PML-RARA

This testing is used to detect the abnormal promyelocytic leukemia/retinoic acid receptor alpha or PML-RARA gene sequence. It is used to help diagnose acute promyelocytic leukemia (APL) in which the PML-RARA gene sequence is present, to guide treatment, to monitor response to treatment, and to monitor for disease recurrence.

A few different test methods are available to evaluate for PML-RARA, and they may be used for various purposes:

• Fluorescence in situ hybridization (FISH) may be used to help diagnose APL and/or help to determine the percentage of a person’s blood or bone marrow cells that contain the abnormal, fused PML-RARA gene. This test method uses fluorescent dye-labeled probes to “light up” the PML-RARA gene sequence when it is present. FISH can also be used to detect the variant translocations involving RARA and genes other than PML. This may help identify drug-resistant (ATRA-resistant) rearrangements.
• A molecular test (real-time quantitative polymerase chain reaction, RQ-PCR) may be ordered to help establish the initial diagnosis of APL. The PML-RARA PCR test is quantitative, that is, it provides a general estimate of the number of PML-RARA gene sequences present in a person’s blood and/or bone marrow samples. A PML-RARA PCR test is typically ordered at the time of the initial diagnosis to establish a baseline value and then periodically to monitor a person’s response to treatment and, if the person achieves remission, to monitor for recurrence. PCR will only detect the PML-RARA fusion, not the more rare combination of RARA with another gene.
• Chromosome analysis (standard cytogenetic analysis) to detect chromosomal abnormalities (e.g., translocations or deletions, or gain or loss of chromosome) may help diagnose APL. This test method involves the evaluation of a person’s chromosomes under a microscope to detect structural and/or numerical abnormalities. Cells in a sample of blood or bone marrow are examined to determine if the PML-RARA t(15;17) chromosome translocation is present. This method can detect the more rare combination of RARA with a gene other than PML, so it may be used if one of the other test methods is negative but APL is still strongly suspected.

PML-RARA testing is often performed along with other blood and/or bone marrow tests if a healthcare practitioner suspects that a person has leukemia and is trying to diagnose or rule out APL. Some of these other tests may include:

• Complete blood count (CBC)—evaluates the number of each type of blood cell
• Differential—identifies and counts different types of white blood cells
• Blood smear—blood cells are examined under a microscope
• Immunophenotyping—classifies cells according to the markers (antigens) on the surfaces of cells

Testing is ordered when a healthcare practitioner suspects that a person has APL. Initial testing may be indicated when a person has abnormal findings on a complete blood count (CBC) and/or blood smear such as an increased or decreased number of white blood cells, decreased platelets, decreased red blood cells, and abnormal, immature white blood cells called leukemic promyelocytes, and nonspecific symptoms that may be related to leukemia such as:

• Fatigue or weakness
• Pale skin (pallor)
• Unexplained weight loss
• Joint or bone pain and/or an enlarged spleen
• Excessive bleeding, bruising, or inappropriate blood clotting

Early in APL, a person may have few or no symptoms. As time passes and normal blood cells are crowded out of the bone marrow and the number of abnormal leukemic cells increases, a person may experience anemia, prolonged bleeding, and recurrent infections. Those with APL may experience both bleeding and inappropriate clotting if they develop disseminated intravascular coagulation (DIC), a potentially life-threatening complication of APL. Once APL has been diagnosed, PML-RARA molecular testing is ordered periodically to monitor the response to treatment and monitor for leukemic cells that remain after treatment (minimal residual disease) or for disease recurrence.

A standard cytogenetic analysis may sometimes be ordered when a PML-RARA gene sequence is not detected and the health care practitioner suspects another rearrangement involving the RARA gene may be present.

If a person has abnormal promyelocytes in the blood and bone marrow and has the PML-RARA gene sequence, then the person is diagnosed as having APL.

The presence of PML-RARA means the individual will likely benefit from treatment with all-trans retinoic acid (ATRA). This is a drug that can help promyelocytic leukemia cells to continue to differentiate and become more mature. ATRA is typically effective in those cases where the PML-RARA fusion gene is present. A small percentage of people with APL have a fusion between RARA and a different gene, and they may or may not benefit from ATRA therapy depending upon the partner gene involved.

When monitoring treatment, a decrease in the amount of PML-RARA in the blood or bone marrow over time means the person is responding to treatment. If the number of cells that have PML-RARA drops below the test’s detection limit and the person’s blood cell counts are normal, then the person is considered to be in remission. An increase in PML-RARA levels over time indicates disease progression or relapse.

If a person with APL is not positive for the PML-RARA gene sequence, then that person may not be given ATRA therapy and PML-RARA molecular testing cannot be used to monitor the person.

Both blood and bone marrow may be evaluated as part of the initial diagnosis, but follow-up monitoring is often performed on blood samples. There is significant test variability among laboratories using different test methods. Therefore, for a given person with APL, PML-RARA molecular testing should be done by the same laboratory, if possible. Rising and falling levels of PML-RARA are usually more important than a single test result.

Possibly. For example, the BCR-ABL fusion gene is a translocation genetic change that is associated with different chromosomes and different leukemias, namely chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL).

No. This genetic change is one that is acquired during a person’s lifetime and is not inherited.

Testing is only indicated when your healthcare practitioner suspects that you have APL or wants to rule it out. APL is a subtype of acute myeloid leukemia (AML). The majority of people with leukemia will not have the PML-RARA gene sequence.

That depends on the laboratory performing the testing. PML-RARA testing requires specialized equipment and expertise. It must be performed by a specialized hospital laboratory or a reference laboratory and it may take several days for results to be available.