Acute promyelocytic leukemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2]
Overview
Acute promyelocytic leukemia is a subtype of acute myelogenous leukemia (AML), a cancer of the blood and bone marrow.
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.
Historical Perspective
The first documentation of the successful treatment of acute promyelocytic leukemia occurred in the late 19th century, at which time physicians and scientists explored the role of arsenic as an anti-leukemic agent. Since that time, multiple advances have been made over the years. Specifically, the use of cytotoxic chemotherapy (anthracycline and cytarabine) has been explored extensively. The use of all-''trans'' retinoic acid in the 20th century has revolutionized the treatment paradigm for acute promyelocytic leukemia. In the early 21st century, a landmark study showed that the combination of arsenic trioxide plus all-''trans'' retinoic acid was superior to conventional chemotherapy for low-risk acute promyelocytic leukemia.
Classification
There are several broad classification schemes for acute promyelocytic leukemia. The most well-accepted classification scheme is risk-based classification, which categories patients into low-risk, intermediate-risk, or high-risk based on the white blood cell count and platelet count. Another classification scheme is based on the origin of the leukemia, which categorized patients as having de novo or therapy-related disease. A final classification scheme is cytogenetic-based, in which case specific chromosomal abnormalities are used to stratify patients.
Pathophysiology
The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene product causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.
Causes
The cause of acute promyelocytic leukemia is sporadic rather than hereditary. It is caused by a reciprocal translocation between chromosomes 15 and 17, which creates a novel protein known as PML-RARA, leading to a differentiation block. In general, the causes of acute leukemia of myeloid origin include chemicals, radiation, cytotoxic chemotherapeutic agents, and specific mutations.
Differential Diagnosis
The differential diagnosis of acute promyelocytic leukemia includes a variety of other hematologic malignancies, specifically acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Each of these conditions has distinct causes and therapies. There is some overlap between the causes and laboratory abnormalities amongst these diseases.
Epidemiology and Demographics
Acute promyelocytic leukemia is relatively rare compared to other diseases. It predominantly affects people of Latin American descent and least commonly affects African Americans. It is more common in older adults.
Risk Factors
Risk factors for acute promyelocytic leukemia are similar to risk factors for acute myeloid leukemia. These include advanced age, benzene exposure, prior myelodysplastic syndrome, and germline mutations.
Natural History, Complications, and Prognosis
The natural history of acute promyelocytic leukemia is characterized by symptoms related to defective normal blood cell production. These symptoms include fatigue, bleeding, and infection. Complications include thrombosis and hemorrhage, which eventually occur in a significant proportion of patients. Early death is common and is related to bleeding complications. Therapy-related complications include differentiation syndrome, QT interval prolongation, and cardiomyopathy. The prognosis of acute promyelocytic leukemia was previously poor, but the advent of arsenic trioxide and all-trans retinoic acid has rendered the prognosis to be far more favorable in the recent years.
Symptoms
Signs and symptoms of acute promyelocytic leukemia are similar to other forms of leukemia, but bleeding and hemorrhagic events are more specific for acute promyelocytic leukemia since these patients are more likely to present with disseminated intravascular coagulation (coagulopathy).