Acute Promyelocytic Leukemia

Definition

Definition of Acute Promyelocytic Leukemia
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)(q24;q21), 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 (RARa or RARA) gene and is unique from other forms of AML in its responsiveness to all trans retinoic acid (ATRA) therapy.

Symptoms

Symptoms of Acute Promyelocytic Leukemia
Normal differentiation of the white blood cells in the marrow starts with the multi-potent hematopietic stem cells (HSC). Several transcription factors such as PU.1 and C/EB protein alpha have been identified to be important in the white blood cell differentiation process. The HSC generates the lymphoid (B cells and T cells of our immune system) cell line and the myeloid cell lines. The myeloid cell lines have granules in their cytoplasm and they are called granulocytes and are important in fighting infections.

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. The bone marrow is unable to produce healthy red blood cells. Either leukopenia (low white cell count) or leukocytosis (high white cell count) may be observed in the peripheral blood.

Epidemiology

Epidemiology of Acute Promyelocytic Leukemia
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). Without proper medicine and treatment, APL is fatal. The incidence is increased in patients originated in Latin American countries.

Diagnosis

Diagnosis of Acute Promyelocytic Leukemia
Acute promyelocytic leukemia can be distinguished from other types of AML based on morphologic examination of a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. Definitive diagnosis requires testing for the PML/RARa 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. This mutation involves a translocation of the long arm chromosomes of 15 and 17.

Treatment

Treatment of Acute Promyelocytic Leukemia
APL is unique among myeloid leukemias due to its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Treatment with ATRA dissociates the NCOR-HDACL complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells. ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA is typically combined with anthracycline based chemotherapy resulting in a clinical remission in approximately 90% of patients. ATRA alone is capable of inducing remission but it is short-lived in the absence of anthracycline. Arsenic trioThe advent of ATRA therapy revolutionized the treatment of APL and markedly improved the prognosis (the outlook). ATRA syndrome is a serious side effect of ATRA treatment and includes fever, respiratory distress, and hypotension (abnormally low blood pressure). The ATRA syndrome can be prevented by the addition of chemotherapy and/or dexamethasone if the WBC is increasing. xide (As2O3) is currently being evaluated for treatment of relapsed / refractory disease. After stable remission is induced, the standard of care is to undergo 2 years of consolidation chemotherapy with Methotrexate, Mercaptopurine, and ATRA. Nearly all patients will relapse without consolidation therapy.

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.

Prognosis

Prognosis of Acute Promyelocytic Leukemia
The advent of ATRA therapy revolutionized the treatment of APL and markedly improved the prognosis (the outlook). ATRA syndrome is a serious side effect of ATRA treatment and includes fever, respiratory distress, and hypotension (abnormally low blood pressure). The ATRA syndrome can be prevented by the addition of chemotherapy and/or dexamethasone if the WBC is increasing.