| Updates pertinent to the disease classification |
| Genetic aberrations are prioritized for defining AML disease classification that are now hierarchical in nature |
| Blast threshold ≥10% with recurrent genetic abnormality is sufficient to diagnose AML [with the exception of AML with t(9;22)(q34.1;q11.2)]∗ |
| Introduction of a new category MDS/AML with 10%-19% blasts with defined genomic abnormalities |
| Removal of therapy-related myeloid neoplasms |
| Dysplastic morphology and prior history of MDS or MDS/MPN are now diagnostic qualifiers rather than separate clinical entities |
| AML with MDS-related gene mutations is considered adverse-risk (unless co-occurring with NPM1, CEBPA, or core binding factor AML) and defined based on specific gene mutations (these cases should lack TP53), irrespective of a history of MDS or evidence of dysplastic morphology |
| Additional recurrent genetic abnormalities variants added as AML-defining entities |
| Both monoallelic and biallelic in-frame bZIP mutations of CEBPA are now considered favorable-risk AMLs |
| TP53 mutations at an allelic fraction of at least 10% define a novel class of AML and MDS |
| Considering germ line predisposition risk for all patients with hematologic malignancies, regardless of age, testing should be performed as early as possible, using a tissue source not likely to undergo somatic mutations (ie, cultured skin fibroblasts or hair follicles), and when identified, germ line variants should be applied as diagnostic qualifiers to the AML category† |
| FLT3-ITD AR is no longer relevant for risk classification; therefore, FLT3-ITD–mutated AMLs are considered in the intermediate-risk category, regardless of the NPM1 mutation status |
| NPM1 mutated AML is considered favorable-risk disease; however, if adverse-risk cytogenetics abnormalities are present, it would be considered an adverse-risk disease |
| AML with hyperdiploid karyotype is no longer considered adverse risk |
| Updates pertinent to the diagnostic procedures and MRD monitoring |
| Identification of LAIP, in addition to the DfN aberrant phenotype, should be performed at diagnosis for subsequent MRD monitoring via MFC |
| Conventional cytogenetics analysis and molecular testing are imperative |
| Risk stratification and management of favorable- and intermediate-risk AML can be modified via MRD testing |
| Isolated detection of a DTA mutation (DNMT3A, TET2, and ASXL1) should not be considered MRD |
| NGS-based MRD lacks standardization and, currently, should not be used alone for MRD assessment; MFC remains the gold standard for AML, except for those with alterations in NPM1, acute promyelocytic, or core binding factor AML |
| General updates pertinent to clinical management |
| Pre-allo-HCT MRD positivity is an independent adverse-risk factor for pos-tallo-HCT outcomes; however, no randomized evidence regarding the positive impact of additional intensive chemotherapy or other interventions used for pre-allo-HCT MRD eradication is available yet |
| MAC regimen is generally preferred for fit patients with pre-allo-HCT MRD positivity |
| Introduction of additional response criteria, that is, CRhMRD– or CRiMRD– |
| Updates pertinent to the disease classification |
| Genetic aberrations are prioritized for defining AML disease classification that are now hierarchical in nature |
| Blast threshold ≥10% with recurrent genetic abnormality is sufficient to diagnose AML [with the exception of AML with t(9;22)(q34.1;q11.2)]∗ |
| Introduction of a new category MDS/AML with 10%-19% blasts with defined genomic abnormalities |
| Removal of therapy-related myeloid neoplasms |
| Dysplastic morphology and prior history of MDS or MDS/MPN are now diagnostic qualifiers rather than separate clinical entities |
| AML with MDS-related gene mutations is considered adverse-risk (unless co-occurring with NPM1, CEBPA, or core binding factor AML) and defined based on specific gene mutations (these cases should lack TP53), irrespective of a history of MDS or evidence of dysplastic morphology |
| Additional recurrent genetic abnormalities variants added as AML-defining entities |
| Both monoallelic and biallelic in-frame bZIP mutations of CEBPA are now considered favorable-risk AMLs |
| TP53 mutations at an allelic fraction of at least 10% define a novel class of AML and MDS |
| Considering germ line predisposition risk for all patients with hematologic malignancies, regardless of age, testing should be performed as early as possible, using a tissue source not likely to undergo somatic mutations (ie, cultured skin fibroblasts or hair follicles), and when identified, germ line variants should be applied as diagnostic qualifiers to the AML category† |
| FLT3-ITD AR is no longer relevant for risk classification; therefore, FLT3-ITD–mutated AMLs are considered in the intermediate-risk category, regardless of the NPM1 mutation status |
| NPM1 mutated AML is considered favorable-risk disease; however, if adverse-risk cytogenetics abnormalities are present, it would be considered an adverse-risk disease |
| AML with hyperdiploid karyotype is no longer considered adverse risk |
| Updates pertinent to the diagnostic procedures and MRD monitoring |
| Identification of LAIP, in addition to the DfN aberrant phenotype, should be performed at diagnosis for subsequent MRD monitoring via MFC |
| Conventional cytogenetics analysis and molecular testing are imperative |
| Risk stratification and management of favorable- and intermediate-risk AML can be modified via MRD testing |
| Isolated detection of a DTA mutation (DNMT3A, TET2, and ASXL1) should not be considered MRD |
| NGS-based MRD lacks standardization and, currently, should not be used alone for MRD assessment; MFC remains the gold standard for AML, except for those with alterations in NPM1, acute promyelocytic, or core binding factor AML |
| General updates pertinent to clinical management |
| Pre-allo-HCT MRD positivity is an independent adverse-risk factor for pos-tallo-HCT outcomes; however, no randomized evidence regarding the positive impact of additional intensive chemotherapy or other interventions used for pre-allo-HCT MRD eradication is available yet |
| MAC regimen is generally preferred for fit patients with pre-allo-HCT MRD positivity |
| Introduction of additional response criteria, that is, CRhMRD– or CRiMRD– |
AML-MRC, acute myeloid leukemia with myelodysplasia-related changes; bZIP, basic leucine zipper; CRh, complete remission with partial hematological recovery; CRi, complete remission with incomplete count recovery; DfN, different from normal; LAIP, leukemia-associated immunophenotypes; MDS, myelodysplasia; MPN, myeloproliferative neoplasm.
for detailed genetic abnormalities, refer to Table 1 in the article by Döhner H. et al5
for detailed germ line disorders, refer to Table 2 in the article by Döhner H. et al5