ABOUT THE DISEASE

What is Acute Promyelocytic Leukemia?

Acute promyelocytic leukemia (APL) is a unique subtype of acute leukemia which occurs when white blood cells remain immature instead of differentiating into their individual subtypes. This halting of the differentiation process causes the bone marrow to become overloaded with immature white blood cells. This also means that there is now a shortage of normal white blood cells, which is what causes most of the symptoms associated with the disease. The discovery and explanation of the development of the disease at the molecular level for APL has led to the first and only targeted therapy for leukemia. APL was first described as an entity in the late 1950s in Norway and France as a fast-acting fatal illness associated with profuse bleeding. ^[1] In 1959, Jean Bernard and others described the association of APL with a severe susceptibility to bleeding that lead to blood clots forming throughout the small blood vessels in the body, as well as hyperactivity of the fibrinolysis system, which is responsible for removing blood clots. Acute promyelocytic leukemia (APL) is defined by the structure and function of the chromosomes of the patient. Over 95% of APL cases are characterized by a genetic mutation involving a crossover of genetic material between chromosome 17 and chromosome 15. This leads to an abnormal fusion protein called PML-RARA, where part of the PML gene fuses with part of the retinoic acid alpha receptor (RARA) gene. The RARA gene is found in the larger portion of chromosome 17. It is mainly expressed in cells that produce blood cells and platelets. It also has an important role in regulating gene expression. In the absence of retinoid acid, RARA is bound by nuclear corepressor factor, which causes the gene to be silenced. In the presence of retinoic acid, RARA is activated and terminal differentiation of immature white blood cells occurs. The promyelocytic gene (PML) is encoded by the larger portion of chromosome 15 and is constantly expressed. PML is thought to be involved in apoptosis and tumor suppression.

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.

Induction

Treatment of most cases of APL is done differently from usual Acute myelocytic leukemia (AML) treatment. Initially, treatment begins with the administration of the non-chemotherapy drug all-trans-retinoic acid (ATRA), which is most often combined with an anthracycline chemotherapy (chemo) drug (either daunorubicin or idarubicin), which may also be used in combination with the chemo drug cytarabine (ara-c). For patients who cannot tolerate an anthracycline drug, another possibility would be to give ATRA plus another differentiating drug called arsenic trioxide (Trisenox). The aim of this phase of treatment is to clear the blood of leukemia cells (called blasts) and reduce the blast number in the bone marrow to normal levels.

Consolidation

After recovering from the initial induction treatment, Patients with APL then receive post-remission treatment. What drugs are used depends on what was given for induction, and are administrated several times over a given number of weeks in cycles. 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

The aim here is to kill whatever few leukemia cells remain that cannot be seen due to their low number.

Maintenance

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. This is common for APL, but rare in other types of AML.