Acute promyelocytic leukemia

Synonyms

8

Overview

Acute promyelocytic leukaemia is an aggressive type of acute myeloid leukemia in which there are too many immature blood-forming cells in the blood and bone marrow. It is usually marked by a translocation of chromosomes 15 and 17. Acute promyelocytic leukemia usually occurs in middle-aged adults. Symptoms may include both bleeding and forming blood clots.

Leukaemia is a cancer of the blood. It affects the white blood cells, which are important part of our immune system that fights infection. There are four main types of leukaemia: 1) acute myeloid leukaemia (AML), 2) acute lymphoblastic leukaemia (ALL), 3) chronic myeloid leukaemia (CML) and 4) chronic lymphocytic leukaemia (CLL).

Symptoms

Signs and symptoms of acute promyelocytic leukemia are similar to AML. Symptoms include

  • Anemia
  • Fatigue
  • Weakness
  • Difficulty breathing (dyspnea)
  • Low platelets (thrombocytopenia) leading to easy bleeding
  • Fever
  • Low white blood cells (leucopenia) leading to infection
  • Decreased platelets, white, and red blood cells (pancytopenia)
  • Elevated white blood cells (leukocytosis) occurs in 10-30%
  • Coagulopathy (including DIC)

Easy bleeding from low platelets may include:

  • Bruising (ecchymosis)
  • Gingival bleeding
  • Nose bleeds (epistaxis)
  • Increased menstrual bleeding (menorrhagia)

In addition, acute promyelocytic leukemia is frequently associated with bleeding caused by disseminated intravascular coagulation (DIC).

Causes

Acute promyelocytic leukemia (APL) is caused by a chromosomal translocation (rearrangement of material) that occurs in some of the body's cells during a person's lifetime (a somatic mutation). The translocation involves the fusion of two genes: the PML gene on chromosome 15 and the RARA gene on chromosome 17.  The protein produced by this fusion is referred to as PML-RARα. The PML-RARα protein functions differently than what is typically produced by the normal PML and RARA genes. 
As a result of the abnormal function, blood cells become "stuck" at the promyelocyte stage and they proliferate (reproduce) abnormally. Excess promyelocytes then accumulate in the bone marrow, disrupting the formation of normal white blood cells and leading to APL. Translocations involving the RARA gene and other genes have been identified in only a few cases of APL.

However, there are a number of things that are known to increase risks of developing APL. These are:

  • Cigarette smoke
  • Having certain bone marrow diseases, namely antecedent haematological disorder (AHD)
  • Some anti-cancer treatments
  • Exposure to high levels of radiation
  • Exposure to some chemicals

People who are receiving radiotherapy or chemotherapy to treat some other cancers may go on to develop APL later on - in particular, women treated with certain drugs for breast cancer. The risk of developing APL from bone marrow disorders is low. When this does happen it is called secondary APL.

APL is not an inherited condition that can be passed on through the family.

Prevention

Avoiding risk-factors :

Smoking is by far the most significant controllable risk factor for AML, and quitting offers the greatest chance to reduce a person’s risk of AML. Of course, non-smokers are also much less likely than smokers to develop many other cancers, as well as heart disease, stroke, and some other diseases.

Treating some other cancers with chemotherapy and radiation may cause secondary (post-treatment) leukemias. Doctors are trying to figure out how to treat these cancers without raising the risk of secondary leukemia. But for now, the obvious benefits of treating life-threatening cancers with chemotherapy and radiation must be balanced against the small chance of getting leukemia years later.

Avoiding known cancer-causing chemicals, such as benzene, can lower the risk of getting AML. But most experts agree that exposure to workplace and environmental chemicals seems to account for only a small portion of leukemia cases.

Diagnosis

Acute promyelocytic leukaemia can’t be diagnosed without doing tests. This involves a routine blood test, where a small sample is taken and examined in a laboratory.

The results of the test will reveal whether there are leukaemia cells in the blood. Almost all patients with acute leukaemia have a high white cell count, almost entirely made up of leukaemia cells. Usually the numbers of normal red and white blood cells and platelets are all reduced.

Modern blood cell counting machines, which are usually used to help diagnose each patient’s type of leukaemia more precisely, cannot distinguish between APL and other types of AML. More sophisticated genetic tests are used to do this. More sophisticated genetic tests are used to do this.

If APL is suspected some parts of a patient’s treatment may be started immediately. This is because APL is a very aggressive blood cancer and there is a strong risk that patients may suffer from fatal bleeding if not treated properly.

Most patients will also have a bone marrow sample taken to confirm the diagnosis. The sample is taken from the hipbone and as the procedure is quite uncomfortable, patients are given local anaesthetic. A high proportion of leukaemia cells in the bone marrow is a sign of APL.

Genetic tests:

Tests that detect genetic changes in cells are used to identify abnormalities that occur once the condition has developed. These are called cytogenetic tests. These tests are really important in helping doctors to decide on the best treatment for every patient.

In the case of APL, the leukaemia cells carry a cancer gene called PML/RARα , which is picked up by cytogenetic tests. A small minority of APL patients, who do not have this gene in their leukaemia cells, do not respond well to conventional APL treatment and so alternative treatments are offered. These tests also help distinguish APL from other forms of AML that appear to be very similar, but actually require very different treatments.

Patients who have been diagnosed with APL are also given tests to check that their blood is clotting properly. This is important as some patients with APL develop a serious condition called disseminated intravascular coagulation (DIC), which causes excessive bleeding.

Various other tests are done to check every patient’s general health before they start full treatment. This is to identify patients who may not be able to tolerate particular treatments. They will be offered alternatives.

All tests are completed before the patient begins treatment to make sure they receive the best possible care. This is particularly important for APL patients, as they may suffer very serious side effects if treated for AML, rather than APL.

Prognosis

Acute promyelocytic leukaemia (APL) is much more successfully treated now than other forms of acute myeloid leukaemia (AML). Following treatment more than 70% of patients with APL are cured.

The likelihood of being cured depends very much on age, general fitness, the subtype of APL and how far the disease had progressed when the patient was diagnosed. Younger patients who are in good general health are more likely to respond better to treatment.

Treatment

Most cases of acute promyelocytic leukemia (APL) are treated with an anthracycline chemotherapy drug (daunorubicin or idarubicin) plus the non-chemotherapy drug, all-trans-retinoic acid (ATRA), which is a relative of vitamin A. This treatment leads to remission in 80% to 90% of patients.

Patients who cannot tolerate an anthracycline drug may get ATRA plus another drug called arsenic trioxide. Arsenic trioxide has also proven to be an effective alternative for the 20% to 30% of patients with APL who don't respond to initial treatment or who relapse. If treatment with arsenic trioxide achieves a remission, further courses of this drug may be given. An autologous stem cell transplant may also be an option. If a second remission is not achieved, treatment options may include an allogeneic stem cell transplant or taking part in a clinical trial.

Approved therapies:

  • Arsenic trioxide (Trisenox) - FDA-approved indication: For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) transloc 
  • Tretinoin (Vesanoid) - FDA-approved indication: Induction of remission in patients with acute promyelocytic leukemia who are refractory to or unable to tolerate anthracycline based cytotoxic chemotherapeutic regimens.

Resources

Refer to Research Publications.