What is the introduction, clinical manifestations, diagnosis, and management of Acute Myeloid Leukemia (AML)?

Acute Myeloid Leukemia: A Comprehensive Review

Acute Myeloid Leukemia (AML) is a rapidly progressive, life-threatening hematologic malignancy requiring prompt diagnosis and risk-stratified treatment to optimize survival outcomes. The management approach must be tailored based on cytogenetic and molecular profiles, with treatment decisions guided by patient-specific factors including age, performance status, and comorbidities.

Introduction

AML is characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia in adults with an estimated 21,450 new cases and 10,920 deaths annually in the United States 1. The median age at diagnosis is 67-71 years, with approximately 54% of patients diagnosed at 65 years or older 1.

Epidemiology

• Annual incidence: 4.1 per 100,000 people in the US 2
• Higher incidence in patients >65 years 1
• Accounts for approximately one-third of all leukemias diagnosed 3
• Therapy-related AML (t-AML) accounts for 5-20% of AML cases 1

Pathophysiology

AML is a genetically heterogeneous disease characterized by:

• Clonal expansion of myeloid precursors
• Arrest of differentiation
• Increased proliferation of immature myeloid cells
• Decreased apoptosis
• Bone marrow failure resulting in cytopenias

Clinical Manifestations

Symptoms Related to Cytopenias

• Anemia: Fatigue, weakness, pallor, dyspnea on exertion
• Neutropenia: Recurrent or severe infections, fever
• Thrombocytopenia: Bleeding manifestations (petechiae, ecchymoses, epistaxis, gingival bleeding)

Symptoms Related to Leukemic Infiltration

• Bone pain: Due to expanding bone marrow
• Hepatosplenomegaly: From leukemic infiltration
• Lymphadenopathy: Less common than in acute lymphoblastic leukemia
• Gingival hypertrophy: Particularly in monocytic subtypes
• Skin infiltration (leukemia cutis): Raised, violaceous lesions
• CNS involvement: Headache, cranial nerve palsies (rare at presentation)

Metabolic Complications

• Tumor lysis syndrome: Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia
• DIC: Particularly in acute promyelocytic leukemia (APL)

Diagnosis

Initial Evaluation

• Complete blood count with differential
• Comprehensive metabolic panel
• Coagulation studies (especially important in suspected APL)
• Serum uric acid and lactate dehydrogenase (prognostic relevance) 1

Definitive Diagnosis

• Bone marrow examination: Core biopsy and aspirate
  • Morphology: ≥20% myeloid blasts in bone marrow or peripheral blood (≥10% for certain genetic subtypes) 4
  • Cytochemistry: Myeloperoxidase, Sudan Black B, non-specific esterase
  • Immunophenotyping: Expression of myeloid markers (CD13, CD33, CD117)

Genetic Studies

• Cytogenetics: Karyotype analysis and FISH
• Molecular testing: Essential for risk stratification and treatment decisions
  • Required mutations: FLT3-ITD, FLT3-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, TP53 1
  • Next-generation sequencing recommended for comprehensive genetic profiling

Additional Studies

• Imaging: CT or PET/CT if extramedullary disease suspected 1
• CNS evaluation: Lumbar puncture if CNS symptoms present
• HLA typing: For patients who are potential candidates for allogeneic stem cell transplantation 1
• Cardiac evaluation: Echocardiography for patients with cardiac risk factors 1

Classification

WHO/ICC Classification

• AML with recurrent genetic abnormalities
  • AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1
  • AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
  • APL with PML-RARA
  • AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A
  • AML with t(6;9)(p23;q34.1); DEK-NUP214
  • AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM
  • AML with mutated NPM1
  • AML with biallelic mutations of CEBPA
  • AML with mutated RUNX1
• AML with myelodysplasia-related cytogenetic abnormalities
• AML with myelodysplasia-related gene mutations
• AML with mutated TP53
• Therapy-related myeloid neoplasms
• AML, not otherwise specified 4

MDS/AML Category

• 10-19% blasts without defining genetic abnormalities 4

Risk Stratification

European LeukemiaNet (ELN) Risk Classification

• Favorable risk:
  • t(8;21), inv(16), t(16;16)
  • Mutated NPM1 without FLT3-ITD
  • Biallelic mutated CEBPA
• Intermediate risk:
  • Mutated NPM1 with FLT3-ITD
  • Wild-type NPM1 without FLT3-ITD
  • t(9;11)
• Adverse risk:
  • Complex karyotype
  • Monosomal karyotype
  • -5, -7, 5q-, 7q-
  • 11q23 abnormalities other than t(9;11)
  • inv(3), t(3;3)
  • t(6;9)
  • Mutated TP53, RUNX1, ASXL1 1, 5

Patient-Related Factors

• Age >60 years
• Poor performance status
• Significant comorbidities
• Prior history of myelodysplastic syndrome
• Therapy-related AML 1

Treatment

General Principles

• Treatment should be initiated promptly after diagnosis and completion of necessary diagnostic studies
• Treatment approach depends on:
  • Patient age and fitness
  • Disease biology (cytogenetics and molecular profile)
  • Prior history of myeloid disorders or chemotherapy exposure

Induction Therapy

Fit Patients (<60-65 years without significant comorbidities)

• Standard "7+3" regimen:
  • Cytarabine 100-200 mg/m² continuous infusion for 7 days
  • Anthracycline (daunorubicin 60-90 mg/m² or idarubicin 12 mg/m²) for 3 days
• For FLT3-mutated AML:
  • Add midostaurin 50 mg twice daily on days 8-21 1
• For APL:
  • All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) for low/intermediate risk
  • ATRA plus anthracycline-based chemotherapy for high-risk disease 1

Older or Unfit Patients

• Hypomethylating agents plus venetoclax:
  • Azacitidine 75 mg/m² for 7 days or decitabine 20 mg/m² for 5 days
  • Venetoclax 400 mg daily (with dose ramp-up)
• Low-dose cytarabine plus venetoclax
• Single-agent therapy:
  • Hypomethylating agents (azacitidine, decitabine) 6
  • Low-dose cytarabine
  • Glasdegib plus low-dose cytarabine
• For IDH1/2-mutated AML:
  • Consider ivosidenib (IDH1) or enasidenib (IDH2) 2

Post-Remission Therapy

Favorable Risk

• High-dose cytarabine consolidation (3-4 cycles)

Intermediate Risk

• High-dose cytarabine consolidation or
• Allogeneic hematopoietic stem cell transplantation (HSCT)

Adverse Risk

• Allogeneic HSCT in first complete remission

Special Situations

Hyperleukocytosis (WBC >100 × 10⁹/L)

• Hydroxyurea 50-60 mg/kg/day until WBC <20 × 10⁹/L
• Consider leukapheresis for symptomatic leukostasis
• Avoid excessive red blood cell transfusions
• Tumor lysis syndrome prophylaxis (hydration, allopurinol or rasburicase) 1

CNS Involvement

• Intrathecal chemotherapy: cytarabine 40-50 mg 2-3 times weekly until clearance of blasts
• Consider liposomal cytarabine 50 mg every other week for approximately 6 cycles
• Craniospinal irradiation for refractory cases 1

Myeloid Sarcoma

• Systemic AML-directed therapy regardless of bone marrow involvement
• Consider local radiation therapy 1

Therapy-Related AML

• Generally poorer prognosis than de novo AML
• Consider allogeneic HSCT in first remission if donor available
• Treatment based on cytogenetic/molecular profile rather than therapy-related status 1

Response Assessment

Complete Remission (CR)

• <5% blasts in bone marrow
• No extramedullary disease
• ANC >1.0 × 10⁹/L
• Platelets >100 × 10⁹/L
• Transfusion independence

Measurable Residual Disease (MRD)

• Assessed by flow cytometry or molecular techniques
• MRD negativity associated with improved outcomes
• Consider MRD-directed therapy for persistent MRD

Relapsed/Refractory Disease

Salvage Options

• High-dose cytarabine-based regimens
• FLAG-IDA (fludarabine, cytarabine, G-CSF, idarubicin)
• MEC (mitoxantrone, etoposide, cytarabine)
• Targeted agents based on molecular profile:
  • FLT3 inhibitors (gilteritinib, quizartinib) for FLT3-mutated AML
  • IDH inhibitors for IDH1/2-mutated AML
  • Venetoclax-based combinations
• Clinical trials
• Allogeneic HSCT for eligible patients

Prognosis

Factors Associated with Poor Prognosis

• Age >60 years
• Secondary AML (therapy-related or evolving from MDS)
• High initial WBC count
• Adverse cytogenetics
• Specific mutations: FLT3-ITD, TP53, ASXL1, RUNX1
• Failure to achieve early blast clearance
• MRD positivity after therapy

Survival Rates

• Overall 5-year survival:
  • Age <60 years: 35-40%
  • Age >60 years: 5-15%
• Survival by risk group:
  • Favorable: 65-70%
  • Intermediate: 30-40%
  • Adverse: 5-15%

Supportive Care

• Prophylactic antimicrobials during neutropenia
• Blood product support (platelets, red blood cells)
• Growth factors in selected situations
• Tumor lysis syndrome prophylaxis
• Nutritional support
• Psychosocial support

Future Directions

• Novel targeted therapies (menin inhibitors, MCL1 inhibitors)
• Immunotherapeutic approaches (BiTEs, CAR-T cells)
• Improved MRD detection and MRD-directed therapy
• Combination strategies with venetoclax
• Novel conditioning regimens for HSCT

AML management has evolved significantly with improved understanding of disease biology and development of targeted therapies. Risk-adapted treatment strategies based on genetic profiling and patient characteristics offer the best chance for improved outcomes in this challenging disease.