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Original Article

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Korean J Hematol 2010; 45(1):

Published online March 31, 2010

https://doi.org/10.5045/kjh.2010.45.1.36

© The Korean Society of Hematology

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

Yeo-Kyeoung Kim1, Hee-Nam Kim2, Se Ryeon Lee3, Jae-Sook Ahn1, Deok-Hwan Yang1, Je-Jung Lee1, Il-Kwon Lee2, Myung-Geun Shin4, and Hyeoung-Joon Kim1,2*

Author Info. +

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.

Correspondence to : Correspondence to Hyeoung-Joon Kim, M.D., Ph.D. Hematology/Oncology Clinics, Chonnam National University Hwasun Hospital, 160 Ilsim-ri, Hwasun-eup, Hwasun-gun 519-809, Korea. Tel: +82-61-379-7637, Fax: +82-61-379-7628, hjoonk@chonnam.ac.kr

Received: February 18, 2010; Revised: March 5, 2010; Accepted: March 9, 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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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≤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.

Keywords NPM1, FLT3-ITD, Acute myeloid leukemia, Normal karyotype

Article

Original Article

Korean J Hematol 2010; 45(1): 36-45

Published online March 31, 2010 https://doi.org/10.5045/kjh.2010.45.1.36

Copyright © The Korean Society of Hematology.

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

Yeo-Kyeoung Kim1, Hee-Nam Kim2, Se Ryeon Lee3, Jae-Sook Ahn1, Deok-Hwan Yang1, Je-Jung Lee1, Il-Kwon Lee2, Myung-Geun Shin4, and Hyeoung-Joon Kim1,2*

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.

Correspondence to: Correspondence to Hyeoung-Joon Kim, M.D., Ph.D. Hematology/Oncology Clinics, Chonnam National University Hwasun Hospital, 160 Ilsim-ri, Hwasun-eup, Hwasun-gun 519-809, Korea. Tel: +82-61-379-7637, Fax: +82-61-379-7628, hjoonk@chonnam.ac.kr

Received: February 18, 2010; Revised: March 5, 2010; Accepted: March 9, 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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≤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.

Keywords: NPM1, FLT3-ITD, Acute myeloid leukemia, Normal karyotype

Fig 1.

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Figure 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.

Blood Research 2010; 45: 36-45https://doi.org/10.5045/kjh.2010.45.1.36

Fig 2.

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Figure 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.

Blood Research 2010; 45: 36-45https://doi.org/10.5045/kjh.2010.45.1.36

Fig 3.

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Figure 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.

Blood Research 2010; 45: 36-45https://doi.org/10.5045/kjh.2010.45.1.36

Fig 4.

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Figure 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.

Blood Research 2010; 45: 36-45https://doi.org/10.5045/kjh.2010.45.1.36

Table 1 . Patient characteristics according to the NPM1mut status..

The values represent either the number (percentage) or the median (range)..

Abbreviations: NPM1wt, wild-type nucleophosmin gene; NPM1mut, nucleophosmin gene mutation NA, not applicable; BM, bone marrow; alloSCT, allogeneic stem cell transplantation autoSCT; autologous stem cell transplantation FLT3-ITD, fms-like tyrosine kinase 3 gene-internal tandem duplication..

Table 2 . Patient characteristics according to the NPM1mut and FLT3-ITD+ status..

The values represent either the number (percentage) or the median (range)..

Abbreviations: NPM1wt, wild-type nucleophosmin gene; NPM1mut, nucleophosmin gene mutation FLT3-ITD, fms-like tyrosine kinase 3-internal tandem duplication; NA, not applicable; BM, bone marrow; alloSCT, allogeneic stem cell transplantation; autoSCT; autologous stem cell transplantation..

Table 3 . Treatment outcomes according to the NPM1mut status..

The values represent either the number (percentage) or the mean±SD..

a)Patients achieved CR after one course of remission induction chemotherapy, b)Patients achieved CR regardless of induction chemotherapy, c)One patient was missing due to follow-up loss..

Abbreviations: NPM1wt, wild-type nucleophosmin gene; NPM1mut, nucleophosmin gene mutation CR, complete remission; NA, not applicable; SCT, stem cell transplantation; RFS, relapse-free survival; OS, overall survival..

Table 4 . Multivariable analysis for outcome according to the NPM1mut and FLT3-ITD+ status..

Abbreviations: NPM1wt, wild-type nucleophosmin gene; NPM1mut, nucleophosmin gene mutation FLT3-ITD, fms-like tyrosine kinase 3 gene-internal tandem duplication; RFS, relapse-free survival; OS, overall survival; OR, odds ratio; 95% CI, 95% confidence interval; NA, not applicable; alloSCT, allogeneic stem cell transplantation..

Table 5 . Treatment outcomes according to the NPM1mut and FLT3-ITD+ status..

The values represent either the number (percentage) or the mean±SD..

a)Patients achieved CR after one course of remission induction chemotherapy, b)Patients achieved CR regardless of induction chemotherapy, c)One patient was missing due to follow-up loss..

Abbreviations: NPM1wt, wild-type nucleophosmin gene; NPM1mut, nucleophosmin gene mutation FLT3-ITD, fms-like tyrosine kinase 3 gene-internal tandem duplication; CR, complete remission; SCT, stem cell transplantation; RFS, relapse-free survival; NA, not applicable; OS, overall survival..
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