AML

Overview of Acute Myeloid Leukemia (AML)

Definition: A group of aggressive hematologic malignancies characterized by the rapid proliferation and accumulation of myeloblasts (immature myeloid cells) in the bone marrow and peripheral blood
Hallmark: >20% blasts in the bone marrow
Classification:
- The World Health Organization (WHO) classification is the most widely used system and is based on:
  - Morphology
  - Immunophenotype
  - Genetic abnormalities (cytogenetics and molecular genetics)
  - Clinical features
- Key Categories (According to WHO):
  - AML with Recurrent Genetic Abnormalities
  - AML with Myelodysplasia-Related Changes
  - Therapy-Related AML (t-AML)
  - AML Not Otherwise Specified (AML-NOS)
Pathophysiology:
- Genetic mutations disrupt normal myeloid differentiation, leading to a buildup of myeloblasts
- Myeloblasts crowd out normal hematopoietic cells in the bone marrow, causing cytopenias (anemia, thrombocytopenia, neutropenia)
Clinical Significance: Rapidly progressive and life-threatening if untreated

Etiology and Risk Factors

Genetic Mutations:
- AML is typically caused by acquired genetic mutations in hematopoietic stem cells or early myeloid progenitors
- These mutations can affect:
  - Transcription factors (e.g., RUNX1, CEBPA)
  - Signal transduction pathways (e.g., FLT3, RAS)
  - Epigenetic modifiers (e.g., DNMT3A, TET2)
  - Spliceosome components (e.g., SF3B1)
Prior Chemotherapy or Radiation Therapy:
- Therapy-related AML (t-AML) is a secondary leukemia that develops after exposure to cytotoxic agents or radiation
- t-AML often has poor prognosis
Underlying Hematologic Disorders:
- Myelodysplastic syndromes (MDS) can transform into AML
- Myeloproliferative neoplasms (MPNs) can transform into AML
Genetic Predisposition:
- Certain inherited genetic syndromes increase the risk of developing AML (e.g., Fanconi anemia, Down syndrome)
Environmental Factors:
- Exposure to benzene or other chemicals
- Smoking

Classification of AML (WHO 2016)

AML with Recurrent Genetic Abnormalities:
- AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1
  - Favorable prognosis
  - Often associated with Auer rods and maturation
- AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
  - Favorable prognosis
  - Often associated with increased eosinophils in the bone marrow
- Acute Promyelocytic Leukemia (APL) with t(15;17)(q24.1;q21.1); PML-RARA
  - Good prognosis with appropriate treatment
  - Associated with disseminated intravascular coagulation (DIC)
  - Abnormal promyelocytes with Auer rods
- AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A
  - Intermediate prognosis
  - Often associated with monocytic differentiation
- AML with t(v;11q23.3); KMT2A rearranged:
- 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 t(1;22)(p13.3;q13.1); RBM15-MKL1
AML with Myelodysplasia-Related Changes:
- History of myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN)
- Multilineage dysplasia in the bone marrow (dysplasia in ≥50% of cells in at least 2 cell lineages)
- Specific cytogenetic abnormalities
Therapy-Related AML (t-AML):
- Occurs after exposure to cytotoxic chemotherapy or radiation therapy
- Often associated with specific cytogenetic abnormalities and poor prognosis
AML Not Otherwise Specified (AML-NOS):
- AML cases that do not meet the criteria for the other WHO subtypes
- Subclassified based on morphology:
  - AML with minimal differentiation
  - AML without maturation
  - AML with maturation
  - Acute myelomonocytic leukemia
  - Acute monoblastic/monocytic leukemia
  - Acute erythroid leukemia
  - Acute megakaryoblastic leukemia
  - Acute basophilic leukemia
  - Acute panmyelosis with myelofibrosis

Clinical Features

Symptoms of Anemia:
- Fatigue
- Weakness
- Pallor (pale skin)
- Shortness of breath
Symptoms of Thrombocytopenia:
- Bleeding (e.g., nosebleeds, gum bleeding, easy bruising)
- Petechiae (small, pinpoint hemorrhages)
- Ecchymoses (bruises)
Symptoms of Neutropenia:
- Frequent infections
- Fever
- Sore throat
Other Symptoms:
- Bone pain
- Splenomegaly (enlarged spleen)
- Hepatomegaly (enlarged liver)
- Lymphadenopathy (swollen lymph nodes) - less common in AML than ALL
- Gingival hyperplasia (swelling of the gums), especially in acute monocytic leukemia
- Skin infiltration (leukemia cutis)
- Disseminated Intravascular Coagulation (DIC):
  - Can occur, especially in acute promyelocytic leukemia (APL)

Laboratory Findings

Complete Blood Count (CBC):
- Hemoglobin (HGB): Decreased (anemia)
- Hematocrit (HCT): Decreased
- Red Blood Cell Count (RBC): Decreased
- Platelet Count: Decreased (thrombocytopenia)
- White Blood Cell Count (WBC): Variable; can be low, normal, or elevated
  - Neutropenia: Often present, but some patients may have elevated neutrophil counts
- Presence of blasts in the peripheral blood (usually >20% of WBCs)
Peripheral Blood Smear:
- Myeloblasts: Large, immature cells with:
  - High nucleus-to-cytoplasm (N:C) ratio
  - Fine chromatin
  - Prominent nucleoli
  - Auer rods: Rod-shaped inclusions in the cytoplasm (especially in AML with t(15;17))
- Decreased mature granulocytes and platelets
Coagulation Studies (PT, aPTT, Fibrinogen, D-dimer):
- May be abnormal, especially in acute promyelocytic leukemia (APL) due to disseminated intravascular coagulation (DIC)
Bone Marrow Aspiration and Biopsy:
- Hypercellular marrow with >20% blasts
- Dysplastic changes in one or more cell lines
- Special stains:
  - Myeloperoxidase (MPO): Positive in myeloblasts
  - Sudan Black B (SBB): Positive in myeloblasts
  - Esterase stains: Differentiate myeloblasts from monoblasts
Flow Cytometry Immunophenotyping:
- Identifies cell surface markers on the blasts to determine the lineage (myeloid) and subtype of AML
- Common markers:
  - Myeloid markers: CD13, CD33, CD117, myeloperoxidase (MPO), CD15
  - Stem cell markers: CD34, HLA-DR
Cytogenetic Analysis:
- Identifies chromosomal abnormalities (e.g., translocations, inversions, deletions) that are used for diagnosis and prognosis
Molecular Testing:
- Detects gene mutations (e.g., FLT3, NPM1, CEBPA) that are used for diagnosis, prognosis, and treatment planning

Diagnosis

Based on the Following Criteria:
- Bone Marrow Aspiration and Biopsy: >20% blasts in the bone marrow
- Peripheral Blood Smear: Presence of blasts
- Immunophenotyping: Identifies the lineage and subtype of AML
- Cytogenetic Analysis: Detects chromosomal abnormalities
- Molecular Testing: Detects gene mutations

Treatment

Goals of Treatment:
- Achieve complete remission (CR): Eradication of blasts from the bone marrow and restoration of normal hematopoiesis
- Prevent relapse
- Prolong survival
Phases of Treatment:
- Induction Chemotherapy:
  - Intensive chemotherapy to rapidly reduce the number of leukemic cells in the bone marrow and peripheral blood
  - Common regimens:
    - “7+3” (cytarabine for 7 days and daunorubicin or idarubicin for 3 days)
  - Patients are at high risk for complications (e.g., infection, bleeding) during induction
- Consolidation Therapy:
  - Administered after achieving remission to eliminate any remaining leukemic cells and prevent relapse
  - Options:
    - Chemotherapy
    - Hematopoietic Stem Cell Transplantation (HSCT):
      - Allogeneic HSCT (from a matched donor) is the preferred consolidation therapy for many patients with high-risk AML
Treatment of Acute Promyelocytic Leukemia (APL):
- All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is the preferred treatment for most patients with APL
- This combination therapy targets the PML-RARA fusion protein and promotes differentiation of promyelocytes
- Chemotherapy may be added in high-risk cases
Supportive Care:
- Transfusions (RBCs and platelets) to manage anemia and thrombocytopenia
- Antibiotics and antifungals to treat infections
- Growth factors (e.g., G-CSF) to stimulate neutrophil production
- Management of tumor lysis syndrome (TLS): A metabolic complication caused by the rapid breakdown of leukemic cells

Prognosis

Factors Influencing Prognosis:
- Cytogenetic Abnormalities: Certain chromosomal abnormalities are associated with favorable or unfavorable outcomes
- Gene Mutations: The presence of certain gene mutations (e.g., FLT3-ITD) is associated with poorer prognosis, while others (e.g., NPM1) are associated with more favorable outcomes
- Age: Younger patients generally have better outcomes than older patients
- Performance Status: Overall health and fitness of the patient
- Response to Induction Chemotherapy: Achievement of complete remission is a key prognostic factor
Risk Stratification:
- Patients are classified into risk groups (favorable, intermediate, or adverse) based on cytogenetic and molecular abnormalities
- Risk stratification guides treatment decisions and helps predict the likelihood of achieving long-term remission

Key Laboratory Findings

CBC:
- Anemia
- Thrombocytopenia
- Neutropenia
- Presence of blasts in the peripheral blood
Peripheral Blood Smear:
- Myeloblasts
- Auer rods (in some cases)
Bone Marrow Examination:
- Hypercellular marrow with >20% blasts
Flow Cytometry:
- Identifies cell surface markers on the blasts
Cytogenetic Analysis:
- Detects chromosomal abnormalities
Molecular Testing:
- Detects gene mutations

Key Terms

Acute Myeloid Leukemia (AML): An aggressive leukemia characterized by >20% blasts in the bone marrow
Myeloblast: Immature myeloid cell
Auer Rods: Rod-shaped inclusions in the cytoplasm of myeloblasts
Cytopenia: Deficiency of blood cells (e.g., anemia, thrombocytopenia, neutropenia)
Complete Remission (CR): Eradication of blasts from the bone marrow and restoration of normal hematopoiesis
Induction Chemotherapy: Initial intensive chemotherapy to achieve remission
Consolidation Therapy: Treatment to prevent relapse after achieving remission
Hematopoietic Stem Cell Transplantation (HSCT): Procedure to replace damaged bone marrow with healthy stem cells
Cytogenetic Analysis: The study of chromosomes and their abnormalities
Molecular Testing: Techniques to detect gene mutations and other molecular abnormalities

Myeloid Neoplasia

Myelodysplastic