Deregulated Expression of EVI1 Defines a Poor Prognostic Subset of MLL-Rearranged Acute Myeloid Leukemias

AML with translocations involving the mixed-lineage leukemia gene (MLL) on chromosome band 11q23 occur in 5–10% of adult cases. Outcome of patients with t(11q23) is generally poor, except for AMLs with t(9;11) that are associated with an intermediate prognosis. Clinical risk factors have been proposed, however, due to the rarity of these AML subtypes and to the great heterogeneity of MLL fusion partners, validation of such risk factors remains a challenge. In two previous studies (Lugthart S et al., Blood 2008; Gröschel S, Lugthart S et al., J Clin Oncol 2010) that included all AML subsets, it has been shown that high expression of the ecotropic viral integration 1 gene (EVI1⁺ ) is associated with t(11q23) AML; furthermore, EVI1⁺ appeared to be associated with inferior prognosis in this subset of AML. The aim of this study was to evaluate the prognostic impact of EVI1⁺ in a large cohort of AMLs with t(11q23) in the context of clinical features and cytogenetic and molecular genetic markers.

In the AMLSG data base we identified 147 AMLs with t(11q23). In 109 cases material was available for EVI1 expression analysis. Patients were treated on seven different prospective treatment protocols of the German-Austrian AMLSG (HD93, HD98A, HD98B, 07–04, 06–04, SHG295, SHG0199).

The 147 MLL -rearranged AMLs were divided into three subgroups: t(9;11)(p22;q23), n=70 (47.6%); t(6;11)(q27;q23), n=26 (17.7%); and t(v; 11q23), n=51 (34.7%). Most common translocation partners within t(v; 11q23) were t(11;19)(q23;p13) (n=15, 29.4%) and t(10;11)(p13;q23) (n=6, 11.8%). Comparison of clinical characteristics between the three subgroups revealed significantly higher LDH levels (median 550 U/L, p=.049), higher rate of therapy-related AML (33.8%, p=.002), and higher incidence of trisomy 8 (25.7%, p=.05) in AML with t(9;11). Deregulated expression of EVI1 was found in 55/109 (50.5%) of all t(11q23) cases; AMLs with t(6;11) showed the highest frequency of EVI1⁺ (85.7%), followed by AMLs with t(9;11) (44.2%), and t(v; 11q23) (38.9%) (p=.001). Concurrent gene mutations were virtually absent in t(9;11) AMLs; only rare FLT3 -ITDs were identified (3/70 cases; 4.3%), whereas no sequence variations were found for all other genes analyzed (CEBPA, NPM1, RUNX1, IDH1/2, ASXL1, TET2, DNMT3A). There was no difference in achievement of complete remission (CR) between EVI1⁻ and EVI1⁺ t(11q23) AMLs. In multivariable analysis of the entire t(11q23) cohort, EVI1⁺ was the only prognostic factor predicting for inferior overall survival (OS) (p=.017, HR 1.88, 95%-CI: 1.12–3.16) and relapse-free survival (RFS) (p=.013, HR 1.96, 95%-CI: 1.15–3.32). EVI1⁺ AMLs with t(11q23) in first CR had significantly better outcome (OS, p=.01; RFS, p=.002) after allogeneic stem-cell transplantation compared with other consolidation therapies; the 5-year OS rate of EVI1⁺ AML was 53 % and 0 % after allogeneic SCT and other consolidation therapies, respectively. We also separately analyzed the subset of t(9;11) AML: compared with EVI1⁻ patients, EVI1⁺ patients had higher white blood cell counts (p=.045); additional presence of trisomy 8 was only found in EVI1^- t(9;11) AMLs (11/29, 37.9%; p=.001). In multivariable analysis, EVI1⁺ again was the sole independent adverse prognostic factor for OS (p=.017, HR 2.55, 95%-CI: 1.18–5.51) and RFS (p=.02, HR 2.39, 95%-CI: 1.14–4.97).

Deregulated expression of EVI1 is found in about half of t(11q23) AMLs. EVI1⁺ is the strongest prognostic factor in all t(11q23) AMLs and in the subset of t(9;11) AMLs. Patients with EVI1⁺MLL -rearranged AML appear to benefit from allogeneic SCT in first CR.

Germing:Celgene: Consultancy, Research Funding.