Acute Myeloid Leukemia

Signs and Symptoms

Acute myeloid leukemia (AML) is a cancer of primitive white blood cells in the bone marrow. It is the most common type of acute leukemia seen in adults, accounting for 80 percent of such cases. AML has eight different subtypes that vary in regards to treatment, prognosis and the type of leukemia cell involved. These include:

• M0 - Undifferentiated Leukemia -- Characterized by the overproduction of very primitive leukemia cells or "blasts," which are so immature it sometimes is difficult to tell if they are AML or ALL cells, this leukemia has a poor prognosis and represents less than 5 percent of AML cases.

• M1 - Acute Myeloblastic Leukemia -- This condition is characterized by the overproduction of very primitive white blood cells or "blasts." In turn, the bone marrow contains few mature white blood cells. This leukemia accounts for approximately 15 percent to 20 percent of AML cases.

• M2 - Acute Myeloblastic Leukemia with Maturation -- This condition is characterized by the overproduction of primitive white blood cells or "blasts," where the bone marrow contains mature white blood cells as well as blast. This leukemia accounts for approximately 20 percent to 30 percent of AML cases. A translocation between chromosomes 8 and 21 commonly occurs and suggests a better prognosis.

• M3 - Acute Promyelocytic Leukemia (APL) -- Characterized by the presence of atypical promyelocytes in the bone marrow and peripheral blood, this type of leukemia can be associated with severe bleeding. A translocation between chromosomes 15 and 17 commonly occurs and suggests a better prognosis. This condition represents approximately 10 percent to 15 percent of AML cases.

• M4 - Acute Myelomonocytic Leukemia -- Characterized by the overproduction of monocytes and myelocytes, which are white blood cells that battle infectious agents throughout the body, this type of leukemia represents approximately 20 percent to 25 percent of AML cases.

• M5 - Acute Monocytic Leukemia -- Characterized by the overproduction of white blood cells, monocytes and monoblasts, which are white blood cells that battle infectious agents throughout the body, this type of leukemia represents approximately 5 percent to 10 percent of AML cases.

• M6 - Acute Erythroblastic Leukemia -- Characterized by the overproduction of primitive red blood cells, this leukemia has a poor prognosis and often evolves from a disorder called myelodysplasia. It represents less than 5 percent of AML cases.

• M7 - Acute Megakaryoblastic Leukemia -- Characterized by the overproduction of primitive megakaryocytes (the cells that give rise to platelets), this is a rare from of AML with an extremely poor prognosis.

Typically AML comes on suddenly, within days or weeks. Less often, a patient has been ill for a few months. AML makes people sick primarily by interfering with normal bone marrow function. The leukemia cells replace and crowd out the normal cells of the bone marrow, thereby causing low blood cell counts. This insufficient number of red blood cells results in a condition called anemia, which causes a person to be tired and pale. Lack of platelets can make you more susceptible to bleeding and bruising, especially in the skin, nose and gums.

Lowered levels of normal white blood cells increase the risk of infection. Although infections can be of any type, typical symptoms include:

• Fever
• Runny nose
• Cough
• Chest pain or shortness of breath
• Pain with urinating
• Diarrhea, occasionally

Infections of the bloodstream, called sepsis, and pneumonia are the most dangerous.

Diagnosis

First, your doctor will perform a physical examination and look for swelling in the liver, spleen, groin, neck and lymph nodes under your arm. Your doctor will order a CBC test, which is a complete blood count that measure the amount of white and red blood cells and platelets in your blood. In addition, a sample of your blood is examined under a microscope to see what the cells look like and to determine the number of mature cells and leukemia cells, called blasts. Although blood tests may reveal that a patient has leukemia, they do not always indicate the type of leukemia.

In order to further check for leukemia cells or to identify what type of leukemia a patient has, a hematologist (blood disorder specialist) or oncologist (cancer specialist) performs a bone marrow aspiration and biopsy. During this procedure, the doctor inserts a needle into a large bone (usually the hip) and removes a small amount of liquid bone marrow (aspiration) and a piece of the spongy tissue inside the bone (biopsy). The procedure takes about 20 minutes. Once the biopsy and aspiration are obtained the hematologist, oncologist or pathologist examines the samples under the microscope.

Additional studies such as peroxi-dase stains and/or immunophenotyping may be necessary to confirm the diagnosis and reveal the exact acute myeloid leukemia (AML) subtype. In addition, a small amount of the liquid bone marrow is sent for a special chromosome test called cytogenetics, which can sometimes reveal important information regarding treatment and prognosis.

Treatment

Patients with acute myeloid leukemia undergo an extensive initial work-up including:

• A history and physical examination
• Blood tests
• Heart tests
• A bone marrow aspiration with biopsy
• Immunophenotyping of the marrow
• Cytogenetics, special chromosome test

The leukemia doctors and pathologist review this material and confirm the specific subtype of acute myeloid leukemia (AML). Then, treatment is started as soon as possible.

The treatment of AML varies according to one's age, general condition at diagnosis and the results of the cytogenetics. For most patients age 65 or younger, an autologous transplant will be recommended as part of the initial consolidation therapy. Overall, typical AML therapy includes three phases:

• First phase -- induction chemotherapy
• Second phase -- consolidation chemotherapy, which may include stem cell transplantation

One AML subtype, called acute promyelocytic leukemia (APL), has a unique biology and is treated differently. This type of leukemia can be treated with a vitamin pill called altransretinoic acid (ATRA) together with chemotherapy. Most people undergo multiple cycles of this therapy. Sometimes, bone marrow transplantation is preferred.

First Phase: Induction Chemotherapy

The goals of induction chemotherapy are to eliminate leukemia cells from the blood and bone marrow and to induce a remission. A complete remission is defined as having no visible leukemia cells in the blood or bone marrow and having normal blood counts without the need of transfusions.

Induction therapy for patients age 65 or younger typically includes high doses of ARA-C and daunorubicin chemotherapy. The medications are given over a six-day period. Although side effects are expected and can be severe, our team is very skilled at caring for patients undergoing induction therapy for AML, administering all needed supportive care measures, such as transfusions, antibiotics and medications.

Chemotherapy is usually given over approximately five to seven days. During most of the hospital stay, patients receive intensive supportive care to protect them during their period of very low blood counts, including transfusions of red blood cells and platelets to correct anemia and to prevent bleeding. Antibiotics are used both preventatively and to treat bacteria and fungal infections. Additional antibiotics may be needed if other infections occur. Growth factors such as G-CSF (Neupogen) can help bring the patient's white blood count back more quickly and may help prevent infections. The chemotherapy agents also are associated with complete but temporary hair loss, sores in the mouth, and throat and skin rashes. Other support care measures include anti-nausea drugs to prevent or decrease nausea, anti-diarrheals to decrease diarrhea, eye drops to prevent irritation and nutrient-rich beverages to improve nutrition.

Patients are expected to be hospitalized for four to five weeks. Once the blood counts have returned to normal and the bowels function normally, patients may be discharged from the hospital. At the end of the induction therapy, a bone marrow biopsy is performed to see if a complete remission has been achieved. Approximately 70 percent to 80 percent of patients are expected to enter complete remission. If a complete remission is achieved, patients are then given a one-month break to prepare for the second (consolidation) treatment cycle.

Second Phase: Consolidation Chemotherapy

Once a patient achieves a complete remission more chemotherapy is needed to destroy any residual leukemia in the body. Consolidation chemotherapy can consist of the following:

• Additional cycles of intensive chemotherapy
• A bone marrow transplant using one's own bone marrow, called an autologous transplant
• A bone marrow transplant using bone marrow from a donor, such as a brother or sister. This is called an allogeneic transplant.

The type of consolidation therapy offered to any particular patient depends on the subtype of leukemia, the initial cytogenetics and the expertise of the leukemia doctor and center.

This second phase of treatment likely will include similar chemotherapy medications including the drug ARA-C (cytarabine). The actual number of chemotherapy cycles required during consolidation as well as the need for a stem cell transplant varies from case to case.

In general, consolidation treatment has similar toxicities as induction therapy and also requires intensive supportive care. At some institutions, the consolidation treatments can be done as an outpatient, but most patients are treated in the hospital and require a four to five week hospitalization. Overall, approximately 30 percent to 40 percent of patients receiving consolidation chemotherapy are cured of their AML.

If a patient is going to have an autologous stem cell transplantation, his or her stem cells are collected after the consolidation chemotherapy stage is complete and once their blood counts recover. A process called "mobilization" enables the collection of stem cells from the blood. When the white blood cell counts are more than 10,000 cells/uL, a large IV catheter called a Quentin catheter is inserted into one of the large veins in the neck. This catheter is connected to an "apheresis" machine that separates the blood into individual components allowing the collection of only the white blood cells. All the other cells, including red blood cells and platelets, are given back to the patient. Each apheresis procedure takes four hours, and two to three procedures are usually necessary to collect enough stem cells.

Once the stem cells are collected, and all other toxicities have resolved, the patients may be discharged from the hospital. The stem cells are frozen and saved for future use. Patients are then given a one-month break to prepare for high-dose chemotherapy and the re-infusion of the stem cells.

High-Dose Chemotherapy and Stem Cell Transplantation

Stem cell transplantation, also called bone marrow transplantation, is often recommended for both intermediate- and poor-risk AML. UCSF Medical Center has an expertise in autologous stem cell transplantation for AML. Autologous stem cell transplantation -- using cells collected from the patient's own bone marrow after they have achieved complete remission -- appears to produce a cure approximately 50 percent to 55 percent of the time for intermediate-risk AML.

This stage of treatment is both the most important and most dangerous. This therapy requires a one-month hospitalization. The goal of this therapy is to utilize much higher doses of chemotherapy to completely destroy any residual leukemia cells. The side effects are rather severe and the chances of dying from complications associated with high-dose chemotherapy are approximately 2 percent to 5 percent.

The chemotherapy medications include Busulfan and etoposide, which are administered over five days. After two days of chemotherapy, the frozen stem cells will be re-infused into an IV catheter. The rest of the hospitalization consists of waiting for the new stem cells to grow, and during this time supportive care is administered as needed. Once the blood counts have improved and the other side effects have resolved, patients may be discharged. Patients are followed closely in the outpatient clinic for approximately three months. Most Patients are able to return to work within three to six months of transplantation.

The preferred treatment for patients with good or intermediate-risk cytogenetics is autologous stem cell transplantation, while allogeneic transplantation is favored for those with bad cytogenetics.

Allogeneic transplantation using stem cells or bone marrow from a matched brother or sister produces cure rates of approximately 50 percent to 60 percent. However, allogeneic transplantation is significantly more difficult and dangerous than either chemotherapy or autologous transplantation, and 20 percent to 30 percent of patients do not survive the first three months of treatment. For this reason, it is often reserved for more difficult cases. Poor-risk AML patients are best treated with allogeneic transplant despite its difficulties and dangers. Cure rates of 20 percent to 25 percent may be achieved. For patients with poor-risk leukemia who do not have a matched sibling donor, an unrelated donor may be sought through the National Marrow Donor Program (NMDP).

Investigational Therapies

Mylotarg is a new treatment for leukemia that combines an antibody that specifically targets leukemia cells and then inserts them with a toxin. This treatment is beneficial because it does not cause hair loss, mouth sores or disturbance of the intestinal tract. However, it does produce long periods of low blood counts. Also, the chance of reaching a remission is not as strong as with chemotherapy. Further work still needs to be done to determine the best role of this agent in the treatment of AML.