Acute Promyelocytic Leukemia (APL)


Acute promyelocytic leukemia (APL) is a clonal myeloproliferative neoplasm, wherein abnormal promyelocytes predominate.  The incidence of APL is approximately 0.1 per 100 000 adults – resulting in approximately 10 new cases per year in British Columbia APL is most often characterized by the reciprocal translocation of chromosomes 15 and 17 – t(15;17)(q24;q12) (Figure 1).

Figure 1:  The reciprocal translocation of chromosomes 15 and 17 characteristic of acute promyelocytic leukemia

This translocation generates a novel fusion gene (PML::RARA) composed of the 5’ portion of the PML gene on chromosome 15 and the 3’ portion of the RARA gene on chromosome 17. Several variants of the PML::RARA fusion transcript are known. The most common variants fuse either exon 3 or exon 6 of PML to exon 3 of RARA (P3R3 and P6R3 respectively, Figure 2).  PML is the major organizing component of the PML-nuclear body, a membrane-less nuclear sub-organelle involved in stress response.  RARa forms a heterodimer with RXR to, in the absence of retinoic acid, promote transcriptional repression of genes involved in granulocytic differentiation.  The novel fusion protein generated by the translocation disrupts not only nuclear bodies but generates a novel transcriptional repressor that is insensitive to natural physiologic levels of retinoic acid. 

Figure 2: Common PML-RARA transcript variants

Treatment of APL is most often with all-trans retinoic acid (ATRA) together with arsenic trioxide (ATO).  Supra-physiologic concentrations of retinoic acid overcome PML::RARA and cause it to dissociate from its protein partners and be degraded; thereby promoting differentiation of the leukemic clone.  Arsenic trioxide, on the other hand, binds to the PML portion of PML-RARA resulting in sumoylation and subsequent degradation.  While both ATRA and ATO promote differentiation, this does not materially impact the leukemic stem cell population.  ATO however has the added benefit of inducing apoptosis.  In so doing, ATO may be viewed as a curative intent therapy in so far as it leads to the elimination of this cell population.  Depending on the clinical context (eg high risk disease), daunorubicin (anthracycline based chemotherapeutic) may be added to the treatment regimen.

The end result of treatment with ATRA/ATO is clearance of PML::RARA and differentiation of promyelocytes into mature neutrophils (which do not replicate).

Natural History

APL is rapidly fatal if untreated; with patients often presenting with severe coagulopathy (both hemorrhage and thromboembolic events).  Thus a prompt diagnosis and initiation of therapy is of paramount importance. Prior to the advent of ATRA/ATO based therapies in APL, treatment was primarily with anthracyclines (eg daunorubicin) in combination with other chemotherapeutic agents (eg, cytarabine, thioguanine).  In this era, the 5 year disease free survival was approximately 35-45%.  The introduction of ATRA to chemotherapy based regimens in the 1980s improved the five year disease free survival to approximately 70%.  Finally, the addition of ATO to the treatment regimen (alone or in combination) increased this to approximately 90%.

Testing – Diagnostic

The laboratory diagnosis of APL is currently and most commonly performed by interphase fluorescent in situ hybridization (FISH) on peripheral blood derived leukocytes or bone marrow specimens. Should a bone marrow specimen be obtained for other investigations, both FISH and karyotype analysis may be performed on this specimen. On occasion, the bone marrow morphology and clinical presentation are highly suggestive of APL, yet both FISH and karyotype return a negative result.  In this situation, molecular testing may be initiated to confirm the presence of a cryptic (cytogenetically invisible) PML::RARA fusion (see below).  It should be underscored that as the negative predictive value of this test is uncertain, it should not be used an up-front diagnostic test.

Testing – Pre-treatment (Baseline testing)

Should the initial diagnosis of APL be made from a peripheral blood specimen, follow-up karyotype analysis is indicated from a bone marrow specimen for disease staging purposes.

Following the initial diagnosis of APL, reflex molecular testing is indicated. This testing allows the laboratory to confirm that the molecular lesion present at diagnosis is amenable to molecular monitoring post initiation of treatment and by which method monitoring should proceed (see below).  In the case of either a P3R3 or P6R3 transcript variant this testing also allows for the establishment of a baseline molecular burden for the patient. While, from a laboratory perspective, it is preferable to forward a peripheral blood specimen to the laboratory for this purpose once a diagnosis is made, it is reasonable to send a peripheral blood or bone marrow specimen to the laboratory (for RNA processing and holding) in anticipation of a formal diagnosis of APL.  If precautionary treatment with ATRA had been initiated prior to a confirmed diagnosis of APL (and before a specimen was forwarded to CGL), reflex testing may be initiated on residual material used for cytogenetic or hemepath assessment.

Testing – Monitoring Response to Treatment (MRD testing)

Monitoring is performed by one of two methods.  For P3R3 and P6R3 positive disease, monitoring is by droplet digital RT-PCR (ddRT-PCR) and reported as a molecular burden (log ratio of [PML-RARA]/[BCR]). For all other transcript variants, monitoring is by standard RT-PCR and is reported simply as positive or negative for the presence of the transcript variant. 

During the course of induction/consolidation, testing may be initiated at the treating physician’s discretion in order to assess early response to treatment.

Most patients will become ddRT-PCR/RT-PCR negative soon after initiation of therapy.  Monitoring then continues at three month intervals for patients with uncomplicated disease.  After three years of ddRT-PCR/RT-PCR negativity post completion of all planned therapy, it is concluded that the patient has entered stable remission and ongoing monitoring ceases.

It should be noted that the above testing intervals are for routine monitoring.  Testing between intervals for non-routine instances is always available (following prior consultation with the laboratory).  Furthermore monitoring for terms exceeding three years is similarly available.

Selected References

Thomas X. Acute promyelocytic leukemia: A history over 60 years – From the most malignant to the most curable form of acute leukemia. Oncol Ther (2019) 7:33-65. PMID: 32700196

Yilmaz M et al. Acute promyelocytic leukemia current treatment algorithms. Blood Cancer J (2021) 11:123. PMID: 34193815

NCCN guidelines – AML v3.2021 (

WHO Classification of Tumours of Haematopoeitic and Lymphoid Tissues – 4th edition (2017)