Practice Essentials
Acute promyelocytic leukemia (APL) is a is a unique subtype of acute leukemia characterized by abnormal proliferation of promyelocytes, life-threatening coagulopathy, and the chromosome translocation t(15;17)(q22;q11-12). The discovery and elucidation of the molecular pathogenesis for APL has led to the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapies, which improved the prognosis of APL patients significantly.
See the images below.
Hypogranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
For patient education information, see the Cancer Center, as well as Leukemia. In addition, patients should visit the Leukemia and Lymphoma Society Web page, www.leukemia-lymphoma.org, for further information.
Background
APL was first described as an entity in the late 1950s in Norway and France as a hyperacute fatal illness associated with a hemorrhagic syndrome. [1] In 1959, Jean Bernard et al described the association of APL with a severe hemorrhagic diathesis that led to disseminated intravascular coagulation (DIC) and hyperfibrinolysis. By 1973, there were reports of complete remissions with treatment of the disease by daunorubicin.
In 1974, Leo Sachs pioneered research on leukemic cell differentiation in vivo. Dr. Zhen Yi Wang, a Chinese hematologist, shared data on the efficacy of all-trans retinoic acid (ATRA) in his APL patients during a visit to France in 1985. In 1990, several publications linked a translocation between chromosomes 15 and 17 to the pathology of APL. In the early to mid 1990s, arsenic trioxide (ATO) was added to the treatment regimen. A potentially fatal complication of ATRA treatment, called retinoic acid syndrome, was also described. Over the past 50 years, APL has transformed from a highly fatal disease to a highly curable one. [2]
Pathophysiology
Acute promyelocytic leukemia (APL) is defined by its cytogenetic properties. Over 95% of cases are characterized by a balanced translocation between chromosome 17q21 and chromosome 15q22. This leads to an abnormal fusion protein called PML-RARA. This translocation can be detected by karyotyping or fluorescence in situ hybridization (FISH) studies, and the transcript can be detected by polymerase chain reaction (PCR) techniques.
The retinoic acid alpha receptor gene (RARA) is encoded by the long arm of chromosome 17. It is mainly expressed in hematopoietic cells and has an important role in regulating gene expression. In the absence of retinoid acid, RARA is bound by nuclear corepressor factor, and this causes transcriptional repression. In the presence of retinoic acid, RARA is activated and terminal differentiation of promyelocytes occurs.
The promyelocytic gene (PML) is encoded by the long arm of chromosome 15 and is expressed ubiquitously. PML is thought to be involved in apoptosis and tumor suppression.
There are three possible isoforms caused by PML-RARA translocations. The breakpoint in chromosome 17 is consistently found in intron 2, but varies in chromosome 15. The three breakpoints on the PML gene can occur at intron 3 (L form), intron 6 (S form), and exon 6 (V form). The S form is reportedly associated with a shorter remission duration and overall survival compared with the L form. [3]
The fusion gene product causes the retinoic acid receptor to bind more tightly to the nuclear co-repressor factor. Therefore, the gene cannot be activated with physiologic doses of retinoic acid. In about 5% of cases, rearrangements of chromosome 17q21 with other gene partners occur. These include the following:
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PZLF (promyelocytic zinc finger) t(11;17)(q23;q21)
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NPM (nucleophosmin) t(5;17)(q35;q12-21)
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NuMa (nuclear mitotic apparatus) t(11;17)(q13;q21)
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STAT5b (17;17)(q11;q21)
Yin et al identified a novel fusion between RARA and the interferon regulatory factor 2 binding protein 2 (IRF2BP2) genes. [4] Cao et al reported on a new karyotype: 46,XY; t(7;16)(q31'q22), t(15;17)(q22;q21). [5]
It is important to note that the nature of the fusion partner significantly impacts the disease characteristics and response to therapy. For example, APL with PLZF-RARA is not sensitive to retinoic acid and is less sensitive to chemotherapy. [6]
About 40% of APL cases also express additional chromosomal abnormalities (trisomy 8 and isochromosome 17). These do not appear to impact the overall prognosis.
Epidemiology
In the United States, acute promyelocytic leukemia (APL) accounts for 5-15% of all adult leukemias. [7] Approximately 30,800 cases of acute leukemia are diagnosed yearly in the US, and about 1000 of those are APL. The annual incidence of APL in Italy is approximately 0.6 per 1 million people.
Douer noted that the APL-specific PML/RARA gene rearrangement is different in Latinos and non-Latinos, and that the incidence rate of APL is higher in patients originating in Latin America. [8] In contrast, Matasar et al reported that lifetime incidence rates of APL were not higher in US Hispanics than in whites, but the age distribution among Hispanics was significantly different from that in non-Hispanic whites, with greater incidence rates for children ages 1-19 years and adults ages 20-44 years. Blacks had lower lifetime incidence rates than non-Hispanic whites, Hispanics, and Asians. [9]
The incidence of APL in males and females is equal. [8] The median age of onset of APL is about age 40 years.
Prognosis
Unlike most leukemias, acute promyelocytic leukemia (APL) has a very good prognosis, with long-term survival rates up to 90% following treatment. [10] However, the incidence of early death remains high, with 29% of APL patients dying within 30 days of their diagnosis; in 35% of those early deaths, the patient never received all-trans retinoic acid (ATRA) therapy. [11] The most common causes of early death in APL are hemorrhage, differentiation syndrome (DS), and infection. [12, 13]
The white blood cell (WBC) count is viewed as an important index associated with prognosis in APL. The National Comprehensive Cancer Network (NCCN) uses WBC counts to classify patients as either low risk (WBC ≤10,000/μL) or high risk (WBC >10,000/μL). [14] In addition to higher WBC counts, the following have also been identified as risk factors for early death [13, 12] :
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Increased serum creatinine level
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Older age
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Male sex
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Elevated fibrinogen level
Molecular and immunophenotypic features associated with a higher risk of relapse include expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2. Often, the expression of these markers is associated with a high WBC count. [15]
Since the early 1990s, there have been reports of extramedullary relapse to the skin and central nervous system with APL that are associated with a poor prognosis.
A retrospective analysis examined the outcome of 155 patients with the microgranular variant (M3V) of APL who were treated with ATRA-based therapy in three clinical trials. The analysis revealed no difference in incidence of complications, survival, and response compared with patients who had classical M3 morphology, when outcomes were adjusted for the WBC count or the relapse risk score. [16]
A long-term observational study of 1025 patients with APL in first complete remission found that therapy-related myeloid neoplasms (t-MNs) are a rare but severe complication. Therapy for APL in these patients consisted of ATRA plus anthracycline chemotherapy. Further research is needed to determine how to decrease the frequency of t-MN following ATRA plus anthracycline-based therapy. [17]
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Bone marrow aspirate hybridized with the RARA dual color break-apart probe set (Abbott-Vysis). The cell to the left shows a normal cell with 2 fusion signals, as the 5'RARA probe (orange) and the 3'RARA probe (green) are not separated. The cell on the right shows split signals for one RARA gene, indicating a chromosomal rearrangement disrupting the RARA gene. Image courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
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Bone marrow aspirate hybridized with PML/RARA dual color translocation probe set (Abbott-Vysis). The cell to the right shows a normal cell with 2 separate PML (orange) and RARA (green) signals each. The cell to the left shows an abnormal cell characterized by a single fusion signal juxtaposing the PML and RARA signals, suggestive of a translocation of the 2 genes. Images courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
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Hypogranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
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Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
