Acute Promyelocytic Leukemia

Updated: May 07, 2015
  • Author: Sandy D Kotiah, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

Acute promyelocytic leukemia (APL) is a unique subtype of the acute leukemias. It has distinct cytogenetics, clinical features, and biologic characteristics. APL is caused by an arrest of leukocyte differentiation at the promyelocyte stage. The discovery and elucidation of the molecular pathogenesis for APL has led to the first and only targeted therapy for leukemia. It is classified as AML M3 by the old French-American-British (FAB) system and as APL with translocation between chromosomes 15 and 17, ie t(15;17) in the World Health Organization (WHO) classification system.

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 lead 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.

See the images below.

Hypogranular subtype of acute promyelocytic leukem Hypogranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
Regularly hypergranular subtype of acute promyeloc Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
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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. [2]

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:

  • PZLF (promyelocytic zinc finger) t(11;17)(q23;q21)
  • NPM (nucleophosmin) t(5;17)(q35;q12-21)
  • NuMa (nuclear mitotic apparatus) t(11;17)(q13;q21)
  • 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. [3] Cao et al reported on a new karyotype: 46,XY; t(7;16)(q31'q22), t(15;17)(q22;q21). [4]

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. [5]

About 40% of APL cases also express additional chromosomal abnormalities (trisomy 8 and isochromosome 17). These do not appear to impact the overall prognosis.

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Epidemiology

Frequency

United States

Acute promyelocytic leukemia (APL) accounts for 5-15% of all adult leukemias. [6] There are approximately 30,800 cases of acute leukemia diagnosed yearly; about 1000 of these are acute promyelocytic leukemia (APL).

International

The annual incidence of acute promyelocytic leukemia (APL) in Italy is approximately 0.6 per 1 million people.

Mortality/Morbidity

About 21,700 patients die of leukemia yearly. It is not clear how many of these patients die from acute promyelocytic leukemia (APL).

Sex

The incidence of acute promyelocytic leukemia (APL) in males and females is equal.

Age

The median age of onset of acute promyelocytic leukemia (APL) is about age 40 years.

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Race-, Sex-, and Age-related Demographics

Demographic information on acute promyelocytic leukemia (APL) is as follows:

  • Some reports indicate a higher incidence of in Hispanics and a lower incidence in blacks
  • The incidence of APL in males and females is equal
  • The median age of onset of APL is about age 40 years
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