PERSISTENCE AND EXPANSION OF HEMATOPOIETIC CLONES IN POST CHEMOTHERAPY AML ASSESED BY TARGET SEQUENCING
(Abstract release date: 05/19/16)
EHA Library. Soriano D. 06/09/16; 132428; E879
Dr. Daniela Soriano
Contributions
Contributions
Abstract
Abstract: E879
Type: Eposter Presentation
Background
Gene variance screening has demonstrated the persistence of pre-leukemic hematopoietic stem cells (HSC) in AML patients during complete morphological remission (CR) (Corces-Zimmerman et al, Proc Natl Acad. 2014 and Terrence et al, Blood. 2015) but very little is known about their gene profile, dynamics and/or clinical associations.
Aims
Assess the dynamics of the gene variance profile and its clinical correlation in 20 AML patients who achieved CR after chemotherapy treatment.
Methods
Bone marrows samples from 18 de novo AML and 2 secondary AML patients were analysed at diagnosis and monitored for 2 to 34 months post chemotherapy initiation. 19 patients received induction/re-induction chemotherapy including both cytarabine and an anthracycline or purine analog, 1 patient received a non intensive chemotherapy consisting of a low dose cytarabine (LDAC) composed regimen.Targeted exon sequencing of 54 genes was carried out using a commercial panel (Illumina TruSight, myeloid panel) with exons fully covered for 17 genes, while a set of specific exonic locations targeted in the other 37 genes. Non-synonymous gene variances with a minimum of 500 reads and ≥5% frequency were reported. Variants were identified using Illumina bio-informatics pipeline augmented by COSMIC, SNP library (dbSNP137), OMIM, 1000 genomes and published data.
Results
Of the 20 patients analysed, 15 patients showed persistence of clonal haematopoiesis with some gene variances reported as ‘polymorphic’ and ‘tolerated’, considered to represent CHIP (Genovese et al., N Engl J Med 2014; McKerrell et al., Cell Reports 2015; Steensma et al., Blood 2015) . None of the AML ‘driver type’ variances seen at diagnosis were detected in the CR samples. Certain variances (in order of frequency) in DNMT3A, TET2, CBLB, ASXL1, ZRSR2, SRSF2, BCORL1, CEBPA, CUX1, CARL, ETV6, CBLC, ABL1 and HRAS genes were found to form three distinct patterns in CR: a) expansion of novel variances concurrent to the persistent diagnostic gene profile (10/20), b) persistence of unique variances seen at diagnosis without novel additions (9/20) and c) no gene variances present after chemotherapy (1/20). Two out of 10 patients from group (a) relapsed during the follow up period with reappearance of the initial FLT3_ITD bearing clone or occurrence of a novel IDH1 variance (p.R132C) respectively, while the rest remained in CR. Interestingly, a patient with a missense TP53 variance (Protein var: NP_000537.3: p.Cys238Tyr) at diagnosis had a clearance of this TP53 AML clone after being treated with LDAC composed regimen.
Conclusion
We report an expansion of hematopoietic clonal populations in 10 out of 20 patients analysed by target next generation sequencing. These results indicate that cell populations harbouring unique age related variances may have a competitive survival advantage after chemotherapy although the clinical importance this phenomenon requires further investigations. Accidentally we came across a promising treatment with LDAC and aminopeptidase inhibitor for unfit AML patients harbouring the classical TP53 mutation. Our findings are in alignment with recent studies showing persistence of clonal haemopoiesis in AML during CR, which warrants the need to monitor residual disease using appropriate gene panel.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, Clonal expansion, Remission, Somatic mutation
Type: Eposter Presentation
Background
Gene variance screening has demonstrated the persistence of pre-leukemic hematopoietic stem cells (HSC) in AML patients during complete morphological remission (CR) (Corces-Zimmerman et al, Proc Natl Acad. 2014 and Terrence et al, Blood. 2015) but very little is known about their gene profile, dynamics and/or clinical associations.
Aims
Assess the dynamics of the gene variance profile and its clinical correlation in 20 AML patients who achieved CR after chemotherapy treatment.
Methods
Bone marrows samples from 18 de novo AML and 2 secondary AML patients were analysed at diagnosis and monitored for 2 to 34 months post chemotherapy initiation. 19 patients received induction/re-induction chemotherapy including both cytarabine and an anthracycline or purine analog, 1 patient received a non intensive chemotherapy consisting of a low dose cytarabine (LDAC) composed regimen.Targeted exon sequencing of 54 genes was carried out using a commercial panel (Illumina TruSight, myeloid panel) with exons fully covered for 17 genes, while a set of specific exonic locations targeted in the other 37 genes. Non-synonymous gene variances with a minimum of 500 reads and ≥5% frequency were reported. Variants were identified using Illumina bio-informatics pipeline augmented by COSMIC, SNP library (dbSNP137), OMIM, 1000 genomes and published data.
Results
Of the 20 patients analysed, 15 patients showed persistence of clonal haematopoiesis with some gene variances reported as ‘polymorphic’ and ‘tolerated’, considered to represent CHIP (Genovese et al., N Engl J Med 2014; McKerrell et al., Cell Reports 2015; Steensma et al., Blood 2015) . None of the AML ‘driver type’ variances seen at diagnosis were detected in the CR samples. Certain variances (in order of frequency) in DNMT3A, TET2, CBLB, ASXL1, ZRSR2, SRSF2, BCORL1, CEBPA, CUX1, CARL, ETV6, CBLC, ABL1 and HRAS genes were found to form three distinct patterns in CR: a) expansion of novel variances concurrent to the persistent diagnostic gene profile (10/20), b) persistence of unique variances seen at diagnosis without novel additions (9/20) and c) no gene variances present after chemotherapy (1/20). Two out of 10 patients from group (a) relapsed during the follow up period with reappearance of the initial FLT3_ITD bearing clone or occurrence of a novel IDH1 variance (p.R132C) respectively, while the rest remained in CR. Interestingly, a patient with a missense TP53 variance (Protein var: NP_000537.3: p.Cys238Tyr) at diagnosis had a clearance of this TP53 AML clone after being treated with LDAC composed regimen.
Conclusion
We report an expansion of hematopoietic clonal populations in 10 out of 20 patients analysed by target next generation sequencing. These results indicate that cell populations harbouring unique age related variances may have a competitive survival advantage after chemotherapy although the clinical importance this phenomenon requires further investigations. Accidentally we came across a promising treatment with LDAC and aminopeptidase inhibitor for unfit AML patients harbouring the classical TP53 mutation. Our findings are in alignment with recent studies showing persistence of clonal haemopoiesis in AML during CR, which warrants the need to monitor residual disease using appropriate gene panel.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, Clonal expansion, Remission, Somatic mutation
Abstract: E879
Type: Eposter Presentation
Background
Gene variance screening has demonstrated the persistence of pre-leukemic hematopoietic stem cells (HSC) in AML patients during complete morphological remission (CR) (Corces-Zimmerman et al, Proc Natl Acad. 2014 and Terrence et al, Blood. 2015) but very little is known about their gene profile, dynamics and/or clinical associations.
Aims
Assess the dynamics of the gene variance profile and its clinical correlation in 20 AML patients who achieved CR after chemotherapy treatment.
Methods
Bone marrows samples from 18 de novo AML and 2 secondary AML patients were analysed at diagnosis and monitored for 2 to 34 months post chemotherapy initiation. 19 patients received induction/re-induction chemotherapy including both cytarabine and an anthracycline or purine analog, 1 patient received a non intensive chemotherapy consisting of a low dose cytarabine (LDAC) composed regimen.Targeted exon sequencing of 54 genes was carried out using a commercial panel (Illumina TruSight, myeloid panel) with exons fully covered for 17 genes, while a set of specific exonic locations targeted in the other 37 genes. Non-synonymous gene variances with a minimum of 500 reads and ≥5% frequency were reported. Variants were identified using Illumina bio-informatics pipeline augmented by COSMIC, SNP library (dbSNP137), OMIM, 1000 genomes and published data.
Results
Of the 20 patients analysed, 15 patients showed persistence of clonal haematopoiesis with some gene variances reported as ‘polymorphic’ and ‘tolerated’, considered to represent CHIP (Genovese et al., N Engl J Med 2014; McKerrell et al., Cell Reports 2015; Steensma et al., Blood 2015) . None of the AML ‘driver type’ variances seen at diagnosis were detected in the CR samples. Certain variances (in order of frequency) in DNMT3A, TET2, CBLB, ASXL1, ZRSR2, SRSF2, BCORL1, CEBPA, CUX1, CARL, ETV6, CBLC, ABL1 and HRAS genes were found to form three distinct patterns in CR: a) expansion of novel variances concurrent to the persistent diagnostic gene profile (10/20), b) persistence of unique variances seen at diagnosis without novel additions (9/20) and c) no gene variances present after chemotherapy (1/20). Two out of 10 patients from group (a) relapsed during the follow up period with reappearance of the initial FLT3_ITD bearing clone or occurrence of a novel IDH1 variance (p.R132C) respectively, while the rest remained in CR. Interestingly, a patient with a missense TP53 variance (Protein var: NP_000537.3: p.Cys238Tyr) at diagnosis had a clearance of this TP53 AML clone after being treated with LDAC composed regimen.
Conclusion
We report an expansion of hematopoietic clonal populations in 10 out of 20 patients analysed by target next generation sequencing. These results indicate that cell populations harbouring unique age related variances may have a competitive survival advantage after chemotherapy although the clinical importance this phenomenon requires further investigations. Accidentally we came across a promising treatment with LDAC and aminopeptidase inhibitor for unfit AML patients harbouring the classical TP53 mutation. Our findings are in alignment with recent studies showing persistence of clonal haemopoiesis in AML during CR, which warrants the need to monitor residual disease using appropriate gene panel.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, Clonal expansion, Remission, Somatic mutation
Type: Eposter Presentation
Background
Gene variance screening has demonstrated the persistence of pre-leukemic hematopoietic stem cells (HSC) in AML patients during complete morphological remission (CR) (Corces-Zimmerman et al, Proc Natl Acad. 2014 and Terrence et al, Blood. 2015) but very little is known about their gene profile, dynamics and/or clinical associations.
Aims
Assess the dynamics of the gene variance profile and its clinical correlation in 20 AML patients who achieved CR after chemotherapy treatment.
Methods
Bone marrows samples from 18 de novo AML and 2 secondary AML patients were analysed at diagnosis and monitored for 2 to 34 months post chemotherapy initiation. 19 patients received induction/re-induction chemotherapy including both cytarabine and an anthracycline or purine analog, 1 patient received a non intensive chemotherapy consisting of a low dose cytarabine (LDAC) composed regimen.Targeted exon sequencing of 54 genes was carried out using a commercial panel (Illumina TruSight, myeloid panel) with exons fully covered for 17 genes, while a set of specific exonic locations targeted in the other 37 genes. Non-synonymous gene variances with a minimum of 500 reads and ≥5% frequency were reported. Variants were identified using Illumina bio-informatics pipeline augmented by COSMIC, SNP library (dbSNP137), OMIM, 1000 genomes and published data.
Results
Of the 20 patients analysed, 15 patients showed persistence of clonal haematopoiesis with some gene variances reported as ‘polymorphic’ and ‘tolerated’, considered to represent CHIP (Genovese et al., N Engl J Med 2014; McKerrell et al., Cell Reports 2015; Steensma et al., Blood 2015) . None of the AML ‘driver type’ variances seen at diagnosis were detected in the CR samples. Certain variances (in order of frequency) in DNMT3A, TET2, CBLB, ASXL1, ZRSR2, SRSF2, BCORL1, CEBPA, CUX1, CARL, ETV6, CBLC, ABL1 and HRAS genes were found to form three distinct patterns in CR: a) expansion of novel variances concurrent to the persistent diagnostic gene profile (10/20), b) persistence of unique variances seen at diagnosis without novel additions (9/20) and c) no gene variances present after chemotherapy (1/20). Two out of 10 patients from group (a) relapsed during the follow up period with reappearance of the initial FLT3_ITD bearing clone or occurrence of a novel IDH1 variance (p.R132C) respectively, while the rest remained in CR. Interestingly, a patient with a missense TP53 variance (Protein var: NP_000537.3: p.Cys238Tyr) at diagnosis had a clearance of this TP53 AML clone after being treated with LDAC composed regimen.
Conclusion
We report an expansion of hematopoietic clonal populations in 10 out of 20 patients analysed by target next generation sequencing. These results indicate that cell populations harbouring unique age related variances may have a competitive survival advantage after chemotherapy although the clinical importance this phenomenon requires further investigations. Accidentally we came across a promising treatment with LDAC and aminopeptidase inhibitor for unfit AML patients harbouring the classical TP53 mutation. Our findings are in alignment with recent studies showing persistence of clonal haemopoiesis in AML during CR, which warrants the need to monitor residual disease using appropriate gene panel.
Session topic: E-poster
Keyword(s): Acute myeloid leukemia, Clonal expansion, Remission, Somatic mutation
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