thromoboembolism. Conclusions Arterial thromboses are quite common in patients of MPN, especially PV. In these MPN patients, the risk of venous thrombosis including thrombosis at unusual sites is also markedly increased. The most important risk factor predisposing to vascular thrombosis (vein and artery) is WBC more than 16000/ul. Our results provide informative clinical data for management of Asian patients with MPN and facilitate further study of these disorders in this area. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    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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