Contributions
Abstract: PB1416
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
FMS-like tyrosine kinase 3 gene (FLT3) internal tandem duplication (ITD) mutation is one of the most frequent genetic mutations in patients with acute myeloid leukemia (AML). Although patients with FLT3-ITD mutations have an unfavorable outcome, variant allelic frequency (VAF), insertion site (IS), insertion length all may potentially impact the prognostic significance of FLT3-ITD mutations.
Aims
The aim of this study is to explore the mutation spectrum of FLT3-ITD positive AML and potential markers, including VAF, IS, insertion length, co-occurring mutations, which may influence the prognoses of this subset of patients.
Methods
Illumina MiSeq™Dx next generation sequencing (NGS) was performed to screen genetic mutations in 145 de novo patients with FLT3-ITD positive AML (excluding acute promyelocytic leukemia). VAF was defined as the fraction of mutant alleles as a percentage of all FLT3 alleles (FLT3-ITD/FLT3-WT + FLT3-ITD).
Results
The median VAF was 36.4% (range 1-81.8%), and median insert length was 45 bp (range 7-186 bp). Patients with FLT3-ITD VAF ≥33% was associated with a higher percentage of bone marrow blasts (0.7959±0.17333 versus 0.7306±0.20225, P=0.038) compared with those with VAF <33%. Forty-one types of other molecular mutations were detected in these patients, and the top three mutated genes were NPM1 (n = 79) (54.5%), DNMT3A (n = 62) (42.8%), and WT1 (n = 25) (17.2%). FLT3-ITD VAF ≥33% was associated with a higher NPM1 mutation ratio (P < 0.05) as compared to the VAF <33%. Based on Cancer Genome Atlas Research Network, the distributions of patient subsets consist of DNA-methylation-related genes (63.4%), the gene encoding nucleophosmin (NPM1) (54.5%), signaling genes (28.3%), myeloid transcription-factor genes (23.4%), tumor suppressor genes (22.8%), cohesin-complex genes (6.2%), and spliceosome-complex genes (6.2%), and chromatin-modifying genes (5.5%).
The CR, ORR, and early mortality rates were 65.3% (64/98), 79.6% (78/98), and 2.7% (3/113), respectively. Finally, 63 cases who achieved CR entered long-term follow-up (including 20 cases who received allo-HSCT). The follow-up time ranged from 3.17 to 60.1 months (median 15.97 months). In total, 42 patients relapsed, and 35 patients died. Our studies showed that longer insertion length (≥45bp) indicated a better RFS (P=0.02) and OS (P=0.016) compared with shorter insert length (<45bp) in patients with normal karyotype who consolidated with chemotherapy only. DNMT3A mutant patients had an inferior RFS and OS (p=0.003 and p=0.011), while NPM1, WT1 mutations had no significant influence on outcomes of patients in this study.
Conclusion
High FLT3-ITD VAF was associated with high levels of blasts in the bone marrow and NPM1 mutations. DNMT3A might be a poor prognostic factor in FLT3-ITD positive AML patients. The impact of insertion length is still unclear, and further investigation is needed to verify this conclusion.
Keyword(s):
Abstract: PB1416
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
FMS-like tyrosine kinase 3 gene (FLT3) internal tandem duplication (ITD) mutation is one of the most frequent genetic mutations in patients with acute myeloid leukemia (AML). Although patients with FLT3-ITD mutations have an unfavorable outcome, variant allelic frequency (VAF), insertion site (IS), insertion length all may potentially impact the prognostic significance of FLT3-ITD mutations.
Aims
The aim of this study is to explore the mutation spectrum of FLT3-ITD positive AML and potential markers, including VAF, IS, insertion length, co-occurring mutations, which may influence the prognoses of this subset of patients.
Methods
Illumina MiSeq™Dx next generation sequencing (NGS) was performed to screen genetic mutations in 145 de novo patients with FLT3-ITD positive AML (excluding acute promyelocytic leukemia). VAF was defined as the fraction of mutant alleles as a percentage of all FLT3 alleles (FLT3-ITD/FLT3-WT + FLT3-ITD).
Results
The median VAF was 36.4% (range 1-81.8%), and median insert length was 45 bp (range 7-186 bp). Patients with FLT3-ITD VAF ≥33% was associated with a higher percentage of bone marrow blasts (0.7959±0.17333 versus 0.7306±0.20225, P=0.038) compared with those with VAF <33%. Forty-one types of other molecular mutations were detected in these patients, and the top three mutated genes were NPM1 (n = 79) (54.5%), DNMT3A (n = 62) (42.8%), and WT1 (n = 25) (17.2%). FLT3-ITD VAF ≥33% was associated with a higher NPM1 mutation ratio (P < 0.05) as compared to the VAF <33%. Based on Cancer Genome Atlas Research Network, the distributions of patient subsets consist of DNA-methylation-related genes (63.4%), the gene encoding nucleophosmin (NPM1) (54.5%), signaling genes (28.3%), myeloid transcription-factor genes (23.4%), tumor suppressor genes (22.8%), cohesin-complex genes (6.2%), and spliceosome-complex genes (6.2%), and chromatin-modifying genes (5.5%).
The CR, ORR, and early mortality rates were 65.3% (64/98), 79.6% (78/98), and 2.7% (3/113), respectively. Finally, 63 cases who achieved CR entered long-term follow-up (including 20 cases who received allo-HSCT). The follow-up time ranged from 3.17 to 60.1 months (median 15.97 months). In total, 42 patients relapsed, and 35 patients died. Our studies showed that longer insertion length (≥45bp) indicated a better RFS (P=0.02) and OS (P=0.016) compared with shorter insert length (<45bp) in patients with normal karyotype who consolidated with chemotherapy only. DNMT3A mutant patients had an inferior RFS and OS (p=0.003 and p=0.011), while NPM1, WT1 mutations had no significant influence on outcomes of patients in this study.
Conclusion
High FLT3-ITD VAF was associated with high levels of blasts in the bone marrow and NPM1 mutations. DNMT3A might be a poor prognostic factor in FLT3-ITD positive AML patients. The impact of insertion length is still unclear, and further investigation is needed to verify this conclusion.
Keyword(s):