What is a comprehensive breakdown of Acute Myeloid Leukemia (AML) for teaching purposes?

Acute Myeloid Leukemia (AML): Comprehensive Teaching Breakdown

Definition and Epidemiology

AML is a clonal hematopoietic malignancy characterized by accumulation of poorly differentiated myeloid cells, defined by ≥20% blasts in peripheral blood or bone marrow. 1

• Incidence: 5-8 cases per 100,000 individuals annually in European adults, with steep increase to 15-25 per 100,000 in patients >70 years 1
• Mortality: 4-6 cases per 100,000 per year 1
• Median age at diagnosis: ~70 years, with higher incidence in males 1
• Accounts for: One-third of all leukemias diagnosed 2

Diagnostic Work-Up

Mandatory Initial Testing

Diagnosis requires examination of both peripheral blood and bone marrow specimens with comprehensive ancillary studies. 1

Essential laboratory studies include: 1

• Bone marrow aspirate and biopsy with morphology and cytochemistry
• Immunophenotyping by flow cytometry of peripheral blood and bone marrow
• Cytogenetics (conventional karyotyping)
• Molecular genetics using PCR and FISH techniques
• Routine chemistry including liver and kidney parameters
• Coagulation profile (critical to detect APL-associated coagulopathy)
• Blood group typing
• HLA typing of patient and family members (for transplant candidates)

Additional imaging and assessments: 1

• CT scan of chest and abdomen (or chest X-ray and abdominal ultrasound)
• Dental survey to identify infectious foci
• Cardiac echocardiography for patients with risk factors or history of heart disease
• Serum pregnancy test in females
• Sperm preservation discussion in males

Classification Systems

The WHO classification (revised 2008, updated 2016) supersedes the historical FAB criteria and incorporates cytogenetic data, molecular genetics, immunophenotype, and clinical information. 1

Key WHO definition: Myeloid neoplasms with >20% blasts are classified as AML, either de novo or evolved from pre-existing MDS 1

The term "myeloid" encompasses: granulocytic, monocyte/macrophage, erythroid, megakaryocytic, and mast cell lineages 1

Risk Stratification

Clinical Risk Factors

Patient age, initial leukocyte count, and co-morbidity are critical prognostic factors, with patients ≥60-65 years having significantly worse outcomes due to treatment complications. 1

AML evolved from previously documented MDS carries adverse prognosis. 1

Cytogenetic Risk Categories

Molecular and genetic risk stratification are the key principles guiding AML therapy. 1

Favorable-risk AML includes: 1

• APL with t(15;17)(q22;q12)
• Core binding factor AML: t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)
• Biallelic CEBPα mutation with normal cytogenetics
• Normal karyotype with NPM1 mutation and no FLT3-ITD

Intermediate-risk AML includes: 1

• Normal cytogenetics without adverse molecular features
• FLT3-ITD with normal karyotype

Adverse-risk AML includes: 1

• Complex karyotype abnormalities (>3 abnormalities)
• Monosomal karyotype
• 11q23 abnormalities (MLL gene rearrangements)

Molecular Genetics

In cytogenetically normal AML, mutations in FLT3, NPM1, and CEBPα are critical prognostic factors. 1

• NPM1 and biallelic CEBPα mutations: Favorable when present as single molecular aberrations 1
• FLT3 alterations: Predict high and early relapse rate, particularly with high allelic ratio 1
• Emerging markers: IDH1, IDH2, TET2, DNMT3A mutations increasingly incorporated into risk stratification 1, 3

Treatment Principles

General Approach

AML treatment should be offered in clinical trials whenever possible and administered only in experienced centers with adequate multidisciplinary infrastructure and high case load. 1

Treatment should be planned with curative intent whenever feasible. 1

Treatment Phases

Intensive chemotherapy is divided into: 1

1. Induction phase: Aims to achieve complete remission
2. Consolidation phase: Prevents relapse
3. Maintenance: Rarely used (except in APL)

Potential allogeneic stem cell transplant candidates must be identified early at diagnosis or during induction chemotherapy. 1

Standard Induction Regimens

For patients <60 years with non-APL AML: 4

• Daunorubicin 45 mg/m²/day IV on days 1,2, and 3
• Cytarabine 100 mg/m²/day IV infusion daily for 7 days (first course) or 5 days (subsequent courses)

For patients ≥60 years: 4

• Daunorubicin 30 mg/m²/day IV on days 1,2, and 3
• Cytarabine 100 mg/m²/day IV infusion daily for 7 days (first course) or 5 days (subsequent courses)

Up to three courses of induction therapy may be required to achieve normal-appearing bone marrow. 4

Pre-Treatment Considerations

All patients undergoing intensive chemotherapy require: 1

• Central intravenous line insertion (under platelet transfusion if necessary)
• Completion of all diagnostic sampling before chemotherapy initiation
• Assessment for active infection with potential treatment delay if present

Patients with excessive leukocytosis and clinical leukostasis: 1

• May require emergency leukapheresis coordinated with chemotherapy start
• Are at particular risk for tumor lysis syndrome requiring appropriate monitoring
• May benefit from single injection of rasburicase

Transplant Planning

For high-risk disease (poor-risk karyotype), early matched unrelated donor allogeneic transplantation must be considered, requiring donor search as early as possible. 1

HLA typing should be performed at diagnosis for patients potentially suitable for allogeneic stem cell transplantation, including available first- and second-degree family members. 1

Special Populations

Elderly Patients

Patients >60 years are more susceptible to treatment complications, particularly severe infections, contributing to higher risk of unfavorable outcome. 1

Patients with poor performance status, considerable co-morbidity, or elderly patients not eligible for curative treatment should receive supportive care. 1

Acute Promyelocytic Leukemia (APL)

APL must be urgently differentiated from other AML forms by cytomorphology (dysplastic promyelocytes, binucleated blasts, faggot cells), signs of hyperfibrinolysis, and molecular evidence of PML-RARA fusion. 1

Coagulation status must be obtained before central line insertion to detect APL-related coagulopathy. 1

Hemorrhagic events are the primary cause of early death in APL, especially during induction therapy due to severe coagulopathy. 5

Pediatric ALL

For pediatric acute lymphocytic leukemia: 4

• Daunorubicin 25 mg/m² IV on day 1 every week
• Vincristine 1.5 mg/m² IV on day 1 every week
• Prednisone 40 mg/m² PO daily
• Complete remission typically obtained within four courses

In children <2 years or <0.5 m² body surface area, daunorubicin dosage should be based on weight (1 mg/kg) instead of body surface area. 4

Dose Modifications

Dosage reduction is recommended for hepatic or renal impairment: 4

• Serum bilirubin 1.2-3 mg%: 25% dose reduction
• Serum bilirubin >3 mg%: 50% dose reduction
• Serum creatinine >3 mg%: 50% dose reduction

Key Pitfalls and Caveats

Cytarabine is a potent bone marrow suppressant requiring close medical supervision with daily leukocyte and platelet counts during induction therapy. 6

Facilities must be available for management of potentially fatal complications including infection from granulocytopenia and hemorrhage from thrombocytopenia. 6

Anaphylaxis requiring resuscitation has been reported immediately after IV cytarabine administration. 6

High-dose experimental cytarabine regimens can cause severe and sometimes fatal CNS, GI, and pulmonary toxicity including reversible corneal toxicity, cerebellar dysfunction, severe GI ulceration, and pulmonary edema. 6

Profound bone marrow suppression is usually required to eradicate leukemic cells and induce complete remission, necessitating evaluation of both peripheral blood and bone marrow in treatment planning. 4