What is the management and prognosis of Acute Myeloid Leukemia (AML)?

Management and Prognosis of Acute Myeloid Leukemia

For newly diagnosed AML patients under 60 years, initiate intensive induction chemotherapy with 7 days of cytarabine plus 3 days of an anthracycline (the "7+3" regimen), which achieves complete remission in >85% of younger patients, followed by risk-stratified consolidation therapy including high-dose cytarabine or allogeneic stem cell transplantation based on cytogenetic risk. 1, 2

Initial Diagnostic Workup and Risk Stratification

Complete diagnostic evaluation must include:

• Peripheral blood and bone marrow examination with morphology, cytochemistry, and immunophenotyping 2
• Cytogenetic analysis of 20 metaphase cells to identify prognostic chromosomal abnormalities 1
• Molecular testing for FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53 mutations 3
• Cardiac assessment with echocardiography for patients with cardiac risk factors, as anthracycline cumulative doses >300 mg/m² carry significant cardiotoxicity risk 2

Risk stratification determines treatment intensity:

• Favorable risk: inv(16), t(16;16), or t(8;21) without KIT mutations 1
• Intermediate risk: Normal cytogenetics, NPM1 mutations without FLT3-ITD 1
• High risk: Complex karyotype (≥3 abnormalities), monosomal karyotype, TP53 mutations, FLT3-ITD with high allelic ratio 1, 3

Induction Therapy

Standard "7+3" induction consists of:

• Cytarabine 100-200 mg/m² continuous infusion for 7 days 1
• Daunorubicin 60-90 mg/m² or idarubicin 12 mg/m² on days 1-3 1, 2

For patients with FLT3 mutations, add midostaurin 50 mg twice daily on days 8-21 to standard induction. 3

Emergency management of hyperleukocytosis (WBC >100,000/μL):

• Initiate hydroxyurea 50-60 mg/kg/day immediately until WBC decreases to <10-20 × 10⁹/L 4
• Start aggressive hydration at 2.5-3 liters/m²/day with rasburicase to prevent tumor lysis syndrome 4
• Do not delay chemotherapy while attempting cytoreduction—coordinate leukapheresis with immediate chemotherapy start if leukostasis symptoms present 4
• Monitor electrolytes, BUN, creatinine, uric acid, and phosphate at least daily during active treatment 4

Response Assessment

Perform bone marrow evaluation:

• After hematological recovery from induction (typically day 14-21) 2
• Between days 28-35 if recovery is lacking 2
• Before each consolidation cycle 2

Complete remission (CR) requires:

• Bone marrow blasts <5% with normal cellularity 1
• Absolute neutrophil count ≥1,000/μL 1
• Platelet count ≥100,000/μL 1
• No extramedullary disease 1

Consolidation Therapy: Risk-Stratified Approach

For favorable-risk patients (<60 years):

• Administer 3-4 cycles of high-dose cytarabine 3 g/m² every 12 hours on days 1,3, and 5 1, 2
• Autologous stem cell transplantation is an option if allogeneic transplant not indicated 1

For intermediate-risk patients:

• Adults <40 years: Proceed to myeloablative allogeneic stem cell transplantation from HLA-compatible sibling in first complete remission 1
• Adults 40-55 years: Consider allogeneic transplantation if achieved CR only after second induction course 1
• Patients without donors: Autologous stem cell transplantation is preferred over chemotherapy alone 1

For high-risk patients:

• All patients <55 years: Myeloablative allogeneic stem cell transplantation from HLA-compatible sibling or matched unrelated donor in first CR 1, 2
• Patients ≤30 years without sibling donor: Proceed to unrelated donor transplantation 1
• Alternative donors (haploidentical, cord blood): Consider only when matched donor unavailable and disease urgency high 1

Management of Relapsed/Refractory AML

Prognostic assessment using validated scoring:

The European LeukemiaNet relapse prognostic index stratifies patients based on: 1

• Duration of first remission: ≥18 months (0 points), 7-18 months (3 points), ≤6 months (5 points)
• Cytogenetics at diagnosis: inv(16)/t(16;16) (0 points), t(8;21) (3 points), other (5 points)
• Prior transplantation: no (0 points), yes (2 points)
• Age at relapse: ≤35 years (0 points), 36-45 years (1 point), >45 years (2 points)

Favorable risk (0-6 points): 70% 1-year survival, 46% 5-year survival 1 Intermediate risk (7-9 points): 49% 1-year survival, 18% 5-year survival 1 Unfavorable risk (10-14 points): 16% 1-year survival, 4% 5-year survival 1

Salvage chemotherapy regimens:

For patients <60 years:

• High-dose cytarabine 3 g/m² every 12 hours on days 1,3,5,7 plus daunorubicin 50 mg/m² or idarubicin 10 mg/m² on days 2,4,6 1
• Alternative: Cytarabine 2-3 g/m² every 12 hours for 6 days as single agent 1

For patients ≥60 years (high-dose cytarabine contraindicated due to unacceptable toxicity):

• Mitoxantrone 10 mg/m²/day plus etoposide 100 mg/m²/day for 5 days 1, 5
• Gemtuzumab ozogamicin for CD33-positive disease, especially if first remission >6 months 1, 2
• Consider investigational agents for short first remissions 1

Post-salvage consolidation:

• Allogeneic stem cell transplantation is the preferred consolidation once second remission achieved 1
• Use HLA-identical sibling, matched unrelated donor, or alternative donor (cord blood, haploidentical) if no matched donor available 1
• Autologous transplantation is second-best option if allogeneic transplant not feasible 1

Treatment for Older/Unfit Patients

For patients ≥60 years or unfit for intensive chemotherapy:

• Azacitidine 75 mg/m² subcutaneously daily for 7 days every 28 days plus venetoclax has revolutionized therapy, extending survival over monotherapy 6, 7, 3
• Azacitidine monotherapy achieves overall response (CR+PR) of 15.7% with median survival of 24.5 months versus 15.0 months for conventional care (hazard ratio 0.58) 6
• Continue treatment until disease progression, relapse, or unacceptable toxicity 6
• 45% of transfusion-dependent patients become transfusion-independent with median duration of 13.0 months 6

Supportive care measures:

• Prophylaxis and management of tumor lysis syndrome 2
• Antimicrobial prophylaxis during neutropenia 2
• Red blood cell and platelet transfusions to maintain hemoglobin >7-8 g/dL and platelets >10,000/μL 1
• Erythroid and myeloid growth factors in selected cases 1

Prognosis

Overall survival by age and risk group:

• Younger patients (<60 years): 65% achieve remission, 25% achieve long-term cure with intensive chemotherapy alone 8
• With allogeneic transplantation in first CR: Cure rates increase to 40-60% for intermediate/high-risk patients 1
• Older patients (≥60 years): Median survival 24.5 months with azacitidine, 15.0 months with conventional care 6

Relapsed disease outcomes:

• Overall response rate to salvage chemotherapy: 25% (mitoxantrone-etoposide regimen) 5
• Median overall survival after relapse: 7.4 months 5
• Patients achieving CR2 and undergoing allogeneic transplant: 35.3 months median survival versus 16.8 months without transplant 5
• 4-week mortality with salvage therapy: 4%; 8-week mortality: 13% 5

Follow-Up After Treatment Completion

Monitoring schedule for patients in remission:

• Bone marrow morphology every 3 months for 24 months 2
• Differential blood counts every 3 months for 5 years 2
• Molecular MRD assessment every 3 months from bone marrow or every 4-6 weeks from peripheral blood for 24 months in patients with molecular markers 2

Critical pitfall: Serial bone marrow examinations in morphologic remission without molecular markers have uncertain value and cannot be generally recommended 1

Key Clinical Pitfalls to Avoid

• Never delay chemotherapy in hyperleukocytosis while correcting electrolytes—tumor lysis syndrome prevention requires concurrent aggressive hydration and rasburicase with immediate chemotherapy 4
• Do not use high-dose cytarabine salvage regimens in patients ≥60 years—unacceptably high toxicity risk mandates alternative regimens 1
• Monitor anthracycline cumulative dose carefully—doses >300 mg/m² carry significant cardiotoxicity risk 2
• Ensure adequate donor search early—matched unrelated donor identification takes time; initiate search at diagnosis for intermediate/high-risk patients 1
• Treatment must be conducted in centers with multidisciplinary expertise and adequate infrastructure—complex supportive care requirements mandate specialized centers 2