Overview of AML Treatment
Acute myeloid leukemia is characterized by clonal proliferation of myeloid blasts in the bone marrow, peripheral blood, and occasionally other tissues. Treatment has been revolutionized over the past decade with FDA approval of multiple targeted agents based on molecular profiling, including FLT3 inhibitors, IDH1/2 inhibitors, BCL-2 inhibitors, and CD33-directed therapies. The standard "7+3" induction chemotherapy (cytarabine and anthracycline) remains backbone therapy for fit patients, while lower-intensity regimens with venetoclax have transformed outcomes for older and unfit patients.
AML Treatment Approaches by Patient Population
Fit Patients (Age <60-65, Good PS)
- Intensive induction: 7+3 (cytarabine + daunorubicin or idarubicin)
- FLT3 inhibitor (midostaurin, gilteritinib) for FLT3-mutated AML
- Consolidation: High-dose cytarabine or allogeneic stem cell transplant
- CPX-351 (liposomal daunorubicin/cytarabine) for therapy-related or MDS-related AML
Unfit/Elderly Patients (Age ≥75 or Significant Comorbidities)
- Venetoclax + hypomethylating agent (azacitidine or decitabine) - new standard
- Venetoclax + low-dose cytarabine (LDAC)
- Glasdegib + LDAC
- Hypomethylating agents alone
Relapsed/Refractory Disease
- Gilteritinib for FLT3-mutated R/R AML
- Ivosidenib for IDH1-mutated R/R AML
- Enasidenib for IDH2-mutated R/R AML
- Gemtuzumab ozogamicin (GO) for CD33+ disease
- Salvage chemotherapy or clinical trial followed by allogeneic transplant if feasible
Epidemiology & Impact
Acute myeloid leukemia (AML) is predominantly a disease of older adults, with a median age at diagnosis of 68 years. Approximately 21,800 new cases are expected in the United States in 2025, making it the most common acute leukemia in adults. The disease accounts for roughly 1.1% of all new cancer diagnoses but carries a disproportionate mortality burden due to its aggressive nature and the challenges of treating elderly patients with significant comorbidities. Incidence rates are higher in men than women and in White compared to other racial groups. Known risk factors include prior chemotherapy or radiation (therapy-related AML), antecedent myelodysplastic syndromes, chronic exposure to benzene, and certain germline predisposition syndromes including Fanconi anemia and Down syndrome. Despite advances in treatment, overall 5-year survival remains approximately 32%, though outcomes vary dramatically by age and molecular subtype.
Molecular Biology & Biomarkers
AML is now understood as a molecularly heterogeneous disease, and the 2022 WHO classification recognizes over 20 subtypes defined by specific genetic alterations. The most clinically actionable mutations include FLT3-ITD (present in approximately 25% of cases), IDH1/IDH2 (15-20%), and NPM1 (25-30%). FLT3 internal tandem duplications confer adverse prognosis but are targetable with midostaurin (in combination with induction chemotherapy) and gilteritinib (in relapsed/refractory disease). IDH1 and IDH2 mutations produce an oncometabolite (2-hydroxyglutarate) that blocks myeloid differentiation and are targeted by ivosidenib and enasidenib respectively. The favorable-risk category includes NPM1-mutated AML without FLT3-ITD, biallelic CEBPA mutations, and core-binding factor AML with t(8;21) or inv(16). Adverse-risk features include TP53 mutations, complex karyotype, and monosomal karyotype. Measurable residual disease monitoring by multiparameter flow cytometry or molecular methods is increasingly used to guide post-remission therapy decisions.
Evolving Treatment Landscape
The AML treatment landscape has undergone a renaissance since 2017, with over a dozen new FDA approvals transforming management. For younger fit patients, intensive induction with cytarabine and daunorubicin ("7+3") remains standard, now augmented by midostaurin for FLT3-mutated disease based on the RATIFY trial. Venetoclax combined with azacitidine has become the standard of care for older or unfit patients, based on the VIALE-A trial which demonstrated a median overall survival of 14.7 months versus 9.6 months for azacitidine alone. Targeted agents for IDH1 (ivosidenib), IDH2 (enasidenib), FLT3 (gilteritinib), and the hedgehog pathway (glasdegib) have provided new options across treatment lines. Gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, has been reapproved for CD33-positive AML. The ongoing challenge is extending the survival gains seen in younger patients to the elderly population, where the disease is most common and outcomes remain poor.
Approved AML Therapies
Approved Indications (US/FDA)
Treatment of newly diagnosed AML in adults age 75 years or older, or who have comorbidities that preclude intensive induction chemotherapy, in combination with azacitidine, or decitabine, or low-dose cytarabine.
Dosing Schedule
Ramp-up Phase (Days 1-3): 100 mg PO on Day 1, 200 mg on Day 2, 400 mg on Day 3
Maintenance: 400 mg PO once daily from Day 4 onwards
With Azacitidine: Venetoclax 400 mg PO daily × 28 days + azacitidine 75 mg/m² SC/IV days 1-7 of each 28-day cycle
With Decitabine: Venetoclax 400 mg PO daily × 28 days + decitabine 20 mg/m² IV days 1-5 of each 28-day cycle
With LDAC: Venetoclax 600 mg PO daily × 28 days + cytarabine 20 mg/m² SC days 1-10 of each 28-day cycle
Cycle Length
28-day cycles, continue until disease progression or unacceptable toxicity
Clinical Evidence
VIALE-A trial: Venetoclax + azacitidine achieved 66.4% CR/CRi vs 28.3% with placebo + azacitidine. Median OS improved from 9.6 to 14.7 months (HR 0.66, p<0.001). VIALE-C trial: Venetoclax + LDAC showed 48% CR/CRi vs 13% with placebo + LDAC. Venetoclax is a selective BCL-2 inhibitor that restores apoptosis in AML cells. Major adverse events include myelosuppression and tumor lysis syndrome (requires hospitalization for first doses in high-risk patients).
Approved Indications (US/FDA)
Treatment of adult patients with relapsed or refractory AML with a FLT3 mutation as detected by an FDA-approved test.
Dosing Schedule
120 mg orally once daily until disease progression or unacceptable toxicity. Take with or without food at approximately the same time each day.
Clinical Evidence
ADMIRAL trial: Gilteritinib monotherapy achieved significantly improved median OS (9.3 vs 5.6 months, HR 0.64, p<0.001) compared to salvage chemotherapy in R/R FLT3-mutated AML. CR/CRh rate was 34% vs 15.3%. Gilteritinib is a potent, selective FLT3/AXL inhibitor effective against both FLT3-ITD and FLT3-TKD mutations. Main adverse events include differentiation syndrome, elevated liver enzymes, and QTc prolongation.
Approved Indications (US/FDA)
Treatment of adult patients with newly diagnosed AML that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
Dosing Schedule
Induction: 50 mg PO twice daily on days 8-21 of each cycle with standard 7+3 (cytarabine 100-200 mg/m² continuous IV days 1-7 + daunorubicin 60 mg/m² IV days 1-3)
Consolidation: 50 mg PO twice daily on days 8-21 of each cycle with high-dose cytarabine 3 g/m² IV every 12 hours on days 1, 3, 5
Maintenance: 50 mg PO twice daily continuously for up to 12 cycles (each cycle 28 days)
Clinical Evidence
RATIFY trial: Adding midostaurin to standard 7+3 induction and consolidation improved median OS from 25.6 to 74.7 months (HR 0.78, p=0.009) in FLT3-mutated newly diagnosed AML. Event-free survival also significantly improved. Midostaurin is a multi-kinase inhibitor targeting FLT3, KIT, and PKC. This was the first trial to demonstrate survival benefit with targeted therapy added to chemotherapy in AML.
Approved Indications (US/FDA)
Treatment of adult patients with newly diagnosed AML with a susceptible IDH1 mutation who are ≥75 years old or who have comorbidities that preclude intensive chemotherapy; Treatment of adult patients with relapsed or refractory AML with a susceptible IDH1 mutation.
Dosing Schedule
500 mg orally once daily with or without food until disease progression or unacceptable toxicity. May combine with azacitidine 75 mg/m² SC/IV days 1-7 of 28-day cycles in frontline setting.
Clinical Evidence
AGILE trial: Ivosidenib + azacitidine showed superior outcomes vs placebo + azacitidine in newly diagnosed IDH1-mutated AML ineligible for intensive chemotherapy (median OS not reached vs 7.9 months). Single-agent ivosidenib achieved 30.4% CR rate in R/R setting. Ivosidenib is a first-in-class oral IDH1 inhibitor that reduces oncometabolite 2-HG and promotes myeloid differentiation. Differentiation syndrome is a key adverse event requiring monitoring.
Approved Indications (US/FDA)
Treatment of adult patients with relapsed or refractory AML with an IDH2 mutation as detected by an FDA-approved test.
Dosing Schedule
100 mg orally once daily with or without food until disease progression or unacceptable toxicity. Continue for at least 6 months to allow time for clinical response.
Clinical Evidence
Phase 1/2 trial demonstrated 23% overall response rate in heavily pretreated R/R AML with IDH2 mutations. Median response duration was 8.2 months and median OS was 8.8 months. Enasidenib inhibits mutant IDH2, leading to decreased 2-HG and restoration of normal cellular differentiation. Unlike traditional cytotoxic agents, responses may be delayed and bone marrow blast clearance can take several months. Main adverse events include indirect hyperbilirubinemia and differentiation syndrome.
Approved Indications (US/FDA)
Treatment of newly diagnosed CD33-positive AML in adults; Treatment of relapsed or refractory CD33-positive AML in adults and pediatric patients 2 years and older.
Dosing Schedule
Newly Diagnosed (Combination): 3 mg/m² IV on Days 1, 4, and 7 during induction, then Day 1 of each consolidation cycle
R/R (Monotherapy): 3 mg/m² IV on Days 1, 4, and 7 (may extend to Day 8 if Day 7 not feasible). May repeat after ≥2 weeks from prior dose
Clinical Evidence
ALFA-0701 trial: Adding gemtuzumab to standard 7+3 improved event-free survival and overall survival in newly diagnosed AML, particularly in favorable/intermediate cytogenetics. Mylotarg is an antibody-drug conjugate consisting of anti-CD33 antibody linked to calicheamicin, a cytotoxic agent. Originally approved in 2000, withdrawn in 2010, then re-approved in 2017 with fractionated dosing schedule showing better safety profile. Main adverse events include hepatotoxicity, veno-occlusive disease (VOD), and myelosuppression.
Approved Indications (US/FDA)
Treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).
Dosing Schedule
Induction: First induction: 44 units/m² (daunorubicin 44 mg/m² + cytarabine 100 mg/m²) IV over 90 minutes on days 1, 3, and 5. Second induction if needed: Same dose on days 1 and 3
Consolidation: 29 units/m² IV over 90 minutes on days 1 and 3 (up to 2 cycles)
Clinical Evidence
Phase 3 trial showed CPX-351 significantly improved median OS (9.6 vs 5.9 months, HR 0.69, p=0.005) and higher rate of allogeneic transplant (34% vs 25%) compared to standard 7+3 in t-AML and AML-MRC. The liposomal formulation delivers daunorubicin and cytarabine in synergistic 1:5 molar ratio with prolonged exposure. Particularly beneficial in high-risk AML subtypes with poor prognosis to standard therapy.