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

Affiliations
  • 1Department of Hematology/Oncology, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Korea.
  • 2Genome Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun, Korea.
  • 3Department of Hematology/Oncology, Korea University Anam Hospital, Seoul, Korea.
  • 4Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea.

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.


Cited by  3 articles

Identification of Two Novel NPM1 Mutations in Patients with Acute Myeloid Leukemia
Yongbum Jeon, Sang Won Seo, Seonyang Park, Seungman Park, So Yeon Kim, Eun Kyung Ra, Sung Sup Park, Moon-Woo Seong
Ann Lab Med. 2013;33(1):60-64.    doi: 10.3343/alm.2013.33.1.60.

Mutations in AML with a normal karyotype: NPM1 and FLT3-ITD, ready to use as a key prognosticator?
Hee-Je Kim
Korean J Hematol. 2010;45(2):79-80.    doi: 10.5045/kjh.2010.45.2.79.

Prognostic significance of the FLT3 ITD mutation in patients with normal-karyotype acute myeloid leukemia in relapse
Sang Hyuk Park, Hyun-Sook Chi, Sook-Kyung Min, Young-Uk Cho, Seongsoo Jang, Chan-Jeoung Park, Jung-Hee Lee, Je-Hwan Lee, Kyoo-Hyung Lee, Ho-Joon Im, Jong-Jin Seo
Korean J Hematol. 2011;46(2):88-95.    doi: 10.5045/kjh.2011.46.2.88.


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