Acute promyelocytic leukemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D.  Shyam Patel  Associate Editor(s)-in-Chief: Sogand Goudarzi, MD ; Grammar Reviewer: Natalie Harpenau, B.S.
Acute promyelocytic leukemia is a sub-type of acute myelogenous leukemia (AML), a cancer of the blood and bone marrow. In acute promyelocytic leukemia, there is an abnormal accumulation of immature granulocytes called promyelocytes. A diagnosis is made when there are greater than 20% blasts, or immature cancerous cells, in the bone marrow. 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 acute myeloid leukemia in its responsiveness to all trans retinoic acid (ATRA) therapy.
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.
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.
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.
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.
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 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.
History and 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).
The physical examination findings in acute promyelocytic leukemia include petechiae, ecchymoses, mucosal bleeding, splenomegaly, and/or pallor. The bleeding-related physical examination findings have a higher specificity for acute promyelocytic leukemia compared to other types of leukemia.
The laboratory abnormalities in acute promyelocytic leukemia can be broadly divided into abnormalities of the complete blood count and abnormalities of the coagulation system. The complete blood count usually shows anemia, thrombocytopenia, leukopenia, and elevated blast count. The coagulation profile usually shows elevated prothrombin time, elevated partial thromboplastin time, elevated thrombin time, elevated reptilase time, and low fibrinogen. This combination of coagulation parameters accounts for high hemorrhagic risk in patients with acute promyelocytic leukemia.
Other Imaging Studies
Additional imaging studies that can be useful in acute promyelocytic leukemia include echocardiogram, chest X-ray, and brain MRI.
Other Diagnostic Studies
There is no significant role for other diagnostic studies in acute promyelocytic leukemia. However, lumbar puncture can be done to assess for central nervous system involvement.
The treatment of acute promyelocytic leukemia is broadly divided into anti-leukemia therapies and supportive therapies. Anti-leukemia therapies function to eliminate cancer cells, whereas supportive therapies are temporizing measures that can control the disease for a short time until anti-leukemic therapy takes effect. Anti-leukemic therapies include all-''trans'' retinoic acid, arsenic trioxide, gemtuzumab ozogamycin, and cytarabine. Supportive therapies include transfusions (such as cryopreciptate or platelet transfusions) and granulocyte colony stimulating factor.
Cost-Effectiveness of Therapy
A limited number of cost-effective studies have been done. In summary, these studies showed that all-trans retinoic acid-based therapy is more cost effective than chemotherapy.
Future or Investigational Therapies
Investigational therapies for acute promyelocytic leukemia include bromodomain inhibitors and RNA-based silencing approaches (gene therapy).