Definition of Acute promyelocytic leukemia

Reviewed on 6/3/2021

Acute promyelocytic leukemia: 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.

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.

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.

The t(15;17) translocation in APL is the result of two chromosome breaks: one in chromosome 15 and the other in chromosome 17. The break in chromosome 15 disrupts the promyelocytic leukemia (PML) gene which encodes a growth suppressing transcription factor. And the break in chromosome 17 interrupts the retinoic acid receptor alpha (RARa) gene which regulates myeloid differentiation. The translocation creates a PML/RARa fusion gene. It produces a chimeric protein that arrests the maturation of myeloid cells at the promyelocytic stage. (It reduces terminal cell differentiation.) And this leads to the increased proliferation of promyelocytes.

The treatment of APL differs from that for all other forms of AML. Most APL patients are now treated with all-trans-retinoic acid (ATRA). ATRA is a form of "differentiation therapy." It activates the retinoid receptor RAR and causes the promyeloctes to differentiate (to mature) and this deters them from proliferating.

ATRA can induce a complete remission in most patients with APL by causing the APL-blasts to mature. However, ATRA cannot eliminate the leukemic clone. ATRA is therefore used in combination with chemotherapy including an anthracycline drug. Survival is better with the combination of ATRA and chemotherapy than chemotherapy alone in newly diagnosed APL, because ATRA + chemotherapy makes for a slightly higher rate of complete remissions while allowing significantly fewer relapses. Maintenance treatment with ATRA, and possibly with low-dose chemotherapy, further reduces the incidence of relapse.

The prognosis for APL depends on a number of factors including the white blood cell (WBC) count at the time of diagnosis, etc. Overall, more than 90% of patients with newly diagnosed APL today can achieve complete remission, and about 75% can be cured by the combination of ATRA and chemotherapy. In patients who relapse after remission, treatment may include arsenic trioxide.

The advent of ATRA therapy revolutionized the treatment of APL and markedly improved the prognosis (the outlook). ATRA syndrome is a serious side effect of ATRA treatment and includes fever, respiratory distress, and hypotension (abnormally low blood pressure). The ATRA syndrome can be prevented by the addition of chemotherapy and/or dexamethasone if the WBC is increasing.

In sum, APL is a form of acute myeloid leukemia caused by a specific chromosome translocation t(15;17). APL is associated with a characteristic cellular picture classified as M3 in the FAB Classification and responds favorably to treatments including retinoids, chemotherapy and, most recently, arsenicals.


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