Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group.
OBJECTIVE
Recently, whole-genome sequencing in acute myeloid leukemia (AML) identified recurrent isocitrate dehydrogenase enzyme isoform (IDH1) mutations (IDH1m), previously reported to be involved in gliomas as well as IDH2 mutations (IDH2m). The prognosis of both IDH1m and IDH2m in AML remains unclear.


METHODS
The prevalence and the prognostic impact of R132 IDH1 and R172 IDH2 mutations were evaluated in a cohort of 520 adults with AML homogeneously treated in the French Acute Leukemia French Association (ALFA) -9801 and -9802 trials.


RESULTS
The prevalence of IDH1m and IDH2m was 9.6% and 3.0%, respectively, mostly associated with normal cytogenetics (CN). In patients with CN-AML, IDH1m were associated with NPM1m (P = .008), but exclusive of CEBPAm (P = .03). In contrary, no other mutations were detected in IDH2m patients. In CN-AML patients, IDH1m were found in 19% of favorable genotype ([NPM1m or CEBPAm] without fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ITD]) and were associated with a higher risk of relapse (RR) and a shorter overall survival (OS). Favorable genotype in CN-AML could thus be defined by the association of NPM1m or CEBPAm with neither FLT3-ITD nor IDH1m. In IDH2m CN-AML patients, we observed a higher risk of induction failure, a higher RR and a shorter OS. In multivariate analysis, age, WBC count, the four-gene favorable genotype and IDH2m were independently associated with a higher RR and a shorter OS.


CONCLUSIONS
Contrarily to what is reported in gliomas, IDH1m and IDH2m in AML are associated with a poor prognosis. Screening of IDH1m could help to identify high-risk patients within the subset of CN-AML with a favorable genotype.
Boissel
Nicolas
N
University of Paris 7, Paris, France.
Nibourel
Olivier
O
Renneville
Aline
A
Gardin
Claude
C
Reman
Oumedaly
O
Contentin
Nathalie
N
Bordessoule
Dominique
D
Pautas
Cécile
C
de Revel
Thierry
T
Quesnel
Bruno
B
Huchette
Pascal
P
Philippe
Nathalie
N
Geffroy
Sandrine
S
Terre
Christine
C
Thomas
Xavier
X
Castaigne
Sylvie
S
Dombret
Hervé
H
Preudhomme
Claude
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D055815:Young Adult
D020033:Protein Isoforms; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human