Treating AML: Current and Novel Approaches

Acute Myeloid Leukemia^1,2,3,4
There are 40,255 people living with Acute Myeloid Leukemia (AML) in the United States, with an estimated 19,950 new cases that will be diagnosed in 2016. According to SEER, the number of new cases of acute myeloid leukemia was 4.1 per 100,000 men and women per year. The number of deaths was 2.8 per 100,000 men and women per year. These rates are age-adjusted and based on 2009-2013 cases and deaths.

AML, a cancer of the bone marrow and the blood, progresses rapidly without treatment, and can be difficult to treat. AML is characterized by a clonal (starting from a single malignant cell) proliferation of myeloid precursors with a reduced capacity to differentiate into the different blood cells. As a result, there is an accumulation of immature leukemic cells, called “blasts.” These are found in the bone marrow, peripheral blood, and occasionally in other tissues, with a variable reduction in the numbers of normal red blood cells, platelets, and mature granulocytes. AML that transforms from a myelodysplastic syndrome (MDS) is still considered to be AML. In disease that transforms from other myeloproliferative or myelodysplastic/myeloproliferative neoplasms, it helps to know if the acute process arose from an underlying chronic disease. Leukemia that arises from an underlying chronic disease or from previous therapy is less likely to respond to current anticancer treatments and, therefore, it is less likely to be cured.

Signs and Symptoms of AML^2,3,4
General signs and symptoms of the early stages of AML may mimic those of the flu or other common diseases. Signs and symptoms may vary.

Signs and symptoms of acute myeloid leukemia include

• fever
• bone pain
• lethargy and fatigue
• shortness of breath
• pale skin
• frequent infections
• easy bruising
• unusual bleeding, such as frequent nosebleeds and bleeding from the gums.

Diagnosis and Classification of AML^2,3,4
There are several AML subtypes. The subtypes are based on the World Health Organization (WHO) classification. Blood and marrow tests are used to diagnose AML and the AML subtypes. A pathology report, cytogenetic analysis report and a molecular genetics report all provide information that is important for making a diagnosis and in the treatment planning process. Cytogenetic category classification is one of the most important ways to classify AML. A lab test called a “polymerase chain reaction (PCR)” may be done to see if there are certain changes in structure or function in genes. AML cells may have features of red cells, platelets, or white blood cells in addition to myeloblasts (immature white blood cells that form in the bone marrow) or promyelocytes (granulocyte precursors, develop from myeloblasts).

AML Treatment^3,4,5
Despite advances in treating other blood cancers, the standard of care for AML patients has not changed in many years. AML requires immediate and aggressive treatment; however, most patients treated with conventional therapies will have a relapse of their disease. The initial goal of treatment usually is to get the patient into remission. The long-term goal is to cure the disease.

Intensive chemotherapy is required to achieve a complete remission. At least two drugs are combined to treat patients initially. Most AML patients are treated with a combination of drugs often called “7 plus 3,” which includes cytarabine which is given for seven to 10 days and an anthracycline, which is usually started at the same time, but given in the first three days of treatment.

More treatment is needed once a remission is achieved to help prevent a relapse. Postremission treatment may consist of chemotherapy, stem-cell transplantation or low-dose maintenance chemotherapy or a combination of the three.

Some patients are treated in clinical trials with new drugs and new drug combinations or new approaches to stem cell transplantation.

A number of factors affect the choice and outcome of treatment, including:

• AML subtype
• The results of cytogenetic analysis
• Whether the patient has received chemotherapy in the past to treat another type of cancer
• Whether the patient had myelodysplastic syndrome (MDS) or another blood cancer
• Whether the AML is in the central nervous system
• Whether the AML has not responded to treatment or has relapsed
• The presence of systemic infection at diagnosis
• The patient’s age and general health.

Treatment of Relapsed or Refractory Disease^3,4,5
Patients whose AML has relapsed following first-line therapy usually receive additional different chemotherapy followed by allogeneic stem-cell transplantation (if, based on their health and age, they are a good fit for this treatment). Some patients receive other investigational therapies.

Treatment recommendations are based on the age and health of the patient. Age alone is not a contraindication to treatment for older AML patients. Physically fit patients in their 70s and 80s can achieve remission.

Treatment Side Effects^3,4
Some of the side effects AML patients may experience from treatment are temporary and subside once the body adjusts to therapy or when therapy is complete. During the course of therapy and after therapy has completed, healthy new cells begin to grow and develop. Severe side effects are treated on an inpatient basis.

AML decreases the production of normal blood cells. In addition, chemotherapy is toxic to both normal blood cells and AML cells. The normal blood cells are eliminated from the marrow along with AML cells.

For the patient, this may result in a severe deficit of the

• red blood cells (anemia)
• platelets (thrombocytopenia)
• white blood cells called “neutrophils” and “monocytes” (neutropenia and monocytopenia).

Transfusion of red blood cells and platelets is almost always needed for several weeks following treatment. After that, the blood cell counts usually return toward normal reference ranges.

Infection^3,4
During treatment for AML, the deficiency of neutrophils and monocytes (types of white cells) can lead to infection from bacteria and fungi normally present in the environment, on the skin and in the nose, mouth or colon. The risk of infection may be increased because chemotherapy damages the lining of the mouth and intestines, making it easier for bacteria to enter the blood. When the white blood cell count is low and the risk of infection is increased, antibiotics are given to either prevent or treat infection. Transfusion of white blood cells is not generally used for patients who have a low neutrophil count, but transfusion can be used in patients who have a high fever, infection that is unresponsive to antibiotics, blood fungal infections, or septic shock.

Growth factors may be given to adult patients to stimulate the marrow to make new white blood cells. In children, they are used only in special circumstances.

Since many patients are immunocompromised and prone to infection due to disease and/or treatment, the medical staff, caregivers, and loved ones, need to practice frequent and vigorous hand washing and take other precautions to avoid exposing patients to bacteria, viruses and other infection-causing agents.

Patients at home should not delay in seeking medical attention if any signs of infection develop. A rise in temperature to 101°F or higher, or the onset of chills, may be the only sign of infection in a patient with a very low white blood cell count. Other signs of infection may include persistent coughing; tenderness at a site prone to infection, such as the area surrounding the anus or the facial sinuses; sore throat; pain on urination; or frequent loose stools. Patients should not take acetaminophen or any other drugs unless the medication has been approved by their physician.

Chemotherapy Side Effects^3,4
Chemotherapy affects tissues that normally have a high rate of cell turnover. Thus, the lining of the mouth, the lining of the intestines, the skin and the hair follicles may be affected. Common side effects are listed in the Overview of Blood Cancer Treatment Section.

As a result of a very high white blood cell count, some AML patients may have a buildup of uric acid (a chemical normally found inside the cell) in their bloodstream. The uric acid is then excreted in the urine. In addition, the use of chemotherapy may also increase uric acid values. If many cells are killed simultaneously by therapy, the amount of uric acid in the urine can be so high that kidney stones can form. This may seriously interfere with the flow of urine. Drugs such as allopurinol (Zyloprim®) or rasburicase (Elitek®) can be given to minimize the buildup of uric acid in the blood.

Peripheral neuropathy (PN), a potential side effect of several cancer therapies, is manifested as weakness, numbness and pain, usually in the hands and feet.

Please visit The Leukemia & Lymphoma Society’s Acute Myeloid Leukemia webpage for additional reading: www.LLS.org/AML

1. www.lls.org/resource-center/download-or-order-free-publications
2. www.lls.org/leukemia
3. www.lls.org/leukemia/acute-myeloid-leukemia?src1=20032&src2
4. www.nccn.org/professionals/physician_gls/pdf/aml.pdf
5. http://www.lls.org/beat-aml