Acute Promyelocytic Leukemia (APL)

Diagnosis of APL

APL is the most distinctive subtype of AML and requires specific treatment. An accurate diagnosis of APL is essential in order to begin appropriate treatment as soon as possible. But first, AML must be diagnosed, and then testing is done to determine the subtype. Your doctor probably made a preliminary or confirmed diagnosis of APL on the basis of several laboratory studies on your blood and bone marrow. The definitive diagnosis of APL is made with identification of the genetic abnormality that is the distinguishing feature of APL. Experts recommend, however, that treatment should not be delayed while waiting for confirmation of the diagnosis; instead, treatment should begin as soon as APL is suspected, to help avoid serious complications. If diagnostic testing indicates a different subtype of AML, treatment can be changed, with few or no harmful effects.

Diagnosis of AML

One of the first tests done to determine if a person has AML (or any type of leukemia) is a complete blood count (CBC) and differential. This test tells your doctor the number of red blood cells, white blood cells, and platelets in the bloodstream. In a person with leukemia, the numbers of these different types of blood cells are low because of the increased number of leukemia cells (also referred to as blasts). But low blood cell counts can be caused by many conditions, so additional tests are needed. Microscopic examination of a sample of fluid or tissue from your bone marrow is done to look for leukemia cells. The specialist reviewing the sample will study various characteristics of the cells to determine the subtype of AML. APL is defined by an abundance of cells that have not matured properly and have stopped their development at the promyelocyte stage.

If your doctor suspects APL, he or she will also order tests that show how long it takes for your blood to clot. These tests are very important because bleeding disorders, known as coagulopathy, are common with APL. Bleeding disorders can be serious, and treatment must be started immediately before excess bleeding becomes life-threatening.

The confirmation of a diagnosis of APL requires cytogenetic analysis, or the evaluation of chromosomes. Cytogenetic analysiscan be done with several testing methods, including karyotyping, fluorescent in situ hybridization (FISH), immunostaining, and reverse transcription–polymerase chain reaction (RT-PCR). The results of RT-PCR can show the distinguishing feature of APL even when other tests cannot. RT-PCR is done on a sample of fluid or tissue obtained from the bone marrow. RT-PCR is also known as molecular testing.

What is the Distinguishing Feature of APL?

Changes in two chromosomes are the hallmark feature of APL. In nearly all cases of APL, there is a translocation of chromosomes 15 and 17, which means that some of the genes from chromosome 15 have broken off and attached themselves to chromosome 17 and some of the genes from chromosome 17 have broken off and attached themselves to chromosome 15. The break in chromosome 15 disrupts the PML gene, or the promyelocytic leukemia gene, and the break in chromosome 17 interrupts the RARA gene, or the retinoic acid receptor alpha gene. Because of the translocation, these two genes become fused together to become an abnormal gene called PML/RARA. This abnormal gene produces a protein that stops myeloid cells from maturing past the promyelocyte stage. The translocation of chromosomes 15 and 17 is abbreviated as t(15;17).

How Does the Presence of t(15;17) Affect Treatment Options?

Since the discovery of the gene mutation as the distinguishing feature of APL, treatment involves the use of molecularly targeted agents. The exact ways these agents work in APL is somewhat unclear, but they seem to activate the RARA and PML genes to allow promyelocytes to mature into healthy blood cells, to cause leukemia cells to die, and to correct the genetic abnormality itself.

Definitions of Terms
Blasts Another term for leukemia cells or myeloblasts
CBC (complete blood count) and differential Laboratory test done on a blood sample to measure the number of red blood cells, white blood cells, and platelets in the blood, as well as the number or relative proportion of the different types of white blood cells present; the results indicate the degree to which APL is affecting the production of normal blood cells
Chromosome Thread-like strand of DNA that carries genes
Coagulopathy Bleeding disorders because of a problem with the blood clotting process; coagulopathy is a common complication of APL
PML gene Promyelocytic leukemia gene; located on chromosome 15; in APL, this gene is disrupted and becomes attached to chromosome 17
PML/RARA gene The abnormal gene caused by the translocation of chromosomes 15 and 17; the distinguishing feature of APL; the abnormal gene produces a protein that causes myeloblasts to stop their development at the stage of the promyelocyte
Promyelocyte Cell stage of development at which myeloblasts stop maturing in APL
RARA gene Retinoic acid receptor alpha gene, located on chromosome 17; in APL, this gene is disrupted and becomes attached to chromosome 15
Reverse transcription–polymerase chain reaction (RT-PCR) “Gold standard,” or recommended and preferred testing method to detect the distinguishing feature of APL
Translocation A chromosomal abnormality in which pieces of two chromosomes break off and exchange chromosome locations; for example, in APL, a piece of chromosome 15 breaks off and relocates to chromosome 17, which has also lost a piece that attaches itself to chromosome 15; this translocation is abbreviated as t(15;17)