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. Choloroma |
| 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.