CHARACTERIZATION AND PROGNOSTIC IMPACT OF FLT3-ITD MUTATIONS IN INTERMEDIATE RISK ACUTE MYELOID LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Amorim M. 06/09/16; 134557; PB1657
Dr. Maria Amorim
Contributions
Contributions
Abstract
Abstract: PB1657
Type: Publication Only
Background
The adverse impact of internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 gene (FLT3) in acute myeloid leukemia (AML) has been related to specific ITD characteristics such as the FLT3-ITD/wt allelic ratio (AR), length of mutation and insertion site.
Aims
To evaluate FLT3-ITD mutations, as well as NPM1 mutations, and the prognostic impact of the FLT3-ITD AR, size, number and the insertion site of ITDS in AML patients with intermediate-risk karyotype.
Methods
This single-centre study included 148 AML patients with intermediate-risk karyotype according to the European LeukemiaNet criteria. Screening of FLT3-ITD and NPM1 mutations was performed in diagnostic bone marrow samples by PCR with labeled primers and GeneScan-based fragment-length analysis. In FLT3-ITD patients, size and number of ITDs were collected and FLT3-ITD AR was calculated. The ITD insertion site was determined by direct sequencing of PCR products in a subgroup of patients. For survival analysis, median (Md) value was used to dichotomize continuous variables.
Results
FLT3-ITD mutations were found in 29% (43/148) of patients. The majority of patients (36/43) had a single ITD, four patients – two ITDs and one patient - three ITDs. Median ITD size was 42 bp (range, 18 to 108 bp). The FLT3-ITD AR varied from 0.02 to 13.48, with a median of 0.57. DNA sequence analysis of 26 single FLT3-ITDs patients revealed that the insertion site was localized in juxtamembrane domain (JMD, amino acids 572-609) in 77% patients and in tyrosine kinase I domain (TKD1, amino acids 610-615) in 23% of patients. A trend for worst overall survival (OS) was noted for patients with insertion site in TKD1 (P=.09). FLT3-ITD was significantly longer in cases with an insertion site in TKD1 compared with ITD insertion in JMD (69 vs 36 bp, P=.008). Concerning pretreatment patients characteristics, white blood counts (P<.001), serum lactate dehydrogenase (P=.002), and bone marrow blasts (P=.03) differed significantly with increasing AR. Regarding clinical outcome, only patients candidates to intensive chemotherapy were included (N=128). FLT3-ITD patients with high mutant level (AR>0.57) had significantly worst OS, median of 7.6 months, than low mutant level and wt patients (25.6 vs 23.2 months, P=.003). A trend for worst Disease Free Survival (DFS) was noted for patients with AR>0.57 (Md=5.7 months) compared with low ratio (Md=15.6 months) and wt patients (Md=23 months), P=.05. When the analysis was restricted to NPM1mut AML patients (60/146), FLT3-ITD patients with high AR had significantly worst OS (Md=7.6 months) than low mutant level (Md=34.7 months); OS for wt patients was not reached (P<.001). FLT3-ITD patients with high AR had a DFS significantly lower (5.8 months) than low AR (15.6 months) and wt type patients (37.9 months), P=.01. No significant difference was observed between low ratio and wt patients for DFS (P=.09), whereas for OS was (P=.02). No significant difference was observed in DFS and OS regarding insertion site, size and number of ITDs.
Conclusion
We confirmed that FLT3-ITD allelic ratio was the only ITD characteristic with significant prognostic marker for OS and DFS within our cohort of FLT3-ITD intermediate-risk AML patients. Nevertheless we were able to identify a trend for worst OS in patients with ITD insertion site in TKD1. Moreover, we were able to show that, among patients with concomitant NPM1 mutation, DFS was not significantly different between ITD low burden and wt patients.
Session topic: E-poster
Keyword(s): Flt3-ITD
Type: Publication Only
Background
The adverse impact of internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 gene (FLT3) in acute myeloid leukemia (AML) has been related to specific ITD characteristics such as the FLT3-ITD/wt allelic ratio (AR), length of mutation and insertion site.
Aims
To evaluate FLT3-ITD mutations, as well as NPM1 mutations, and the prognostic impact of the FLT3-ITD AR, size, number and the insertion site of ITDS in AML patients with intermediate-risk karyotype.
Methods
This single-centre study included 148 AML patients with intermediate-risk karyotype according to the European LeukemiaNet criteria. Screening of FLT3-ITD and NPM1 mutations was performed in diagnostic bone marrow samples by PCR with labeled primers and GeneScan-based fragment-length analysis. In FLT3-ITD patients, size and number of ITDs were collected and FLT3-ITD AR was calculated. The ITD insertion site was determined by direct sequencing of PCR products in a subgroup of patients. For survival analysis, median (Md) value was used to dichotomize continuous variables.
Results
FLT3-ITD mutations were found in 29% (43/148) of patients. The majority of patients (36/43) had a single ITD, four patients – two ITDs and one patient - three ITDs. Median ITD size was 42 bp (range, 18 to 108 bp). The FLT3-ITD AR varied from 0.02 to 13.48, with a median of 0.57. DNA sequence analysis of 26 single FLT3-ITDs patients revealed that the insertion site was localized in juxtamembrane domain (JMD, amino acids 572-609) in 77% patients and in tyrosine kinase I domain (TKD1, amino acids 610-615) in 23% of patients. A trend for worst overall survival (OS) was noted for patients with insertion site in TKD1 (P=.09). FLT3-ITD was significantly longer in cases with an insertion site in TKD1 compared with ITD insertion in JMD (69 vs 36 bp, P=.008). Concerning pretreatment patients characteristics, white blood counts (P<.001), serum lactate dehydrogenase (P=.002), and bone marrow blasts (P=.03) differed significantly with increasing AR. Regarding clinical outcome, only patients candidates to intensive chemotherapy were included (N=128). FLT3-ITD patients with high mutant level (AR>0.57) had significantly worst OS, median of 7.6 months, than low mutant level and wt patients (25.6 vs 23.2 months, P=.003). A trend for worst Disease Free Survival (DFS) was noted for patients with AR>0.57 (Md=5.7 months) compared with low ratio (Md=15.6 months) and wt patients (Md=23 months), P=.05. When the analysis was restricted to NPM1mut AML patients (60/146), FLT3-ITD patients with high AR had significantly worst OS (Md=7.6 months) than low mutant level (Md=34.7 months); OS for wt patients was not reached (P<.001). FLT3-ITD patients with high AR had a DFS significantly lower (5.8 months) than low AR (15.6 months) and wt type patients (37.9 months), P=.01. No significant difference was observed between low ratio and wt patients for DFS (P=.09), whereas for OS was (P=.02). No significant difference was observed in DFS and OS regarding insertion site, size and number of ITDs.
Conclusion
We confirmed that FLT3-ITD allelic ratio was the only ITD characteristic with significant prognostic marker for OS and DFS within our cohort of FLT3-ITD intermediate-risk AML patients. Nevertheless we were able to identify a trend for worst OS in patients with ITD insertion site in TKD1. Moreover, we were able to show that, among patients with concomitant NPM1 mutation, DFS was not significantly different between ITD low burden and wt patients.
Session topic: E-poster
Keyword(s): Flt3-ITD
Abstract: PB1657
Type: Publication Only
Background
The adverse impact of internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 gene (FLT3) in acute myeloid leukemia (AML) has been related to specific ITD characteristics such as the FLT3-ITD/wt allelic ratio (AR), length of mutation and insertion site.
Aims
To evaluate FLT3-ITD mutations, as well as NPM1 mutations, and the prognostic impact of the FLT3-ITD AR, size, number and the insertion site of ITDS in AML patients with intermediate-risk karyotype.
Methods
This single-centre study included 148 AML patients with intermediate-risk karyotype according to the European LeukemiaNet criteria. Screening of FLT3-ITD and NPM1 mutations was performed in diagnostic bone marrow samples by PCR with labeled primers and GeneScan-based fragment-length analysis. In FLT3-ITD patients, size and number of ITDs were collected and FLT3-ITD AR was calculated. The ITD insertion site was determined by direct sequencing of PCR products in a subgroup of patients. For survival analysis, median (Md) value was used to dichotomize continuous variables.
Results
FLT3-ITD mutations were found in 29% (43/148) of patients. The majority of patients (36/43) had a single ITD, four patients – two ITDs and one patient - three ITDs. Median ITD size was 42 bp (range, 18 to 108 bp). The FLT3-ITD AR varied from 0.02 to 13.48, with a median of 0.57. DNA sequence analysis of 26 single FLT3-ITDs patients revealed that the insertion site was localized in juxtamembrane domain (JMD, amino acids 572-609) in 77% patients and in tyrosine kinase I domain (TKD1, amino acids 610-615) in 23% of patients. A trend for worst overall survival (OS) was noted for patients with insertion site in TKD1 (P=.09). FLT3-ITD was significantly longer in cases with an insertion site in TKD1 compared with ITD insertion in JMD (69 vs 36 bp, P=.008). Concerning pretreatment patients characteristics, white blood counts (P<.001), serum lactate dehydrogenase (P=.002), and bone marrow blasts (P=.03) differed significantly with increasing AR. Regarding clinical outcome, only patients candidates to intensive chemotherapy were included (N=128). FLT3-ITD patients with high mutant level (AR>0.57) had significantly worst OS, median of 7.6 months, than low mutant level and wt patients (25.6 vs 23.2 months, P=.003). A trend for worst Disease Free Survival (DFS) was noted for patients with AR>0.57 (Md=5.7 months) compared with low ratio (Md=15.6 months) and wt patients (Md=23 months), P=.05. When the analysis was restricted to NPM1mut AML patients (60/146), FLT3-ITD patients with high AR had significantly worst OS (Md=7.6 months) than low mutant level (Md=34.7 months); OS for wt patients was not reached (P<.001). FLT3-ITD patients with high AR had a DFS significantly lower (5.8 months) than low AR (15.6 months) and wt type patients (37.9 months), P=.01. No significant difference was observed between low ratio and wt patients for DFS (P=.09), whereas for OS was (P=.02). No significant difference was observed in DFS and OS regarding insertion site, size and number of ITDs.
Conclusion
We confirmed that FLT3-ITD allelic ratio was the only ITD characteristic with significant prognostic marker for OS and DFS within our cohort of FLT3-ITD intermediate-risk AML patients. Nevertheless we were able to identify a trend for worst OS in patients with ITD insertion site in TKD1. Moreover, we were able to show that, among patients with concomitant NPM1 mutation, DFS was not significantly different between ITD low burden and wt patients.
Session topic: E-poster
Keyword(s): Flt3-ITD
Type: Publication Only
Background
The adverse impact of internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 gene (FLT3) in acute myeloid leukemia (AML) has been related to specific ITD characteristics such as the FLT3-ITD/wt allelic ratio (AR), length of mutation and insertion site.
Aims
To evaluate FLT3-ITD mutations, as well as NPM1 mutations, and the prognostic impact of the FLT3-ITD AR, size, number and the insertion site of ITDS in AML patients with intermediate-risk karyotype.
Methods
This single-centre study included 148 AML patients with intermediate-risk karyotype according to the European LeukemiaNet criteria. Screening of FLT3-ITD and NPM1 mutations was performed in diagnostic bone marrow samples by PCR with labeled primers and GeneScan-based fragment-length analysis. In FLT3-ITD patients, size and number of ITDs were collected and FLT3-ITD AR was calculated. The ITD insertion site was determined by direct sequencing of PCR products in a subgroup of patients. For survival analysis, median (Md) value was used to dichotomize continuous variables.
Results
FLT3-ITD mutations were found in 29% (43/148) of patients. The majority of patients (36/43) had a single ITD, four patients – two ITDs and one patient - three ITDs. Median ITD size was 42 bp (range, 18 to 108 bp). The FLT3-ITD AR varied from 0.02 to 13.48, with a median of 0.57. DNA sequence analysis of 26 single FLT3-ITDs patients revealed that the insertion site was localized in juxtamembrane domain (JMD, amino acids 572-609) in 77% patients and in tyrosine kinase I domain (TKD1, amino acids 610-615) in 23% of patients. A trend for worst overall survival (OS) was noted for patients with insertion site in TKD1 (P=.09). FLT3-ITD was significantly longer in cases with an insertion site in TKD1 compared with ITD insertion in JMD (69 vs 36 bp, P=.008). Concerning pretreatment patients characteristics, white blood counts (P<.001), serum lactate dehydrogenase (P=.002), and bone marrow blasts (P=.03) differed significantly with increasing AR. Regarding clinical outcome, only patients candidates to intensive chemotherapy were included (N=128). FLT3-ITD patients with high mutant level (AR>0.57) had significantly worst OS, median of 7.6 months, than low mutant level and wt patients (25.6 vs 23.2 months, P=.003). A trend for worst Disease Free Survival (DFS) was noted for patients with AR>0.57 (Md=5.7 months) compared with low ratio (Md=15.6 months) and wt patients (Md=23 months), P=.05. When the analysis was restricted to NPM1mut AML patients (60/146), FLT3-ITD patients with high AR had significantly worst OS (Md=7.6 months) than low mutant level (Md=34.7 months); OS for wt patients was not reached (P<.001). FLT3-ITD patients with high AR had a DFS significantly lower (5.8 months) than low AR (15.6 months) and wt type patients (37.9 months), P=.01. No significant difference was observed between low ratio and wt patients for DFS (P=.09), whereas for OS was (P=.02). No significant difference was observed in DFS and OS regarding insertion site, size and number of ITDs.
Conclusion
We confirmed that FLT3-ITD allelic ratio was the only ITD characteristic with significant prognostic marker for OS and DFS within our cohort of FLT3-ITD intermediate-risk AML patients. Nevertheless we were able to identify a trend for worst OS in patients with ITD insertion site in TKD1. Moreover, we were able to show that, among patients with concomitant NPM1 mutation, DFS was not significantly different between ITD low burden and wt patients.
Session topic: E-poster
Keyword(s): Flt3-ITD
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