Abstract
Discussion Forum (0)
Abstract: P541
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
Abstract: P541
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
PRELEUKEMIC CLONES IN NPM1-MUTATED AML MAY BE ASSOCIATED WITH EVOLUTION TO MYELODYSPLASTIC SYNDROME (MDS) OR MYELOPROLIFERATIVE NEOPLASM (MPN)
Abstract
Discussion Forum (0)
Abstract: P541
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
Abstract: P541
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
Type: Poster Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00
Location: Poster area (Hall H)
Background
Nucleophosmin 1 gene (NPM1) mutations account for 30% of AML and 50% of cytogenetically normal (CN) AML. NPM1 mutated AML without FLT3-ITD (NPM 1+FLT3 ITD–) is classified in the favorable risk group. Recent studies, including from our group, showed that most NPM1+FLT3-ITD– AML also carry mutations in other genes such as DNMT3A, IDH1, IDH2, TET2 mutations which may constitute “preleukemic” clones, as suggested by the fact that those mutations often persist in patients with undetectable NPM1 minimal residual disease (MRD) after intensive chemotherapy (Peterlin Haematologica 2015, Corces-Zimmerman PNAS 2014). On the other hand, a recent report showed that virtually all relapses in NPM1+ AML carried NPM1 mutation, arguing against the fact that relapse can emerge from those preleukemic clones, independently of the presence of NPM1 mutation (Hills NEJM 2016).
Aims
To better understand the genetic mechanisms underlying disease evolution in patients with de novo CN NPM1+ FLT3-ITD- AML in complete remission (CR).
Methods
Over a 10-year period, 34 de novo CN NPM1+ FLT3-ITD- AML (median age 55 years) were treated with intensive chemotherapy at our center, and 32 achieved CR. 12 (37%) remained in hematological CR with undetectable NPM1-MRD, 14 (44%) relapsed with the same NPM1 mutation, and 6 (19%) developed MDS or MPN while still in molecular CR for NPM1 (Figure 1A). 12 of the relapsing patients and all 6 patients with MDS or MPN evolution had sequential molecular analysis using NGS of PCR-amplified exons of a panel of the 26 genes most frequently mutated in myeloid malignancies.
Results
The 6 patients who developed MDS or MPN with undetectable NPM1-MRD, after a median of 14 months (range: 4-30), were all aged > 55 years, and included 2 RARS, 2 RCMD, 1 CMML type 1 and 1 primary myelofibrosis (PMF). In all 6 cases, a “preleukemic” clone with at least 1 mutation in TET2 (n=4), JAK2 (n=2), ASXL1 (n=1), IDH2 (n=3) or spliceosome genes (SRSF2, SF3B1, U2AF1, (n=3)) was found at AML diagnosis, and was still present (with stable or increasing variant allele frequency) at the time of MDS or MPN diagnosis (Figure 1B). In the 12 relapsing patients, “preleukemic” mutations were also present at AML diagnosis in 10/12 cases. However, they possibly differed between the 2 groups: At AML diagnosis, TET2 mutation was identified in 4/6 (66%) patients who developed MDS or MPN, versus 2/12 (16%) patients who relapsed, p=0.1). Conversely, 8/12 patients who relapsed had mutations in DNMT3A or IDH1, versus 0/6 patients who developed MDS or MPN (p=0.025). At AML relapse, mutations co-occurring with NPM1 mutation were identical to those observed at AML diagnosis
Conclusion
Our study suggests that a significant proportion of patients with de novo NPM1+FLT3-ITD- CN-AML (19% in our series) may subsequently develop MDS or MPN in the absence of NPM1 mutation recurrence, and that this type of hematological evolution seems to be related to the persistence and expansion of preleukemic clones. The high incidence of such evolution may be related to the relatively advanced age of our patient cohort, due to our hospital unit recruitment (mostly elderly AML). Interestingly, in most patients with AML relapse, preleukemic clones were also observed at AML diagnosis but with a different mutational pattern, possibly pointing out different pathophysiological mechanisms. If those findings are confirmed in a larger number of patients, NPM1+ AML patients may have to be closely followed-up after CR achievement even when NPM1 MRD remains undetectable, due to the relatively high risk of MDS or MPN, at least in elderly patients.
Session topic: Acute myeloid leukemia - Biology 2
Keyword(s): Mutation analysis, Myelodysplasia, Myeloproliferative disorder, Relapsed acute myeloid leukemia
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