Prognostic Utility of the European LeukemiaNet (ELN) Genetic-Risk Classification in Adults with De Novo Acute Myeloid Leukemia (AML): A Study of 1,550 Patients (Pts)
Authors: Mrózek Krzysztof , Marcucci Guido , Maharry Kati , Nicolet Deedra , Becker Heiko , Whitman Susan P. , Metzeler Klaus H. , Schwind Sebastian , Wu Yue-Zhong , Kohlschmidt Jessica , Pettenati Mark J. , Koduru Prasad R. K. , Heerema Nyla A. , Block Annemarie W. , Patil Shivanand R. , Baer Maria R. , Kolitz Jonathan E. , Moore Joseph O. , Carroll Andrew J. , Larson Richard A. , Bloomfield Clara D. 
Published: October 2019

Abstract
Abstract 414
The ELN standardized system for reporting cytogenetic and select molecular findings was created to enable comparisons of studies correlating treatment outcome with genetic data in AML (Döhner et al. Blood 2010;115:453). The ELN classification is based on published reports on prognostic import of cytogenetic and molecular alterations, but has not been tested in large cohorts of similarly treated AML pts, except for 1 study comprising ∼20% secondary AML pts (Röllig et al. JCO 2011;29:2758). Thus our goal was to assess the prognostic utility of the ELN classification in a relatively large cohort lacking the confounding effects of AML type (de novo v secondary) or different therapies [chemotherapy v allogeneic stem cell transplant (SCT)]. We analyzed 1,550 de novo AML pts (excluding AML M3, which is not part of the ELN classification) treated with cytarabine-daunorubicin-based chemotherapy on Cancer and Leukemia Group B frontline protocols; no pt received SCT in 1st complete remission (CR). Since consolidation therapy of younger [<60 years (y)] and older ('60 y) pts differed in intensity, we analyzed younger (n=818; median age 44 y, range 17–59) and older (n=732, median age 69 y, range 60–86) pts separately.
The pts were classified into the 4 ELN Genetic Groups: Favorable (Fav), Intermediate I (Int I), Intermediate II (Int II) or Adverse (Adv). Younger pts were classified in the Fav Group twice as often and in the Int II and Adv Groups ∼30% less often than older pts (Table 1). Within the Fav Group, core binding factor AML [t(8;21), inv(16) or t(16;16)] was twice as common (P<.001) and NPM1-mut/FLT3-ITD– half as common in younger than in older pts. In the Int I Group, NPM1-mut/FLT3-ITD+ was more common in younger and NPM1-wt/FLT3-ITD– in older pts, whereas in the Int II Group, t(9;11) was twice more common in younger pts. In the Adv Group, pts with balanced cytogenetic abnormalities (abns), ie, inv(3) or t(3;3), t(6;9) and t(v;11)(v;q23), were mainly younger, and pts with –7 mainly older (Table 1).Table 1.Distribution of ELN Groups and subsets in 818 younger and 732 older ptsGenetic Group SubsetYounger Pts %*Older Pts %*PFav4120<.001    t(8;21)2213.01    inv(16) or t(16;16)3312<.001    NPM1-mut, no FLT3-ITD†2854<.001    CEBPA-mut†1720.44Int I1819.64    NPM1-mut & FLT3-ITD†5538.006    NPM1-wt & FLT3-ITD†1012.85    NPM1-wt, no FLT3-ITD†3550.01Int II1930<.001    t(9;11)115.05    Cytogenetic abns not classified as Fav or Adv8995.05Adv2231<.001    inv(3) or t(3;3)83.03    t(6;9)41.02    t(v;11)(v;q23)156.01    −5 or del(5q)33.78    −7512.02    abn(17p)00—    Complex karyotype (≥3 abns)6575.04*For genetic subsets, % are calculated within each Genetic Group†Pts with cytogenetically normal AML
After a median follow-up for younger and older pts alive of, respectively, 7.6 y (range, 0.6–19.1) and 6.1 y (range, 2.3–16.4), CR rates, disease-free (DFS) and overall (OS) survival differed significantly across the ELN Groups in both age groups (Table 2, Fig. 1). Pairwise comparisons between individual ELN Groups also yielded significant differences for all of them, except for the comparison between the Int I and Int II Groups, which did not show significant differences for any outcome endpoint in older pts nor for CR rates or DFS in younger pts; OS of younger Int II pts was longer than OS of Int I pts (P=.02; Fig. 2). For each ELN Group, the outcome of older pts was worse than that of younger pts. We conclude that despite differences in frequencies of younger and older pts classified into Fav, Int II and Adv ELN Groups and subsets within these Groups, the ELN classification allows prognostic grouping of both younger and older de novo AML pts. It is hoped that new markers (eg, TET2, ASXL1 mut) will improve pt classification to ELN Int I and Fav Groups.Table 2.Outcomes according to the ELN GroupsOutcomeFavInt IInt IIAdvPYounger pts, n=818n=339n=144n=156n=179    CR rate, %96767950<.001    DFS, median, y5.50.81.20.6.001    OS, median, y11.51.22.10.8<.001Older pts, n=732n=145n=136n=222n=229    CR rate, %83616339<.001    DFS, median, y1.10.60.70.5<.001    OS, median, y1.60.90.90.5<.001

Disclosures:
No relevant conflicts of interest to declare.