What is the classification, diagnosis, and prognosis of Acute Myeloid Leukemia (AML) in adults, particularly those over 60 years old with a history of myelodysplastic syndromes, radiation exposure, or previous chemotherapy?

Acute Myeloid Leukemia: Classification, Diagnosis, and Prognosis

Classification

AML classification has evolved significantly, with the International Consensus Classification eliminating the traditional "AML with myelodysplasia-related changes" category and creating more precise genetic-based categories. 1

Current Classification Framework

• AML with recurrent genetic abnormalities requires only ≥10% blasts (not 20%) when specific defining mutations like NPM1 are present 1
• AML with myelodysplasia-related cytogenetic abnormalities is now a distinct category separate from morphologic dysplasia 1
• AML with myelodysplasia-related gene mutations represents a new classification group 1
• AML with mutated TP53 is recognized as a separate high-risk entity 1
• MDS/AML is a new category for cases with 10-19% blasts that don't meet criteria for specific AML subtypes 1
• Therapy-related AML and antecedent myeloid neoplasms should be documented as qualifiers to the primary diagnosis 1

Key Molecular Alterations

The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53, with incidence varying by age, prior hematologic disease, and previous chemotherapy/radiation exposure 2

Diagnosis

Diagnosis requires ≥20% blasts in bone marrow or peripheral blood, with bone marrow aspiration being mandatory—never initiate chemotherapy before obtaining adequate diagnostic material. 3

Essential Diagnostic Studies (Must Complete Before Treatment)

• Bone marrow aspirate with count of ≥500 nucleated cells on marrow smears containing spicules 3
• Bone marrow core biopsy with trephine touch preparations evaluated jointly with aspirates 3, 4
• Peripheral blood smear for morphological evaluation 4
• Complete blood count with differential 3, 4

Mandatory Molecular and Cytogenetic Testing

• Conventional cytogenetic analysis (karyotype) is mandatory and cannot be replaced by molecular testing or FISH alone—this provides critical prognostic information as chromosomal abnormalities are detected in the majority of cases 3, 4
• FLT3-ITD mutation testing is required for all patients for prognostic stratification and targeted therapy decisions 3
• Multiparameter flow cytometry (minimum 3-4 color) on bone marrow aspirate to distinguish AML from ALL and acute leukemia of ambiguous lineage 3
• NPM1, CEBPA, and RUNX1 mutational analysis for non-core binding factor AML and non-APL cases 3
• KIT mutation analysis for core binding factor AML (t(8;21) or inv(16)/t(16;16)) 3
• Rapid PML-RARA detection if morphology suggests acute promyelocytic leukemia 3

Pre-Treatment Evaluations

• Comprehensive medical history documenting prior growth factor therapy, transfusions, medications, family history of hematologic disorders, and comorbidities (particularly diabetes and coronary heart disease) 3
• Coagulation tests before central venous catheter insertion 4
• Echocardiography for patients with cardiac risk factors or history of heart disease 4
• Emergency leukapheresis may be required for patients with excessive leukocytosis before induction chemotherapy 5, 4

Critical Diagnostic Pitfall

Postpone chemotherapy until all satisfactory diagnostic material has been harvested—starting treatment before completing cytogenetics and molecular testing eliminates the ability to accurately risk-stratify and select appropriate therapy 3, 4

Prognosis

Prognosis in AML varies dramatically based on age, cytogenetic/molecular risk group, and disease history, with 5-year survival ranging from >60% in favorable-risk younger patients to <10% in adverse-risk older patients. 5

Age-Stratified Outcomes

• Younger patients (<60 years) achieve complete remission rates of 60-80% with 5-year survival of 40-50% 5
• Older patients (≥60 years) have significantly worse outcomes with complete remission rates of only 40-50% and 5-year survival below 20% due to higher treatment-related mortality from comorbidities, reduced organ function, and higher frequency of unfavorable cytogenetics 5, 3, 4
• Patients up to 80 years can achieve better survival with intensive induction chemotherapy, except those with unfavorable genomic risk abnormalities or major comorbidities 6

Cytogenetic and Molecular Risk Stratification

Favorable-Risk Features (5-year survival >60%)

• t(15;17) (acute promyelocytic leukemia) 5, 3, 4
• t(8;21) 5, 3, 4
• inv(16)/t(16;16) 5, 3, 4
• NPM1 mutations without FLT3-ITD 5, 3
• Biallelic CEBPA mutations 3

For favorable-risk disease, chemotherapy-based consolidation is recommended rather than immediate allogeneic transplant in first remission 5

Adverse-Risk Features (5-year survival <10%)

• Complex aberrant karyotype 5, 3, 4
• Therapy-related AML with complete remission rates of only 28-40% and overall survival of 20-30% even with allogeneic transplant 5
• Antecedent or concomitant myelodysplastic syndrome 5, 3, 4
• FLT3 gene alterations 3
• Age >60 years 3, 4
• High initial leukocyte count 4
• TP53 mutations 1

Important Prognostic Nuances

• AML with multilineage dysplasia (AML-MRC-M) and AML with history of untreated MDS (AML-MRC-H) have better outcomes than other MDS-related AML subtypes and may have similar outcomes to intermediate-risk AML, suggesting these patients may benefit from intensive therapy 7
• Secondary-type mutations (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) appear in 39% of evaluable patients, with mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tending to appear in dominant clones 7

Relapsed Disease

• Patients relapsing after allogeneic transplant have particularly poor prognosis with less than 20% alive at 5 years 5
• European LeukemiaNet provides a validated prognostic scoring system for relapsed AML in patients 15-60 years 5

Treatment-Related Mortality Risk Factors

• Poor performance status 5
• Significant comorbidities 5
• Complex karyotypes 5

Critical Prognostic Pitfall

Cytogenetic and molecular profiling is mandatory before making prognostic assessments—the difference between favorable-risk and adverse-risk disease is dramatic, with 5-year survival ranging from >60% to <10% respectively, and comprehensive diagnostic workup should not be delayed to start treatment as this information is essential for accurate prognostication and treatment planning 5

Targeted Therapy Impact on Prognosis

• FLT3-mutated AML treated with midostaurin plus standard chemotherapy demonstrated superior overall survival (HR 0.77; 95% CI 0.63-0.95; p=0.016) compared to placebo plus chemotherapy in a randomized trial of 717 patients with newly-diagnosed FLT3-mutated AML 8
• Event-free survival improved with median of 8.2 months for midostaurin plus chemotherapy versus 3.0 months for placebo plus chemotherapy (HR 0.78; 95% CI 0.66-0.93; p=0.005) 8
• Gemtuzumab ozogamicin is increasingly added to induction therapy for AML patients up to 70 years with favorable or intermediate risk profile 6