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. 2016 Feb;172(4):573-80.
doi: 10.1111/bjh.13873. Epub 2015 Dec 21.

The value of molecular stratification for CEBPA(DM) and NPM1(MUT) FLT3(WT) genotypes in older patients with acute myeloid leukaemia

Glenda J Dickson  1 , Sophia Bustraan  1 , Robert K Hills  2 , Akbar Ali  1 , Anthony H Goldstone  3 , Alan K Burnett  2 , David C Linch  1 , Rosemary E Gale  1
Affiliations

The value of molecular stratification for CEBPA(DM) and NPM1(MUT) FLT3(WT) genotypes in older patients with acute myeloid leukaemia

Glenda J Dickson et al. Br J Haematol. 2016 Feb.

Abstract

Older adult patients (≥60 years) with acute myeloid leukaemia (AML) are generally considered to be poor-risk and there is limited information available regarding risk stratification based on molecular characterization in this age group, particularly for the double-mutant CEBPA (CEBPA(DM) ) genotype. To investigate whether a molecular favourable-risk genotype can be identified, we investigated CEBPA, NPM1 and FLT3 status and prognostic impact in a cohort of 301 patients aged 60 years or more with intermediate-risk cytogenetics, all treated intensively. Overall survival (OS) at 1 year was highest in the 12 patients (4%) that were CEBPA(DM) compared to the 76 (28%) with a mutant NPM1 and wild-type FLT3 (NPM1(MUT) FLT3(WT) ) genotype or all other patients (75%, 54%, 33% respectively), with median survival 15·2, 13·6 and 6·6 months, although the benefit was short-term (OS at 3 years 17%, 29%, 12% respectively). Combination of the CEBPA(DM) and NPM1(MUT) FLT3(WT) genotype patients defined a molecular group with favourable prognosis (P < 0·0001 in multivariate analysis), with 57% of patients alive at 1 year compared to 33% for all other patients. Knowledge of genotype in older cytogenetically intermediate-risk patients might influence therapy decisions.

Keywords: CEBPA genotype; NPM1 and FLT3 genotype; acute myeloid leukaemia; molecular prognostication.

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Figures

Figure 1
Figure 1
Location and type of mutation detected in CEBPA‐single mutant and CEBPA‐double mutant patients. Amino acids (AA) encoding the transactivation domains (TAD1 and TAD2), DNA‐binding domain (DBD) and leucine zipper domain (LZD) and the ATG start site for the p30 isoform are indicated.
Figure 2
Figure 2
Kaplan–Meier curves stratified according to CEBPA genotype. (A) Cumulative incidence of relapse. (B) Overall survival. WT, wild type.
Figure 3
Figure 3
Kaplan–Meier curves stratified according to CEBPA DM and NPM1 MUT FLT3 WT genotype. (A) Cumulative incidence of relapse and (B) overall survival in the three genotype groups. (C) Overall survival for the combined favourable‐risk CEBPA DM and NPM1 MUT FLT3 WT group compared with all other patients. (D) Overall survival stratified according to age in the favourable‐risk group. CEBPA double, CEBPA DM genotype; ITD wt NPM1 mut, NPM1 MUT FLT3 WT genotype.
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