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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 - Korean J Hematol (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, Research Institute of Medical Sciences, 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≤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.

No MeSH data available.


Related in: MedlinePlus

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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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.

Mentions: We also conducted further analysis for the overall RFS following alloSCT compared with chemotherapy alone as a consolidation therapy. In the isolated NPM1mut group, 13 patients (37.1%) underwent alloSCT whereas 20 (57.1%) received chemotherapy alone. The CR rate in the alloSCT group and chemotherapy-alone group was 69.2% and 55%, respectively (P=0.49). Twelve patients (92.3%) achieved CR at transplantation. One (7.7%) was refractory to all three courses of previous remission induction chemotherapy; in spite of alloSCT, the patient could not achieve CR and died of pneumonia 3 months after SCT. Peripheral blood stem cells collected from sibling donors (s-PBSCs, N=11), unrelated bone marrow stem cells (u-BMs, N=1), and unrelated PBSCs (u-PBSCs, N=1) were used as the hematopoietic stem cell sources. Conditioning regimens consisted of Flu/Bu (fludarabine at 30 mg/m2/day for 6 days and busulfan at 3.2 mg/kg/day for 4 days, N=9), TBI/Cy (total body irradiation at 13.2 Gy in 4 days with cyclophosphamide at 60 mg/day in 2 days, N=3), and Bu/Cy (busufan with cyclophosphamide, N=1). The median number of infused CD34+ cells was 5.3×106/kg (range=0.7-13.2). As depicted in Fig. 4, alloSCT significantly influenced the longer (5-year) RFS in the isolated NPM1mut group (alloSCT versus chemotherapy alone, 87.5%. versus 42.7%, P=0.03; Fig. 4A). In addition, we conducted a subgroup analysis of 21 patients who achieved CR after one cycle of induction chemotherapy (9 in alloSCT group, 11 in chemotherapy-alone group, and 1 in autoSCT group). The alloSCT group showed a significantly lower rate of overall relapse (0% versus 36.4%, P=0.04) and higher 5-year overall RFS (100% versus 52.5%, P=0.04) than the chemotherapy-alone group. Although statistically insignificant, the patients with NPM1wt/FLT3- ITD- or NPM1mut/FLT3-ITD+ who underwent alloSCT (5-year RFS=63.6%) showed better overall RFS than the chemotherapy-alone patients (15.1%, P=0.12; Fig. 4B). Among the patients with isolated FLT3-ITD+, the overall RFS in the alloSCT group (N=6) was not significantly different from that in the chemotherapy-alone group (N=9; Fig. 4C). s-PBSCs (N=4), u-PBSCs (N=1), and u-BMs (N=1) were used as the stem cell sources and all patients underwent alloSCT at CR status. The conditioning regimens consisted of Flu/Bu (N=4) and TBI/Cy (N=2). The median number of infused CD34+ cells was 4.5×106/kg (range=2.6-7.8). Four patients in the alloSCT group died of leukemic relapse, and there was no significant correlation between the relapse rate or RFS and the conditioning regimen or the stem cell source.


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 - Korean J Hematol (2010)

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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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.
Mentions: We also conducted further analysis for the overall RFS following alloSCT compared with chemotherapy alone as a consolidation therapy. In the isolated NPM1mut group, 13 patients (37.1%) underwent alloSCT whereas 20 (57.1%) received chemotherapy alone. The CR rate in the alloSCT group and chemotherapy-alone group was 69.2% and 55%, respectively (P=0.49). Twelve patients (92.3%) achieved CR at transplantation. One (7.7%) was refractory to all three courses of previous remission induction chemotherapy; in spite of alloSCT, the patient could not achieve CR and died of pneumonia 3 months after SCT. Peripheral blood stem cells collected from sibling donors (s-PBSCs, N=11), unrelated bone marrow stem cells (u-BMs, N=1), and unrelated PBSCs (u-PBSCs, N=1) were used as the hematopoietic stem cell sources. Conditioning regimens consisted of Flu/Bu (fludarabine at 30 mg/m2/day for 6 days and busulfan at 3.2 mg/kg/day for 4 days, N=9), TBI/Cy (total body irradiation at 13.2 Gy in 4 days with cyclophosphamide at 60 mg/day in 2 days, N=3), and Bu/Cy (busufan with cyclophosphamide, N=1). The median number of infused CD34+ cells was 5.3×106/kg (range=0.7-13.2). As depicted in Fig. 4, alloSCT significantly influenced the longer (5-year) RFS in the isolated NPM1mut group (alloSCT versus chemotherapy alone, 87.5%. versus 42.7%, P=0.03; Fig. 4A). In addition, we conducted a subgroup analysis of 21 patients who achieved CR after one cycle of induction chemotherapy (9 in alloSCT group, 11 in chemotherapy-alone group, and 1 in autoSCT group). The alloSCT group showed a significantly lower rate of overall relapse (0% versus 36.4%, P=0.04) and higher 5-year overall RFS (100% versus 52.5%, P=0.04) than the chemotherapy-alone group. Although statistically insignificant, the patients with NPM1wt/FLT3- ITD- or NPM1mut/FLT3-ITD+ who underwent alloSCT (5-year RFS=63.6%) showed better overall RFS than the chemotherapy-alone patients (15.1%, P=0.12; Fig. 4B). Among the patients with isolated FLT3-ITD+, the overall RFS in the alloSCT group (N=6) was not significantly different from that in the chemotherapy-alone group (N=9; Fig. 4C). s-PBSCs (N=4), u-PBSCs (N=1), and u-BMs (N=1) were used as the stem cell sources and all patients underwent alloSCT at CR status. The conditioning regimens consisted of Flu/Bu (N=4) and TBI/Cy (N=2). The median number of infused CD34+ cells was 4.5×106/kg (range=2.6-7.8). Four patients in the alloSCT group died of leukemic relapse, and there was no significant correlation between the relapse rate or RFS and the conditioning regimen or the stem cell source.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, Research Institute of Medical Sciences, 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≤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.

No MeSH data available.


Related in: MedlinePlus