Acute Myeloid Leukemia

Introduction And Epidemiology

• Accounts for 15-20% of childhood leukemias.
• Incidence approximates 500 new cases annually in United States.
• Age distribution exhibits bimodal peaks during neonatal period and adolescence.
• Survival rates improved from <20% historically to 60-70% currently.
• Accounts for majority of acute leukemia deaths in children.

Etiology And Predisposing Conditions

• Pathogenesis follows multihit hypothesis; initial oncogenic mutation creates preleukemic cell, subsequent promotional mutation drives malignant transformation.

Inherited Genetic Syndromes

Syndrome	Clinical Implication
Down Syndrome (Trisomy 21)	15-20 fold increased risk of acute leukemia; 500-fold increased risk of acute megakaryoblastic leukemia (AMKL); associated with GATA1 mutation.
Fanconi Anemia	50% risk of developing acute myeloid leukemia (AML); requires chemotherapy protocol modifications due to severe toxicity.
Severe Congenital Neutropenia	21% risk of developing AML; often preceded by granulocyte colony-stimulating factor receptor gene mutation; partial/total loss of chromosome 7 common.
Shwachman-Diamond Syndrome	30% risk of AML development; associated with chromosome 7 abnormalities.
Other Congenital Disorders	Diamond-Blackfan anemia, Dyskeratosis congenita, Neurofibromatosis-1, Bloom syndrome, Li-Fraumeni syndrome, Ataxia telangiectasia.

Acquired And Environmental Factors

• Therapy-Related AML (t-AML): Secondary to alkylating agents, topoisomerase II inhibitors (epipodophyllotoxins), radiation.
  • Epipodophyllotoxins: Induce French-American-British (FAB) M4 or M5 subtypes; involve KMT2A (MLL) gene rearrangement (11q23); short latency (6-36 months).
  • Alkylating Agents: Produce AML with poor-risk cytogenetics; longer latency (3-10 years).
• Preceding Hematologic Disorders: Aplastic anemia, myelodysplastic syndrome (MDS), paroxysmal nocturnal hemoglobinuria.
• Twin Concordance: Identical twin faces nearly 100% concordance risk if sibling diagnosed during infancy; implies shared placental clonal origin.

Cellular Classification

Morphologic Features

Feature	Myeloblast	Lymphoblast
Cell Size	14-20 μm (Large)	10-20 μm (Small)
Nuclear/Cytoplasmic Ratio	Low	High
Chromatin	Spongy, loose, finely developed	Smooth, homogeneous
Nucleoli	2-5, distinct, “punched-out”	0-2, indistinct
Cytoplasm	Abundant, blue-gray	Scant, thin blue rim
Granules / Auer Rods	Present	Absent

French-American-British (FAB) Classification

Subtype	Nomenclature	Diagnostic Nuances
M0	Acute undifferentiated leukemia	Minimal differentiation.
M1	Myeloblastic without maturation	Morphologically mimics L2 ALL.
M2	Myeloblastic with maturation	Frequently exhibits t(8;21); Auer rods common.
M3	Acute promyelocytic leukemia (APML)	Hypergranular promyelocytes; multiple Auer rods (faggot cells); t(15;17); prominent coagulopathy.
M4	Acute myelomonocytic leukemia	Exhibits myelocytic and monocytic differentiation; M4eo variant features abnormal eosinophils and inv(16).
M5	Acute monocytic leukemia	Common in children <2 years; prominent extramedullary disease (gums, skin).
M6	Erythroleukemia	Di Guglielmo disease.
M7	Acute megakaryoblastic leukemia	Associated with myelofibrosis; overwhelmingly common in Down syndrome.

Immunophenotypic Profile

• Myeloid lineage defined by markers: cMPO, CD11b, CD13, CD14, CD15, CD33, CD34, CD117, HLA-DR.
• Megakaryoblastic (M7) defined by: CD41, CD42, CD61 positivity.

Clinical Manifestations

• Bone Marrow Failure: Anemia (pallor, fatigue), neutropenia (fever, severe bacterial infections), thrombocytopenia (petechiae, purpura, frank hemorrhage).
• Extramedullary Disease (EMD): Occurs in 10-20% of patients. Manifests as myeloid sarcoma (chloroma), gingival hypertrophy, leukemia cutis (blueberry muffin lesions). Common in M4, M5, infant AML, and associated with t(8;21), inv(16), 11q23 rearrangements.
• Central Nervous System (CNS) Involvement: Present in 5-15% at diagnosis. Higher incidence than ALL. Associated with hyperleukocytosis, M4/M5 subtypes, young age (<2 years).
• Hyperleukocytosis: White blood cell (WBC) count >100,000/mm³. Myeloblasts large and non-deformable. High risk for microcirculatory leukostasis leading to pulmonary hemorrhage, hypoxia, stroke, confusion, coma.
• Disseminated Intravascular Coagulation (DIC): Markedly common in M3 (APML). Severe life-threatening hemorrhage.

Diagnostic And Monitoring Studies

• Complete Blood Count: Median WBC 20,000/mm³. 20% present with WBC >100,000/mm³. Hemoglobin <9 g/dL in 50%. Platelets <100,000/mm³ in 75%.
• Bone Marrow Evaluation: Requires >20% blasts for World Health Organization (WHO) criteria. Presence of clonal abnormalities [t(8;21), inv(16), t(15;17)] confirms AML irrespective of blast percentage.
• Coagulation Profile: Screen for hypofibrinogenemia, DIC, reduced factors V, IX, X.
• Cerebrospinal Fluid: Perform lumbar puncture to assess CNS involvement.
• Minimal Residual Disease (MRD): Assessed via multidimensional flow cytometry or polymerase chain reaction. MRD >0.1% post-induction defines high risk for relapse. Directs stem cell transplant indications.

Cytogenetics And Molecular Genetics

Favorable Risk Markers

• Translocations: t(8;21) [RUNX1-RUNX1T1], inv(16) [CBFB-MYH11], t(15;17) [PML-RARA].
• Molecular: NPM1 mutation, biallelic CEBPA mutation.
• Down syndrome associated AMKL (GATA1 mutation).

Unfavorable Risk Markers

• Deletions/Monosomies: Monosomy 7, Monosomy 5, del(5q).
• Translocations: 11q23 abnormalities [KMT2A (MLL) rearrangements].
• Molecular: FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplication). Associated with high WBC, normal cytogenetics, poor prognosis.

Management And Treatment Strategies

Aggressive Supportive Care

• Infection Prophylaxis: Mandatory hospitalization during induction. High incidence of Streptococcus viridans bacteremia and invasive fungal infections. Empiric broad-spectrum antibiotics (cefepime/vancomycin) and antifungal coverage indicated for fever.
• Hyperleukocytosis Management: Aggressive hydration, leukapheresis, exchange transfusion (contraindicated in APML).
• Cardioprotection: Dexrazoxane administered prior to anthracyclines to mitigate severe acute and late cardiotoxicity.

Systemic Chemotherapy

• Features extremely intensive myelosuppressive regimens.
• Induction: Cytarabine, Daunorubicin, Etoposide (ADE regimen). Gemtuzumab ozogamicin (anti-CD33 monoclonal antibody) routinely added on day 6 for CD33+ disease, markedly improving event-free survival.
• Consolidation: High-dose cytarabine forms therapy backbone. Total 4-5 cycles administered depending on protocol and risk group.
• Targeted FLT3 Inhibition: Gilteritinib, sorafenib, or midostaurin incorporated for FLT3-ITD positive disease.

Hematopoietic Stem Cell Transplantation (HSCT)

• Curative modality for high-risk patients.
• Indications in First Complete Remission (CR1): Unfavorable cytogenetics (Monosomy 7, 5q-), FLT3-ITD positive disease, therapy-related AML, FAB M6, primary induction failure, or persistent MRD >0.1%.
• Contraindications in CR1: Favorable risk genetic profiles do not benefit from upfront HSCT; reserved strictly for relapse.

Management Of Specific AML Subtypes

Acute Promyelocytic Leukemia (APML - FAB M3)

• Constitutes 5-10% of pediatric AML.
• Pathophysiology: t(15;17) translocates PML gene with retinoic acid receptor alpha (RARA) gene, arresting promyelocyte maturation.
• Therapy: Highly curable (>95% survival) without conventional HSCT.
• Targeted Agents: All-trans retinoic acid (ATRA) induces terminal differentiation. Arsenic trioxide (ATO) binds PML moiety inducing apoptosis.
• Complications: Differentiation syndrome features respiratory distress, capillary leak, pulmonary infiltrates, fever. Treated emergently with Dexamethasone.

Myeloid Leukemia Of Down Syndrome (DS-ML)

• Children <5 years with Down syndrome face 500-fold increased risk of AMKL.
• Transient Myeloproliferative Disorder (TMD): Precursor condition in 4-10% of DS neonates. Characterized by circulating megakaryoblasts. Spontaneously remits by 3 months. Severe organ infiltration requires low-dose cytarabine.
• AMKL: Develops in 20% of TMD patients by age 4.
• Genetics: Harbors acquired GATA1 mutations.
• Therapy: Blasts exhibit exquisite sensitivity to cytarabine. Treated with reduced-intensity regimens. Excellent prognosis (survival >90%).

Infant AML

• Occurs in children <2 years. Over 50% harbor KMT2A (MLL) rearrangements.
• Increased incidence of CNS disease, leukemia cutis, and high WBC.
• High susceptibility to anthracycline-induced cardiotoxicity; necessitates body-weight based dosing.

Relapsed And Refractory AML

• Relapse occurs in 30-40% of patients despite remission achievement.
• Reinduction: Utilizes FLAG-Ida regimen (Fludarabine, Cytarabine, Granulocyte colony-stimulating factor, Idarubicin).
• Consolidation: Second HSCT strictly indicated post-reinduction upon achieving MRD-negative second complete remission.
• Novel Investigational Therapies:
  • Venetoclax (BCL-2 inhibitor) combined with azacitidine.
  • CPX-351 (Liposomal 5:1 cytarabine/daunorubicin formulation).
  • Menin inhibitors and DOT1L inhibitors for KMT2A-rearranged leukemias.