What is the initial treatment for Acute Myeloid Leukemia (AML)?

Initial Treatment for Acute Myeloid Leukemia (AML)

The initial treatment for AML depends critically on patient fitness and molecular/cytogenetic risk stratification, with fit patients receiving intensive induction chemotherapy consisting of cytarabine plus an anthracycline (7+3 regimen), often enhanced with targeted agents based on specific mutations, while unfit or elderly patients receive lower-intensity therapy with hypomethylating agents combined with venetoclax. 1, 2

Immediate Pre-Treatment Decisions

Before initiating therapy, several urgent clinical scenarios require immediate intervention:

• For suspected acute promyelocytic leukemia (APL), start all-trans retinoic acid (ATRA) immediately without waiting for confirmatory molecular/cytogenetic results to prevent fatal coagulopathy 3
• For hyperleukocytosis (WBC >100 × 10⁹/L), administer cytoreduction with hydroxycarbamide 50-60 mg/kg/day, or intravenous cytarabine or daunorubicin to prevent leukostasis and tumor lysis syndrome 3, 1, 2
• Avoid leukapheresis in APL as it exacerbates coagulopathy; in non-APL AML, leukapheresis does not reduce early mortality and is not generally recommended 3
• For CNS involvement, administer intrathecal cytarabine twice weekly until blast clearance from cerebrospinal fluid, but delay in APL patients until coagulopathy resolves 3, 1

Risk Stratification Before Treatment Selection

Cytogenetic and molecular testing must guide treatment decisions 1, 2:

Favorable risk:

• Core binding factor (CBF) AML: t(8;21) or inv(16)/t(16;16) 1, 4
• NPM1-mutated without FLT3-ITD 1, 2
• Biallelic CEBPA mutations 1, 2

Intermediate risk:

• Normal karyotype without favorable mutations 1, 2

Adverse risk:

• Complex karyotype (≥3 abnormalities) 1, 4
• Monosomy 5/del(5q), monosomy 7/del(7q) 1, 2
• FLT3-ITD mutations 1, 2
• Therapy-related AML or AML with myelodysplasia-related changes 1, 2

Induction Therapy for Fit Patients

Standard 7+3 Backbone

The foundation remains cytarabine 100-200 mg/m²/day continuous infusion for 7 days with daunorubicin 60-90 mg/m² or idarubicin 10-12 mg/m²/day for 3 days 3, 1, 2. However, standard 7+3 alone is now considered undertreatment for most patients, as adding targeted agents improves outcomes 5.

Mutation-Specific Enhancements

For FLT3-mutated AML (any risk category):

• Add midostaurin 50 mg twice daily on days 8-21 to standard 7+3, which improves 4-year overall survival by 7.1% to 51.4% 1, 2

For CD33-positive CBF-AML:

• Use 7+3 plus gemtuzumab ozogamicin (GO) 3 mg/m² on days 1,4, and 7, which improves 6-year overall survival by 20.7% to 75.5% 3, 1, 2
• Critical pitfall: Maintain at least 2 months between last GO dose and allogeneic transplantation to reduce sinusoidal obstruction syndrome risk 1

For therapy-related AML or AML with myelodysplasia-related changes in patients ≥60 years:

• Use CPX-351 (liposomal daunorubicin 29 mg/m² and cytarabine 65 mg/m²), which improves 2-year overall survival by 18.8% to 31.1% compared to standard 7+3 1, 2
• This represents a paradigm shift for this high-risk population 6

For younger CD33-positive patients with favorable or intermediate risk:

• Consider adding GO to 7+3, which improves 6-year overall survival by 5.7% in intermediate-risk cytogenetics 1

APL-Specific Induction

APL requires ATRA in addition to anthracycline-based chemotherapy 3. Arsenic trioxide can induce remission in relapsed/refractory APL 3.

Treatment for Older or Unfit Patients

For patients ineligible for intensive chemotherapy (poor performance status, significant comorbidities):

• Hypomethylating agents (azacitidine or decitabine) combined with venetoclax has revolutionized therapy in older adults and extends survival over monotherapy 2, 4
• Alternative options include low-dose cytarabine with or without targeted agents 3, 1, 2
• Best supportive care alone for those with very poor performance status 3, 4

The evidence strongly favors venetoclax combinations over hypomethylating agents alone in this population 2.

Post-Induction Assessment

• Perform bone marrow assessment 14-21 days after induction to evaluate early response 1, 2
• Assess for complete remission (CR) after 4-6 weeks following hematologic recovery 2
• CR criteria: Normal bone marrow cellularity with <5% blasts and recovery of normal hematopoiesis 3
• Measure measurable residual disease (MRD) after 2 cycles of chemotherapy and at end of treatment 1, 2

Consolidation Strategy (Risk-Adapted)

Favorable risk patients:

• Administer 3-4 cycles of high-dose cytarabine consolidation 3, 1, 2
• Allogeneic transplantation is NOT justified in first remission as transplant-related mortality exceeds benefit in this group with ≤35% relapse risk 2

Intermediate risk patients:

• Proceed to allogeneic hematopoietic cell transplantation with HLA-matched sibling or unrelated donor if available 1, 2, 4
• If transplant not feasible, administer high-dose cytarabine 1, 2

Adverse risk patients:

• Allogeneic transplantation is the only curative option and should be pursued with HLA-matched sibling or unrelated donor if age and performance status permit 1, 2, 4
• Candidates should be identified early during induction 3

Critical Treatment Infrastructure Requirements

Treatment should occur in centers with 3, 4:

• Full hematology and medical oncology service
• Close collaboration with bone marrow transplant unit
• Infectious disease service
• Adequate transfusion service
• Multidisciplinary approach

Common Pitfalls to Avoid

• Delaying ATRA in suspected APL while awaiting confirmatory testing can be fatal 3
• Using leukapheresis in APL worsens coagulopathy 3
• Administering GO too close to transplant (<2 months) increases sinusoidal obstruction syndrome risk 1
• Postponing chemotherapy before diagnostic material is obtained compromises accurate classification 3
• Failing to identify transplant candidates early during induction delays optimal consolidation 3
• Treating favorable-risk patients with allogeneic transplant in first remission increases mortality without benefit 2