How do you approach risk stratification in patients with acute myeloid leukemia (AML)?

Risk Stratification in Acute Myeloid Leukemia (AML)

Comprehensive cytogenetic and molecular genetic analysis is mandatory at diagnosis for risk stratification in AML patients to guide treatment decisions and predict outcomes.

Cytogenetic Risk Stratification

Cytogenetic analysis forms the backbone of AML risk stratification and should be performed for all newly diagnosed patients 1. Based on karyotype, patients can be categorized into:

Favorable Risk

• t(8;21)(q22;q22) - Core Binding Factor AML (CBF-AML)
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22) - CBF-AML
• t(15;17)(q22;q12) - Acute Promyelocytic Leukemia (APL)

Intermediate Risk

• Normal karyotype
• Cytogenetic abnormalities not classified as favorable or adverse

Adverse Risk

• Complex karyotype (≥5 chromosomal abnormalities)
• Monosomal karyotype
• Monosomy 5 or del(5q)
• Monosomy 7 or del(7q)
• 11q23 abnormalities (MLL gene rearrangements)
• inv(3) or t(3;3)
• t(6;9)
• t(9;22)

Molecular Genetic Risk Stratification

For patients with normal karyotype (intermediate risk), molecular genetic testing is essential to further refine risk assessment 1:

Favorable Molecular Markers

• NPM1 mutation without FLT3-ITD
• Biallelic CEBPA mutations
• RUNX1-RUNX1T1 fusion gene (from t(8;21))
• CBFB-MYH11 fusion gene (from inv(16) or t(16;16))

Adverse Molecular Markers

• FLT3-ITD mutations (particularly with high allelic ratio)
• TP53 mutations
• RUNX1 mutations
• ASXL1 mutations
• DNMT3A mutations

Comprehensive Risk Assessment Algorithm

1. Obtain cytogenetic analysis of bone marrow samples at diagnosis

   • If favorable cytogenetics (t(8;21), inv(16), t(15;17)) → Favorable risk
   • If adverse cytogenetics (complex, monosomal, -5/5q-, -7/7q-, etc.) → Adverse risk
   • If normal karyotype or other non-classified abnormalities → Proceed to molecular testing

2. Perform molecular genetic testing (mandatory for normal karyotype AML) 1:

   • NPM1, FLT3 (ITD and TKD), CEBPA, RUNX1, ASXL1, DNMT3A, and TP53
   • For pediatric patients <5 years with normal karyotype, test for cryptic t(5;11)(q35.2;p15.4);NUP98-NSD1 1

3. Risk stratification based on combined cytogenetic-molecular profile:

   • Favorable risk: t(8;21), inv(16), t(15;17), or normal karyotype with NPM1+/FLT3-ITD- or biallelic CEBPA mutations
   • Intermediate risk: Normal karyotype without favorable or adverse molecular markers
   • Adverse risk: Complex karyotype, monosomal karyotype, -5/5q-, -7/7q-, 11q23 abnormalities, or normal karyotype with FLT3-ITD+, TP53, RUNX1, or ASXL1 mutations

4. Special considerations:

   • Test for c-kit mutations in CBF-AML (t(8;21) or inv(16)) as these confer adverse prognosis despite favorable cytogenetics 1, 2
   • For patients with CBF-AML and c-kit mutations, consider more intensive therapy 2

Integrating Minimal Residual Disease (MRD) Assessment

Post-treatment MRD assessment by flow cytometry significantly improves risk stratification 3:

• Patients with favorable/intermediate cytogenetics who achieve MRD-negative status have significantly better outcomes (4-year RFS: 63-70%, OS: 67-84%)
• Patients with favorable/intermediate cytogenetics who remain MRD-positive have poor outcomes similar to adverse-risk patients (4-year RFS: 15-17%, OS: 23-38%)

Age-Related Considerations

• For patients ≥60 years, even favorable molecular markers (CEBPA-DM, NPM1mut/FLT3wt) provide only short-term benefit 4
• Combined CEBPA-DM and NPM1mut/FLT3wt genotype defines a relatively favorable molecular group in older patients (57% alive at 1 year vs 33% for others) 4

Clinical Application

1. Low-risk patients (favorable cytogenetics or normal karyotype with favorable molecular markers):

   • Standard induction chemotherapy followed by high-dose cytarabine consolidation
   • No indication for allogeneic stem cell transplantation in first complete remission

2. Intermediate-risk patients:

   • Standard induction chemotherapy
   • Consider allogeneic stem cell transplantation based on MRD status and other factors

3. High-risk patients (adverse cytogenetics or molecular markers):

   • Consider clinical trials if available
   • Prompt HLA testing for potential allogeneic stem cell transplantation 1
   • Consider targeted therapies when applicable (e.g., midostaurin for FLT3-mutated AML) 5

Common Pitfalls to Avoid

1. Relying solely on cytogenetics without molecular testing, particularly in normal karyotype AML
2. Failing to test for cryptic translocations when suspected clinically or morphologically
3. Not integrating MRD assessment into post-treatment risk evaluation
4. Overlooking germline predisposition in certain cases (e.g., CEBPA, GATA2, TP53 mutations) 1
5. Delaying HLA typing for high-risk patients who may need allogeneic transplantation

By systematically applying this comprehensive risk stratification approach, treatment can be tailored to optimize outcomes based on the biological characteristics of each patient's disease.