Understanding Acute Myeloid Leukemia

Why Study Therapy-Related Acute Myeloid Leukemia?

Therapy-related acute myeloid leukemia (t-AML) is a major survivorship issue for today’s cancer patients. Over the past 30 years, tremendous progress has been made in the treatment of cancer, increasing the number of cancer survivors in the United States from 3 to nearly 14 million (this represents almost 4% of the population). Unfortunately, an unanticipated consequence of this success is that an increasing number of cancer survivors are developing secondary or therapy-related cancers, particularly t-AML. The disease is a direct result of mutational events that are induced by chemotherapy or radiotherapy used in the treatment of primary malignancies, such as breast and colon cancer. Approximately 8-10% of all patients treated for cancer will develop t-AML an average of 5 years after receiving treatment. The average life expectancy after diagnosis is a scant eight months. Patients who have received immunosuppressive agents for organ transplantation and the elderly are also at risk for developing t-AML and AML, respectively.

Although leukemia and lymphoma develop far less frequently (collectively representing only 9.6% of cancers) than the leading cancers in the US, such as prostate, lung, breast, and colorectal cancer, research in these diseases has been some of the most productive of all cancer research. Virtually all of the major advances in cancer were first made in blood-related cancers, and subsequently transferred to other diseases. For example,

  • The first chemotherapy was developed in leukemia patients;
  • The first bone marrow transplants were performed in leukemia;
  • The first targeted therapies were developed in leukemia; and
  • Leukemia research led to the discovery that cancer is the result of genetic mutations.

Approximately 8 to 10% of all patients treated for cancer will develop t-AML an average of 5 years after receiving treatment.

Many of these discoveries were, in fact, made at the University of Chicago, which has been recognized as an international leader in leukemia for as long as the Cancer Research Foundation has been in existence. One reason that leukemia and lymphoma have been such fertile grounds for scientific discovery is that work in “liquid” tumors, or malignancies of the blood, provide extraordinary flexibility for researchers. Blood cells can be obtained from patients easily, and continue to be studied once outside the body. For example, a researcher can test blood cells for reactions to treatments that are likely to be similar inside the body. Once a doctor biopsies or removes a tumor, the tissue is dead, and any reactions to treatments or agents are much less meaningful. In addition, cancerous blood cells can be drawn regularly from a patient receiving treatment with very little pain or difficulty to the patient. This allows the effect of a particular treatment to be followed very closely, whereas it would be very problematic (if possible at all) to biopsy a tumor at regular intervals.

Therapy-related acute myeloid leukemia also provides a unique opportunity to examine the role of genetics, and how it influences cancer susceptibility. We know that the development of cancer relies on a combination of genetic and environmental factors. Only a subset of all patients treated for cancer develops t-AML (8 to 10%), suggesting that these individuals are genetically predisposed to the disease. Researchers already know what environmental factors cause t-AML (the chemotherapy or radiation a patient received for treating his or her primary cancer), so they can focus on identifying the genetic factors.

With the recent development of high-throughput screening technologies and computational methodologies, we now have the analytical tools to search for the genetic basis of how individuals may be susceptible to t-AML using a genome-wide research approach. The University of Chicago Comprehensive Cancer Center’s partnership with the Cancer Research Foundation is essential for this success, which will allow researchers to assess cancer risk and develop targeted therapies to treat this devastating disease.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow that is known by many former names, including acute myelogenous leukemia, acute non-lymphocytic leukemia, and acute granulocytic leukemia. AML develops in the bone marrow, moves to the blood, and can spread to other parts of the body including the liver, spleen, and brain. If not treated, this disease can be fatal in just a few months. AML, the most common type of acute leukemia, develops in over 12,000 patients in the United States every year.

Normal Blood Cell Production

The bone marrow produces blood stem cells (called hematopoietic stem cells), or immature cells that will develop into mature blood cells. Blood stem cells can become either lymphoid progenitor cells, which mature into white blood cells, or myeloid progenitor cells, which mature into red blood cells, white blood cells, or platelets. These types of cells have very specific functions:

  • Red blood cells – carry oxygen throughout the body
  • White blood cells – fight infection
  • Platelets – control bleeding

Myeloid progenitor cells develop into immature cells, called myeloblasts. AML develops when a change occurs in the stem or progenitor cells, making them abnormal and unable to form mature white blood cells. As a result, these abnormal myeloblast cells, or leukemia cells, grow quickly and crowd out the normal blood cells that the body requires to function properly. Leukemia cells can spread from the blood to other parts of the body, including the brain.

Causes of AML

Individuals may be more susceptible to developing AML if they are exposed to certain risk factors. These risk factors include smoking, exposure to chemicals, such as benzene or chemotherapeutic drugs, and exposure to high dose radiation. The risk from exposure to low dose radiation, for example from radiation treatment or CT scans, is less clear. Individuals with certain blood dysfunctions, such as a low production of platelets, or congenital syndromes including Down syndrome, Bloom syndrome, Fanconi anemia, severe congenital neutropenia, and Blackfan-Diamond syndrome may also be at increased risk. Additionally, having an identical twin with AML may increase an individual’s risk.

Disease Symptoms

The majority of AML symptoms are caused by a shortage of normal blood cells, which occurs when leukemia cells crowd out normal blood-producing cells. Some of these symptoms are common to many illnesses and may include:

  • Anemia (fatigue, shortness of breath, pale skin, nails, and gums)
  • Shortage of white blood cells (may cause fever or signs of infection)
  • Shortage of blood platelets (may cause bruising, frequent nosebleeds, bleeding gums)
  • Slow healing or prolonged bleeding of minor cuts
  • Red spotting under the skin
  • Bone or joint aches
  • Mild fever
  • Swelling in the belly
  • Enlarged lymph nodes

Many of these symptoms may be cause by other ailments, such as infections. A person who experiences these symptoms should be seen by their healthcare provider to determine whether or not leukemia is the cause.

Diagnosis

Human Chromosomes

AML is diagnosed by testing blood and bone marrow samples for leukemia cells. Bone marrow aspirations are performed to determine the type of leukemia cells present and whether certain cell abnormalities exist. Aspirates can be used for cytogenetic analyses, which are lab tests that examine the chromosomes of leukemic blast cells. Bone marrow biopsies are performed to determine the stage of the disease in the marrow and also to determine chromosomal and genetic abnormalities. The information gathered from these tests, including the number of healthy blood cells, the number and size of leukemia cells, chromosomal abnormalities, and other genetic abnormalities are used to identify what type of leukemia a patient has, and the best treatment option.

Treatment

Treatment for patients with AML may include chemotherapy, stem cell transplant, and investigational drugs being studied in clinical trials.

Chemotherapy
Chemotherapy for AML often consists of a combination of 2 or 3 drugs, for example, cytarabine and daunorubicin. The standard treatment plan consists of 2 phases of chemotherapy, known as induction and consolidation therapy. The goal of induction therapy is to induce cancer remission. Remission is achieved when a patient’s bone marrow samples show no sign of disease (<5% of cells are leukemic) and when blood counts return to normal. This first round of chemotherapy usually lasts one week, but additional rounds are often necessary to induce remission. The success rate for remission varies widely between individuals, depending on the type of leukemia a patient has.

Additional therapy is usually required after a patient with AML is in remission, because induction therapy typically does not kill all of the leukemia cells. Consolidation chemotherapy is used to destroy any remaining leukemia cells and to prevent cancer relapse. A common treatment is three or more rounds of high-dose cytarabine. Doctors may recommend consolidation chemotherapy, with or without stem cell transplantation, depending on several factors, including the patient’s age and overall health, how much chemotherapy was required to induce remission, whether or not a matched stem cell donor is available, and whether or not healthy bone marrow stem cells can be retrieved from the patient.

Stem Cell Transplantation
Chemotherapy used to treat AML kills both leukemic and healthy stem cells in the bone marrow. A stem cell transplant restores the patient’s bone marrow and allows doctors to use high-dose chemotherapy to kill more leukemic cells. Stem cell transplantation may offer some patients the best chance for long-term cancer remission. However, a transplant has risks of serious side effects and is not suitable for all patients with AML.

Stem cells for transplantation can come from two sources, either the blood (known as peripheral blood stem cell transplant, PBSCT) or the bone marrow. Two main types of stem cell transplants exist: autologous and allogeneic.

In an autologous transplant, stem cells are collected from the patient’s own blood. These cells are frozen and stored until the patient is ready for the transplant, for example after induction chemotherapy or after consolidation chemotherapy. Following treatment, the stem cells are given to the patient through a blood transfusion. The goal of this procedure is to restore the patient’s ability to produce normal blood cells after receiving high-dose chemotherapy. After several days, the transplanted stem cells will replace the abnormal cells and settle into the patient’s bone marrow.

In an allogeneic transplant, stem cells are collected from a matched donor, who can be a family member or unrelated donor. This type of transplant carries a higher risk for serious side effects compared to an autologous transplant, and patients must take drugs to prevent rejection. The closeness of a donor’s match may affect the success of the transplant.

Clinical Trials
Some patients may be good candidates for clinical trials. Clinical trials are carefully-controlled studies that are performed on patient volunteers to test new treatments. These research studies have helped increase the number of patients with AML who are in remission or are cured. Scientists are performing many types of clinical trials to identify improved therapies that may be used in the future to treat AML. For example, scientists are testing immune therapies to boost the body’s ability to attack leukemia cells, therapies that will help patients overcome drug resistance, and new treatments that can attack cancer-causing genes. Patients who would like to participate in a clinical trial should speak with their doctor for more information.