Acute promyelocytic leukemia

Acute promyelocytic leukemia is a subtype of acute myelogenous leukemia (AML), a cancer of the blood and bone marrow. It is also known as acute progranulocytic leukemia; APL; AML with t(15;17)(q24;q21), PML-RARA and variants; FAB subtype M3 and M3 variant.

In APL, there is an abnormal accumulation of immature granulocytes called promyelocytes. The disease is characterized by a chromosomal translocation involving the retinoic acid receptor alpha (RARα or RARA) gene and is unique from other forms of AML in its responsiveness to all trans retinoic acid (ATRA) therapy.

Acute promyelocytic leukemia was first characterized in 1957. From 1950s until the elucidation of its developmental mechanisms in the 1970s, APL had a 100% mortality rate as there was no effective treatment.

Signs and symptoms
Normal differentiation of the white blood cells in the marrow starts with the multi-potent hematopietic stem cells (HSC). Several transcription factors such as PU.1 and C/EB protein alpha have been identified to be important in the white blood cell differentiation process. The HSC generates the lymphoid (B cells and T cells of our immune system) cell line and the myeloid cell lines. The myeloid cell lines have granules in their cytoplasm and they are called granulocytes and are important in fighting infections.

The accumulation of promyelocytes in the bone marrow results in a reduction in the production of normal red blood cells and platelets, resulting in anemia and thrombocytopenia. The bone marrow is unable to produce healthy red blood cells. Either leukopenia (low white cell count) or leukocytosis (high white cell count) may be observed in the peripheral blood.

Symptoms include:
 * Fatigue, weakness, shortness of breath (from anemia)-the decrease of normal red blood cell production or lack there of.
 * Easy bruising and bleeding (from thrombocytopenia and coagulopathy, which prevents blood clotting)
 * Fever and infection (from lack of normal white blood cells)
 * Enlargement of the spleen may cause minor abdominal discomfort

In addition, acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulation (DIC). It is characterized by rapid increase in immature white blood cells resulting in rapid progression of the malignant cell and crowds the bone marrow. This will result in very low red blood cells (anemia) and low platelets which can cause serious bleeding.

Epidemiology
Acute promyelocytic leukemia represents 5-8% of AML in adults. The median age is approximately 40 years, which is considerably younger than the other subtypes of AML (70 years). Without proper medicine and treatment, APL is fatal. The incidence is increased in patients originated in Latin American countries.

APL has a high rate of relapse with conventional chemotherapy.

Pathogenesis
Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor-alpha gene on chromosome 17 (RARα). In 95% of cases of APL, retinoic acid receptor-alpha (RARα) gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene (PML) on chromosome 15, a translocation denoted as t(15;17)(q24;q21). The RAR receptor is dependent on retinoic acid for regulation of transcription.

Four other gene rearrangements have been described in APL fusing RARα to promyelocytic leukemia zinc finger (PLZF), nucleophosmin (NPM), nuclear matrix associated (NUMA), or signal transducer and activator of transcription 5b (STAT5B) genes. All of these rearrangements are ATRA-sensitive, except for PLZF/RARα, which is resistant to ATRA.

The fusion of PML and RAR creates a hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR)molecule and histone deacetylase (HDACL). Although the chromosomal translocation involving RARα is believed to be the initiating event, additional mutations are required for the development of leukemia.

APL most distinguishable trait is the presence of overt coagulopathy (disseminated intravascular coagulation) at diagnosis. The bleeding diathesis is due to the enhanced fibrinolytic activity due to annexin II overexpression and expression of tissue factor by abnormal promyelocytes.

The hypergranular form of APL features faggot cells. This term is applied to these blast cells because of the presence of numerous Auer rods in the cytoplasm. The accumulation of these Auer rods gives the appearance of a bundle of sticks, from which the cells derive their name.

Diagnosis
Acute promyelocytic leukemia can be distinguished from other types of AML based on morphologic examination of a bone marrow aspirate or biopsy as well as finding the characteristic rearrangement. Definitive diagnosis requires testing for the PML/RARα fusion gene. This may be done by polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), or conventional cytogenetics of peripheral blood or bone marrow. This mutation involves a translocation of the long arm chromosomes of 15 and 17.

RARα is a member of the nuclear family of receptors; its ligand, retinoic acid is a form of Vitamin A and acts as a regulator of DNA transcription at multiple sites.

Monitoring for relapse using PCR tests for PML/RARα transcript allows early re-treatment which is successful in many instances.

Treatment
APL is unique among myeloid leukemias due to its sensitivity to all-trans retinoic acid (ATRA), a derivative of vitamin A. Treatment with ATRA dissociates the NCOR-HDACL complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells. ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA is typically combined with anthracycline based chemotherapy resulting in a clinical remission in approximately 90% of patients. ATRA alone is capable of inducing remission but it is short-lived in the absence of anthracycline. Arsenic trioxide is currently being evaluated for treatment of relapsed / refractory disease. After stable remission is induced, the standard of care is to undergo 2 years of consolidation chemotherapy with Methotrexate, Mercaptopurine, and ATRA. Nearly all patients will relapse without consolidation therapy.

ATRA therapy is associated with the unique side effect of retinoic acid syndrome. This is associated with the development of dyspnea, fever, weight gain, peripheral edema and is treated with dexamethasone. The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from the differentiating promyelocytes.

Allogeneic bone marrow or stem cell transplantation are the preferred treatment options for relapsed or refractory disease. Remission with arsenic trioxide has been reported. Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein. Arsenic also increases caspase activity which then induces apoptosis. It does reduce the relapse rate for high risk patients.