Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia

Santamaría, Carlos; Chillón, María Carmen; García‐Sanz, Ramón; Pérez, Cristina Fernández; Caballero, Marı́a Dolores; Ramos, Fernando; Coca, Alfonso García de; Alonso, José M.; Giraldo, Pilar; Bernal, Teresa; Queizán, José Antonio; Rodríguez, Juan Nicolás; Fernández-Abellán, Pascual; Bárez, Abelardo; Peñarrubia, María Jesús; Balanzategui, Ana; Vidriales, María‐Belén; Sarasquete, María Eugenia; Alcoceba, Miguel; Dı́az-Mediavilla, Joaquı́n; Miguel, Jesús F. San; González, Marcos

doi:10.1182/blood-2008-11-187724

Cited by 82 publications

(65 citation statements)

References 20 publications

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“…PRAME expression analysis was evaluated using quartiles as cut-off points, as reported previously. 33 To determine the expression levels of EVI1, a relative quantification was calculated using the equation 2 Ϫ⌬⌬Ct , as previously described. 44 Descriptive pairwise comparisons were performed by 2-sided 2 tests for categorical variables and by 2-sided Mann-Whitney U tests for comparison of 2, or 2-sided Kruskal-Wallis tests for comparison of 3 continuous variables, and are provided for exploratory purposes.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, other risk scores based on molecular markers have been proposed for CN-AML patients. 33,52 In contrast to these studies, we analyzed a larger number of more homogeneously treated patients up to the age of 60 years. Moreover, we weighted the different risk factors according to their HR in univariate analysis.…”

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confidence: 99%

“…5 Patients with low ERG, low EVI1, and high PRAME levels were also shown to have a good prognosis. 33 In addition, WT1 single nucleotide polymorphism (SNP) rs16754, a recently described prognostic marker in CN-AML patients, identified a favorable subgroup in the NPM1/FLT3 high-risk group. 34 The availability of sequence information from whole AML genomes is expected to lead to identification of even more prognostic markers in AML patients.…”

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confidence: 99%

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Integrative prognostic risk score in acute myeloid leukemia with normal karyotype

Damm¹,

Heuser²,

Morgan

et al. 2011

Blood

100

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To integrate available clinical and molecular information for cytogenetically normal acute myeloid leukemia (CN-AML) patients into one risk score, 275 CN-AML patients from multicenter treatment trials AML SHG Hannover 0199 and 0295 and 131 patients from HOVON/SAKK protocols as external controls were evaluated for mutations/polymorphisms in NPM1, FLT3, CEBPA, MLL, NRAS, IDH1/2, and WT1. Transcript levels were quantified for BAALC, ERG, EVI1, ID1, MN1, PRAME, and WT1. Integrative prognostic risk score (IPRS) was modeled in 181 patients based on age, white blood cell count, mutation status of NPM1, FLT3-ITD, CEBPA, single nucleotide polymorphism rs16754, and expression levels of BAALC, ERG, MN1, and WT1 to represent low, intermediate, and high risk of death. Complete remission (P ‫؍‬ .005), relapse-free survival (RFS, P < .001), and overall survival (OS, P < .001) were significantly different for the 3 risk groups. In 2 independent validation cohorts of 94 and 131 patients, the IPRS predicted different OS (P < .001) and RFS (P < .001). High-risk patients with related donors had longer OS (P ‫؍‬ .016) and RFS (P ‫؍‬ .026) compared with patients without related donors. In contrast, intermediate-risk group patients with related donors had shorter OS (P ‫؍‬ .003) and RFS (P ‫؍‬ .05). Donor availability had no impact on outcome of patients in the low-risk group. Thus, the IPRS may improve consolidation treatment stratification in CN-AML patients. Study registered at www.clinicaltrials.gov as #NCT00209833. IntroductionAcute myeloid leukemia (AML) is characterized by uncontrolled proliferation of hematopoietic progenitor cells, blocked maturation resulting from interruption of normal differentiation pathways, and activation of antiapoptotic pathways. In a large proportion of AML patients, standard cytogenetic analyses can identify specific recurrent chromosomal aberrations that are important for disease pathogenesis, response to therapy, and patient survival. 1,2 However, almost half of all AML patients are classified as cytogenetically normal (CN-AML). 2 Many efforts have been made to identify genetic mutations (eg, FLT3,3,4 NPM1, 5,6 CEBPA, 7-10 MLL, 11,12 NRAS, 13 IDH1/ 2, [14][15][16][17][18][19][20] and WT1 [21][22][23] ) that allow further subclassification and possibly risk-directed therapeutic intervention. In addition to mutations, modulated expression of genes important for proliferation, survival, and differentiation have also been shown to be predictive for CN-AML patient outcome (eg, MN1, 24,25 BAALC, 26 ERG, 27 ID1, 28 and WT1 29,30 ). This molecular heterogeneity of CN-AML is not fully reflected in current classification systems. 31,32 Recently, 2 or 3 prognostic markers were combined to define patient subgroups with distinct prognosis. Most importantly, patients with mutated NPM1 and wild-type FLT3 have a favorable prognosis. 5 Patients with low ERG, low EVI1, and high PRAME levels were also shown to have a good prognosis. 33 In addition, WT1 single nucleotide polymorphism (SNP) rs16754, a recently ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Integrative prognostic risk score in acute myeloid leukemia with normal karyotype

Damm¹,

Heuser²,

Morgan

et al. 2011

Blood

100

View full text Add to dashboard Cite

show abstract

“…Relative quantification was calculated using the equation 2 À DDCt , where DCt ¼ Ct FLT3 -Ct ABL1 and DDCt ¼ DCt PATIENT -DCt HEALTHY BM as previously described. 23 In addition, FLT3 gene expression of 10 BM samples from healthy volunteers was used as a calibrator.…”

Section: Quantification Of Flt3 Gene Expressionmentioning

confidence: 99%

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

et al. 2012

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There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n ¼ 49) or T-ALL (n ¼ 5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3-ITD. None of the T-ALL and E2A-PBX1 þ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4 þ B-ALL but also ETV6-RUNX1 þ , BCR-ABL þ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P ¼ 0.002) and disease-free survival (DFS; 0 vs 43%; P ¼ 0.03) in MLL-AF4 þ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age414 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4 þ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4 þ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors.

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“…Other chromosomal abnormalities are also candidate cause of EVI-1 activation such as 11q23 rearrangements, abnormalities of chromosome 7, MLL fusion proteins [12]. Today it has become evident that EVI-1 is a crucial gene for HSC regulation as well as an oncogene, the expression of which predicts poor patient survival in haematological malignancies [13,14].…”

Section: Introductionmentioning

confidence: 99%

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities

et al. 2015

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Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation.

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Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia

Cited by 82 publications

References 20 publications

Integrative prognostic risk score in acute myeloid leukemia with normal karyotype

Integrative prognostic risk score in acute myeloid leukemia with normal karyotype

Prognostic significance of FLT3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia

Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities

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