Acute Promyelocytic Leukemia (APL)

Background

• APL is an aggressive subtype of acute myeloid leukemia with a distinct cellular morphology and clinical presentation that may be associated with early death due to potentially fatal coagulopathy.
• APL comprises 10% of acute myeloid leukemia diagnoses, presents at median age 44 years, and may arise de novo or as the result of chemotherapy.
• APL is typically characterized by chromosomal translocation t(15;17)(q22;q12), which produces a PML-RARA fusion gene, although other variant translocations have been reported, including the most common variant t(11;17)(q23;q12).
• The characteristic fusion gene PML-RARA produces a protein that suppresses signaling by all-trans retinoic acid, preventing differentiation of myeloid cells.
• Risk factors for the development of therapy-related APL include the use of topoisomerase II-targeted drugs for malignant and nonmalignant diseases, especially epirubicin and mitoxantrone.

Evaluation

• Perform the following workup
  • complete blood count with platelets, differential, and chemistry profile
  • assess cardiac function due to high cumulative doses of cardiotoxic agents used in treatment
  • prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen
  • human leukocyte antigen (HLA) typing to identify sibling or unrelated donor (unless patient has major contraindication to hematopoietic stem cell transplant)
  • peripheral blood films
  • bone marrow aspiration with cytogenetics, immunophenotyping, cytochemistry, and molecular analyses
• Other testing for select patients may include
  • computed tomography (CT) or magnetic resonance imaging (MRI) if neurologic symptoms
  • lumbar puncture if major neurologic signs of symptoms are present, or in cases of persistent symptoms after excluding bleeding and masses/lesions on imaging studies
  • G6PD testing in the event that rasburicase will be needed for tumor lysis syndrome

Management

• When APL is first suspected, treat the disease as a medical emergency and initiate all-trans retinoic acid (ATRA) immediately (Strong recommendation).
• Confirm the diagnosis by molecular detection of PML-RARA fusion (or rare molecular variants) after starting empiric therapy (Strong recommendation).
• All patients should be considered for enrollment in a clinical trial (Strong recommendation).
• For induction therapy
  • Offer ATRA plus anthracycline-based chemotherapy, unless the patient is unable to tolerate anthracyclines or patient has low or intermediate risk disease (Strong recommendation).
  • Consider ATRA plus arsenic trioxide (ATO) as an alternative to ATRA plus chemotherapy or for patients:
    • who are unable to tolerate anthracyclines (Weak recommendation)
    • with white blood cell count ≤ 10,000/mcL and low or intermediate risk disease (Weak recommendation)
• For consolidation therapy:
  • offer 2-3 anthracycline-containing chemotherapy cycles (Strong recommendation)
  • consider arsenic trioxide followed by ATRA with or without anthracycline-based chemotherapy as an alternative treatment (Weak recommendation)
• Perform a response assessment after consolidation therapy to confirm molecular remission and assess need for maintenance therapy (Strong recommendation).
• For relapsed disease:
  • In patients with first relapse, offering ATO-based treatment is recommended, with specific regimen depending on duration of first remission and prior exposure to ATO (Strong recommendation).
  • In patients with second relapse or who are at high risk of later additional relapses, consider hematopoietic stem cell transplant if patient is a candidate, otherwise consider arsenic trioxide (Weak recommendation).
• At first signs or symptoms of APL differentiation syndrome, start dexamethasone 10 mg IV twice daily for 3-5 days with taper over 2 weeks and consider interrupting all-trans retinoic acid (ATRA) therapy until hypoxia resolves (Strong recommendation).