DEFINITION
- Sub-type of acute myeloid leukemia (AML), classified as variant M3 under the French-American-British (FAB) classification.
- Malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid line and an excess of immature, abnormal, heavily granulated cells called promyelocytes.
- Results in the accumulation of these atypical promyelocytes in the bone marrow and peripheral blood, and replaces normal blood cells.
EPIDEMIOLOGY
- APL represents 5-10% of AML in adults.
- APL represents 5-15% of AML in children.
- The median age is approximately 40 years, which is considerably younger than the other subtypes of AML (70 years).
- The incidence is increased in patients originated in Latin American countries.
0,6 case/1.000.000/year
SIGNS AND SYMPTOMS
- Signs and symptoms of acute promyelocytic leukemia are similar to other forms of AML.
- The accumulation of promyelocytes in the bone marrow results in a reduction in the production of normal red blood cells and platelets resulting in anemia and thrombocytopenia.
Either leukopenia or leukocytosis may be observed in the peripheral blood.
There is usually pancytopenia and patients with APL may therefore receive transfusions.
- The signs and symptoms are generalized and include:
- Fatigue, palor, weight loss or loss of appetite, weakness, shortness of breath with exertion (from anemia)
- Easy bruising and bleeding, slow healing of cuts, petechiae, small ecchymosis, epistaxis, bleeding in the mouth, bleeding from the gums, hematuria, bleeding from venipuncture and bone marrow sites, menometrorrhagia (from thrombocytopenia and coagulopathy)
- Mild fever, swollen glands and persistent or frequent minor infections (from leukopenia)
- Discomfort in bones or joints. Some patients with APL may have bone pain or joint pain caused by the spread of leukemic cells to the surface of the bone or into the joint from the marrow cavity. When leukemia cells spread outside the bone marrow, the condition is called extramedullary spread.
DIAGNOSIS
- Acute promyelocytic leukemia can be distinguished from other types of AML based on morphologic examination of a bone marrow biopsy or aspirate.
- Bone marrow biopsy shows extensive hypercellularity with immature cells.
- Bone marrow aspirate shows promyelocytic leukemia cells with Auer rod.
- Definitive diagnosis requires testing for the RARα fusion gene. This may be done by polymerase chain reaction (PCR).
- Fluorescent in situ hybridization (FISH) or conventional cytogenetics show the 15:17 translocation typical of AML M3.
- Monitoring for relapse using PCR tests for RARα allows early re-treatment which is successful in many instances.
PATHOGENESIS
In 95% of cases, acute promyelocytic leukemia is characterized by chromosomal reciprocal translocation involving:
- the retinoic acid receptor-alpha gene (which regulates myeloid differentiation) on chromosome 17 (RARα or RARA)
- the promyelocytic leukemia gene (PML) on chromosome 15 (which encodes a growth suppressing transcription factor)
- This translocation (fig. 1) , denoted as t(15;17)(q22;q12), creates a PML/RARa fusion gene. It produces a chimeric protein that arrests the maturation of myeloid cells at the promyelocytic stage. (It reduces terminal cell differentiation.) And this leads to the increased proliferation of promyelocytes.
- Four other gene rearrangements have been described in APL fusing RARα to
- promyelocytic leukemia zinc finger (PLZF)
- nucleophosmin (NPM)
- nuclear matrix associated (NUMA) or
- signal transducer and activator of transcription 5b (STAT5B) genes.
The resultant fusion proteins disrupt the function of RARα which blocks the normal maturation of granulocytes.
Although the chromosomal translocation involving RARα is believed to be the initiating event, additional mutations are required for the development of leukemia.
COMPLICATIONS
- Patients are at a higher bleeding risck caused by a severe thrombocytopenia which results from reduced medullar production and increased consumption. This increased consumption is due to the release of the granular content of promyelocytes and laboratory tests disclose signs of disseminated intravascular coagulation (DIC).
