Acute promyelocytic leukemia
ACUTE PROMYELOCYTIC LEUKEMIA
ACUTE PROMYELOCYTIC LEUKEMIA DEFINITION
Acute promyelocytic leukemia is a form of acute myeloid leukemia, a cancer of the blood-forming tissue (bone marrow). In normal bone marrow, hematopoietic stem cells produce red blood cells (erythrocytes) that carry oxygen, white blood cells (leukocytes) that protect the body from infection, and platelets (thrombocytes) that are involved in blood clotting. In acute promyelocytic leukemia, immature white blood cells called promyelocytes accumulate in the bone marrow. The overgrowth of promyelocytes leads to a shortage of normal white and red blood cells and platelets in the body, which causes many of the signs and symptoms of the condition.
People with acute promyelocytic leukemia are especially susceptible to developing bruises, small red dots under the skin (petechiae), nosebleeds, bleeding from the gums, blood in the urine (hematuria), or excessive menstrual bleeding. The abnormal bleeding and bruising occur in part because of the low number of platelets in the blood (thrombocytopenia) and also because the cancerous cells release substances that cause excessive bleeding.
The low number of red blood cells (anemia) can cause people with acute promyelocytic leukemia to have pale skin (pallor) or excessive tiredness (fatigue). In addition, affected individuals may heal slowly from injuries or have frequent infections due to the loss of normal white blood cells that fight infection. Furthermore, the leukemic cells can spread to the bones and joints, which may cause pain in those areas. Other general signs and symptoms may occur as well, such as fever, loss of appetite, and weight loss.
Acute promyelocytic leukemia is most often diagnosed around age 40, although it can be diagnosed at any age.
ACUTE PROMYELOCYTIC LEUKEMIA CAUSES
Commonly called APL, a malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid line of cells and an excess of immature cells called promyelocytes. APL is due to a translocation (an exchange of chromosome material) between chromosomes 15 and 17 which is symbolized t (15;17). This translocation is not a mere marker of APL. It is the cause of APL.
APL was first recognized as a distinct disease entity in 1957. It accounts for 5-10% of cases of acute myeloid leukemia (AML). The peak incidence of APL is in young adults. APL is considered a type of AML and is classified as the M3 variant of AML in the internationally accepted French-American-British (FAB) Classification.
ACUTE PROMYELOCYTIC LEUKEMIA 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.
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. Cao et al reported on a new karyotype: 46,XY; t(7;16)(q31’q22), t(15;17)(q22;q21).
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.
About 40% of APL cases also express additional chromosomal abnormalities (trisomy 8 and isochromosome 17). These do not appear to impact the overall prognosis.
ACUTE PROMYELOCYTIC LEUKEMIA SYMPTOMS
The signs and symptoms of APL are nonspecific and include fatigue (feeling tired), minor infections, or a tendency to bleed (hemorrhagic diathesis). There is usually pancytopenia with low levels of red blood cells (anemia), low levels of the granulocytes and monocytes (types of white blood cells that fight infections), and low levels of platelets (that are needed for blood to clot normally). Patients with APL may therefore receive transfusions.
ACUTE PROMYELOCYTIC LEUKEMIA DIAGNOSIS
APL is consistently associated with a disorder that resembles (but is not identical to) disseminated intravascular coagulation (DIC). There is in APL a pronounced tendency to hemorrhage (bleeding). The bleeding can manifest itself as petechiae (little bleeding spots in the skin or elsewhere), small ecchymosis (bruises), epistaxis (nose bleeds), bleeding in the mouth, hematuria (blood in the urine), bleeding from venipuncture and bone marrow sites and in girls and women who are menstruating may have menometrorrhagia (excessive irregular menstrual bleeding). The hemorrhagic diathesis (bleeding condition) may precede the diagnosis of leukemia by 2-8 weeks.
ACUTE PROMYELOCYTIC LEUKEMIA TREATMENT
Early diagnosis and treatment of acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia (AML), is important because patients with APL can develop serious blood-clotting or bleeding problems. This is less often a problem now that treatment includes differentiating drugs like all-trans-retinoic acid (ATRA). Other treatments might include chemotherapy and transfusions of platelets or other blood products.
The treatment of most cases of APL differs from usual AML treatment. Initial treatment includes the non-chemotherapy drug all-trans-retinoic acid (ATRA), which is most often combined with an anthracycline chemotherapy (chemo) drug (daunorubicin or idarubicin), sometimes also with the chemo drug cytarabine (ara-c).
Another option is to give ATRA plus another differentiating drug called arsenic trioxide (Trisenox). This is often used in patients who can’t tolerate an anthracycline drug, but it’s an option for other patients as well.
As with other subtypes of AML, patients with APL then receive post-remission treatment. What drugs are used depends on what was given for induction. Some of the options include:
- An anthracycline along with ATRA for a few cycles (sometimes different anthracyclines are used in different cycles)
- An anthracycline plus cytarabine for at least 2 cycles
- Arsenic trioxide for 2 cycles (over about 2½ months), then ATRA plus an anthracycline for 2 cycles
- ATRA plus arsenic trioxide for several cycles
For some patients, consolidation may be followed by maintenance therapy with ATRA for at least a year. Sometimes low doses of the chemo drugs 6-mercaptopurine (6-MP) and methotrexate are given as well.