AML Risk Stratification According to ELN 2022
Overview of the Three-Tier Risk System
The 2022 European LeukemiaNet (ELN) classification stratifies acute myeloid leukemia patients into favorable, intermediate, and adverse risk groups based on specific cytogenetic abnormalities and molecular mutations identified at diagnosis, with this genetic classification being essential to guide clinical decisions, predict prognosis, and determine indications for allogeneic hematopoietic cell transplantation. 1
The ELN risk stratification system has evolved from the 2017 version, with the 2022 update reclassifying approximately 13-22% of patients into different risk categories, primarily moving patients from favorable to intermediate risk or from intermediate to adverse risk. 2, 3, 4
Essential Diagnostic Testing Requirements
Before risk stratification can be performed, specific genetic testing must be completed:
Conventional cytogenetic analysis (karyotype) is mandatory and cannot be replaced by molecular or FISH testing alone, as it remains the strongest prognostic factor for response to induction therapy and survival. 5, 1
Molecular genetic testing for NPM1, FLT3-ITD (with allelic ratio calculation), and CEBPA mutations is necessary for accurate risk classification. 1
FISH testing is recommended for rapid detection of key translocations if conventional cytogenetics are delayed. 1
At least 20 metaphases should be examined during conventional cytogenetic analysis to ensure adequate detection of chromosomal abnormalities. 6
Critical pitfall: Do not start intensive chemotherapy before obtaining adequate material for cytogenetic and molecular testing, as these results fundamentally determine treatment strategy and transplant decisions. 1
Favorable-Risk AML
Patients in this category have a predicted low relapse risk when treated with induction and consolidation chemotherapy alone:
Cytogenetic Abnormalities
- t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 (core-binding factor AML) 5, 1
- inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB-MYH11 (core-binding factor AML) 5, 1
- t(15;17)(q22;q21)/PML-RARA (acute promyelocytic leukemia) 1, 7
Molecular Genetic Profiles
- NPM1 mutation WITHOUT FLT3-ITD 5, 1
- NPM1 mutation WITH FLT3-ITD having allelic ratio <0.5 5, 1
- Biallelic CEBPA mutation 5, 1
Important caveat: A large retrospective analysis showed that 3.6% of NPM1-mutated/FLT3-ITD-low patients have adverse cytogenetic aberrations, which confer an equally poor prognosis as adverse cytogenetics in NPM1-wildtype patients—these patients should be reclassified as adverse risk. 5
Intermediate-Risk AML
This group comprises patients with molecular or cytogenetic abnormalities not classified as favorable or adverse:
- Normal karyotype (cytogenetically normal AML) without favorable molecular markers 1, 7
- NPM1 mutation WITH high allelic ratio FLT3-ITD (≥0.5) 5, 1
- Isolated trisomy 8 1, 7
- t(9;11)(p22;q23)/MLLT3-MLL 1, 7
The 2022 ELN update has added patients with myelodysplasia-related (MR) gene mutations to this category, though recent validation studies suggest these patients show heterogeneous outcomes ranging between intermediate and adverse risk, with some mutations (EZH2, STAG2, ZRSR2) showing intermediate-like survival. 4
Adverse-Risk AML
This group includes patients with the poorest prognosis:
Cytogenetic Abnormalities
- Complex karyotype (≥3 unrelated chromosomal abnormalities, excluding favorable translocations) occurs in 10-12% of patients and is consistently associated with very poor outcomes 5, 1, 7
- Monosomal karyotype (single monosomy plus additional abnormalities, or ≥2 monosomies) 1
- Abnormalities of chromosome 5 or 7 (monosomy 5, del(5q), monosomy 7, del(7q)) 1, 6
- t(6;9)(p23;q34)/DEK-NUP214 1, 7
- inv(3)(q21q26.2) or t(3;3)(q21;q26.2)/RPN1-EVI1 1, 7
- t(v;11)(v;q23)/MLL rearrangements (excluding t(9;11)) 1, 7
Molecular Genetic Profiles
- FLT3-ITD with high allelic ratio (≥0.5) as sole abnormality 1, 7
- TP53 mutations (frequently associated with complex karyotype, occurring in approximately two-thirds of complex karyotype cases) 5, 1, 7
Clinical Features
Complex karyotype features: These cases show a paucity of balanced rearrangements and a predominance of chromosomal imbalances, with losses most frequently affecting 5q, 17p, and 7q, and gains affecting 8q, 11q, and 21q. 5
Dynamic Risk Reclassification
All patients failing to achieve complete remission after 2 induction cycles must be reclassified as adverse-risk patients, regardless of their initial genetic/cytogenetic profile. 5, 1
This dynamic adjustment recognizes that treatment response is a powerful prognostic indicator that supersedes initial genetic risk stratification. 5
Clinical Implications and Treatment Decisions
The ELN risk stratification plays a critical role in guiding selection of the optimal post-remission approach:
Favorable-risk patients: Low relapse risk with induction and consolidation chemotherapy alone; allogeneic transplantation in first complete remission (CR1) is generally not indicated. 5
Intermediate-risk patients: Allogeneic transplantation is beneficial for those who achieve CR1. 3
Adverse-risk patients: Highest indication for allogeneic hematopoietic cell transplantation in CR1, though outcomes remain poor even with transplantation (2-year overall survival 53.9%, disease-free survival 45.3%, relapse rate 37.5%). 8, 9
Validation and Performance of ELN 2022
Recent validation studies demonstrate that the 2022 ELN classification effectively distinguishes patients into three groups with distinct outcomes:
- The 2022 ELN favorable-risk group shows significantly longer survival outcomes than intermediate or adverse groups. 2
- The system improves prognostic discrimination compared to the 2017 version (3-year area under the curve 0.71 vs 0.67 for overall survival). 4
- Multivariable analysis identifies the 2022 ELN risk stratification, along with age and receiving allogeneic transplantation, as significant independent prognostic factors for survival. 2
Ongoing controversy: Within the ELN 2022 adverse-risk group, marked survival differences exist across mutational subgroups (5-year overall survival 21% for MR gene mutations vs. 3% for TP53 mutations), suggesting the need for further refinement. 4