What is the recommended treatment strategy for acute myeloid leukemia, including induction, consolidation, and options for older or unfit patients?

Acute Myeloid Leukemia Treatment Strategy

Overview of Treatment Approach

For acute myeloid leukemia, treatment consists of intensive induction chemotherapy with cytarabine plus an anthracycline ("7+3" regimen), followed by risk-stratified consolidation therapy—with high-dose cytarabine for favorable-risk disease and allogeneic stem cell transplantation for intermediate and high-risk patients in first remission. 1

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Induction Chemotherapy

Standard Intensive Therapy (Age <65 and Fit Patients)

The backbone of induction is the "7+3" regimen: 2, 1, 3

• Cytarabine: 100-200 mg/m² continuous IV infusion for 7 consecutive days 2, 1, 3
• Anthracycline options: 2, 1, 3
  • Daunorubicin 60-90 mg/m² IV on days 1-3, OR
  • Idarubicin 12 mg/m² IV on days 1-3

Mutation-Specific Modifications to Induction

For FLT3-mutated AML (FLT3-ITD or FLT3-TKD): Add midostaurin 50 mg orally twice daily with food on days 8-21 of each induction cycle to standard 7+3 chemotherapy, which improved 4-year overall survival to 51.4%. 2, 3

For therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC): Consider CPX-351 [liposomal daunorubicin 29 mg/m² and cytarabine 65 mg/m²] instead of standard 7+3, as it showed superior median overall survival (10.25 vs 4.6 months in high-risk subgroups). 2

For CD33-positive non-core binding factor AML with favorable or intermediate ELN risk: Consider adding gemtuzumab ozogamicin (GO) to 7+3 in younger patients, which improved 6-year overall survival by 5.7% in intermediate-risk cytogenetics. 2

For ELN adverse-risk AML in patients ≤60 years: Consider adding cladribine or fludarabine to 7+3, or upfront FLAG-Ida (fludarabine, cytarabine, G-CSF, idarubicin) for 2 cycles, which improved relapse-free survival. 2

Response Assessment After Induction

Perform bone marrow assessment between day 14-21 after first induction cycle: 2

• If ≥5% blasts persist: Administer second induction cycle (either repeat same regimen or switch to intermediate-dose cytarabine-based regimen like FLAG-Ida) 2
• If <5% blasts (CR/CRi achieved): Proceed directly to consolidation therapy 2
• If no CR/CRi after 2 induction cycles: Patient is classified as primary refractory—consider clinical trial, low-intensity therapy, allogeneic transplant, or best supportive care 2

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Consolidation Therapy (Post-Remission)

Risk-Stratified Approach

The consolidation strategy is determined by ELN risk classification based on cytogenetics and molecular genetics: 2, 1

Favorable-Risk AML (e.g., CBF-AML, NPM1-mutated without FLT3-ITD, double-mutant CEBPA)

Consolidate with chemotherapy alone—allogeneic transplant is NOT indicated in first remission: 2, 1, 4

• Standard regimen: High-dose cytarabine (HIDAC) 1-3 g/m² IV every 12 hours on days 1,3,5 for 3-4 cycles 2, 1
• Alternative: Autologous stem cell transplant may be considered, which results in better relapse-free survival but not overall survival compared to chemotherapy alone 2
• For CBF-AML specifically: 3 cycles of intermediate-dose cytarabine are recommended, with optional addition of GO 3 mg/m² on day 1 of consolidation cycles 1 and 2 2

Intermediate-Risk and Adverse-Risk AML

Proceed to allogeneic stem cell transplantation in first complete remission if feasible: 2, 1, 4

• Donor hierarchy: HLA-identical sibling donor preferred, followed by matched unrelated donor 2, 1
• If no suitable donor available or transplant contraindicated: Consolidate with high-dose cytarabine chemotherapy or autologous transplant 2

Continuation of Targeted Therapy During Consolidation

For FLT3-mutated AML: Continue midostaurin 50 mg orally twice daily on days 8-21 of each consolidation cycle, then as maintenance for total 12 months of therapy. 3

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Treatment for Older or Unfit Patients

Age 60-74 Years

Fit patients in this age group with good performance status and no significant comorbidities should receive standard intensive "7+3" induction: 2

• Particularly beneficial for: Core binding factor AML (75% CR rate, 16% early death rate) and NPM1-mutated AML 2
• Consolidation: Multiple cycles of modest-dose or intermediate-dose cytarabine (1-2 g/m² every 12 hours for 6 doses per cycle, repeated every 4-6 weeks for 3-6 cycles total) 2, 3

Age ≥75 Years

Treatment selection depends critically on performance status, comorbidities, and cytogenetics: 2

Fit Patients (Performance Status 0-1, No Major Comorbidities)

With favorable cytogenetics (CBF-AML) or NPM1-mutated AML: Standard intensive "7+3" induction is reasonable, as these patients achieve 75% CR rates with only 16% early death rate. 2, 3

Consolidation for fit elderly patients: 3-6 cycles of intermediate-dose cytarabine 1-2 g/m² every 12 hours for 3 days per cycle. 3

Unfit Patients (Performance Status ≥2, Comorbidities, or Organ Dysfunction)

Low-intensity therapy is preferred over intensive chemotherapy: 2

• Hypomethylating agents (HMAs) plus venetoclax: This combination has revolutionized therapy for older adults and extends survival over monotherapy 2, 5, 6
• Low-dose cytarabine (LDAC): 20 mg subcutaneously twice daily for 10 days, which showed longer survival than hydroxyurea but with 26% 30-day mortality 2
• Venetoclax plus LDAC: Alternative low-intensity option 2
• Glasdegib plus LDAC: Another approved low-intensity combination 2

For IDH-mutated AML in unfit patients: 2

• Ivosidenib for IDH1-mutated disease
• Enasidenib for IDH2-mutated disease

For FLT3-mutated AML in unfit patients: Consider HMAs combined with sorafenib 2

Adverse Cytogenetics in Elderly

Low-dose cytarabine provides no benefit in patients with adverse cytogenetics—consider clinical trial, best supportive care, or HMA-based therapy instead. 2

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Response Assessment and Maintenance

After Lower-Intensity Therapy

Perform bone marrow assessment at 8-12 weeks to document remission status: 2

• If response achieved: Continue low-dose therapies until progression, or consider allogeneic transplant in select patients 2
• If no response or progression: Switch to clinical trial, therapies for relapsed/refractory disease, or best supportive care 2

After Intensive Therapy

Perform bone marrow assessment at 4-6 weeks after hematologic recovery: 2

• If CR achieved: Proceed to risk-stratified consolidation as outlined above 2
• If induction failure: Consider clinical trial, low-intensity therapy, allogeneic transplant (preferably in clinical trial context), or best supportive care 2

Maintenance Therapy

For patients who received HMAs during induction: Maintenance with HMAs or observation may be appropriate, as some patients maintain CR without further treatment. 2

For FLT3-mutated AML treated with midostaurin: Continue maintenance midostaurin for total 12 months from start of induction. 3

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Critical Pitfalls to Avoid

Age alone should never exclude intensive therapy: Patients age 75 or older with excellent performance status, no comorbidities, and favorable cytogenetics can achieve outcomes comparable to younger patients with standard intensive therapy. 2, 3

Do not underestimate early mortality risk: Even with careful patient selection, 26-30% of older patients may die during or shortly after induction with intensive therapy. 2, 3

Cytogenetics and molecular genetics are mandatory before treatment decisions: These determine whether intensive therapy is worthwhile—patients with adverse cytogenetics have poor outcomes even with intensive therapy and may benefit more from clinical trials or palliative approaches. 2, 1

Cardiac assessment is mandatory before anthracycline administration: Perform echocardiography in patients with cardiac risk factors or history of heart disease, as anthracycline cardiotoxicity is cumulative and potentially life-threatening. 1, 3

Do not abbreviate consolidation therapy: Six cycles of consolidation provide superior disease-free survival and overall survival compared to single-cycle consolidation in patients who can tolerate it. 3

Obtain HLA typing immediately at diagnosis: This identifies candidates for allogeneic transplantation and allows donor search to proceed during induction therapy. 1

Recognize that clinical trial results overestimate real-world effectiveness: Only a small, biased subset of older patients are enrolled in trials—population-based registries show 70% of Medicare beneficiaries ≥65 years do not receive intensive chemotherapy. 2