Acute Myeloid Leukemia (AML) - In Detail

Definition

Epidemiology

• Most common acute leukemia in adults; median age at diagnosis is 60 years
• Incidence rises with age: ~10/100,000/year in those over 60
• ~13,000 new cases per year in the United States
• In children, AML accounts for approximately one-third of acute leukemias; ALL dominates in this age group
• Risk factors: ionizing radiation, benzene, cytotoxic chemotherapy, smoking; most cases are idiopathic

Pathogenesis

1. Transcription Factor Mutations

• t(8;21) - disrupts RUNX1 (core binding factor-alpha), blocks myeloid maturation
• inv(16) - disrupts CBFB (core binding factor-beta)
• Both create fusion proteins that interfere with the RUNX1/CBFB transcription factor complex required for normal hematopoiesis
• t(15;17) (APL) - creates PML-RARα fusion protein that represses transcription of genes needed for myeloid differentiation

2. Signaling Pathway Mutations (proliferation)

• FLT3-ITD (internal tandem duplication) - constitutively activates myeloid cell proliferation; present in ~30% of AML
• KIT mutations (exons 8 and 17) - adversely affect prognosis in CBF-AML (~30%)
• RAS mutations - less common activating mutations

3. Epigenetic Regulators

• DNMT3A, TET2, IDH1/IDH2 mutations - produce the oncometabolite 2-hydroxyglutarate, disrupting DNA methylation and histone modification
• ASXL1, EZH2, SRSF2, SF3B1, U2AF1, ZRSR2, STAG2, BCOR - associated with myelodysplastic features and adverse prognosis

4. NPM1 Mutations

• NPM1 mutations cause abnormal cytoplasmic localization of nucleophosmin; one of the most common recurrent mutations in AML (~30%)
• Favorable prognosis when present without concurrent FLT3-ITD

Classification (WHO 5th Edition, 2022)

I. AML with Specific Genetic Aberrations

II. AML Defined by Differentiation (NOS types, no specific genetic aberration)

• AML with minimal differentiation
• AML without maturation
• AML with maturation
• Acute myelomonocytic leukemia
• Acute monocytic leukemia
• Acute erythroid leukemia
• Acute megakaryoblastic leukemia
• Acute basophilic leukemia

Diagnosis

Peripheral Blood & Bone Marrow

• Diagnosis requires ≥20% blasts in the marrow or blood (note: CBF-AML and APL are diagnostic regardless of blast count)
• Myeloblasts: central nuclei, fine chromatin, prominent nucleoli (3-5), variable cytoplasm with possible granules
• Auer rods - eosinophilic rod-like cytoplasmic inclusions; essentially pathognomonic for AML when present; formed from abnormal primary granule fusion

Immunophenotyping (Flow Cytometry)

• Immature AML: CD34, CD117, HLA-DR
• More differentiated: CD13, CD33
• Monocytic AML: CD14, CD15, CD11b, CD64, CD36
• Erythroid: CD36, CD71, CD235a (glycophorin A)
• Megakaryocytic: CD41, CD61
• 10-20% of AML co-expresses lymphoid antigens (CD2, CD7, CD19, CD56) - "aberrant" phenotypes useful for MRD monitoring

Cytochemistry (less used now)

• MPO (myeloperoxidase), Sudan Black B (SBB), CAE (chloroacetate esterase) - positive in myeloid lineage
• NSE (non-specific esterase / ANA, ANB) - positive in monocytic AML; inhibited by sodium fluoride

Molecular & Cytogenetic Workup

• Conventional karyotype (G-banding)
• FISH for t(15;17), t(8;21), inv(16) at diagnosis
• RT-PCR / qRT-PCR for disease monitoring (MRD)
• NGS panels: NPM1, FLT3, CEBPA, IDH1/IDH2, TP53, DNMT3A, ASXL1, RUNX1, SRSF2, U2AF1, and others

Clinical Presentation

• Fatigue, pallor (anemia)
• Infections, fever, mouth ulcers (neutropenia)
• Bruising, petechiae, bleeding (thrombocytopenia)

• Gum hypertrophy (especially monocytic AML)
• Skin nodules/infiltration (leukemia cutis)
• Lymphadenopathy, splenomegaly, hepatomegaly (less prominent than in ALL)
• Back pain / lower extremity weakness (spinal granulocytic/myeloid sarcoma, especially with t[8;21])
• CNS involvement: papilledema, retinal infiltrates, cranial nerve palsies

• Elevated WBC (may be very high = hyperleukocytosis) or low WBC with circulating blasts
• Elevated LDH, uric acid, phosphorus (tumor lysis risk)
• DIC (especially in APL and monocytic AML)

Prognostic Risk Stratification (ELN 2022 Criteria)

• Older age (most important clinical factor)
• Prior MDS or myeloproliferative neoplasm
• Secondary/therapy-related AML
• High WBC at presentation
• Poor performance status

Treatment

Initial Workup Before Treatment

1. Induction Chemotherapy (Non-APL AML)

• Cytarabine 100-200 mg/m² as a continuous IV infusion for 7 days (S-phase specific antimetabolite, inhibits DNA synthesis via triphosphate form)
• Anthracycline on days 1, 2, 3: daunorubicin 60-90 mg/m² or idarubicin 12 mg/m² (topoisomerase II inhibitors, DNA intercalators)
• Gemtuzumab ozogamicin (anti-CD33 immunoconjugate) can be added for favorable/intermediate risk patients

• FLT3-mutated AML: add midostaurin to 7+3 (RATIFY trial, 2017) or gilteritinib for relapsed/refractory disease
• IDH1-mutated AML: ivosidenib (approved for newly diagnosed IDH1-mutant AML)
• IDH2-mutated AML: enasidenib
• KMT2A/NPM1-rearranged AML: revumenib (menin inhibitor, 2023)
• Older/unfit patients: venetoclax + azacitidine or decitabine (hypomethylating agent combinations)

2. Post-Remission (Consolidation) Therapy

• Favorable risk (CBF-AML, NPM1 without FLT3-ITD): high-dose cytarabine (HiDAC) consolidation; allogeneic HCT generally not needed in CR1
• Intermediate risk: allogeneic HCT in CR1 if a suitable donor is available
• Adverse risk: allogeneic HCT in CR1 is strongly recommended

3. Acute Promyelocytic Leukemia (APL) - Special Treatment

• ATRA (all-trans retinoic acid) + ATO (arsenic trioxide) - standard of care for non-high-risk APL
• ATRA at pharmacologic doses binds to PML-RARα, displaces transcriptional repressors, and restores differentiation gene expression; liganded PML-RARα is also targeted for proteasomal degradation
• The result is terminal differentiation of malignant promyelocytes into short-lived neutrophils, clearing the marrow - this is the first successful example of differentiation therapy in oncology
• Cure rate with ATRA + ATO: ~85-90%

4. Measurable Residual Disease (MRD) Monitoring

• Quantitative RT-PCR for fusion transcripts (e.g., PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11) or NPM1 mutations
• Flow cytometry for aberrant immunophenotypes
• MRD positivity after treatment predicts relapse and guides decisions on transplantation

Complications

Summary of Key Points

1. AML = clonal proliferation of immature myeloid blasts; diagnosis requires ≥20% blasts (exceptions: CBF-AML, APL)
2. Pathogenesis involves transcription factor mutations, signaling mutations (FLT3, KIT), and epigenetic dysregulation (IDH1/2, DNMT3A, TET2)
3. Classification is now predominantly genetic (WHO 5th Ed. 2022 / ICC 2022)
4. APL is uniquely treated with ATRA + ATO (differentiation therapy) with excellent outcomes
5. Standard induction: 7+3 (cytarabine + anthracycline); targeted agents added based on molecular profile
6. Prognosis is determined primarily by cytogenetics and molecular mutations (ELN risk stratification)
7. Allogeneic HCT remains the only potentially curative approach for adverse-risk disease
8. Novel targeted agents (FLT3 inhibitors, IDH inhibitors, venetoclax, menin inhibitors) have substantially expanded treatment options