High EVI1 Expression Predicts Outcome in Younger Adult Patients With Acute Myeloid Leukemia and Is Associated With Distinct Cytogenetic Abnormalities

Abstract

PURPOSE The purpose of this study was to investigate frequency and prognostic significance of high EVI1 expression in acute myeloid leukemia (AML). PATIENTS AND METHODS A diagnostic assay detecting multiple EVI1 splice variants was developed to determine the relative EVI1 expression by single real-time quantitative polymerase chain reaction in 1,382 newly diagnosed adult patients with AML younger than 60 years. Patients were treated on four Dutch-Belgian HOVON (n = 458) and two German-Austrian AML Study Group protocols (n = 924). Results The EVI1 assay was tested in the HOVON cohort and validated in the AMLSG cohort. High EVI1 levels (EVI1(+)) were found with similar frequencies in both cohorts combined, with a 10.7% incidence (148 of 1,382). EVI1(+) independently predicted low complete remission (CR) rate (odds ratio, 0.54; P = .002), adverse relapse-free survival (RFS; hazard ratio [HR], 1.32; P = .05), and event-free survival (EFS; HR, 1.46; P < .001). This adverse prognostic impact was more pronounced in the intermediate cytogenetic risk group (EFS; HR, 1.64; P < .001; and RFS; HR, 1.55; P = .02), and was also apparent in cytogenetically normal AML (EFS; HR, 1.67; P = .008). Besides inv(3)/t(3;3), EVI1(+) was significantly associated with chromosome abnormalities monosomy 7 and t(11q23), conferring prognostic impact within these two cytogenetic subsets. EVI1(+) was virtually absent in favorable-risk AML and AML with NPM1 mutations. Patients with EVI1(+) AML (n = 28) who received allogeneic stem cell transplantation in first CR had significantly better 5-year RFS (33% +/- 10% v 0%). CONCLUSION EVI1 expression in AML is unequally distributed in cytogenetic subtypes. It predicts poor outcome, particularly among intermediate cytogenetic risk AML. Patients with EVI1(+) AML may benefit from allogeneic transplantation in first CR. Pretreatment EVI1 screening should be included in risk stratification.

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…In adult AML, overexpression of EVI1 is an independent poor prognostic factor, and in half of the cases an MLL rearrangement was identified. 101,102 We confirmed this in pediatric AML, where overexpression of EVI1 is mainly associated with a subset of MLL-rearranged AML. 103 All cases with a t(6;11)(q27;q23), that carry a very poor outcome, showed overexpression of EVI1, consistent with adult t(6;11)(q27;q23) cases.…”

De novo acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2): a clinicopathologic and cytogenetic study of an entity recently added to the WHO classification

“…2 Recently, elevated levels of EVI1 have been shown to predict adverse outcome and poor response to therapy in acute myeloid leukemia patients. 15,16 Unlike some other types of acute myeloid leukemia with recurrent genetic abnormalities, additional cytogenetic abnormalities are common in acute myeloid leukemia associated with inv(3)/t(3;3). Only five cases in this study cohort had inv(3)/t(3;3) as a sole cytogenetic abnormality.…”

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

“…Detailed treatment protocols have been reported previously. 3,17,18 To analyze the incidence of ND4 mutations in healthy controls, peripheral blood samples from 124 healthy blood donors (age 18-60 years) were obtained from the Institute of Transfusion Medicine, Hannover Medical School. Written informed consent was obtained according to the Declaration of Helsinki, and the study was approved by the institutional review board of Hannover Medical School.…”