Contents
Subset of acute myeloid leukemia characterized by the fusion gene transcript PML-RAR-α and is now the most frequently curable acute leukemia in adults if promptly diagnosed and adequately treated.
- MEDICAL EMERGENCY (with very high pre-treatment mortality)
- Most curable subtype of all the acute myeloid leukaemias (AML)
- 7-8% of adult AML cases
- Seen in middle-aged people with a median age of 47 years

History
First described in 1957 in patients with severe bleeding tendencies with fibrinolysis, rapid deterioration of the clinical condition, and the presence of promyelocytes in peripheral blood and bone marrow.
Pathophysiology
Morphologically:
- AML-M3 (French-American-British (FAB) classification)
Cytogenetically:
Balanced reciprocal translocation
t (15:17) PML/RARα gene (90% cases)
(Promyelocytic leukaemia gene (17) + Retinoic acid receptor α (RARα) gene (15))
↓
PML/RARα protein heterodimerizes with the retinoid X receptor (RXR)
↓
PML/RARα-RXR complex
binds to
retinoic acid-responsive elements in target genes
↓
Cessation of myeloid differentiation at promyelocytic stage
↓
Procoagulant state
(excessive promyelocytes express tissue factor (TF) which forms a complex with factor VII and activates factor X and IX)
&
Immunosuppression
(immature promyelocytes also cannot build
defenses against infections)
Presentation
- Generalized weakness & fatigue (anaemia)
- Bleeding occurrence:
- Gingival bleeding, petechiae or ecchymoses
- Visual changes (secondary to retinal hemorrhages)
- Epistaxis
- Menorrhagia
- Infections
Complications:
- Disseminated intravascular coagulation (DIC) (life threatening)
- Frank bleeding
Diagnosis
Coagulopathy workup:
- Platelet count
- Prothrombin time (PT), activated partial thromboplastin time (PTT)
- d-dimer or fibrin split products
- Fibrinogen
Peripheral blood smear (PBS):
- Large atypical promyelocytes and other myeloid precursors (in various stages of development) (CHARACTERISTIC)

Immunophenotyping (flow cytometry):
- Unique immunophenotypic profile (CD34- CD117+ HLA-DR-) with characteristic CD11b and CD11c negativity
Gene testing:
- Fluorescence in situ hybridization (FISH): Fusion of PML/RARA should be expedited for rapid diagnosis of this time-sensitive disease
- Conventional karyotyping: Detects rare molecular subtypes of APL and other additional coexistent cytogenetic abnormalities
- Reverse transcriptase polymerase chain reaction (RT-PCR) (for PML-RARA RNA): For confirming the diagnosis of APL and can also be used can for monitoring minimal residual disease

Risk stratification:
- Low-risk (WBC ≤ 10,000/µl & platelets ≥ 40,000/µl)
- Intermediate-risk (WBC ≤ 10,000/µl & platelets ≤ 40,000/µl)
- High-risk (WBC > 10,000/microL)
Bone marrow biopsy:
- Hypercellular bone marrow
- APL promyelocytes: 30% myeloid cells (classic variant)

Management
All-trans retinoic acid (ATRA; tretinoin) therapy:
ATRA (acid form of vitamin A) does not directly kill the malignant cells but induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own.

- Initial therapy:
- ATRA-ATO regimen: ATRA (45 mg⁄m2⁄ day orally for 45–90 days) + anthracycline chemotherapy (for induction)
- ATRA-ATO regimen: ATRA (45 mg⁄m2⁄ day orally for 45–90 days) + anthracycline chemotherapy (for induction)
- Maintainance therapy:
- Maintenance chemotherapy with methotrexate, mercaptopurine and ATRA (2 years)
- Relapsed/refractory diseases:
- Arsenic trioxide (As2O3)
- Complications:
- Differentiation syndrome “Retinoic acid syndrome”
Supportive treatment:
- High suspicion for infections and appropriate management
Prognosis
Poor prognostic factors:
- Older age
- ↑ WBC
- ↓ Platelets
- CD56 expression