Korean J Hematol.  2010 Mar;45(1):36-45. 10.5045/kjh.2010.45.1.36.

Prognostic significance of nucleophosmin mutations and FLT3 internal tandem duplication in adult patients with cytogenetically normal acute myeloid leukemia

• Kim YK
• Kim HN
• Lee SR
• Ahn JS
• Yang DH
• Lee JJ
• Lee IK
• Shin MG
• Kim HJ

• KMID: 2252083
• DOI: http://doi.org/10.5045/kjh.2010.45.1.36

Abstract

BACKGROUND
Nucleophosmin (NPM1) gene and fms-like tyrosine kinase 3 gene-internal tandem duplication (FLT3-ITD) mutations are the most frequent mutations in patients with cytogenetically normal (CN)-AML. We analyzed the prognostic impact of these mutations and their interactions in adults with CN-AML.
METHODS
NPM1 mutation (NPM1mut) and FLT3-ITD mutation (FLT3-ITD+) were analyzed by GeneScan and PCR assays of bone marrow samples obtained from 121 adult patients with CN-AML (age< or =60 years at diagnosis).
RESULTS
The incidence of FLT3-ITD+ was higher in the NPM1mut group than in the wild-type NPM1 gene (NPM1wt) group. The patients were divided according to their mutation status into the NPM1mut/FLT3-ITD (isolated NPM1mut), NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-, and NPM1wt/FLT3-ITD+ (isolated FLT3-ITD+) groups. The isolated NPM1mut group showed significantly better clinical outcomes in terms of relapse rate, 5-year relapse-free survival (RFS), and overall survival (OS) than the other groups. In contrast, the isolated FLT3-ITD+ group had a higher relapse rate and shorter RFS and OS than the other groups. The 5-year RFS rate was much higher among the patients who underwent allogeneic stem cell transplantation (alloSCT) than among those treated with high-dose cytarabine chemotherapy (HDAC) only as consolidation therapy in the isolated NPM1mut group and the NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD- group.
CONCLUSION
Adult patients with CN-AML carrying isolated NPM1mut and isolated FLT3-ITD+ exhibit different clinical outcomes than those with NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-. Although isolated NPM1mut leads to favorable clinical outcomes of CN-AML, the role of alloSCT in such patients remains to be considered.

Keyword

NPM1; FLT3-ITD; Acute myeloid leukemia; Normal karyotype

MeSH Terms

Adult
Bone Marrow
Cytarabine
fms-Like Tyrosine Kinase 3
Humans
Incidence
Leukemia, Myeloid, Acute
Lifting
Nuclear Proteins
Polymerase Chain Reaction
Recurrence
Stem Cell Transplantation
Cytarabine
Nuclear Proteins
fms-Like Tyrosine Kinase 3

Figure

• 

  Fig. 1 Kaplan-Meier analysis of CN-AML according to the NPM1mut status. (A) RFS and OS before SCT. (B) Overall RFS and OS. Abbreviations: CN, cytogenetically normal; NPM1mut, nucleophosmin gene mutation; NPM1wt, wild-type nucleophosmin gene; RFS, relapse-free survival; OS, overall survival; SCT, stem cell transplantation.

• 

  Fig. 2 RFS analysis of the alloSCT patients versus the chemotherapy-alone patients according to the NPM1mut status. (A) Overall RFS in the NPM1wt group. The overall RFS was significantly longer among the alloSCT patients than among the chemotherapy-alone patients (P=0.01). (B) Overall RFS in the NPM1mut group. A trend of longer survival was observed among the alloSCT patients than among the chemotherapy-alone patients, but the difference was not statistically significant (P=0.34). Abbreviations: NPM1mut, nucleophosmin gene mutation; NPM1wt, wild-type nucleophosmin gene; RFS, relapse-free survival; alloSCT, allogeneic stem cell transplantation.

• 

  Fig. 3 Kaplan-Meier analysis of CN-AML for RFS and OS according to the combined NPM1mut and FLT3-ITD+ status. (A) RFS and OS before transplantation. (B) Overall RFS and OS. Abbreviations: CN, cytogenetically normal; NPM1mut, nucleophosmin gene mutation; NPM1wt, wild-type nucleophosmin gene; FLT3-ITD, fms-like tyrosine kinase 3 gene-internal tandem duplication; RFS, relapse-free survival; OS, overall survival.

• 

  Fig. 4 RFS analysis of the alloSCT patients versus the chemotherapy-alone patients according to the combined NPM1mut and FLT3-ITD+ status. (A) NPM1mut/FLT3-ITD- (isolated NPM1mut) group. (B) NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD- group. (C) NPM1wt/FLT3-ITD+ (isolated FLT3-ITD+) group. In the NPM1mut/FLT3-ITD- group, the alloSCT patients had significantly longer RFS than the chemotherapy- alone patients (A). The NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD- group also displayed a longer trend of RFS with alloSCT (B). In contrast, the patients with NPM1wt/FLT3-ITD+ showed significantly shorter RFS and alloSCT did not improve the outcome of this subset (C). Abbreviations: NPM1mut, nucleophosmin gene mutation; NPM1wt, wild-type nucleophosmin gene; FLT3-ITD, fms-like tyrosine kinase 3 gene-internal tandem duplication; RFS, relapse-free survival; alloSCT, allogeneic stem cell transplantation.

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