Integrative prognostic risk score in acute myeloid leukemia with normal karyotype

Abstract

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 ...

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

“…2,3 Advances in the molecular characterization of AML have facilitated the establishment of more detailed risk scores, which proved to be particularly useful in patients without distinct cytogenetic profiles. 56,57 Further extension of these scores by inclusion of new molecular markers with prognostic significance will be a pivotal step in the development of personalized risk profiles for patients diagnosed with AML. In this study, we present loss of the RKIP protein expression as a potential new prognostic marker.…”

Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia

“…To assess the impact of gene expression of MLL5, MN1, BAALC, ERG or WT1 on patient outcome, expression values were dichotomized (only for MLL5 quartiles were used 29 ) at the median expression value and used as categorical variables (median normalized copy number, gene transcripts per ABL transcripts). 31 For 34 de novo vs secondary AML, and ND4 mutation status. In all multivariable models no variable selection was performed and full models were presented.…”

“…24 BAALC, 25 ERG, 26 MN1, 27,28 MLL5 29 and WT1 24 expression levels were quantified as previously described using cDNA from the KG1A cell line (BAALC, ERG and MLL5) or plasmids (MN1 30 and WT1 24 ) to construct a standard curve. 31 …”

Concise Review: The Role of Hematopoietic Stem Cell Transplantation in the Treatment of Acute Myeloid Leukemia

“…For example, the favorable effect of NPM1 mutations now appears limited to patients with IDH mutations, and these patients benefit from more intensive induction chemotherapy [32]. With greater numbers of prognostic markers identified, integrated approaches based on both clinical and molecular markers and their interactions have been proposed to help better predict outcomes for patients and identify those who will benefit from more intensive therapies [33].…”