Myeloid malignancies are cancers that affect one family of cells in the blood and bone marrow. Bone marrow is the soft, inner component of the bone. All types of blood cells are produced in the bone marrow, including:

• White blood cells – cells that fight infection
  
  
• Red blood cells – cells that carry oxygen to tissues all over the body
  
  
• Platelets – cells that help develop blood clots and control bleeding

There are three types of myeloid malignancies that can occur in children:

• Acute myeloid leukemia (AML). The most common type of childhood myeloid malignancy. In AML, the bone marrow manufactures a large number of abnormal blood cells. Over time these cells begin to build up, crowding out normal white blood cells, red blood cells and platelets. The result is a type of leukemia that quickly spreads from bone marrow into the bloodstream.
  
  
• Myelodysplastic syndromes (MDS). A group of conditions caused by changes in the blood-forming cells of the bone marrow. Although it is most common in adults over the age of 70, it can occur in children. In MDS, the stem cells do not mature into healthy red blood cells, white blood cells or platelets. In some children, myelodysplastic syndromes can progress to AML.
  
  
• Juvenile myelomonocytic leukemia (JMML). A type of myeloid malignancy in which the bone marrow produces too many white blood cells.  JMML is a rare form of childhood leukemia that produces many of the same symptoms as AML.

The exact cause of these diseases has not been identified. Researchers, however, have gained a greater understanding of how specific changes in DNA can cause bone marrow cells to develop into leukemia and myelodysplastic syndromes. A number of risk factors have been identified, including treatment for previous cancers and certain genetic syndromes. 

Symptoms of myeloid malignancies vary depending on where they have spread in the body. General signs and symptoms include weight loss, fever, loss of appetite and weakness.

Although symptoms and a physical examination may suggest a myeloid malignancy, additional tests, including bone marrow tests, are typically necessary to verify the diagnosis.

The treatment and prognosis for a myeloid malignancy depends on the subtype of the disease, as well as certain additional factors including the patient’s age. Typical treatment includes chemotherapy, radiation therapy, and bone marrow/stem cell transplantation. Individuals with myeloid malignancies may receive a combination of these therapies.

Myeloid malignancies are diseases that affect the blood and bone marrow. Those that can occur during childhood include acute myeloid leukemia (AML), myelodysplastic syndromes and juvenile myelomonocytic leukemia (JMML).

Acute myeloid leukemia (AML) is a type of leukemia, or cancer of the body’s blood-forming cells. Also known as acute myelogenous leukemia, AML affects the body’s blood making system, specifically the bone marrow. Leukemia is the most common cancer in children and adolescents, with acute leukemias being the most common.

The American Cancer Society (ACS) predicts that in 2006 there will be 2,800 new cases of leukemia in children in the United States. Of these, 78 percent will be cases of acute lymphocytic leukemia (ALL), which arises from a different family of blood cells than AML.  Most of the remaining cases will be AML, which is most common during the first two years of life and is less common among older children.

AML develops in the bone marrow but typically spreads quickly into the blood. Bone marrow is the soft, inner component of bones. It is composed of blood-forming cells, fat cells, and tissues that support the growth of blood cells. All forms of blood cells are produced in the bone marrow from a cell called the stem cell. Blood cells produced from stem cells in the bone marrow include:

• White blood cells to fight infection
  
• Red blood cells to carry oxygen to tissues throughout the body
  
• Platelets to help develop blood clots and control bleeding

In children with AML, the stem cells usually develop into a form of immature white blood cell called myeloblasts, or myeloid blasts. These cells are abnormal and fail to develop into healthy white blood cells. Since they are defective, these cells are unable to defend the body from disease. In other cases of AML, too many stem cells develop into abnormal red blood cells or platelets.

As the leukemia progresses, the abnormal cells (known as leukemia cells) can begin to increase, crowding out normal white blood cells, red blood cells and platelets. As a result, production of normal white blood cells is affected and the body’s ability to fight infection is impaired. In addition, the decrease in production of red blood cells and platelets results in anemia and bleeding disorders. Although AML begins in the bone marrow, it may eventually spread through the bloodstream to organs, including the liver, brain, spinal cord, ovaries, skin and testicles.

A less common type of myeloid malignancy in children is known as myelodysplastic syndrome (MDS). MDS is a group of diseases that affects the blood and bone marrow. In children with these diseases, the stem cells do not mature into healthy red blood cells, white blood cells or platelets. Some physicians consider MDS as an early form of leukemia or pre-leukemia. According to the ACS, approximately 30 percent of MDS cases eventually progress to acute leukemia. The ACS estimates that between 10,000 and 20,000 new cases of myelodysplastic syndromes are diagnosed each year. However, these syndromes are rare in young children with more than 50 percent of the cases occurring in adults over age 70.

Juvenile myelomonocytic leukemia (JMML) is a third type of children’s cancer in which the bone marrow produces too many white blood cells. A rare type of childhood cancer, JMML occurs most often in children under the age of 2. According to the National Cancer Institute (NCI), it accounts for less than 1 percent of all childhood leukemias.

As with AML, children with myelodysplastic syndromes and JMML are likely to develop anemia, infection or easy bleeding due to a decrease in normal red blood cells, white blood cells and platelets. 

The exact cause of myeloid malignancies in children has not been identified. Researchers, however, have gained a greater understanding of how specific changes in DNA can cause bone marrow cells to develop into leukemia and myelodysplastic syndromes.

Some forms of cancer are caused by DNA mutations that “turn on” oncogenes (genes that speed up cell division) or “turn off” tumor suppressor genes (genes that slow down cell division or cause cells to die at the right time). In children with leukemia and myelodysplastic syndromes, these mutations are normally acquired after birth. The mutations may occur from exposure to radiation or cancer-causing chemicals, but many times the mutations occur for no apparent reason.

One form of DNA abnormality, known as translocation, can cause myeloid malignancies to develop. Translocation is the transfer of DNA from one chromosome to another. This abnormality can turn on oncogenes, which causes rapid cell division. Although they occur less often, deletions (the loss of part of a chromosome) and inversions (the rearrangement of DNA in part of a chromosome) are other chromosome changes that can cause leukemia to develop.

In addition, researchers have identified a number of factors that may make a child more likely to develop myeloid malignancies including:

• Family history. Children who have a brother or sister with leukemia are at a higher risk of developing AML.
  
  
• Race. Hispanic children are at an increased risk of developing the AML.
  
  
• Gender. AML, myelodysplastic syndromes and JMML are more common in males.
  
  
• Exposure to cigarette smoke or alcohol before birth. Children who were exposed to cigarette smoke or alcohol in the womb have an increased risk of developing AML.
  
  
• Having a history of a myelodysplastic syndrome. Children with a history of a myelodysplastic syndrome are at a higher risk of developing AML.
  
  
• Having a history of aplastic anemia. Children with a history of aplastic anemia (a rare disease in which the bone marrow fails to produce enough blood cells) have an increased risk of developing AML.
  
  
• Chemotherapy. Children treated for other cancers with certain chemotherapy drugs are at an increased risk of developing AML and myelodysplastic syndromes.
  
  
• Exposure to very high levels of radiation. Children who have received radiation therapy as treatment for other forms of cancer have an increased risk of developing AML and myelodysplastic syndromes later in life. In addition, children exposed to radiation from atomic blasts, such as those in Japan during World War II, and nuclear accidents have an increased risk of developing AML and myelodysplastic syndromes.
  
  
• Environmental factors. Chemicals, such benzene (a solvent found in gasoline and cigarette smoke), can increase a child’s risk of developing myeloid malignancies. Long term exposure to other chemicals found in the petroleum and rubber industries can also place a child at higher risk. Several studies conducted by the National Cancer Institute (NCI) have investigated nearby high-voltage power lines as a risk factor for leukemias. To date, the results have indicated either no risk or only a slightly greater risk.
  
  
• Genetic syndromes. Children with certain genetic syndromes including Down syndrome and Fanconi’s syndrome have an increased risk of developing AML and myelodysplastic syndromes. Also, children with neurofibromatosis type 1 or Noonan’s syndrome are at an increased risk of developing JMML.

Myeloid malignancies can cause a variety of signs and symptoms depending on the type of disease. General signs and symptoms include:

• Weight loss
• Fever
• Loss of appetite
• Weakness

Signs and symptoms of AML, myelodysplastic syndromes and JMML may develop from the reduction of normal red blood cells, white blood cells, and platelets caused by the disease. These blood abnormalities may cause the following conditions and symptoms:

• Anemia. An abnormally low amount of red blood cells. It can trigger a variety of signs and symptoms including yellowing of the skin (jaundice), fatigue and shortness of breath.
  
  
• Infection. Decreased normal white blood cells weaken the immune system and cause a greater risk for infection. The infection may or may not be accompanied by a fever.
  
  
• Thrombocytopenia. An abnormally low amount of platelets. This condition can lower the ability to repair holes in damaged blood vessels and result in excessive bleeding or bruising.
  
  
• Enlargement of spleen or liver. This can cause a feeling of fullness between the ribs or swelling of the abdomen.
  
  
• Bone or joint pain. Caused by spread of the disease to the bone.
  
  
• Leukemia cutis and chloromas. Painless blue, blue-green or purple colored lumps that may occur in children with AML. They may appear in the neck, underarm, stomach or eye areas.
  
  
• Rashes. Spread of these malignancies to the skin may cause small spots that look like an ordinary rash.

Early symptoms of these diseases may be overlooked because they can resemble symptoms of more common illnesses, such as influenza. Parents are encouraged to contact their physician when their child experiences any symptom of these diseases which does not promptly resolve. The earlier a disease is diagnosed, the earlier treatment may begin.

When physicians suspect that an individual may have a type of myeloid malignancy they will obtain a detailed medical history and perform a complete physical examination. During the physical examination, the physician may inspect the lymph nodes, spleen and liver for swelling.

Following the exam, a variety of tests may be ordered to diagnose and classify the disease. Samples of cells from the blood and bone marrow will be examined and additional tissue and cell samples may be obtained to guide treatment. For a diagnosis of myelodysplastic syndrome or juvenile myelomonocytic leukemia (JMML), a child must have less than 20 percent blasts (immature cells) in the bone marrow. The presence of more than 20 percent blasts is required for a diagnosis of acute myeloid leukemia (AML).

Common tests include:

• Complete blood count (CBS) and blood smear. A CBC is a blood test that measures the number of red blood cells, white blood cells and platelets in a sample of blood. A blood sample can also measure other elements, such as the amount of hemoglobin in the red blood cells. A blood smear is the examination of cells under a microscope. It is used to detect the presence of blast cells as well as any abnormalities.
  
  
• Blood chemistry tests. These tests measure the level of specific chemicals in the blood. They are used to monitor changes in liver or kidney function caused by disease or treatment with certain chemotherapy drugs. The tests may also be ordered to determine whether treatment is required to correct abnormally low or high levels of certain minerals.
  
  
• A bone marrow aspiration and biopsy. A bone marrow aspiration involves using a needle to collect a small sample of liquid bone marrow. A bone marrow biopsy uses a larger needle to remove a piece of bone marrow, both under local anesthesia. Usually performed at the same time, these procedures may be ordered to diagnose leukemia and myelodysplastic syndromes and to classify the disease. The test may be used after diagnosis to monitor treatment or to determine if a child’s myelodysplastic syndrome is transforming into AML or is in remission.
  
  
• Tumor biopsy. A biopsy of cells in chloroma may be done. Chloroma are painless blue-green lumps that may appear around the eyes of children with AML. In addition, biopsies may be performed on other suspected tissue, including areas of the skin or organs.
  
  
• Lymph node biopsy. This procedure involves removing all or part of a lymph node and examining its tissue for cancer cells under a microscope. Malignant cells in the lymph node indicate that the cancer has spread into the lymphatic system and can invade organs in the body.
  
  
• Lumbar puncture. Also known as a spinal tap, this procedure uses a needle to remove a sample of cerebrospinal fluid (CSF) from between the bones in the lower spine. CSF is the fluid that flows around the brain and spinal cord. The sample is then examined for cancer cells. This test may be used to determine if the cancer has spread outside of the blood and bone marrow.
  
  
• Biopsy of the testicles, ovaries or skin. This procedure involves removing cells or tissue from the testicles, ovaries or skin. The sample is then examined under a microscope for signs of cancer. These tests may be ordered to detect if cancer has spread outside of the blood and bone marrow when a physician notices abnormalities in one of these areas during a physical examination.  

Additional tests which may be used to diagnose and classify myeloid malignancies include the following:

• Flow cytometry. This procedure uses fluorescent antibodies to detect certain molecules on the surface of leukemia cells. The cells are then measured and analyzed by a computer. 
  
  
• Cytogenetics. This test uses a microscope to evaluate the characteristics of cells including their formation, function and structure. It may be ordered to determine if the cells have too many chromosomes, or if the chromosomes have any abnormalities.
  
  
• Molecular genetic studies. These tests examine leukemia cell DNA. Molecular genetic studies are useful in classifying leukemia and myelodysplastic syndromes because many of their subtypes have distinctive DNA.

In addition to diagnosing and classifying myeloid malignancies, cytogenetics and molecular genetic studies may be useful in determining a person’s risk of developing such diseases. Genetic tests are currently available to identify certain genetic abnormalities, and additional genetic tests are being developed.

Leukemias rarely form visible tumors or discrete lumps or masses in internal organs - diffuse (generalized) swelling of these organs is more common. For that reason, imaging tests have limited value. If imaging tests are done on children with myeloid malignancies, they are usually conducted to diagnose infections, metastasis, or other cancer–related problems. Imaging tests that may be ordered include:

• Chest x-ray. Uses low doses of radiation to produce images of the chest on film paper or fluorescent screens. It can reveal signs of a lung infection and detect enlarged lymph nodes in the chest.
  
  
• CAT scan (computed axial tomography, also known as CT scan or computed tomography). Allows for multiple x-rays to be taken from different angles around a patient. CAT scans can detect enlarged organs, large collections of cancer cells and abscesses (collections of pus caused by an infection). CAT scans may also be used to guide a biopsy needle into an enlarged lymph node located deep in the body. This procedure is known as a CT-guided needle biopsy.

• Magnetic resonance imaging (MRI). Uses a powerful magnetic field to create images of structures and organs within the body allowing a computer to produce very clear cross-sectional or three-dimensional images. It may be ordered to determine if the disease has spread to the spinal cord, brain or other areas. As with CAT scans, a contrast material may be used to provide a more detailed image.
  
  
• Gallium scan and bone scan. Involves an injection of a radioactive substance that may be absorbed by areas of the body where cancer cells are present or bone is damaged. A scanner detects where the radioactive material has accumulated in the body and the image is recorded on film. The tests may be ordered when a child has bone pain that may be due to cancer or an infection.
  
  
• Ultrasound. Uses high-frequency sound waves to produce images of internal organs. This test is useful for detecting enlarged kidneys, liver or spleen in individuals with suspected leukemias. 

As with all cancers, treatment for myeloid malignancies is typically coordinated by a cancer care team, typically  coordinated by a medical oncologist. For children, other specialists on the team may include:

• Pediatric oncologist
• Hematologist
• Radiation oncologist
• Pediatric surgeon

Treatments for myeloid malignancies may be provided alone or in various combinations. Common methods used to these diseases include:

• Chemotherapy. Uses powerful drugs to destroy cancer cells and to help prevent the cancer from spreading to other areas in the body. 
  
  
• Radiation therapy. Uses high-energy rays to destroy cancer cells and shrink tumors. It may be ordered to treat leukemia that has spread to the spinal fluid or organs. Radiation therapy may be ordered before a child undergoes a bone marrow or peripheral blood stem cell transplantation. On rare occasions, radiation treatment may be ordered as an emergency treatment to reduce the size of a mass pressing on the trachea.
  
  
• Bone marrow/stem cell transplant. Transplantation of bone marrow cells or peripheral blood stem cells. The stem cells may come from a matched donor or from the patients themselves. This is not a direct treatment for cancer, but helps the body to tolerate higher levels of chemotherapy, radiation therapy or a combination of both. In addition to destroying cancer cells, high dose therapies also destroy normal blood cells in the bone marrow. Patients who undergo transplantation receive an infusion of healthy stem cells through a vein after high-dose therapies. As a result of the infusion, new blood cells begin to develop from the transplanted cells.
  

Children with myeloid malignancies are usually treated immediately and aggressively in order to destroy the cancer cells and put the disease in remission. This is known as remission induction therapy. Once the signs and symptoms of the disease disappear, additional therapy may be given to destroy any remaining cancer cells and prevent a relapse. This is known as postremission therapy or consolidation therapy.

Usually, stem cell transplantation is considered the only treatment option for children with myelodysplastic syndromes. Among children with juvenile myelomonocytic leukemia (JMML), transplantation also offers the best chance of a cure. Watchful waiting is a method of closely monitoring a child’s condition without providing any treatment until symptoms appear or change. This method is occasionally used to treat myelodysplastic syndromes.

A child’s prognosis and treatment options for these diseases depend on a number of factors. The factors vary for the specific type of malignancy; however, general considerations include:

• The child’s age and overall health
• The type or subtype of malignancy
• The white cell, red cell, and platelet blood count at diagnosis
• The presence and number of blast cells (immature cells)
• Any signs of metastasis
• Genetic and chromosome abnormalities
• Severity of cell abnormality
• Any previous cancers or cancer treatment

There are no specific ways to prevent myeloid malignancies in children. Avoidance of controllable risk factors offers the only possibility of preventing the disease. Exposure to smoking and alcohol use before birth is the biggest controllable factor for acute myeloid leukemia (AML). Pregnant women should not smoke and should limit their exposure to second-hand smoke. Also, they should not use alcohol during their pregnancy.

Avoiding the chemical benzene can also reduce a child’s risk of developing the disease.   

Many experts agree, however, that occupational and environmental chemicals are responsible for only a small number of leukemia and myelodysplastic syndrome cases. 

Although chemotherapy and radiation therapy for other cancers can cause secondary myeloid malignancies, the life-saving benefits of these treatments should be carefully weighed against the small risk of developing leukemia later in life.

There is a great deal of research being conducted in the area of acute myeloid leukemia (AML), myelodysplastic syndromes and juvenile myelomonocytic leukemia (JMML) including clinical trials and scientific studies. Areas of research for myeloid malignancies include:

• Biological therapy (also called immunotherapy). This method uses substances naturally produced by the immune system to kill cancer cells, slow the growth of the cancer cells or increase the immune system. Substances currently being studied include monoclonal antibodies, which are designed to attack myeloma cells.
  
  
• Growth factors. Hematopoietic growth factors are hormone-like substances that stimulate blood cell production in the bone marrow. Researchers are studying growth factors that can promote the production of platelets. Additional studies are trying to determine the best method to predict which children will benefit from growth factors.
  
  
• Differentiating agents. Differentiating agents are drugs that cause bone marrow blasts (immature cells) to develop into mature blood cells. Researchers are testing several differentiating agents including retinoids (chemicals related to Vitamin A) and Vitamin D to determine the best method of combining these agents with other treatments.
  
  
• Stem cell transplantation. Researchers are looking for ways to increase the effectiveness of stem cell transplantation, as well as reduce complications and determine which children benefit most from the procedure. Several studies have focused on “mini” transplants, or a modified stem cell transplant. These procedures may be effective at treating the disease with reduced toxic side effects and easier recovery.
  
  
• Chemotherapy. Studies have focused on developing new drugs, preventing cancer cells from becoming resistant to chemotherapy, and determining the most effective combination of drugs. Researchers are also trying to determine whether children with a poor prognosis benefit from intensive chemotherapy.  

Preparing questions in advance can help patients and their families have more meaningful discussions with their physicians about medical conditions. Patients or parents may wish to ask the following questions about myeloid malignancies:

1. How will I know if my child’s symptoms may be due to a myeloid malignancy?
   
   
2. What tests will be used to diagnose these cancers in my child?
   
   
3. What type of myeloid malignancy does my child have?
   
   
4. What are the treatment options for my child?
   
   
5. What are the risks and side effects associated with these treatments?
   
   
6. How will the cancer be monitored during treatment?
   
   
7. What are the chances that the cancer will spread to other areas?
   
   
8. What is my child's prognosis?
   
   
9. How will I know if the cancer is in remission?
   
   
10. What are the chances that the disease will return?
    
    
11. If I have one child with a myeloid malignancy, what are the odds of my other children developing the same condition?
    
    
12. Can you recommend some support groups for parents and children with this type of cancer?