Expression and Clinical Significance of Antiapoptotic Gene Aven in De Novo acute Myeloid Leukemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4132-4132
Author(s):  
SuXia Geng ◽  
Xin Du ◽  
Jianyu Weng ◽  
Liye Zhong ◽  
Rong Guo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Mrna Level ◽  
Normal Individuals ◽  
Median Level ◽  
The Difference ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 4132 The objective was to definite the expression level of aven mRNA of white blood cells from peripheral blood(PB)of de novo acute myeloid leukemia and preliminary analyze its clinical significance, providing a experimental basis for evaluating prognosis. Aven mRNA levels in PB samples from 69 AML patients were detected by using real-time quantitative PCR. The relation of aven mRNA level with clinical and hematological characteristics (age, sex, WBC, Hb, Plt, LDH, Blast% in PB and BM,FAB subtype) and treatment outcome (complete remission rate and relapse rate)were analyzed. Twenty-one normal individuals served as controls. The level of aven mRNA was between 11.72% and 178.93 %(median 37.2%) in de novo AML and between 10.81% and 50.98 %(median 28.81%) in normal individuals. Aven mRNA level was higher in the AML group than in the controls (p=0.006). When we compared aven mRNA with other clinical and hematological parameters, there were significant correlations between aven mRNA and age(r=0.25,p=0.039),aven mRNA and hemoglobin level (r=0.29,p=0.019),aven mRNA and FAB subtype(r=0.253,p=0.036). We found that median level of aven mRNA in group whose age older than median age was higher than group whose age younger than median level(p=0.018).The complete remission rate after two cycles chemotherapy in group with lower aven mRNA level(25/30,83.33%)was higher than group with higher aven mRNA level(21/30,70%). But the difference was not significant(p=0.22).The difference of aven mRNA expression level between AML patients with relapse and that without relapse was not significant (p=0.076). In conclusions, the level of aven mRNA in de novo AML is overexpression. The overexpression of aven mRNA is likely to play an important role in tumorigenesis of AML. Association of aven mRNA expression with treatment outcome and relapse was not observed. Disclosures: No relevant conflicts of interest to declare.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic 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.

scholarly journals Distinct clinical and biological characteristics of acute myeloid leukemia with higher expression of long noncoding RNA KIAA0125

2020 ◽  
Author(s):  
Yu-Hung Wang ◽  
Chien-Chin Lin ◽  
Chia-Lang Hsu ◽  
Sheng-Yu Hung ◽  
Chi-Yuan Yao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
De Novo ◽  
Remission Rate ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Biological Characteristics ◽  
Acute Myeloid

AbstractExpression of long non-coding RNA KIAA0125 has been incorporated in various gene expression signatures for prognostic prediction in acute myeloid leukemia (AML) patients, yet its functions and clinical significance remain unclear. This study aimed to investigate the clinical and biological characteristics of AML bearing different levels of KIAA0125. We profiled KIAA0125 expression levels in bone marrow cells from 347 de novo AML patients and found higher KIAA0125 expression was closely associated with RUNX1 mutation, but inversely correlated with t(8;21) and t(15;17) karyotypes. Among the 227 patients who received standard chemotherapy, those with higher KIAA0125 expression had a lower complete remission rate, shorter overall survival (OS) and disease-free survival (DFS) than those with lower expression. The prognostic significance was validated in both TCGA and GSE12417 cohorts. Subgroup analyses showed that higher KIAA0125 expression also predicted shorter DFS and OS in patients with normal karyotype or non-M3 AML. In multivariable analysis, higher KIAA0125 expression remained an adverse risk factor independent of age, WBC counts, karyotypes, and mutation patterns. Bioinformatics analyses revealed that higher KIAA0125 expression was associated with hematopoietic and leukemic stem cell signatures and ATP-binding cassette transporters, two predisposing factors for chemoresistance.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

1997 ◽  
Vol 15 (6) ◽  
pp. 2262-2268 ◽  
Author(s):  
M Wetzler ◽  
M R Baer ◽  
S H Bernstein ◽  
L Blumenson ◽  
C Stewart ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Poor Response ◽  
Significant Difference ◽  
De Novo Aml ◽  
Cd34 Expression ◽  
Acute Myeloid

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

scholarly journals Adult Patients With De Novo Acute Myeloid Leukemia and t(9; 11)(p22; q23) Have a Superior Outcome to Patients With Other Translocations Involving Band 11q23: A Cancer and Leukemia Group B Study

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4532-4538 ◽  
Author(s):  
Krzysztof Mrózek ◽  
Kristiina Heinonen ◽  
David Lawrence ◽  
Andrew J. Carroll ◽  
Prasad R.K. Koduru ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Extra Chromosome ◽  
Response To Therapy ◽  
High Dose ◽  
Postremission Therapy ◽  
De Novo Aml ◽  
Group B ◽  
Acute Myeloid

Abstract Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.

The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
Author(s):  
Sabine Kayser ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Negative Impact ◽  
Primary Malignancy ◽  
De Novo Aml ◽  
The Impact ◽  
Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

BCL2 Gene Polymorphism Could Predict the Treatment Outcomes in Patients with De Novo Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3973-3973
Author(s):  
Kyoung Ha Kim ◽  
Dong Hwan Kim ◽  
Su Jin Lee ◽  
Joon Ho Moon ◽  
Myung Hee Chang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Outcomes ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Chemotherapy Resistance ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
The Difference ◽  
Bcl2 Gene ◽  
Acute Myeloid

Abstract The bcl-2 protein inhibits apoptosis (programmed cell death) of hematopoietic stem cells induced by a variety of noxious stimuli, thus mediate chemoresistance and decrease chemosensitivity. Higher bcl-2 expression was demonstrated to correlate with an adverse outcome in acute myeloid leukemia (AML). The current study attempted to determine whether BCL2 gene single nucleotide polymorphism (SNP) could affect treatment outcomes of 109 AML patients. Two genotypes were tested including BCL2 −938 C&gt;A (rs2279115) and +21 A&gt;G (rs1801018) using Light cycler-assisted analyses. Neither −938 C&gt;A nor +21 A&gt;G BLC2 genotype was not associated with the difference of the probability to achieve complete remission (CR) after chemotherapy. While −938 A&gt;C BCL2 genotype did not affect leukemia free survival (LFS), event free survival (EFS) or overall survival (OS), of interest, BCL2 +21 A&gt;G genotype correlated with LFS and EFS significantly. The group with +21 AA genotype had a significantly longer median LFS (p&lt;0.001) or EFS (p=0.014), and marginally better OS (p=0.08). The multivariate analyses confirmed that BCL2 gene SNP is independent prognostic factor for LFS (p=0.05, HR 2.57, 95% C.I. [1.02–6.62]) and EFS (p=0.02, HR 2.38, 95% C.I. [1.11–5.13]), but not for OS (p=0.3) considering previously known risk factors. These data indicate that chemotherapy resistance may involve the bcl-2 mediated mechanism in AML.

Acute Myeloid Leukemia with Coexpression of Lymphoid-Associated Antigens: Clinicobiological Associations and Prognostic Implications,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3596-3596
Author(s):  
Georgia Voutiadou ◽  
Konstantina Kotta ◽  
Barbara Tachynopoulou ◽  
Apostolia Papalexandri ◽  
Chryssanthi Vadikolia ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Critical Role ◽  
Flow Cytometric Analysis ◽  
Prognostic Impact ◽  
Prognostic Implications ◽  
Cytogenetic Profile ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 3596 Immune phenotyping plays a critical role in the diagnosis and classification of acute leukemia. Several studies have reported a variable proportion of patients with acute myeloid leukemia (AML) expressing lymphoid-associated antigens (LAA). The exact frequency and true clinical significance of this phenomenon remains undefined due to inconsistencies between series, likely related to methodological aspects or potential case selection biases. We retrospectively evaluated the expression of LAA in blast cells from 278 consecutive and unselected patients with AML diagnosed in our Department between 2002 and 2010. The patient cohort included 168 males and 110 females with a median age of 61 years (range, 10–88); 146/278 cases were above the age of 60. Within this cohort, 190 cases (68%) had de novo AML, whereas the remaining 88 cases (32%) concerned secondary AML (sAML) to either MDS (n=80) or other non-hematologic malignancies (n=8). Patients were treated uniformly according to age with Aracytin/Idarubicin induction regimens (“3+7” or “2+5” for ages \q60 or ≥60, respectively). The immunophenotype was determined by flow cytometric analysis of (mainly) bone marrow aspirate and/or peripheral blood samples utilizing a primary CD45/side scatter (SSC) gating procedure with antibodies against CD7, CD13, CD19, CD33, CD4, CD10, CD34, CD117, CD64, HLA-DR, CD20, CD2, CD15, CD56, CD14, CD8, MPO, CD3, CD79a, CD22, TdT and lysozyme; a cut-off value for positivity of 20% was adopted. Overall, we identified 153/278 cases (55%) expressing at least one LAA. The most commonly expressed LAAs were CD4 (outside AML with monocytic differentiation), CD56, CD7, CD2, CD10 and CD79a (in 39%, 33%, 29%, 14%, 10% and 8% of LAA+ AML cases, respectively); interestingly, all CD79a-positive cases co-expressed at least one more LAA. A significant association was identified between LAA expression and cytogenetic profile: in particular, at least one LAA was detected in 37/50 cases (74%) with adverse cytogenetics (SWOG unfavorable and/or monosomal karyotype), compared to 24/41 (58%) cytogenetically favorable cases and 68/134 (51%) cytogenetically intermediate risk cases (p=0.01). No other statistically significant associations were found for LAA expression (positive vs. negative) in respect to age and complete remission (CR) rate. Furthermore, the frequency of LAA-positive cases was identical (55%) in both de novo AML (105/190 cases) and sAML (48/88 cases). Monoparametric statistical analysis was also performed individually for each of the six more frequent LAAs. Significant associations (p<0.05) were identified between: (i) CD7 expression and adverse cytogenetics; (ii) CD10 expression and adverse cytogenetics as well as failure to achieve CR, at both cohort level as well as patients \q60 years with de novo AML; and (iii) CD2 expression and shorter overall and disease-free survival (DFS and OS, respectively). Cox-multivariate analysis identified CD2 expression in addition to advanced age, sAML and adverse cytogenetic profile as negative prognostic indicators (p=0.05) for both DFS and OS. In conclusion, expression of LAAs is frequent in AML, among both de novo AML and sAML cases, and significantly associated with adverse cytogenetics. Although the negative prognostic impact of CD2 expression is noteworthy, however, the precise prognostic implications of the expression of individual LAAs are hard to define on single institution retrospective series and will require evaluation in large prospective and well-controlled studies. Disclosures: No relevant conflicts of interest to declare.

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