What is Acute Promyelocytic Leukemia (APL)?

Acute Promyelocytic Leukemia (APL)

Acute Promyelocytic Leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by the PML-RARA fusion gene resulting from the t(15;17) chromosomal translocation, which is highly curable with current treatments combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

Definition and Epidemiology

• APL constitutes approximately 10% of all AML cases with an age-adjusted annual incidence of 0.23 per 100,000 persons 1
• The median age at diagnosis is 44 years, which is younger than the median age of 67 years for other AML subtypes 1
• APL is distinguished cytogenetically by the presence of the translocation t(15;17)(q24.1;q21.1), which creates the PML-RARA fusion gene 1

Clinical Presentation and Diagnosis

Clinical Features

• APL is considered a medical emergency due to the high risk of life-threatening hemorrhage from severe coagulopathy 1
• Patients may present with:
  • Peripheral blood cytopenias
  • Hyperleukocytosis (less common)
  • Severe coagulopathy with bleeding manifestations 1

Diagnostic Workup

• Bone marrow aspirate is essential for diagnosis 1
• Morphologic features typically show abnormal promyelocytes with:
  • Hypergranular (typical) or microgranular (variant) forms
  • Positive myeloperoxidase or Sudan black B stains 1
• Immunophenotyping shows characteristic features:
  • CD34-/+ heterogeneous, CD117-/+ dim, HLADR-/+ dim
  • CD13+/++, CD11b+
  • Abnormally low levels of CD15 (CD15-/+ dim) 1
• Genetic confirmation is mandatory and can be performed by:
  • Conventional karyotyping
  • Fluorescence in situ hybridization (FISH)
  • Reverse transcriptase polymerase chain reaction (RT-PCR)
  • Anti-PML monoclonal antibodies 1

Risk Stratification

• Risk stratification is based primarily on white blood cell (WBC) count 1:
  • Low-risk: WBC count ≤10,000/mcL
  • Intermediate-risk: WBC count ≤10,000/mcL (often grouped with low-risk)
  • High-risk: WBC count >10,000/mcL 1

Treatment Approach

Initial Management

• ATRA should be started immediately upon clinical suspicion of APL, even before genetic confirmation 1
• Aggressive supportive care to manage coagulopathy is critical to prevent early hemorrhagic death 1

Induction Therapy

• Standard induction regimens combine ATRA with anthracycline-based chemotherapy 1
• ATRA is administered at 45 mg/m² daily in adults (25 mg/m² daily in children) 1, 2
• Complete remission rates exceed 90% with ATRA-based induction regimens 1

Consolidation Therapy

• Risk-adapted approaches are used for consolidation 1:
  • Low/intermediate-risk patients may receive less intensive consolidation
  • High-risk patients typically receive more intensive therapy, often including cytarabine 1
• ATRA combined with anthracyclines, with or without cytarabine, is commonly used 1

Maintenance Therapy

• ATRA-based maintenance therapy is generally recommended 1
• With current treatment approaches, more than 80% of APL patients can be cured 1

Novel Approaches

• Arsenic trioxide (ATO) has shown high efficacy in relapsed APL and is now incorporated into frontline regimens 3, 4
• For relapsed APL, ATO is considered the best treatment option 3, 5
• Chemotherapy-free regimens combining ATRA and ATO are now available for low-risk patients 4

Monitoring and Follow-up

• Molecular monitoring for PML-RARA fusion transcript using RT-PCR is essential during remission 1, 5
• Persistent molecular positivity or reappearance of the fusion transcript strongly predicts clinical relapse 5, 6

Complications and Management

Differentiation Syndrome

• Occurs in approximately 10% of patients treated with ATRA or ATO 1, 3
• Characterized by fever, weight gain, respiratory distress, pleural and pericardial effusions 3
• Management includes immediate high-dose corticosteroids and temporary discontinuation of ATRA/ATO if severe 3

Cardiac Complications

• ATO can cause QTc interval prolongation and arrhythmias 3
• Requires baseline ECG and electrolyte monitoring during treatment 3

Pseudotumor Cerebri

• More common in children (11%) receiving ATRA 1
• Can be managed with steroids and dose reduction if necessary 1

Prognosis

• With current treatment strategies, APL has transformed from one of the most fatal forms of acute leukemia to the most curable form of AML 5, 4
• Long-term disease-free survival and potential cure rates of 70-80% can be expected 5, 7
• Early death from hemorrhage remains the primary cause of treatment failure 1