Acute Promyelocytic Leukemia (APML)

Overview

Acute promyelocytic leukemia (APL) is an aggressive type of acute myeloid leukemia in which there are too many immature blood-forming cells (promyelocytes) in the blood and bone marrow. This build up of promyelocytes leads to a shortage of normal white and red blood cells and platelets in the body. The signs and symptoms of APL include an increased risk to both bleed and form blood clots. Individuals may also experience excessive tiredness, pain in affected areas, loss of appetite, and weight loss. APL usually occurs in middle-aged adults, but can be diagnosed at any age. It is caused by a mutation that is acquired over a person's lifetime, usually involving a translocation between chromosomes 15 and 17. Treatment may include the use of all-trans retinoic acid (ATRA) and arsenic trioxide or anthracycline-based chemotherapy.

Cause

APL is caused by a chromosomal translocation (rearrangement of material) that occurs in some of the body's cells during a person's lifetime (a somatic mutation). The translocation involves the fusion of two genes: the PML gene on chromosome 15 and the RARA gene on chromosome 17. The protein produced by this fusion is referred to as PML-RARα. The PML-RARα protein functions differently than what is typically produced by the normal PML and RARA genes. As a result of the abnormal function, blood cells become "stuck" at the promyelocyte stage and they proliferate (reproduce) abnormally. Excess promyelocytes then accumulate in the bone marrow, disrupting the formation of normal white blood cells and leading to APL. Translocations involving the RARA gene and other genes have been identified in only a few cases of APL.

Inheritance

APL is not inherited. The condition arises from a translocation in some of the body's cells (somatic cells) that occurs after conception. This is referred to as a somatic mutation. Somatic mutations may affect the individual by causing cancers or other diseases, but they are not passed on to offspring.

Diagnosis

We were unable to locate information about the availability of predictive testing for APL. Predictive genetic testing is primarily an option for individuals at risk for inherited cancers and other inherited disorders; APL is not an inherited cancer. Predictive genetic tests are generally available if a close family member has had a genetic test which has identified a specific mutation that is associated with an inherited predisposition to cancer. APL is caused by a somatic mutation which is acquired during a person's lifetime and is not passed on to children. Furthermore, it is not necessarily known when during a person's lifetime a somatic mutation might occur.

Testing Resources

• The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Treatment

Acute promyelocytic leukemia is a medical emergency because life-threatening bleeding and clotting complications can occur early. If APL is suspected, ATRA should be started immediately while urgent testing for the PML::RARA fusion confirms the diagnosis.

Treatment depends on the white blood cell count, risk category, age, and overall health. Low- and intermediate-risk disease is commonly treated with ATRA plus arsenic trioxide. High-risk disease requires additional cytoreductive treatment according to a specialist treatment protocol. Treatment should be individualized by a hematology team.

If treatment achieves a remission, further courses of treatment may be given. A stem cell transplant may also be an option. If a second remission is not achieved, treatment options may include a stem cell transplant or taking part in a clinical trial.

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

Arsenic trioxide (Brand name: Trisenox) - Manufactured by Cephalon

FDA-approved indication: In combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL) whose APL is characterized by the presence of the t(15;17). Also approved for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation.

Tretinoin (Brand name: Vesanoid®) - Manufactured by Roche Pharmaceuticals

FDA-approved indication: Induction of remission in patients with acute promyelocytic leukemia who are refractory to or unable to tolerate anthracycline based cytotoxic chemotherapeutic regimens.