AML With Genetic Abnormalities Other Than Translocations
AML With Genetic Abnormalities Other Than Translocations
Objectives: Session 2 of the workshop focused on cases of acute myeloid leukemia (AML) with gene mutations in the setting of a normal karyotype.
Methods: Among 22 AML cases submitted, 14 had the NPM1 mutation, most also accompanied by mutations of other genes such as FLT3-ITD, DNMT3A, or, rarely, TP53; three cases had the heterozygous CEBPA mutation; and two cases had MYC amplification.
Results: We explored prognostic implications of gene mutations such as DNMT3A, issues related to the classification of AML cases with the NPM1 mutation, and myelodysplasia-related changes arising from chronic myelomonocytic leukemia after a short latency interval. Disparate patterns of treatment response to targeted therapy using an FLT3 inhibitor, designated as cytotoxic or differentiation, and their genetic underpinnings were described. Finally, a minimal screening panel for gene mutations and the optimal approach for monitoring minimal residual disease were discussed.
Conclusions: In aggregate, this session highlighted the need for a refined molecular classification of AML as well as improved risk stratification based on systematic assessment for genetic alterations and their evolution over time.
Morphologic, cytogenetic, and molecular genetic alterations are the basis of disease classification and risk stratification in acute myeloid leukemia (AML). Conventional cytogenetic (CG) and fluorescence in situ hybridization (FISH) may identity abnormalities in about 50% to 60% of cases that can be further stratified into favorable-, intermediate-, or poor-risk subgroups. The remaining 40% to 50% cases with a normal karyotype (cytogenetically normal; CN) are heterogeneous and carry a variety of molecular aberrations. In the 2008, World Health Organization (WHO) classification, mutations of NPM1, FLT3-ITD, and CEBPA are listed among the most common recurrently mutated genes, and those with the NPM1 or CEBPA mutation are designated as provisional entities with distinct biological and clinical features. According to the 2010 European LeukemiaNet (ELN) proposal Table 1, AML with the NPM1 mutation and FLT3-ITD wild-type or CEBPA double mutations belong to the low-risk group, with a survival rate similar to that of AML with core binding factor abnormalities. By contrast, AML with the FLT3-ITD mutation, with or without the NPM1 mutation, belongs to the intermediate-risk group. Low-risk patients are generally managed with chemotherapy, whereas intermediate- and high-risk patients may require allogeneic stem cell transplantation (SCT). Since the publication of the WHO classification and the initial ELN proposal, additional novel recurrent gene mutations have been identified.DMNT3A, TET2, IDH1/2, ASXL1, RUNX1, and PTPN11 are among the genes most commonly mutated, some of which are considered initiating or "founder" mutations, whereas others are secondary events involved in disease progression. Mapping of the genomic landscape of AML has revealed clonal hierarchy and clonal evolution, providing a new framework for disease classification, risk stratification, and targeted therapy. Updated risk models incorporating newly identified gene mutations have been introduced, although these models need further clinical validation based on large cohorts of similarly treated patients.
This session of the workshop focused mainly on cases of CN-AML or related diseases with recurrent molecular aberrations. Of the 22 cases included in the session Table 2, 14 had the NPM1 mutation, with most accompanied by other gene mutations. Rare cases with additional karyotypic abnormalities were included to illustrate their prognostic impact in the context of otherwise well-characterized cases of CN-AML with the NPM1 mutation. These cases included three AMLs with the heterozygous CEBPA mutation, alone or concomitant with other gene mutations, and two cases of AML with MYC amplification with unusual morphologic features.
In view of the newly identified mutations and their therapeutic implications, a practical approach to refined molecular subtypes of AML was emphasized. Specific issues related to clinical practice were discussed and are summarized in this report, including (1) significance of the DNMT3A mutation in NPM1-mutated AML; (2) classification of cases of AML with the NPM1 mutation that also meet WHO classification criteria for AML with myelodysplasia-related changes (MRCs) based on morphologic evidence of dysplasia, cytogenetic aberrations, or a history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML); (3) prognostic significance of the heterozygous vs homozygous CEBPA mutation; (4) recommendations for a minimal screening panel of genes mutated in CN-AML in routine practice; (5) monitoring of minimal residual disease (MRD) by molecular methods; and (6) two distinct patterns of treatment response (cytotoxic vs differentiation) and FLT3-ITD mutant burden in the bone marrow of patients with AML treated with an FLT3 inhibitor.
Abstract and Introduction
Abstract
Objectives: Session 2 of the workshop focused on cases of acute myeloid leukemia (AML) with gene mutations in the setting of a normal karyotype.
Methods: Among 22 AML cases submitted, 14 had the NPM1 mutation, most also accompanied by mutations of other genes such as FLT3-ITD, DNMT3A, or, rarely, TP53; three cases had the heterozygous CEBPA mutation; and two cases had MYC amplification.
Results: We explored prognostic implications of gene mutations such as DNMT3A, issues related to the classification of AML cases with the NPM1 mutation, and myelodysplasia-related changes arising from chronic myelomonocytic leukemia after a short latency interval. Disparate patterns of treatment response to targeted therapy using an FLT3 inhibitor, designated as cytotoxic or differentiation, and their genetic underpinnings were described. Finally, a minimal screening panel for gene mutations and the optimal approach for monitoring minimal residual disease were discussed.
Conclusions: In aggregate, this session highlighted the need for a refined molecular classification of AML as well as improved risk stratification based on systematic assessment for genetic alterations and their evolution over time.
Introduction
Morphologic, cytogenetic, and molecular genetic alterations are the basis of disease classification and risk stratification in acute myeloid leukemia (AML). Conventional cytogenetic (CG) and fluorescence in situ hybridization (FISH) may identity abnormalities in about 50% to 60% of cases that can be further stratified into favorable-, intermediate-, or poor-risk subgroups. The remaining 40% to 50% cases with a normal karyotype (cytogenetically normal; CN) are heterogeneous and carry a variety of molecular aberrations. In the 2008, World Health Organization (WHO) classification, mutations of NPM1, FLT3-ITD, and CEBPA are listed among the most common recurrently mutated genes, and those with the NPM1 or CEBPA mutation are designated as provisional entities with distinct biological and clinical features. According to the 2010 European LeukemiaNet (ELN) proposal Table 1, AML with the NPM1 mutation and FLT3-ITD wild-type or CEBPA double mutations belong to the low-risk group, with a survival rate similar to that of AML with core binding factor abnormalities. By contrast, AML with the FLT3-ITD mutation, with or without the NPM1 mutation, belongs to the intermediate-risk group. Low-risk patients are generally managed with chemotherapy, whereas intermediate- and high-risk patients may require allogeneic stem cell transplantation (SCT). Since the publication of the WHO classification and the initial ELN proposal, additional novel recurrent gene mutations have been identified.DMNT3A, TET2, IDH1/2, ASXL1, RUNX1, and PTPN11 are among the genes most commonly mutated, some of which are considered initiating or "founder" mutations, whereas others are secondary events involved in disease progression. Mapping of the genomic landscape of AML has revealed clonal hierarchy and clonal evolution, providing a new framework for disease classification, risk stratification, and targeted therapy. Updated risk models incorporating newly identified gene mutations have been introduced, although these models need further clinical validation based on large cohorts of similarly treated patients.
This session of the workshop focused mainly on cases of CN-AML or related diseases with recurrent molecular aberrations. Of the 22 cases included in the session Table 2, 14 had the NPM1 mutation, with most accompanied by other gene mutations. Rare cases with additional karyotypic abnormalities were included to illustrate their prognostic impact in the context of otherwise well-characterized cases of CN-AML with the NPM1 mutation. These cases included three AMLs with the heterozygous CEBPA mutation, alone or concomitant with other gene mutations, and two cases of AML with MYC amplification with unusual morphologic features.
In view of the newly identified mutations and their therapeutic implications, a practical approach to refined molecular subtypes of AML was emphasized. Specific issues related to clinical practice were discussed and are summarized in this report, including (1) significance of the DNMT3A mutation in NPM1-mutated AML; (2) classification of cases of AML with the NPM1 mutation that also meet WHO classification criteria for AML with myelodysplasia-related changes (MRCs) based on morphologic evidence of dysplasia, cytogenetic aberrations, or a history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML); (3) prognostic significance of the heterozygous vs homozygous CEBPA mutation; (4) recommendations for a minimal screening panel of genes mutated in CN-AML in routine practice; (5) monitoring of minimal residual disease (MRD) by molecular methods; and (6) two distinct patterns of treatment response (cytotoxic vs differentiation) and FLT3-ITD mutant burden in the bone marrow of patients with AML treated with an FLT3 inhibitor.
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