PML-RAR-alpha t(15;17), |
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Test Highlights |
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Clinical Use
| • | Diagnose acute promyelocytic leukemia (APL) |
| • | Predict response to all-trans-retinoic acid or arsenic trioxide therapy |
| • | Assess effectiveness of therapy |
| • | Monitor minimal residual disease (MRD) |
| • | Predict early relapse |
Clinical Background
Acute promyelocytic leukemia (APL or AML-M3) is a subtype of acute myeloid leukemia with distinct clinical and histopathologic features. Historically one of the most lethal forms of acute myeloid leukemia, APL leads to disseminated intravascular coagulation and death when not diagnosed and treated. Treatment with all-trans-retinoic acid substantially improves survival in patients who have failed anthracycline chemotherapy or for whom anthracycline is contraindicated. Similarly, arsenic trioxide is beneficial in APL patients who have failed or have contraindications for treatment with anthracycline or retinoid -based therapy.
Genetically, APL is characterized by a unique chromosomal anomaly: More than 99% of APL patients harbor a translocation between chromosomes 15 and 17, which fuses the retinoic acid receptor alpha (RARA) gene on chromosome 17 with the PML gene on chromosome 15. A short or a long transcript isoform is produced, depending on the PML breakpoint; the short isoform has been linked to poor outcome, but this association remains controversial. Detection of the PML/RARA t(15;17) translocation is diagnostic for APL, although the diagnosis can also be based on morphology. The presence of this translocation is necessary for response to all-trans-retinoic acid and arsenic trioxide. Thus, the PML/RARA t(15;17) assay is useful for diagnosis and predicting treatment response. It is also helpful for monitoring therapeutic response and MRD and for detecting early relapse.
Method
In this assay, extracted RNA is subjected to 2 separate quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) procedures to detect the 2 types of PML/RARA fusion transcripts (long and short isoforms). An additional amplification for the abl gene is performed as a control for sample RNA quality and as a reference for relative quantification. The results are reported as positive or negative; the ratio of target (PML/RARA) to control (ABL) mRNA is reported for positive specimens. The isoform (short or long) is also reported. If available, a previously stored sample will be tested alongside the current specimen to assess quantitative changes with time (trend). The analytical sensitivity of this test is 1 tumor cell in 100,000 normal cells.
Interpretive Information
Positive results indicate that the cells carry the PML/RARA t(15;17) translocation and are diagnostic for APL. The short isoform may be associated with shorter disease-free and overall survival. If the PML/RARA t(15;17) translocation is detected, the ratio of amplified PML/RARA fusion transcript to the control ABL transcript is reported. If there is no PML/RARA amplification (ratio = 0), the result is reported as negative. Because the efficacy of all-trans-retinoic acid and arsenic trioxide has not been demonstrated in patients who lack the PML/RARA t(15;17) translocation, other forms of treatment should be considered for patients without this rearrangement.
To monitor MRD, we recommend evaluating changes with time (trend) rather than the absolute ratio from one measurement.
Specimen Requirements
| • | 3 mL room-temperature or refrigerated EDTA (lavender-top tube) whole blood; 1 mL minimum |
| • | Alternatively, submit 3 mL bone marrow in an EDTA (lavender-top) tube; 0.5 mL minimum |
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