Acute Promyelocytic Leukemia (APL)

Treatment of APL

The identification of t(15;17) as the driver of APL and the discovery of treatment targeting this genetic abnormality transformed APL from a rapidly fatal disease to the most curable subtype of AML. Now, appropriate treatment leads to complete remission in about nine of every 10 people with newly diagnosed APL.

The success in remission and cure rates over the past decade is also due to a change in the goal of treatment. The goal was once to achieve a hematologic response, which was defined as a return to normal blood cell counts and no evidence of leukemia cells in the bone marrow. However, studies showed that relapse occurred in many people who had a complete hematologic response. Researchers believed that relapse occurred because leukemia cells were still present but at an amount that was too low to be detected with standard testing. This low level of leukemia cells is known as minimal residual disease.

Advances in technology now allow for a goal of molecular response, which is defined as no evidence of the PML/RAR? gene on RT-PCR testing. Molecular response is much more precise, and complete molecular response (or remission) is associated with lower relapse rates and higher survival rates than complete hematologic response. Because of the importance of response to outcome, your doctor will monitor disease response at several points during treatment.

Components of Treatment: Chemotherapy and a Molecularly Targeted Agent

Treatment of APL involves conventional chemotherapy, such as that used for other types of cancer, as well as one of two molecularly targeted agents, or drugs that are directed at the molecular cause of APL. Conventional chemotherapy drugs are also known as cytotoxic drugs because they kill cells. Chemotherapy drugs are designed to kill cancer cells but they can also harm healthy cells. The dosing of chemotherapy drugs is carefully studied to determine the dose that has the greatest effect against cancer cells while minimizing damage to healthy cells. The type of conventional chemotherapy drug used is usually an anthracycline. Drugs in the anthracycline class are used to treat several types of cancer, especially leukemias. These drugs act by damaging the DNA in cancer (or leukemia) cells, which causes the cells to die.

The molecularly targeted agents used as part of treatment of APL are all-trans retinoic acid (ATRA), a substance that comes from vitamin A, and arsenic trioxide. Currently, ATRA is used more often as first-line treatment of APL, and arsenic trioxide is used for second-line treatment; that is, for relapsed disease. Treatment with either of these drugs is often referred to as differentiation therapy because the drugs help promyelocytes to differentiate, or continue their maturation process. ATRA is the first differentiation therapy to be used for any type of cancer. Arsenic trioxide targets the fused, abnormal gene and acts by promoting differentiation as well as by causing leukemia cells to die.

Three Phases of Treatment

Treatment of APL is divided into three phases, each with its own goal. These phases are induction, consolidation, and maintenance therapy (Table 1). Many clinical trials have been done to evaluate the effectiveness of various drug regimens for each phase. Researchers have found that it is extremely important to use the regimens in the three phases exactly as they were used in a clinical trial; for example, the induction regimen from one trial should be used only with the consolidation and maintenance regimens used in the same trial. The exact regimen and doses used during each phase of treatment are modified according to the risk for relapse, which is determined by the white blood cell count at the time of diagnosis.

Induction Therapy

Induction therapy is started immediately after diagnosis and has three goals: kill as many leukemia cells as possible, restore blood cell counts to normal, and eliminate all signs of disease for an extended period of time. Thus, the overall goal is to induce, or cause a complete hematologic response.

Induction therapy involves treatment with ATRA and anthracycline-based chemotherapy, either idarubicin or daunorubicin and cytarabine. Both combinations have had similar effectiveness in clinical trials. ATRA is taken orally (as a pill), and conventional chemotherapy drugs are given intravenously (through a vein in the arm). The drugs are given on specific days in a cycle of 8-10 days, and the cycle is repeated until a complete hematologic response is achieved.

Your doctor will assess the hematologic response to treatment by determining blood cell counts in a sample of blood drawn from your arm and by evaluating the appearance of blood cells in a sample of bone marrow. Testing on bone marrow is usually done 4-6 weeks after the blood cell counts have returned to normal. RT-PCR testing to monitor response is not done during induction therapy, as it usually takes a longer period of time for a molecular response to occur. Induction therapy leads to complete hematologic response in most people with APL.

During induction therapy, you may receive other types of treatment, known as supportive care. Supportive care involves treatments that prevent, control, or relieve complications and that may improve your quality of life by managing side effects. For people with APL, the supportive care measure used most often is transfusion of fresh frozen plasma and platelets, which helps prevent or control hemorrhage or other possible bleeding disorders. Bleeding complications are common with APL and occur most frequently in the induction therapy phase of treatment. Bleeding complications can be serious, but treatment with ATRA and transfusions has reduced the number of people with APL who are adversely affected by these complications.

Consolidation Therapy

The goal of consolidation therapy is to convert the hematologic response to a durable molecular response. Several combinations of either ATRA or arsenic trioxide and conventional chemotherapy drugs, or conventional chemotherapy drugs alone can be used as consolidation therapy (Table 1). The goal of consolidation therapy is to convert the hematologic response to a durable molecular response. Consolidation therapy may involve lower doses of drugs than those used in induction therapy. Consolidation therapy is usually given as two to four cycles.

The molecular response is assessed at the end of consolidation therapy. If molecular testing indicates a complete response (remission), maintenance therapy is begun. Molecular testing after consolidation is very important, as it can help predict the likelihood of relapse. Positive molecular testing—the presence of t(15;17) and the PML/RARA gene—after consolidation therapy has been shown to be a predictor of relapse; conversely, negative molecular testing—a complete molecular response—has been associated with long-term relapse-free survival. Additional cycles of consolidation therapy can be given if molecular remission has not occurred.

Maintenance Therapy

The goal of maintenance therapy is to ensure that molecular remission is maintained over time. Several studies have shown that using maintenance therapy after consolidation therapy decreases the likelihood of relapse, especially for people with a high risk of relapse. The role of maintenance therapy is unclear, however, for people with low risk of relapse. If recommended by your doctor, maintenance therapy is started only after molecular remission has been shown by RTPCR. The regimen used during maintenance therapy is usually ATRA in some combination with a cytotoxic agent, and lower doses may be used. Maintenance therapy is usually continued for 1-2 years.

If you receive maintenance therapy, your doctor will likely want to continue to monitor your response to treatment. Once molecular testing of a bone marrow sample indicates molecular remission, further testing usually can be done on peripheral blood samples or blood drawn from your arm. Clinical guidelines recommend monitoring with molecular testing at least every 3 months for 2 years for individuals who are at high risk for relapse. Your doctor will decide what testing intervals are best for your particular case. If molecular testing is positive, it is recommended that testing be repeated within 4 weeks and that treatment for relapsed APL be started only if the second test is also positive.

Table 1. Phases of APL Treatment*

Treatment Phase Goal
Destroy as many leukemia cells as possible
Get blood cell counts back to normal levels
Eliminate all signs of the leukemia for an extended period of time
Consolidation Convert hematologic response into durable molecular response
Maintenance Maintain molecular remission

*Treatment drugs according to guidelines developed by the National Comprehensive Cancer Network

Treatment of Relapsed APL

Relapse occurs in up to 30% of people with APL. Arsenic trioxide is an effective treatment for relapsed APL, according to recommendations from cancer experts.

A small number of relapses will be associated with APL in the central nervous system (CNS). Relapse with CNS disease usually occurs in people who have very high white blood cell counts. A treatment option is to deliver chemotherapy drugs directly into the CNS, which is known as intrathecal therapy. Intrathecal therapy may be done as a preventive measure in people with very high white blood cell counts after a second hematologic remission has been achieved. Your doctor can discuss with you the benefits and risks of intrathecal therapy and whether it is necessary or the best option in your particular case. Stem cell transplants, otherwise known as bone marrow transplants, were once recommended for relapsed disease. However, they are now done far less frequently because of the success achieved with ATRA and arsenic trioxide. Stem cell transplant is currently recommended after second-line therapy has produced a second molecular remission. This procedure is high risk and may not be appropriate for some people.

Complications and Treatment Side Effects

Your health care team will monitor you closely during your treatment to prevent and/or control complications and to manage side effects immediately. Make sure to tell your doctor or another member of your health care team if you have any symptoms of side effects. There are many drugs available to manage side effects so you can be more comfortable during treatment and have a better quality of life. In addition, some side effects can be more serious, and early recognition of these effects means they can be treated sooner.

Conventional chemotherapy drugs are associated with a range of side effects, but it is important to remember that side effects do not necessarily occur in everyone who receives the same chemotherapy drug, and that the severity of a side effect will also differ among people. The most common side effects for anthracycline drugs are nausea and vomiting, diarrhea, abdominal cramps, alopecia (hair loss), and infection. Studies have also indicated that anthracyclines can have a late effect on the heart. This side effect usually occurs months or years after treatment has stopped. Talk to your doctor about what follow-up is best to detect any cardiac effects early.

The most common side effects of ATRA are headache, nasal stuffiness, dry red skin, nausea and vomiting, and swelling of the hands and feet. The most common side effects of arsenic trioxide are nausea and vomiting, fatigue, headache, rash, and swelling of the hands and feet. In addition, arsenic trioxide can affect your heart rhythm, and the levels of essential minerals in your blood (such as potassium, magnesium, and calcium) should be monitored before and during treatment with ATRA, to ensure that they stay within a range that will help minimize the risk of this potentially serious side effect. Your doctor will probably order routine blood work and electrocardiograms to monitor any negative effects of the drug. Early interventions may help resolve any negative effects of the drug.

Both ATRA and arsenic trioxide have been associated with a less common but more serious side effect, APL differentiation syndrome, which is characterized by fever, shortness of breath, and weight gain. If these symptoms occur, chest x-rays can confirm the diagnosis of the syndrome. Treatment with a corticosteroid (dexamethasone) is effective at resolving the signs and symptoms of APL diff erentiation syndrome. If your white blood cell count is very high, your doctor may decide to treat you with dexamethasone to prevent APL differentiation syndrome.

Definitions of Terms
Anthracycline Type of chemotherapy drug that kills cancer cells by destroying DNA, which prevents the cells from dividing and proliferating
APL differentiation syndrome Syndrome that may be caused by treatment with ATRA or arsenic trioxide; fluid builds up in the lungs and around the heart; the syndrome can be prevented or controlled with use of a corticosteroid (dexamethasone)
Complete remission Disappearance of the signs and symptoms of cancer (or other disease)
Cytotoxic Defines a drug, such as a chemotherapy agent, that kills cells
Differentiation therapy Treatment that helps promyelocytes differentiate, or continue developing and maturing; ATRA and arsenic trioxide are drugs considered to be differentiation therapy
First-line therapy The first treatment given after diagnosis; first-line therapy for APL is usually ATRA + anthracycline-based chemotherapy
Fresh frozen plasma Clear liquid portion of blood that is frozen and preserved quickly after blood donation; it contains elements that help aid blood clotting and is transfused to help prevent or control bleeding disorders, which can occur with APL
Hematologic response Response to treatment defined by normal blood cell counts and normal morphology
Hemorrhage Excessive bleeding; may be caused by APL, especially early after diagnosis
Intrathecal therapy Treatment that is given by direct injection of a drug into the fluid-filled space between the layers of tissue that cover the spinal cord
Minimal residual disease Level of leukemia cells in the bone marrow that is too low to be detected by standard testing methods; minimal residual disease can lead to relapse
Molecular response Response to treatment defined by the absence of the PML/RARA gene, the cause of APL; molecular response (remission) is more precise than hematologic response and is determined with use of RT-PCR
Molecularly targeted agents Agents that are directed at a specific molecular target; in APL, ATRA and arsenic trioxide are molecularly targeted agents because they act directly on the chromosome translocation that causes APL
Relapse Recurrence of disease
Refractory Failure to respond to standard treatment
Second-line therapy Treatment given when disease does not respond to first-line therapy