Potential Clinical Impact of Genetic Mutations in Acute Myeloid Leukemia (AML)1-3

Genetic Mutation Incidence Clinical Impact
NPM1 25-35% of AML; 45%-60% of CN-AML; ~40% with FLT3-ITD; 10%-15% with FLT3-TKD; 35%-40% with del(9q) outside of a CK; ~15% with trisomy 8; higher prevalence in females
  • Clinicopathologic entity
  • In younger patients, normal AML with NPM1 mutation without FLT3-ITD associated with favorable outcome
  • Older patients (aged >60 y) benefit from conventional intensive chemotherapy
CEBPA 6%-10% in CN-AML; ~40% in del(9q) outside of a CK
  • Only AML with biallelic mutations defines clinicopathologic entity
  • Incidence decreases with older age
  • Favorable outcome for double mutations only
FLT3-ITD ~20% of AML; 28%-34% of CN-AML
  • High allelic ratio linked to increased relapse rate and poorer OS
  • Allelic ratio may be predictive of alloHSCT outcome
  • Insertion site predictive of low CR and OS rates
FLT3-TKD 5%-10% of AML; 11%-14% of CN-AML
  • Prognostic significance unclear; trials underway
MLL-PTD 5%-11% of CN-AML, and ≤90% of AML with trisomy 11
  • In initial studies: shorter CR duration, inferior RFS and EFS, but not OS
NRAS ~15% of CN-AML, ≤40% in CBF-AML
  • Most frequently in CN-AML, AML with inv(16)/t(16;16), and AML with inv(3)/t(3;3)
  • May predict sensitivity to cytarabine
WT1 10%-13% of CN-AML
  • Most studies: negative prognostic impact
  • Poor prognosis with post-remission high-dose cytarabine
  • WT1 SNP rs16754 associated with inferior outcome in CN-AML
IDH1/2 IDH1 ~7%-14%; IDH2 ~8%-19%2; 25%-30% in CN-AML; association with NPM1 mutations (except IDH2R172)
  • Incidence of IDH2 R140 mutation increases with older age
  • Prognostic significance depending on mutational context and mutation type; IDH1 R132 and IDH2 R172 with adverse effect and IDH2 R140 with favorable outcome
  • Higher risk of relapse and inferior OS in molecular low-risk CN-AMLa
KIT <5% of AML; mainly in CBF-AML (25%-30%)
  • Unfavorable prognosis in AML with t(8;21); unfavorable effect in AML with inv(16)/t(16;16)
  • Inferior outcome in CBF-AML
RUNX1 5%-15% of AML; association with trisomy 13, trisomy 21, CN-AML, MLL-PTD; inverse correlation with NPM1 and CEBPA mutations
  • Incidence increases with older age and with other mutations (eg, in ASXL1, SRSF2, IDH2, and KMT2A)
  • Associated with secondary AML evolving from MDS
  • Predictive of resistance to induction therapy and of inferior outcome
  • Lower CR rate and shorter RFS and OS indicated
TP53 ~8% of AML; mainly in AML with CK (56%-78%)
  • Incidence increases with older age
  • Associated with inferior outcome
DNMT3A 18%-22% of AML; 30%-37% of CN-AML
  • Early event in leukemogenesis
  • Incidence increases with older age
  • Associated with NPM1 and FLT3-ITD mutations
  • Moderate adverse effect on outcome


aMutated NPM1 without FLT3-ITD.
AlloHSCT, allogeneic hematopoietic stem cell transplant; AML, acute myeloid leukemia; ASXL1, additional sex combs like 1; CBF-AML, core binding factor AML; c-KIT, KIT proto-oncogene receptor tyrosine kinase; CEBPA, CCAAT enhancer binding protein alpha; CK, complex karyotype; CN-AML, cytogenetically normal AML; CR, complete remission; EFS, event-free survival; FLT3, FMS-related receptor tyrosine kinase 3; IDH, isocitrate dehydrogenase; ITD, internal tandem duplication; KMT2A, lysine methyltransferase 2A; MDS, myelodysplastic syndrome; MLL, mixed-lineage leukemia; NPM1, nucleophosmin 1; NRAS, NRAS proto-oncogene, GTPase; OS, overall survival; PTD, partial tandem duplication; RFS, relapse-free survival; RUNX1, runt-related transcription factor 1; SNP, single-nucleotide polymorphism; SRSF2, serine and arginine rich splicing factor 2; TKD, tyrosine kinase domain; WT1, Wilms tumor 1.

References: 1. Marcucci, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29(5):475-486. 2. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136-1152. 3. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD–positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441-3449.