VLA-4 and CXCR4 expression levels show contrasting prognostic impact (favorable and unfavorable, respectively) in acute myeloid leukemia

2015 ◽  
Vol 94 (10) ◽  
pp. 1631-1638 ◽  
Author(s):  
Mi Hyun Bae ◽  
Sung-Hee Oh ◽  
Chan-Jeoung Park ◽  
Bo-Ra Lee ◽  
Young Jin Kim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cxcr4 Expression ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Acute Myeloid

Incidence and Prognostic Influence of DNMT3A Mutations in Acute Myeloid Leukemia

2011 ◽  
Vol 29 (21) ◽  
pp. 2889-2896 ◽  
Author(s):  
Felicitas Thol ◽  
Frederik Damm ◽  
Andrea Lüdeking ◽  
Claudia Winschel ◽  
Katharina Wagner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Direct Sequencing ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Entire Patient Cohort ◽  
Risk Patients ◽  
Acute Myeloid

Purpose To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. Patients and Methods A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). Results DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. Conclusion DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.

High Expression Levels of Iaps Predict Poor Overall Survival in Childhood De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4396-4396
Author(s):  
Ingo Tamm ◽  
Stephan Richter ◽  
Doreen Oltersdorf ◽  
Ursula Creutzig ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
High Expression ◽  
Prognostic Impact ◽  
Poor Overall Survival ◽  
Expression Levels ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. Using flow cytometry and western blot analysis, we therefore investigated 45 leukemic cell samples of children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins (CD95, Bcl-2, Bax, Bcl-xL, Procaspase-3, XIAP, cIAP-1, Survivin). XIAP (p&lt;0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by FAB morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (p&lt;0.01) and Bcl-xL (p&lt;0.01) expression was lower in patients with favorable than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP {30 (n=10) vs. 41 months (n=34); p&lt;0.05} and Survivin {27 (n=10) vs. 41 months (n=34); p&lt;0.05}. We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics and poor overall survival should be confirmed within prospective pediatric AML trials.

Prognostic Impact of BAALC Expression in the Context of Other Molecular Markers in Cytogenetically Normal Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3485-3485
Author(s):  
Konstanze Dohner ◽  
Andrea Corbacioglu ◽  
Karina Eiwen ◽  
Judith Ewert ◽  
Stefan Frohling ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Molecular Markers ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Significant Variable ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Expression Levels ◽  
Family Donor ◽  
Acute Myeloid

Abstract Background: In previous studies, high blood expression values of BAALC (brain and acute leukemia cytoplasmic) have been shown to be an adverse risk factor in cytogenetically normal acute myeloid leukemia (CN-AML). So far, the prognostic value of BAALC expression has not been evaluated in the context of other relevant molecular markers such as mutations (mut) in the NPM1 or CEBPA genes. Aims: To evaluate the prognostic impact of BAALC expression in the context of NPM1, FLT3-ITD (internal tandem duplication)/TKD (tyrosine kinase domain mutations at codons 835/836), CEBPA, and MLL-PTD (partial tandem duplication) mutation status on response to induction therapy, relapse-free (RFS) and overall survival (OS). Methods: Patients (pts) 16 to 60 years of age were entered on three treatment trials conducted by the German-Austrian AML Study Gorup (AML HD93, AML HD98A, AML04–07). In all three trials, a genetic randomization was performed assigning all pts with an HLA-matched family donor to allogeneic stem cell transplantation (SCT) in first complete remission (CR). BAALC expression was determined in peripheral blood from 339 CN-AML pts by real-time RT-PCR as recently described; gene mutation screening was performed as previously reported. Results: BAALC expression levels were heavily scattered in the 339 pts, with a median of 4,716 (range 11–1,120,212). High and low BAALC expression was determined by dichotomizing BAALC at the median. Correlation of BAALC expression levels with FLT3-ITD/TKD, NPM1, CEBPA and MLL-PTD mutation status revealed high BAALC expression to be significantly associated with FLT3-ITDpos (p=0.001), NPM1WT (p<0.0001) and CEBPAmut (p=0.006). In addition, when correlating BAALC expression levels with the combined FLT3-ITD/NPM1 genotypes that recently have been shown to be of prognostic relevance in CN-AML, a significant correlation of low BAALC expression and the favorable FLT3-ITDneg/NPM1mut (p<0.0001) genotype was present. In contrast, high expression levels were significantly correlated with the other unfavorable genotypes. There was a trend towards a lower CR rate in high BAALC expressers (p=0.07). However, in a multivariable logistic regression model, BAALC was not significant (p=0.75); the only significant variables for induction success were the FLT3-ITDneg/NPM1mut (p=0.03) and CEBPAmut genotypes (p=0.04), as well as logarithm of white blood cell count (WBC, p=0.03). In univariable analyses for OS and RFS, high BAALC expressers had significantly inferior clinical outcome (p=0.05 and p=0.02, respectively). Again, multivariable Cox proportional hazard models for RFS and OS revealed no significant impact of BAALC expression (p=0.15 and p=0.96, respectively); significant variables for OS and RFS were the FLT3-ITDneg/NPM1mut (p<0.0001 and p<0.0001) genotype, availability of an HLA-matched family donor (p=0.02 and p=0.001), and WBC (p=0.0002 and p=0.0001); in addition, the CEBPAmut genotype was a significant variable for OS (p=0.002). Conclusions: In our study on a large series of molecularly well characterized CN-AML, BAALC expression levels were significantly correlated with FLT3-ITD/NPM1 genotypes. In the context of these genotypes, BAALC expression lost its independent prognostic impact.

scholarly journals BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5660-5669 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Distinct Gene ◽  
Acute Myeloid

AbstractBAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (≥ 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene–embedded microRNAs were up-regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients.

scholarly journals Prognostic Implications of Pri-Mir-320a Expression in Acute Myeloid Leukemia Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1037-1037
Author(s):  
Taqiuddine Gaber ◽  
Marius Bill ◽  
Madlen Jentzsch ◽  
Karoline Schubert ◽  
Heike Weidner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosome 8 ◽  
Entire Group ◽  
Prognostic Impact ◽  
Trisomy 8 ◽  
Expression Levels ◽  
Cell Counts ◽  
Expression Status ◽  
Acute Myeloid

Abstract Background: Most acute myeloid leukemia (AML) patients (pts) stilldo not achieve long-term survival. Better risk stratification and novel therapeutic avenues are needed to improve pts outcomes. The expression of microRNAs has been demonstrated to be altered in AML & miR-based therapies are entering clinical trials. MiR-320a, maps to chromosome 8p21.3 & is known to play a role in several tumors; e.g. higher miR-320a expression suppresses the progression of colorectal cancer. In AML miR-320a has been shown to inhibit cell proliferation, likely by targeting the transferrin receptor 1. Objective: The objective of this study was to investigate whether a differential expression of pri-miR-320a associated with outcome in AML pts. Methods: We assessed the expression levels of pri-miR-320a, a precursor molecule of mature miR-320a. The pri-miR-320a expression levels in 129 AML pts were assessed by quantitative reverse transcription polymerase chain reaction & normalized to a housekeeping gene (18S). The 75th percentile was chosen as a cut-off discriminating between high & low pri-miR-320a expressers. We analyzed 129 AML pts (median age at HCT 64 years [y]; range 22–74 y) who received reduced intensity conditioning (RIC; Fludarabine 30mg/m^2 at day -4 to -2 & 2 Gy total body irradiation at day 0)-hematopoietic cell transplantation (HCT) at the University of Leipzig, with pretreatment bone marrow available. The median follow-up was 4.5 y for pts alive. European LeukemiaNet (ELN) genetic classification was: favorable (n=33; 25.6%), intermediate I (n=33; 25.6%), intermediate II (n=29; 22.5%) or adverse (n=30; 23.3%). The pts were also characterized for FLT3-ITD status, CEBPA, IDH1, IDH2 and NPM1 mutations. Results: At diagnosis high pri-miR-320a expression associated by trend with lower hemoglobin levels (P=.094), lower white blood cell counts (P=.079) & lower peripheral blast counts (P=.096). High pri-miR-320a expressers less frequently had NPM1 (P=.038) or CEBPA (P=.025) mutations. Interestingly, pri-miR-320a expression was significantly lower in pts with trisomy 8 (P=.018) compared to non-trisomy 8 pts & in the ELN intermediate II group none of the trisomy 8 pts was in the high pri-miR-320a expressing group. Analysis of our AML pts, showed a significant association between pri-miR-320a expression status & clinical outcome. In the entire group of pts high pri-miR-320a expressers had a longer overall survival (OS; P=.086; Figure 1) by trend & a significantly longer event-free survival (EFS; P=.032). The strongest impact of pri-miR-320a was found in the ELN intermediate II group, where high pri-miR-320a expression was associated by trend with longer OS (P=.059; Figure 1) & a significantly longer EFS (P=.034). In multivariate analysis, the prognostic impact of pri-miR-320a expression status was confirmed in the entire group of pts (OS: P<.01, hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.27-0.75; EFS: P<.01, HR 0.45, 95% CI 0.28-0.71). Conclusion: High expression of pri-miR-320a associates with distinct clinical & molecular features. Interestingly, in AML pts with trisomy 8 pri-miR-320a that maps to chromosome 8 has a significantly lower expression, indicating a possible leukemogenic link to trisomy 8 associated AML. High pri-miR-320a expression significantly associates with better outcome especially in the ELN intermediate II group. These results suggest that pri-miR-320a could be used as a marker to refine current AML risk stratifications. Increasing miR-320a, by e.g. miR-replacement therapies, might improve outcomes of AML pts. Figure 1: Figure 1:. OS (A) and EFS (B) in AML pts according to pri-miRNA-320a expression status, OS (C) and EFS (D) in AML pts in the ELN intermediate II group according to pri-miRNA-320a expression status Disclosures No relevant conflicts of interest to declare.

scholarly journals Low-Density Granulocytes Are Decreased in Acute Myeloid Leukemia and in Myelodysplastic Syndromes with Negative Prognostic Factors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4448-4448
Author(s):  
Valentina Giudice ◽  
Marisa Gorrese ◽  
Idalucia Ferrara ◽  
Rita Pepe ◽  
Angela Bertolini ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
World Health ◽  
Prognostic Impact ◽  
Low Density ◽  
Expression Levels ◽  
Increased Risk ◽  
Acute Myeloid

Abstract Introduction. Myelodysplastic syndromes (MDS), a group of clonal hematological diseases, are characterized by ineffective hematopoiesis, progressive peripheral blood (PB) cytopenia(s), and increased risk of developing acute myeloid leukemia (AML). Classification and risk stratification are constantly under revision for a better estimation of prognosis in those patients. Investigation of immune biomarkers is needed, because immune dysregulation also plays an important role in dysplastic hemopoiesis and immunological escape of neoplastic clones. Here, we studied frequency of low-density granulocytes (LDGs), a neutrophil subset with immunoregulatory functions, in MDS and AML at diagnosis and during treatments. Methods. A total of 17 patients (M/F, 14/12; median age, 69 years old; range, 21-84 years) and seven healthy subjects were enrolled at the Hematology and Transplant Center, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy, between October 2020 and July 2021. Patients were diagnosed with AML (N = 7), or MDS (N = 10) according to the 2016 World Health Organization criteria. For immunophenotyping, fresh EDTA whole PB was stained with the ollowing antibodies: CD45; HLA-DR; CD15; CD3; CD56; CD19; CD11b; CD33; CD34; CD14; and CD16 (all from Beckman Coulter, Brea, CA). Acquisition was carried out using a Navios EX flow cytometer, and Navios software v1.3 (Beckman Coulter). Post-acquisition compensation and analysis were performed using FlowJo software (v.10.7.1, Becton Dickinson). LDGs were identified as CD3-CD56-CD19-CD11b+CD33+CD14-CD15+ cells, following previously published gating strategies (Rahman S, et al. Ann Rheum Dis. 2019). Data were analyzed using Prism (GraphPad software, La Jolla, CA). A P &lt; 0.05 was considered statistically significant. Results. Frequencies of circulating LDGs were significantly reduced in AML patients at diagnosis compared to controls (P = 0.0018) and MDS (P = 0.0077) and were slightly decreased compared to AML in complete remission (P = 0.1605). MDS patients were then divided based on Revised International Prognostic Scoring System (IPSS-R), and very-low and low-risk MDS patients displayed significantly higher circulating LDG frequencies compared to AML at diagnosis (P = 0.0083), while no differences were described between AML at baseline and intermediate-risk MDS (P = 0.1103). Subsequently, LDGs were correlated with clinical and phenotypic features by correlation analysis showing significant negative correlations between LDGs and blasts identified by flow cytometry (r = -0.5463; P = 0.0057) but not by cytology (P = 0.1346), between LDGs and lymphocytes (r = -0.4407; P = 0.0311) or flow cytometric normalized blast count (NBC; r = -0.5283; P = 0.0096) as previously defined (Giudice V, et al. Biomedicines. 2021). A slight negative correlation was described between LDGs and WT1 expression levels (r = -0.5369; P = 0.0719), particularly evident in MDS patients (r = -0.9980; P = 0.0402), supporting our previous findings of negative prognostic impact of WT1 expression in MDS and AML. Finally, we investigated CD16 expression on LDGs, because CD16 is essential for neutrophil degranulation. Despite no differences were described between percentage of LDG subsets among patients' groups, various correlations were identified by Pearson analysis. In particular, CD16+ LDGs negatively correlated with blasts (P = 0.0229), while positively correlated with lymphocytes (P = 0.0404) detected by flow cytometry. Conversely, CD16int and CD16- LDGs negatively correlated with lymphocytes (P = 0.0109 and P = 0.0021, respectively) and positively correlated with granulocytes identified by flow cytometry (P = 0.0024 and P = 0.0008, respectively). In addition, CD16int LDGs negatively correlated with blasts detected by flow cytometry (r = -0.65; P = 0.0414). Conclusions. Our preliminary results suggested a possible role of LDGs in prognostic definition of AML and MDS patients especially when combined with other biomarkers, such as WT1 expression levels or NBC. Moreover, our data supported the hypothesis of biological heterogeneity of granulocytes, as LDG subsets variously correlated with lymphocytes and leukemic cells suggesting different roles in suppression or activation of immune responses. However, our findings need further validation in larger cohorts and in in vitro studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Impact of KMT2C and SPRY4 Expression Levels in Intensively Treated Younger Adult Acute Myeloid Leukemia Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1663-1663
Author(s):  
Sabine Kayser ◽  
Maximilian Feszler ◽  
Julia Krzykalla ◽  
Matthias Schick ◽  
Thomas Hielscher ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Prognostic Impact ◽  
Risk Class ◽  
Expression Levels ◽  
Blast Cells ◽  
Pharmaceutical Industries ◽  
Acute Myeloid

Abstract Background:Recent publications suggest important roles of lysine methyltransferase 2C (KMT2C, located on 7q) and sprouty 4 (SPRY4, located on 5q) as candidate genes in leukemogenesis of acute myeloid leukemia (AML). The prognostic impact of the gene expression levels (ELs) of both genes on outcome in AML patients (pts) is currently unclear. Aim:To evaluate the prognostic impact of KMT2C and SPRY4 expression in correlation to clinical characteristics and genetic abnormalities assessed at diagnosis in a cohort of intensively treated adult AML pts. Methods: We retrospectively studied 268 AML pts (median age, 48 years; range, 17-60 years) who had been enrolled on 2 AML SHG trials (0295 and 0199, n=148; only normal cytogenetics pts (CN)) and the SAL-AML2003 trial (n=120; only abnormal cytogenetics pts (CA)). Acute promyelocytic and core-binding factor leukemia pts were excluded. Type of AML was de novo in 235 (88%), secondary in 19 (7%) and therapy-related in 14 (5%) of the 268 pts. Regarding baseline characteristics, CN pts had significantly higher white blood counts (WBC; p=0.001) and blast cells in peripheral blood (p=0.02) as compared to CA pts; all other factors were comparable. Cytogenetic analyses could be performed in 263 (98%) of the 268 pts. Cytogenetic risk classification according to ELN guidelines was intermediate-II in 55 (47%) and adverse in 63 (53%) of the CA pts, respectively. Abnormalities (abn) of 5q were present in 21 (18%) and abn of 7q in 16 (14%) of the CA pts. NPM1 and FLT3-ITD were analyzed in 145 (98%) of the CN pts. Of those, 59 (41%) were only NPM1 positive (pos), 12 (8%) were only FLT3-ITD pos, 34 (23%) were double pos and 40 (28%) were double negative (neg). KMT2C and SPRY4 ELs, normalized to ABL1and log2-transformed for analysis, were measured in triplets on cDNA obtained at diagnosis by RT-qPCR. Based on cDNA availability, KMT2C ELs could be analyzed in 143 (97%) of the CN and in all of the 120 CA pts, respectively. SPRY4 ELs could be measured in 30 (21%) of the CN and 107 (89%) of the CA pts, respectively. Results: KMT2C ELs were significantly lower in CN pts with de novo as compared to secondary AML (p= 0.02), whereas there was no difference in CA pts. No significant association was found for SPRY4 and type of AML. KMT2C ELs were significantly lower in FLT3-ITD pos as compared to FLT3-ITD neg CN pts (p=0.046), whereas there was no difference for SPRY4 ELs between the two groups (p=0.57). In addition, there was a significantly lower KMT2C expression in CN pts with intermediate-I risk as compared to NPM1 pos / FLT3-ITD neg pts (p=0.01). Regarding CA pts, there was no difference of KMT2C or SPRY4 ELs in adverse as compared to intermediate-II risk pts (p=0.08; p=0.20, respectively). When focusing on specific subgroups, KMT2C ELs were significantly lower in abn7q CA pts as compared to those without abn7q (p=0.002), whereas there was no difference of SPRY4 ELs in CA pts with or without abn5q (p=0.27). In univariate analysis higher SPRY4 ELs showed a significant favorable impact on relapse-free (RFS, p=0.03) and a trend towards a beneficial impact on overall survival (OS, p=0.06) for CA patients. A similar effect for KMT2C was not observed (RFS, p=0.96; OS, p=0.92). In subgroup analyses of pts with adverse risk cytogenetics, there was no impact of KMT2C or SPRY4 ELs on RFS (p=0.73; p=0.39) or OS (p=0.49; p=0.46), respectively. The same was true for FLT3-ITD pos CN pts (RFS, p=0.73; p=0.37; OS, p=0.91; p=0.36, respectively). In multivariate analyses on RFS and OS in CA pts including age, gender, KMT2C and SPRY4 ELs, logarithm of WBC, blast cells in bone marrow and cytogenetic risk group as variables, only higher age (OS, Hazard ratio (HR),1.28 per 10 years; 95%-confidence interval (CI): 1.02-1.59; p=0.03) and complex karyotype as compared to intermediate-II risk cytogenetics (RFS, HR: 2.25; 95%-CI: 1.20-4.22; p=0.01; OS, HR: 2.97; 95%-CI: 1.65-5.35; p<0.001) had an adverse impact. An effect of KMT2C or SPRY4 on RFS (p=0.84; p=0.16) or OS (p=0.85; p=0.45) was not found in the multivariate setting. In addition, in a multivariate model on CN pts (risk class according to NPM1 and FLT3-ITD mutational status instead of cytogenetic risk class) neither KMT2C nor SPRY4 had an impact on RFS (p=0.13; p=0.39, respectively) or OS (p=0.36; p=0.56, respectively). Conclusions:Lower KMT2C and SPRY4 ELs are associated with distinct genetic risk groups. An impact on prognosis was evident in univariable analyses for SPRY4 but not for KMT2C ELs in CA pts. Disclosures Kayser: Novartis: Consultancy. Platzbecker:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Heuser:Tetralogic: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Thiede:AgenDix: Employment, Other: Ownership.

scholarly journals Epigenetics Meets Genetics in Acute Myeloid Leukemia: Clinical Impact of a Novel Seven-Gene Score

2014 ◽  
Vol 32 (6) ◽  
pp. 548-556 ◽  
Author(s):  
Guido Marcucci ◽  
Pearlly Yan ◽  
Kati Maharry ◽  
David Frankhouser ◽  
Deedra Nicolet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Expression ◽  
Prognostic Impact ◽  
Sequencing Analysis ◽  
Gene Score ◽  
Expression Levels ◽  
Acute Myeloid

PurposeMolecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML.MethodsNext-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older (≥ 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355).ResultsIn the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P ≤ .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively).ConclusionA seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

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