What is the recommended initial treatment for acute promyelocytic leukemia, including risk‑stratified therapy based on presenting white‑blood‑cell count?

Acute Promyelocytic Leukemia (APL) Initial Treatment

For non-high-risk APL patients (WBC <10 × 10⁹/L), treat with arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) without chemotherapy; for high-risk patients (WBC ≥10 × 10⁹/L), add an anthracycline to ATRA plus ATO, or use ATRA plus anthracycline-based chemotherapy (AIDA regimen). 1

Risk Stratification

Risk classification is determined solely by presenting white blood cell count:

• Non-high-risk (low/intermediate): WBC <10 × 10⁹/L 1
• High-risk: WBC ≥10 × 10⁹/L 1

Treatment by Risk Category

Non-High-Risk Patients (WBC <10 × 10⁹/L)

Induction therapy:

• ATRA 45 mg/m² orally in two divided doses daily until day 28, or up to day 60 if complete remission (CR) is not achieved by day 28 1
• ATO 0.15 mg/kg IV daily until day 28, or up to day 60 if CR is not achieved by day 28 1
• Missed doses due to adverse events should be appended to the treatment schedule 1

Consolidation therapy:

• Four 8-week consolidation cycles with ATO/ATRA after count recovery 1
• This regimen provides excellent cure rates without requiring maintenance therapy 1

Alternative if ATO unavailable:

• ATRA plus anthracycline-based chemotherapy (e.g., AIDA regimen with idarubicin) is acceptable but requires 2-year maintenance with methotrexate and 6-mercaptopurine 1

High-Risk Patients (WBC ≥10 × 10⁹/L)

Two acceptable approaches:

Option 1 (preferred when available):

• ATRA 45 mg/m² orally in two divided doses daily 1
• ATO 0.15 mg/kg IV daily (note: ATO is not formally approved for high-risk APL) 1
• Plus an anthracycline (idarubicin during induction) 1
• Followed by ATRA/ATO consolidation and 2-year maintenance with ATRA, 6-mercaptopurine, and methotrexate 1

Option 2 (conventional):

• ATRA plus anthracycline-based chemotherapy (AIDA regimen: ATRA and idarubicin) 1
• Followed by anthracycline-based consolidation and 2-year maintenance 1

Critical Management Principles

Immediate Initiation

• Start ATRA 45 mg/m² immediately upon clinical suspicion of APL without waiting for genetic confirmation to prevent lethal hemorrhagic complications 1, 2
• If cytogenetic and molecular testing do not confirm APL, discontinue ATRA and treat as conventional AML 1, 2

Prevention of Life-Threatening Complications

Differentiation syndrome prophylaxis:

• Prophylactic corticosteroids (prednisolone 0.5 mg/kg/day) should be started as soon as ATRA is initiated 1
• Hydroxycarbamide should be added when WBC rises above 5-10 × 10⁹/L 1

Coagulopathy management:

• Maintain platelets ≥30-50 × 10⁹/L through transfusions 1
• Maintain fibrinogen ≥1.0-1.5 g/L with fresh-frozen plasma or cryoprecipitate 1
• Bleeding is the most frequent cause of early death in APL patients 1

Treatment Consistency

• Use one complete regimen consistently through all phases—do not mix induction from one protocol with consolidation from another 1, 2
• This principle is critical to achieving the excellent outcomes reported in clinical trials 1, 2

Response Assessment

Avoid premature evaluation:

• Do not perform bone marrow assessment at day 10-14, as it can be misleading 1, 2
• Patients often remain molecularly positive at the end of induction despite morphologic remission 1, 2
• The first molecular remission assessment should be performed after consolidation therapy 1, 2

Timing of marrow evaluation:

• Repeat bone marrow assessment only after hematological recovery for non-high-risk patients on ATO/ATRA 1
• Nearly all patients will achieve CR with this regimen 1

Special Considerations

Centralization of care:

• APL patients should be treated in hospitals with proven experience in APL management and hematological intensive care 1

Therapy-related APL:

• Treat the same as de novo APL 1

Evidence strength:

• The ATO/ATRA regimen for non-high-risk patients has Level I, Grade A evidence from the 2020 ESMO guidelines 1
• High-risk treatment options have Level II, Grade A evidence 1
• Real-world data confirm excellent long-term outcomes with 5-year overall survival of 80-93% using ATO/ATRA without chemotherapy across all risk groups 3

Common Pitfalls

• Do not delay ATRA initiation while awaiting molecular confirmation—early hemorrhagic death is preventable 1, 2
• Do not omit prophylactic steroids in patients receiving ATRA, as differentiation syndrome can be fatal 1
• Do not under-transfuse platelets and fibrinogen—aggressive coagulopathy correction is essential 1
• Do not assess molecular remission prematurely—wait until after consolidation 1, 2