Acute promyelocytic Leukemia (APML) with t(15;17).
APML is classified as part of the acute myeloid leukemia (AML) with recurrent genetic abnormalities group. It comprises approximately 5-8% of all AML and is seen mostly in middle aged individuals but can present at any age (2). The incidence appears to rise during the second decade of life, with a plateau during adulthood, and then a decline in incidence after age 60 (1). APML may also arise as a secondary leukemia, following therapy with topoisomerase II inhibitors and radiotherapy (1).
Prompt diagnosis is important since APML may present as a medical emergency because this leukemia can often be associated clinically with disseminated intravascular coagulation. Intracerebral and pulmonary hemorrhages related to DIC may result in death. Factors that identify patients with a greater likelihood for developing fatal hemorrhages include: active bleeding, low levels of fibrinogen (<100 mg/dL), or elevated fibrin degradation products or D-dimers combined with elevated prothrombin time or activated partial thromboplastin time, and those patients with increased WBC or circulating blast counts, abnormal creatinine values, or poor performance status (2).
Two morphologic variants of APML have been described: typical (hypergranular) type and the microgranular (hypogranular) type. Typical APML has hypergranular abnormal promyelocytes with irregular shaped nuclear contours that frequently have a bilobed appearance. Their cytoplasm usually contains numerous large azurophilic granules and Auer rods, some of which can be so abundant that they completely obscure the nucleus. Cells with many prominent Auer rods are often present and have been referred to as term "faggot cells" due to the resemblance to a bundle of straw. Occasionally, more typical myeloblasts with Auer rods can also be seen. (2)
In the microgranular type, the abnormal promyelocytes mostly have bilobed nuclei with very few or complete absence of granules. However, usually a few of the characteristic cells described in the hypergranular type can be found. (2)
The cytochemical myeloperoxidase stain is strongly positive in the abnormal promyelocytes. (2)
The characteristic immunophenotypic profile of APML is positivity for myeloperoxidase (MPO) and CD117 (although sometimes weak) while negative for HLA-DR and CD15. (1 and 2) In the microgranular type, there is often expression of CD34 and CD2 in a portion of the cells. In some cases of APML (approximately 20%), there is CD56 positivity which may be associated with a poorer prognosis. (2)
The common genetic abnormality in APML is the translocation (15;17) which results in the fusion of the retinoic acid receptor alpha gene with a nuclear regulatory factor gene creating a fusion protein. Infrequently, some cases do not have this characteristic genetic abnormality and carry a more complex cytogenetic change, called a cryptic translocation. (2) Alternate translocations involving RARA and other fusion partners, such as ZBTB16, nuclear matrix associated gene (NUMA1), nucleophosmin gene (NPM1), and STAT5B, have also been described. The classical PML1/RARA fusion protein is responsive to all trans-retinoic acid (ATRA) therapy, which restores the intracellular signaling that results in maturation of cells to mature neutrophils. (3) Although remission with ATRA alone can be achieved, this does not remove the underlying leukemic clone and relapse occurs. Therefore, additional treatment with more typical anthracycline-based therapy is also needed.
APML is very responsive to treatment with ATRA in combination with anthracycline-based chemotherapy resulting in a complete remission of 90-95% of cases (1) and relapsed or recurrent cases are often very responsive to arsenic trioxide therapy (2). Arsenic trioxide therapy appears to have two mechanisms that complement ATRA therapy. At low doses, arsenic trioxide also appears to induce differentiation of leukemic cells and at higher concentrations induces apoptosis (3). ATRA therapy is usually immediately started even as soon as it is suspected, as it has been shown to rapidly improve coagulopathy (1), as well as providing supportive care with measures such as plasma and platelet transfusions. (4)
Contributed by Kelly Garner, MD and Raymond Felgar, MD, PhD