Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia

Abstract

Purpose: To evaluate the prognostic significance of the international European LeukemiaNet (ELN) guidelines for reporting genetic alterations in acute myeloid leukemia (AML).

Patients and methods: We analyzed 1,550 adults with primary AML, treated on Cancer and Leukemia Group B first-line trials, who had pretreatment cytogenetics and, for cytogenetically normal patients, mutational status of NPM1, CEBPA, and FLT3 available. We compared complete remission (CR) rates, disease-free survival (DFS), and overall survival (OS) among patients classified into the four ELN genetic groups (favorable, intermediate-I, intermediate-II, adverse) separately for 818 younger (age < 60 years) and 732 older (age ≥ 60 years) patients.

Results: The percentages of younger versus older patients in the favorable (41% v 20%; P < .001), intermediate-II (19% v 30%; P < .001), and adverse (22% v 31%; P < .001) genetic groups differed. The favorable group had the best and the adverse group the worst CR rates, DFS, and OS in both age groups. Both intermediate groups had significantly worse outcomes than the favorable but better than the adverse group. Intermediate-I and intermediate-II groups in older patients had similar outcomes, whereas the intermediate-II group in younger patients had better OS but not better CR rates or DFS than the intermediate-I group. The prognostic significance of ELN classification was confirmed by multivariable analyses. For each ELN group, older patients had worse outcomes than younger patients.

Conclusion: The ELN classification clearly separates the genetic groups by outcome, supporting its use for risk stratification in clinical trials. Because they have different proportions of genetic alterations and outcomes, younger and older patients should be reported separately when using the ELN classification.

Fig 1.

Overview of the study design. AML, acute myeloid leukemia; CALGB, Cancer and Leukemia Group B; CR, complete remission; ITD, internal tandem duplication; SCT, stem-cell transplantation.

Fig 2.

Distribution of the European LeukemiaNet genetic groups in younger (A) and older (B) adults with primary acute myeloid leukemia. The favorable group is more (P < .001) and the intermediate-II and adverse groups are less (P < .001) common among younger patients compared with older patients.

Fig 3.

Distribution of the genetic subsets within European LeukemiaNet genetic groups in younger and older adults with primary acute myeloid leukemia (AML). (A) The favorable group consists of four genetic subsets. The first two subsets are patients with core-binding factor AML (CBF-AML) with either t(8;21) (ie, t(8;21)(q22;q22)/RUNX1-RUNX1T1) or inv(16)/t(16;16) (ie, inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB-MYH11). The second two subsets are patients with cytogenetically normal AML (CN-AML) with either NPM1-mut/FLT3-ITD– (ie, mutated NPM1 without FLT3-ITD [internal tandem duplication]) or CEBPA-mut (ie, mutated CEBPA). (B) The intermediate-I group consists of three genetic subsets of patients with CN-AML and either NPM1-mut/FLT3-ITD+ (ie, mutated NPM1 and FLT3-ITD) or NPM1-wt/FLT3-ITD+ (ie, wild-type NPM1 and FLT3-ITD) or NPM1-wt/FLT3-ITD– (ie, wild-type NPM1 without FLT3-ITD). (C) The intermediate-II group consists of two genetic subsets of patients with either t(9;11) (ie, t(9;11)(p22;q23)/MLLT3-MLL) or other abnormalities (ie, cytogenetic abnormalities not classified as favorable or adverse). (D) The adverse group consists of seven genetic subsets: (1) inv(3)/t(3;3) (ie, inv(3)(q21q26.2) or t(3;3)(q21;q26.2)/RPN1-EVI1), (2) t(6;9) (ie, t(6;9)(p23;q34)/DEK-NUP214), (3) t(v;11) (ie, t(v;11)(v;q23)/MLL rearranged), (4) −5/del(5q) (ie, monosomy of chromosome 5 or deletion of q), (5) −7 (ie, monosomy of chromosome ), (6) abnl(17p) (ie, abnormalities of the short arm or chromosome; no patient had this abnormality in our study), or () “complex karyotype” (ie, a complex karyotype containing three or more cytogenetic abnormalities).

Fig 4.

Outcome of patients with primary acute myeloid leukemia classified into the four European LeukemiaNet genetic groups according to the European LeukemiaNet recommendations. (A) Disease-free survival and (B) overall survival of patients younger than age 60 years; (C) disease-free survival and (D) overall survival of patients age 60 years or older.

Fig 5.

Forest plots summarizing multivariable analyses for (A) complete remission (CR), (B) disease-free survival (DFS), and (C) overall survival (OS) in younger and older patients. (A) Odds ratios (ORs) of less than 1 indicate lower CR rate for the first category listed for the categorical variables and the higher values of the continuous variables. (B and C) Hazard ratios (HRs) greater than 1 indicate higher risks and those less than 1 indicate lower risks of relapse or death (DFS) or death (OS) for the first category listed for the categorical variables and the higher values of the continuous variables. Variables considered for inclusion in the multivariable models had to have a univariable P value of less than .2 and were as follows for younger patients: for CR, European LeukemiaNet (ELN) groups, age (in 10-year increments), sex (male v female), and extramedullary involvement (present v absent); for DFS, ELN groups, WBC count (in 50-unit increments), platelets (in 50-unit increments), and extramedullary involvement; for OS, ELN groups, age, WBC count, sex, and extramedullary involvement; and for older patients: for CR, ELN groups, age, WBC count, and platelets; for DFS, ELN groups, platelets, sex, and extramedullary involvement; for OS, ELN groups, age, and sex. Only variables that were significant remained in the final models and are depicted in the forest plots.