Acute Myeloid Leukemia

Clonal myeloid malignancy — ELN risk stratification, FLT3/IDH/NPM1 mutations, venetoclax-based lower-intensity therapy, and allogeneic transplantation

Key Points

• AML is a clonal malignancy of myeloid progenitors characterized by ≥20% myeloid blasts in bone marrow or blood; it is the most common acute leukemia in adults (~20,800 new cases in the US in 2024).
• The 2022 ELN risk classification (favorable, intermediate, adverse) drives treatment decisions; favorable-risk includes NPM1-mutated (without FLT3-ITD) and biallelic CEBPA; adverse includes TP53, RUNX1, ASXL1 mutations and complex karyotype.
• Intensive induction with "7+3" (cytarabine × 7 days + anthracycline × 3 days) remains the standard for fit patients; CPX-351 (liposomal cytarabine + daunorubicin) is preferred for therapy-related AML and AML with myelodysplasia-related changes.
• FLT3-mutated AML: midostaurin (RATIFY trial) added to induction/consolidation improves OS; gilteritinib for FLT3+ relapsed/refractory AML.
• IDH1/2-mutated AML: ivosidenib (IDH1) and enasidenib (IDH2) are approved for relapsed/refractory disease; olutasidenib (IDH1) and ivosidenib+azacitidine for unfit newly diagnosed IDH1-mutant AML.
• Venetoclax + azacitidine (VIALE-A trial) is the standard frontline regimen for patients ineligible for intensive chemotherapy, transforming outcomes in older/unfit patients.
• Allogeneic stem cell transplantation (alloSCT) in first complete remission is the standard consolidation for intermediate- and adverse-risk AML in fit patients.

Epidemiology & Classification

Acute myeloid leukemia is the most common acute leukemia in adults, with approximately 20,800 new cases and 11,220 deaths projected in the United States in 2024. The median age at diagnosis is 68 years; AML increases steeply with age, and approximately 60% of cases occur in patients ≥60 years. The overall 5-year survival rate is ~31% but is highly age-dependent: ~50–60% in younger patients (<60) with favorable-risk disease vs. <10% in older patients with adverse-risk disease. The 2022 WHO Classification and 2022 European LeukemiaNet (ELN) guidelines have fundamentally reclassified AML,…

Molecular Landscape & ELN Risk Stratification

The 2022 ELN risk stratification is the cornerstone of AML treatment planning: Favorable risk (~35% of AML): • t(8;21)(q22;q22.1); RUNX1-RUNX1T1 • inv(16)(p13.1q22) or t(16;16); CBFB-MYH11 • NPM1-mutated without FLT3-ITD • CEBPA biallelic mutations • Median OS >5 years; alloSCT not routinely recommended in CR1 for favorable-risk. Intermediate risk (~40% of AML): • NPM1-mutated with FLT3-ITD • Wildtype NPM1 without FLT3-ITD (no other adverse features) • t(9;11)(p21.3;q23.3); KMT2A-MLLT3 • FLT3-ITD allelic ratio ≥0.5 (high allelic burden — may trend adverse) • AlloSCT in CR1 recommended for…

Clinical Presentation & Diagnosis

AML presents acutely with symptoms reflecting bone marrow failure and leukostasis: Bone marrow failure symptoms (most common): • Anemia: Fatigue, dyspnea, pallor — from erythroid precursor displacement by blasts • Thrombocytopenia: Petechiae, easy bruising, mucosal bleeding, menorrhagia — hemorrhagic complications are major causes of early mortality • Neutropenia: Fever, infections — fungal and bacterial infections (Aspergillus, Pseudomonas, Staphylococcus) are major AML mortality drivers Leukostasis (occurs when WBC >50,000–100,000/μL from circulating blasts): • Pulmonary: Dyspnea,…

Treatment: Fit Patients (Intensive Chemotherapy)

Induction chemotherapy ("7+3"): • Cytarabine 100–200 mg/m² continuous infusion × 7 days + daunorubicin 60–90 mg/m² (or idarubicin 12 mg/m²) × 3 days. Achieves CR in ~60–80% of younger patients and ~40–60% of older fit patients. • CPX-351 (liposomal cytarabine:daunorubicin 5:1 molar ratio): Preferred over 7+3 for therapy-related AML and AML-MRC (CLASSIC I trial; improved OS 9.56 vs. 5.95 months). • Gemtuzumab ozogamicin (GO, anti-CD33 ADC): Added to 7+3 for CD33+ favorable- and intermediate-risk AML (ALFA-0701, AML19 trials); OS benefit in favorable and intermediate risk. FLT3-mutated AML:…

Treatment: Unfit Patients & Relapsed/Refractory AML

Venetoclax + azacitidine — the VIALE-A standard for unfit patients: • VIALE-A trial (DiNardo, NEJM 2020): Venetoclax (400 mg daily × 28 days) + azacitidine (75 mg/m² days 1–7) significantly improved OS (14.7 vs. 9.6 months) and CR rate (36.7% vs. 17.9%) vs. azacitidine alone in newly diagnosed AML ineligible for intensive chemotherapy. Now the standard of care for unfit patients. • Venetoclax + decitabine or low-dose cytarabine are alternatives. • Response rates are highest in NPM1-mutated and IDH1/2-mutated AML; lowest in TP53-mutated and FLT3-ITD-high AML. Targeted therapies for specific…