Acute promyelocytic leukemia

Overview
Acute promyelocytic leukemia is a subtype of acute myelogenous leukemia (AML), a cancer of the blood and bone marrow. It is also known as acute progranulocytic leukemia; APL; AML with t(15;17)(q22;q12), PML-RARA and variants; FAB subtype M3 and M3 variant.

In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARα or RARA) gene and is unique from other forms of AML in its responsiveness to all trans retinoic acid (ATRA) therapy.

Signs and symptoms
Signs and symptoms of acute promyelocytic leukemia are similar to other forms of AML. Symptoms include fever, fatigue, weight loss or loss of appetite, shortness of breath with exertion, anemia, easy bruising or bleeding, petechiae (flat, pin-head sized spots under the skin caused by bleeding), bone pain and joint pain and persistent or frequent infections.[8]

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 (low white cell count) or leukocytosis (high white cell count) may be observed in the peripheral blood. Symptoms include:
 * Fatigue, weakness, shortness of breath (from anemia)
 * Easy bruising and bleeding (from thrombocytopenia and coagulopathy)
 * Fever and infection (from lack of normal white blood cells)

In addition, acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulation (DIC).

Epidemiology
Acute promyelocytic leukemia represents 5-8% of AML in adults. 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.(Douer et al.)

Pathogenesis
Acute promyelocytic leukemia is characterized by chromosomal translocation involving the retinoic acid receptor-alpha gene on chromosome 17 (RARα). In 95% of cases of APL, retinoic acid receptor-alpha (RARα) gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene (PML) on chromosome 15, a translocation denoted as t(15;17)(q22;q12).

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.

Diagnosis
Acute promyelocytic leukemia can be distinguished from other types of AML based on morphologic examination of a bone marrow biopsy or aspirate. 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 of peripheral blood or bone marrow.

Monitoring for relapse using PCR tests for RARα allows early re-treatment which is successful in many instances.

Treatment
APL is unique among the leukemias distinguished by its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Treatment with ATRA causes differentiation of the immature leukemic promyelocytes into mature granulocytes. ATRA is typically combined with anthracycline based chemotherapy resulting in a clinical remission in approximately 90% of patients.

ATRA therapy is associated with the unique side effect of retinoic acid syndrome. This is associated with the development of dyspnea, fever, weight gain, peripheral edema and is treated with dexamethasone. The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes.

Treatment options for patients with relapsed disease include arsenic trioxide and allogeneic stem cell transplant.