How do you determine if a patient with Acute Myeloid Leukemia (AML) is at intermediate, favorable, or adverse risk?

Risk Stratification in Acute Myeloid Leukemia

Risk stratification in AML is determined by the 2017 ELN classification system, which categorizes patients into favorable, intermediate, or adverse risk groups based on specific cytogenetic abnormalities and molecular mutations identified at diagnosis. 1

Essential Testing Required for Risk Classification

Before assigning risk category, you must obtain:

• Conventional cytogenetic analysis (karyotype) - this cannot be replaced by molecular or FISH testing alone 1, 2
• Molecular genetic testing for NPM1, FLT3-ITD (with allelic ratio), and CEBPA mutations 1, 2
• FISH testing for rapid detection of key translocations if cytogenetics are delayed 1

Favorable-Risk AML

This group includes patients with low predicted relapse risk when treated with chemotherapy alone: 1

• t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 1
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB-MYH11 1
• t(15;17)(q22;q21)/PML-RARA (acute promyelocytic leukemia) 1
• NPM1 mutation WITHOUT FLT3-ITD 1
• NPM1 mutation WITH FLT3-ITD having allelic ratio <0.5 1
• Biallelic CEBPA mutation 1

Critical caveat: 3.6% of NPM1-mutated/FLT3-ITD-low patients harbor adverse cytogenetic aberrations that override the favorable molecular profile and confer equally poor prognosis as adverse cytogenetics in NPM1-wildtype patients. 1

Intermediate-Risk AML

This category comprises patients with molecular or cytogenetic abnormalities not classified as favorable or adverse: 1

• Normal karyotype (cytogenetically normal AML) without favorable molecular markers 1, 3
• NPM1 mutation WITH high allelic ratio FLT3-ITD (≥0.5) 1
• Isolated trisomy 8 1
• t(9;11)(p22;q23)/MLLT3-MLL 1
• Other cytogenetic abnormalities not meeting criteria for favorable or adverse groups 1

The intermediate-risk group represents the most heterogeneous category, particularly among cytogenetically normal AML patients who lack the three key favorable mutations (FLT3-wildtype/NPM1-wildtype/CEBPA-wildtype). 3, 4

Adverse-Risk AML

This group includes patients with complex cytogenetics and poor-risk genetic aberrations: 1

• Complex karyotype (≥3 unrelated chromosomal abnormalities, excluding favorable translocations) 1, 5
• Monosomal karyotype (single monosomy plus additional abnormalities, or ≥2 monosomies) 1
• t(6;9)(p23;q34)/DEK-NUP214 1
• inv(3)(q21q26.2) or t(3;3)(q21;q26.2)/RPN1-EVI1 1
• t(v;11)(v;q23)/MLL rearrangements (excluding t(9;11)) 1
• Abnormalities of chromosome 5 or 7 (monosomy 5, del(5q), monosomy 7, del(7q)) 1
• FLT3-ITD with high allelic ratio as sole abnormality 1
• TP53 mutations (frequently associated with complex karyotype) 1
• Secondary AML (evolved from prior MDS or therapy-related) 1

Functional adverse risk: All patients failing to achieve complete remission after 2 induction cycles should be reclassified as adverse-risk patients, regardless of their initial genetic/cytogenetic profile. 1

Key Clinical Pitfalls to Avoid

Do not start chemotherapy before obtaining adequate material for cytogenetic and molecular testing, as these results fundamentally determine treatment strategy and transplant decisions. 2 In patients with hypoproliferative disease or those safely managed with hydroxyurea, await genetic results if they will influence therapeutic choice. 1

Do not rely solely on FISH or molecular testing - conventional cytogenetics remains mandatory as it can identify complex karyotypes and rare abnormalities not detected by targeted molecular panels. 2

Do not overlook the FLT3-ITD allelic ratio - the distinction between low (<0.5) and high (≥0.5) allelic ratio in NPM1-mutated patients determines whether they belong to favorable versus intermediate risk categories. 1