eMedicine Specialties > Hematology > Stem Cells and Disorders

Acute Promyelocytic Leukemia

Author: Sandy D Kotiah, MD, Fellow in Hematology Oncology, Thomas Jefferson University Hospital
Coauthor(s): Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Contributor Information and Disclosures

Updated: Mar 13, 2009

Introduction

Background

Acute promyelocytic leukemia (APL) is a unique subtype of the acute leukemias. It has distinct cytogenetics, clinical features, and biologic characteristics. Acute promyelocytic leukemia (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 acute promyelocytic leukemia (APL) with translocation between chromosomes 15 and 17, ie t(15;17) in the World Health Organization (WHO) classification system.

Acute promyelocytic leukemia (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 acute promyelocytic leukemia (APL) patients during a visit to France in 1985. There were several publications in 1990 that 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 of acute promyelocytic leukemia (APL). A potentially fatal complication of ATRA treatment, called retinoic acid syndrome, was also described. Over the past 50 years, acute promyelocytic leukemia (APL) has transformed from a highly fatal disease to a highly curable disease. 

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Leukemia.

Acute promyelocytic leukemia. Image courtesy of D...

Acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.

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Acute promyelocytic leukemia. Image courtesy of D...

Acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.


Hypergranular subtype of acute promyelocytic leuk...

Hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.

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Hypergranular subtype of acute promyelocytic leuk...

Hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.


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-RAR alpha. 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 (RAR alpha) 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, the retinoid acid alpha gene is bound by nuclear corepressor factor, and this causes transcriptional repression. In the presence of retinoic acid, the genes are activated and terminal differentiation of promyelocytes occurs.

The promyelocytic gene (PML) is encoded by the long arm of chromosome 15, is expressed ubiquitously, and is thought to be involved in apoptosis and tumor suppression. There are 3 possible isoforms caused by these translocations. The breakpoint in chromosome 17 is consistently found in intron 2, but varies in chromosome 15. The 3 breakpoints on the PML gene can occur at intron 3 (L form), intron 6 (S form), and exon 6 (V form). It has been reported that the S form is associated with a shorter remission duration and overall survival compared with the L form.2

The fusion gene product between the 2 chromosomes causes the retinoic acid receptor to bind more tightly to the nuclear corepressor factor. Therefore, the gene cannot be activated with physiologic doses of retinoic acid. In about 5% of cases, there are alternative rearrangements of chromosome 17q21 with other gene partners. These include 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), and STAT5b (17;17)(q11;q21).

It is important to note that the nature of the fusion partner significantly impacts the disease characteristics and response to therapy. For example, acute promyelocytic leukemia (APL) with PLZF-RAR alpha is not sensitive to retinoic acid or as sensitive to chemotherapy.3

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

Frequency

United States

Acute promyelocytic leukemia (APL) accounts for 5-15% of all adult leukemias.4  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).

Race

Some reports indicate a higher incidence of acute promyelocytic leukemia (APL) in Hispanics and a lower incidence in blacks.

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.

Clinical

History

The majority of signs and symptoms of acute promyelocytic leukemia (APL) are also seen with the other cases of acute myelogenous leukemia (AML). These include fatigue, weakness, and dyspnea related to anemia; easy bruising or bleeding caused by thrombocytopenia or coagulopathy; and fever and infection related to leukopenia. Most cases present as pancytopenia. About 10-30% of cases present with leukocytosis.5

Acute promyelocytic leukemia (APL) differs from AML in that most patients present with coagulopathy. The coagulopathy has been described as DIC with associated hyperfibrinolysis. Acute promyelocytic leukemia (APL) has been associated with low levels of plasminogen, alpha2-plasmin inhibitor, and plasminogen activator inhibitor 1 found in fibrinolytic states. There is increased expression of annexin II, a receptor for plasminogen and plasminogen-activating factor, on the surface of leukemic promyelocytes.6 This leads to overproduction of plasmin and fibrinolysis.

It is important to treat the coagulopathy as a medical emergency. In 40% of untreated patients, pulmonary and cerebral hemorrhages can occur. It takes 5-8 days for coagulopathy to improve with treatment.

Physical

The physical examination can reveal pallor, petechiae, and areas of ecchymoses. There can be bleeding from the gums. A flow murmur can be heard with severe anemia. Patients can present with neurologic deficits or headaches if there is central nervous system (CNS) involvement.

More on Acute Promyelocytic Leukemia

Overview: Acute Promyelocytic Leukemia
Differential Diagnoses & Workup: Acute Promyelocytic Leukemia
Treatment & Medication: Acute Promyelocytic Leukemia
Follow-up: Acute Promyelocytic Leukemia
Multimedia: Acute Promyelocytic Leukemia
References
Further Reading
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References

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Keywords

acute promyelocytic leukemia, APL, acute leukemia, progranulocytic leukemia, acute myeloid leukemia, ATRA, all-trans retinoic acid, all-trans retinoic acid syndrome, APL differentiation syndrome, disseminated intravascular coagulation, DIC,

genetics, pathology, PML-RAR alpha fusion protein, fibrinolysis, coagulopathy, PETHEMA, European APL 2000, GINEMA, hypergranular, microgranular variant, Auer rods, arsenic trioxide, relapse, RT-PCR assay, induction therapy, consolidation therapy, maintenance therapy, bone marrow transplant

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Contributor Information and Disclosures

Author

Sandy D Kotiah, MD, Fellow in Hematology Oncology, Thomas Jefferson University Hospital
Disclosure: Nothing to disclose.

Coauthor(s)

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Clarence Sarkodee-Adoo, MD, Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ronald A Sacher, MB, BCh, MD, FRCPC, Director of the Hoxworth Blood Center, Professor, Departments of Internal Medicine and Pathology, University of Cincinnati Medical Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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