Acute Promyelocytic Leukaemia

Acute promyelocytic leukaemia is a rare blood cancer that was once rapidly fatal but has been transformed into one of the most curable forms of leukaemia through revolutionary treatment advances.

Table of contents

• What is acute promyelocytic leukaemia?
• Other names for this condition
• How common is APL?
• What causes APL?
• Risk factors
• Signs and symptoms
• Complications
• How is APL diagnosed?
• Treatment
• Outlook and survival
• Historical development

What is acute promyelocytic leukaemia?

Acute promyelocytic leukaemia (APL) is a rare blood cancer and a distinct subtype of acute myeloid leukaemia (a cancer affecting the bone marrow and blood)^[1]. APL happens when immature white blood cells called promyelocytes (white blood cells at an early stage of development) don’t fully develop and become cancerous^[8].

In APL, a genetic mutation (a change in the DNA) creates abnormal white blood cells that multiply uncontrollably in your bone marrow (the soft, spongy tissue inside bones where blood cells are made)^[1]. These abnormal cells accumulate in the bone marrow, reducing its ability to make normal red blood cells, white blood cells and platelets (cells that help blood clot)^[7].

The disease is characterized by a specific chromosomal abnormality involving a translocation between chromosomes 15 and 17^[2]. This means pieces of two different chromosomes break off and swap places.

APL leukemia, M3-leukemia, APML

How common is APL?

APL is rare, affecting approximately 30,000 people in the United States each year^[1]. Another source indicates that about 600 to 800 people are diagnosed with APL every year in the United States^[4]. The condition occurs in approximately one in every 250,000 people^[7].

APL accounts for about 10 to 15 percent of all newly diagnosed acute myeloid leukaemia cases^[2][11]. In children, APL accounts for 4 to 10 percent of all acute myeloid leukaemia cases^[7].

Most people are in their 30s when they receive an APL diagnosis^[1]. The average age at diagnosis is around 40 years old^[4], though APL most commonly occurs in adults around age 40 and in children between ages eight to ten^[7].

What causes APL?

APL results from a specific genetic change that is not inherited. This condition happens when two genes that drive blood cell development fuse together to create an abnormal gene called PML-RARα^[1]. You don’t inherit this genetic mutation—it happens randomly during your lifetime, and experts don’t know what triggers the change^[1].

In about 95 percent of APL cases, this involves a balanced translocation, commonly written as t(15;17)(q22;q12-21), which leads to the fusion of the PML gene on chromosome 15 with the RARA gene on chromosome 17^[4][7]. The mutation occurs after a person’s conception and is acquired during their lifetime, present only in certain cells^[5].

The PML-RARα fusion protein functions differently than the normal proteins produced by the PML and RARA genes. The RARA gene produces a protein called RARα that helps control the production of other genes important in the maturation of white blood cells beyond the promyelocyte stage^[5]. The PML gene acts as a tumour suppressor, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way^[5].

The abnormal PML-RARα protein interferes with the normal function of both the PML and RARα proteins. As a result, blood cells are stuck at the promyelocyte stage, and they proliferate abnormally^[5]. The mutation keeps white blood cells from developing as they should, and the immature white blood cells multiply uncontrollably, crowding out healthy blood cells and platelets^[1].

In about 10 percent of cases, a successful cytogenetic analysis may lack the classic t(15;17) translocation. In the majority of such cases, molecular analysis nevertheless reveals an underlying PML-RARα fusion transcript formed as a result of cytogenetically cryptic or complex insertion events^[11]. In other rare cases, rearrangements of chromosome 17 lead to the fusion of RARA to alternative partner genes^[11].

Risk factors

Several factors may increase the risk of developing APL, though the disease is not inherited. Risk factors include^[7]:

• Age—risk increases as age increases
• Hispanic ethnicity
• Obesity
• Occupational exposures such as electromagnetic fields and toxic chemical agents such as benzene
• Previous treatment with chemotherapy or radiation

Signs and symptoms

Acute promyelocytic leukaemia symptoms develop when your bone marrow can’t make normal numbers of red blood cells, white blood cells and platelets. If you have low blood cell levels (a condition called pancytopenia), you may develop serious symptoms, including anaemia (low red blood cells), bleeding issues, and infections^[1].

The symptoms of APL tend to be similar to acute myeloid leukaemia in general. Common symptoms include^[1][4][7]:

• Fatigue and weakness from anaemia
• Frequent infections or fever because of low levels of infection-fighting white blood cells
• Unintentional weight loss because your metabolism speeds up and you burn energy from food
• Pale skin
• Difficulty breathing
• Pain in joints and bones
• Chills
• Depression

Bleeding symptoms

People with APL are especially susceptible to developing bleeding problems because they don’t have enough platelets or blood clotting factors^[5]. Platelets slow or stop bleeding, and blood clotting factors help make clots in your blood^[1]. The abnormal bleeding and bruising occur in part because of the low number of platelets in the blood (a condition called thrombocytopenia) and also because the cancerous cells release substances that cause excessive bleeding^[5].

APL bleeding symptoms include^[1][4][7]:

• Easy bruising from blood pooling under your skin
• Small red dots under the skin called petechiae
• Bleeding from any site, including bleeding gums, nosebleeds, or heavy menstrual bleeding
• Blood in the urine
• Poop that looks black or has red streaks of blood, which happens if you have bleeding in your gut
• Difficulty moving your arms and legs, headaches, or vision issues from bleeding into your brain

Complications

APL can be life-threatening, causing severe bleeding that quickly gets worse^[1]. The disease is characterized by a severe bleeding tendency, and historically had been considered one of the most fatal types of acute myeloid leukaemia^[2][11].

Disseminated intravascular coagulation (a serious disorder in which proteins that control blood clotting become overactive) is the most common life-threatening complication associated with APL^[15]. Because of the high risk for this condition, a diagnosis of APL does not need to be confirmed before beginning treatment^[15].

You should contact a healthcare provider or go to the emergency department if you have bleeding that you can’t control, like bleeding from a cut or injury, or if there’s lots of blood in the toilet after you poop or pee, or if you have bleeding gums^[1].

During treatment, unique complications such as disseminated intravascular coagulation and differentiation syndrome (a complication that can occur during treatment with certain medications) can occur. Prompt recognition of complications is imperative^[2].

How is APL diagnosed?

Healthcare providers typically order several tests to diagnose APL. Doctors will look at your blood, bone marrow, and genes^[8]. Because the disease can progress rapidly and become life-threatening if treatment doesn’t start right away, fast diagnosis and initiation of appropriate treatment are vital^[2][7].

Your doctor will give you a physical exam and review your medical history to diagnose APL^[7]. Common diagnostic tests include:

Complete blood count (CBC): APL creates abnormal white blood cells. This test shows the number of blood cells and platelets in a blood sample. It also determines the number of platelets, white blood cells, and red blood cells in a sample of your blood, and allows doctors to assess liver and kidney function and detect signs of inflammation and infection^[1][7].

Peripheral blood smear: Providers may see high levels of granules or Auer rods (distinctive rod-shaped structures) inside promyelocytes, a specific type of white blood cell^[1].

Bone marrow biopsy or aspiration: Providers order these to get samples of your bone marrow cells or bone tissue for analysis. Your doctor removes a small bone marrow or bone tissue sample using a thin, hollow needle. Analysis of the sample detects abnormal white blood cells or promyelocytes^[1][7].

Flow cytometry: In this test, pathologists examine the surface of abnormal cells, checking for specific protein patterns that confirm APL^[1].

Polymerase chain reaction and other molecular tests: These tests identify the PML-RARα fusion gene that characterizes APL^[1].

Clotting tests: These tests measure how quickly your blood can clot after an injury. Doctors determine your risk for bleeding with these tests^[7].

Imaging tests: X-rays and other imaging studies may be performed to check for complications or the spread of disease^[7].

Treatment

APL is a serious condition with life-threatening symptoms, including excessive bleeding, which come on suddenly and quickly get worse. Thanks to treatment that’s an innovative combination of chemotherapy and non-chemotherapy drugs, healthcare providers can treat and often cure acute promyelocytic leukaemia^[1].

With advances in treatment regimens, outcomes have drastically improved, with complete remission rates approaching 100 percent in regimens based on all-trans retinoic acid (ATRA, also known as tretinoin) and event-free survival rates recorded as more than 90 percent^[2]. Furthermore, two-year overall survival probability and disease-free survival rates exceed 90 percent with these regimens^[2].

The management of patients with APL is comprised of three phases: induction, consolidation, and maintenance^[10][15]. This requires many patients to be on some type of therapy for several years^[15].

Induction treatment

Induction is the first phase of treatment given for newly diagnosed APL. The goal of induction treatment is to kill all the leukaemia cells in the blood and lessen the number of leukaemia cells in the bone marrow to normal, bringing about a complete remission or complete response^[10].

Since patients often present with bleeding and clotting problems, the initial goal of treatment is to reduce the risk of severe bleeding and death^[15]. Because of the high risk for life-threatening complications, a diagnosis of APL does not need to be confirmed to begin treatment^[15].

Induction treatment usually involves all-trans retinoic acid (ATRA) along with chemotherapy. ATRA is a drug derived from vitamin A^[10]. It must be followed by other chemotherapy drugs or given with other chemotherapy drugs to bring about remission, which might take about two months^[10].

The chemotherapy drugs used in combination will depend on whether the cancer is low or high risk. Low risk is defined as having a white blood cell count less than or equal to 10,000 per cubic millimeter; high risk is a white blood cell count greater than 10,000 per cubic millimeter^[10].

Induction treatment for APL may include^[10]:

• ATRA and arsenic trioxide (ATO)
• ATRA and idarubicin or daunorubicin
• ATRA, idarubicin or daunorubicin, and arsenic trioxide
• ATRA, arsenic trioxide, and gemtuzumab ozogamicin (a targeted therapy drug)
• ATRA and idarubicin or daunorubicin with or without cytarabine

A bone marrow biopsy is usually done about a month or two after treatment starts. Once APL is in remission, consolidation therapy can start^[10].

Consolidation treatment

Consolidation is the second phase of treatment given for APL. Consolidation treatment starts once APL is in remission. The goal of consolidation treatment is to treat any leukaemia cells that are still in the blood or bone marrow once remission is reached. It is done to maintain complete remission and prevent relapse^[10].

Consolidation usually involves the same drugs used during induction, though the specific regimen depends on how the patient responded to initial treatment and their risk category^[10].

Maintenance treatment

Maintenance is a third phase of treatment. It follows consolidation and involves low-dose chemotherapy for a longer period of time^[10]. The specific drugs and treatments used in the different phases of APL treatment depend on whether you are low or high risk or have any cardiac issues^[10].

Management of complications

Management of coagulopathy (abnormal blood clotting) may include transfusions, administration of fresh frozen plasma, cryoprecipitate, and fibrinogen. When patients experience differentiation syndrome, they must be educated on the need to hold treatment with ATRA and arsenic trioxide until severe symptoms, such as renal failure or respiratory distress, resolve. They must also understand that medication dosages will need to be adjusted when treatment is resumed^[15].

Outlook and survival

Today, prognoses for APL have drastically improved. Ten-year survival rates are estimated to be approximately 80 to 90 percent according to one study^[4]. Around 85 to 90 percent of individuals treated for APL achieve complete remission, and around 75 percent of people in remission for APL survive cancer-free for five years^[7].

Most people with APL respond well to treatment and have a good prognosis (outlook)^[8]. With current therapy, it is now possible to treat this disease without the use of traditional cytotoxic chemotherapy^[9].

Treatment can cure most cases of APL, but it can come back^[1]. Patients who have been diagnosed with APL and have maintained a complete response for at least three years have a very low incidence of late recurrences^[15].

As part of long-term follow-up and survivorship care, patients should be screened for second malignancies on a regular basis via mammograms and colonoscopies^[15].

Historical development

Acute promyelocytic leukaemia was first characterized in 1957 by French and Norwegian physicians as a hyperacute fatal illness, with a median survival time of less than a week^[4][11]. It was defined for the first time in the literature as a distinct clinical entity with a “rapid downhill course” characterized by a severe bleeding tendency^[2][11].

Before using anthracyclines in APL therapy in 1973, no effective treatment was available^[11]. Anthracycline monotherapy was first successfully used in APL in 1973. Induction therapy with anthracyclines improved response rates (55 to 88 percent) and survival in APL; however, these improvements were suboptimal^[11].

The breakthrough in the treatment of APL came with the introduction of ATRA in the mid-1980s, which increased the remission rate, but approximately 30 percent of patients would still relapse^[2]. Subsequent trials investigated the combination of ATRA and chemotherapy, which raised the event-free survival rate^[2].

Later, the development of ATRA, chemotherapy, and arsenic trioxide combinations turned APL into a highly curable malignancy^[2]. Regimens have been altered in recent years with the addition of arsenic trioxide and anthracyclines, which have further improved outcomes^[2].