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Leukemia - Chronic Myelomonocytic (CMML)

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What is chronic myelomonocytic leukemia?

Chronic myelomonocytic leukemia (CMML) is a type of cancer that starts in blood-forming cells of the bone marrow and invades the blood.

Normal bone marrow

Bone marrow is found inside certain bones such as the skull, ribs, pelvis, and spine. It is made up of blood-forming cells, fat cells, and supporting tissues that help the blood-forming cells grow. A small fraction of the blood-forming cells are a special type of cell known as stem cells. Stem cells are needed to make new cells. When a stem cell divides it makes 2 cells: one cell that stays a stem cell and another cell that can keep changing and dividing to make blood cells.

There are 3 types of blood cells: red blood cells, white blood cells, and platelets.

Red blood cells pick up oxygen in the lungs and carry it to the rest of the body. These cells also bring carbon dioxide back to the lungs. Having too few red blood cells is called anemia. It can cause people to appear pale and feel tired and weak. Severe anemia can cause shortness of breath.

White blood cells (also known as leukocytes) are important in defending the body against infection. The 2 major types of white blood cells are lymphocytes and granulocytes.

Lymphocytes are immune cells that are found in the bone marrow, the blood, and in lymph nodes. They make the antibodies that help the body fight germs. They can also directly kill invading germs by producing toxic substances that damage the cells.

Granulocytes are a group of white blood cells that destroy bacteria. They are called granulocytes because they contain granules that can be seen under the microscope. These granules are made up of enzymes and other substances which can destroy germs that cause infections.

In the bone marrow, granulocytes develop from young cells called myeloblasts. The most common type of granulocyte is the neutrophil; this cell is crucial in fighting bacteria. Other types of granulocytes are basophils, and eosinophils. When the number of neutrophils in the blood is low, it is called neutropenia. This can lead to severe infections.

Monocytes are related to the granulocyte family. They also help protect the body against bacteria. The early cells in the bone marrow that turn into monocytes are called monoblasts. When monocytes leave the bloodstream and go into tissue, they become macrophages. Macrophages can destroy germs by surrounding and digesting them. They are also important in helping lymphocytes to recognize germs and begin producing antibodies to fight them.

Platelets are thought of as a type of blood cell, but they are actually small pieces of a cell. They start as a large cell in the bone marrow cell called the megakaryocyte. Pieces of this cell break off and enter the bloodstream as platelets. Platelets are needed for your blood to clot. They plug up damaged areas of blood vessels caused by cuts or bruises. A shortage of platelets, called thrombocytopenia, can result in excessive bleeding and bruising.

Chronic myelomonocytic leukemia

In CMML, patients have an elevated number of monocytes in the blood, with a monocyte count of at least 1,000 (per mm3). Often, the monocyte count is much higher, causing the total white blood cell count to become very high as well. Usually there are abnormal cells in the bone marrow, but the amount of blasts (very early/immature cells) is below 20%. Many patients have enlarged spleens (an organ that lies just below the left rib cage). About 15% to 30% of patients go on to develop acute myeloid leukemia.

Because CMML patients have abnormal looking (dysplastic) cells in their bone marrow, for a long time CMML was considered to be a type of myelodysplastic syndrome. Still, it didn't fit in well with other diseases in that category. That is because the major problem in myelodysplastic syndrome is having too few blood cells.

Patients with CMML may have shortages of some blood cells, but a main problem is too many of a certain type of white blood cell (the monocyte). In this way CMML is more like a myeloproliferative disease (myelo -- bone marrow,proliferative -- excessive growth). Chronic myeloid leukemia is an example of a myeloproliferative disease where the problem is an overproduction of white blood cells. Since CMML has features of both myelodysplastic syndrome and myeloproliferative disorder, experts created a new category for it: myelodysplastic/myeloproliferative diseases. CMML is the most common disease in this group. Much less common diseases in this group are atypical chronic myeloid leukemia and juvenile myelomonocytic leukemia. All of these diseases produce a lot of abnormal blood cells.

What are the risk factors for chronic myelomonocytic leukemia?

A risk factor is anything that changes your chance of getting a disease such as cancer. Different cancers have different risk factors. For example, exposing skin to strong sunlight is a risk factor for skin cancer. Smoking is a risk factor for cancer of the lung and many other cancers. But risk factors don’t tell us everything. People without any risk factors can still get the disease. And having a risk factor, or even several, does not mean that you will get the disease. Because chronic myelomonocytic leukemia (CMML) is rare, it has been hard to study. For a long time it was grouped with myelodysplastic syndrome. As a result, only a few risk factors are known for this disease.


The risk of CMML increases with age. This disease is rare in those younger than 40, with most cases found in people over 60.


CMML is more common in men.

Cancer treatment

Prior treatment with chemotherapy seems to increase the risk of CMML. The risk of CMML after cancer chemotherapy is not as high as the risk of other blood problems, such as myelodysplastic syndrome and acute myeloid leukemia.

Do we know what causes chronic myelomonocytic leukemia?

Some cases of chronic myelomonocytic leukemia (CMML) are linked to cancer treatment, but in most cases the cause is unknown.

Over the past few years, scientists have made progress in understanding how certain changes in the DNA of bone marrow cells may cause CMML to develop. DNA is the chemical that carries the instructions for nearly everything our cells do. We usually look like our parents because they are the source of our DNA. However, DNA affects more than the way we look.

Some genes (parts of DNA) contain instructions for controlling a cell’s growth and division process. Certain genes that promote cell division are called oncogenes. Other genes called tumor suppressor genes can slow down cell division or even cause cells to die at an appropriate time. Cancers can be caused by DNA mutations (gene defects) that turn on oncogenes or turn off tumor suppressor genes.

In some diseases, mutations may be passed down from a parent. Inherited mutations do not seem to cause CMML. Instead, the mutations are acquired during the person’s lifetime. Exposure to radiation or cancer-causing chemicals can cause mutations that lead to CMML. Sometimes these gene changes occur for no apparent reason. Every time a cell prepares to divide into 2 new cells, it must copy its DNA. This process is not perfect, and copying errors can occur. Fortunately, cells have repair enzymes that read and fix DNA. However, some errors may slip past, especially if the cells are growing rapidly.

Human DNA is packaged in 23 pairs of chromosomes. In up to half of patients, CMML cells contain altered chromosomes. Sometimes part of one chromosome attaches to a different chromosome. This is called atranslocation. Like mutations, translocations can turn on oncogenes or turn off tumor suppressor genes. Acquired translocations are seen in some cases of CMML. Another chromosome abnormality that can be seen in CMML is called a deletion. This involves the loss of all or part of a chromosome. Another type of chromosome abnormality is called a duplication. This is when there is an extra copy of all or part of a chromosome.

Can chronic myelomonocytic leukemia be prevented?

Since most cases of chronic myelomonocytic leukemia (CMML) have no known cause, this disease can rarely be prevented.

Treating cancer with chemotherapy and radiation may cause CMML. Doctors are studying ways to minimize the risk of CMML developing in patients receiving these treatments. In some cancers, doctors may try to avoid using the chemotherapy drugs that are more likely to lead to CMML. For certain cancers, however, these drugs may be needed. Often, the obvious benefits of treating life-threatening cancers with chemotherapy and radiation therapy must be balanced against the small chance of developing CMML several years later.

How is chronic myelomonocytic leukemia diagnosed?

Signs and symptoms

Some of the symptoms of chronic myelomonocytic leukemia (CMML) are caused by having too many monocytes. These monocytes can settle in the spleen or liver, causing these organs to enlarge. An enlarged spleen (calledsplenomegaly) can cause pain in the upper left part of the abdomen. It can also cause people to complain of feeling full too fast when they eat. If the liver gets too large (called hepatomegaly), it mainly causes discomfort in the upper right part of the abdomen.

Low numbers of certain types of blood cells cause many of the signs and symptoms of CMML:

A shortage of red blood cells (anemia) can lead to feeling very tired, with shortness of breath and pale skin.

Not having enough normal white blood cells (leukopenia) can lead to frequent or severe infections.

A shortage of blood platelets (thrombocytopenia) can lead to problems with easy bruising and bleeding. Some people notice frequent or severe nosebleeds or bleeding from the gums.

Other symptoms can include weight loss, fever, and loss of appetite. Of course, these problems occur not only with CMML but are more often caused by something other than cancer.

Tests to diagnose chronic myelomonocytic leukemia

If signs and symptoms suggest you may have chronic myelomonocytic leukemia (CMML), the doctors will look at cells from your blood and bone marrow to confirm this diagnosis.

Blood cell counts and blood cell examination

The complete blood count (CBC) is a test that measures different cells in the blood, such as the red blood cells, the white blood cells, and the platelets. The CBC is often done with a differential count (or “diff”), which is a count of the different types of white blood cells in the blood sample. In a blood smear, some of the blood is put on a slide to see how the cells look under the microscope.

Patients with CMML have higher numbers of monocytes, with a monocyte count of at least 1,000 (per mm3). Sometimes they have low numbers of other white blood cells. They may have shortages of red blood cells and blood platelets as well. Some patients may have a small number of monoblasts in the blood. Monoblasts are the early, immature cells that grow and divide to make mature monocytes. Normally, these cells are only found in the bone marrow. It is never normal to see blasts in the blood, and it often signals a bone marrow problem. Blood cells from CMML patients may also have certain abnormalities in size, shape, or other features that can be seen under the microscope. Blood abnormalities may suggest CMML, but the doctor cannot make an exact diagnosis without examining a sample of bone marrow cells.

Other blood tests

The doctor may also order tests to check for other possible causes of low blood counts, such as low levels of vitamin B12 and folate. Tests may also be done to look for other causes of a high white blood cell count, such as infection.

Bone marrow tests

Bone marrow samples are obtained from a bone marrow aspiration and biopsy, procedures that are usually done at the same time. The samples are usually taken from the back of the pelvic (hip) bone. These tests are used first for diagnosis and classification and may be repeated later to tell if the CMML is responding to therapy or is transforming into an acute leukemia.

For bone marrow aspiration, you lie on a table (either on your side or on your belly). After cleaning the area, the skin over the hip and the surface of the bone is numbed with local anesthetic, which may cause a brief stinging or burning sensation. A thin, hollow needle is then inserted into the bone and a syringe is used to suck out a small amount of liquid bone marrow (about 1 teaspoon). Even with the anesthetic, most patients still have some brief pain when the marrow is removed.

A bone marrow biopsy is usually done just after the aspiration. A small piece of bone and marrow (about 1/16 inch in diameter and 1/2 inch long) is removed with a slightly larger needle that is twisted as it is pushed down into the bone. The biopsy may also cause some brief pain. Once the biopsy is done, pressure will be applied to the site to help prevent bleeding.

A pathologist (a doctor specializing in the diagnosis of diseases using laboratory tests) examines the bone marrow samples under a microscope. A hematologist (a doctor specializing in medical treatment of diseases of the blood and blood-forming tissues) or an oncologist (a doctor specializing in medical treatment of cancer) usually reviews these as well.

Morphology: The doctors will look at the bone marrow aspirate and biopsy to evaluate the types and amount of blood-forming cells and to determine if the bone marrow shows evidence of infections, cancer cells, or other disorders. They will examine the size and shape of the cells and determine whether the red cells contain iron particles or the other cells contain granules (microscopic collections of enzymes and other chemicals that help white blood cells to fight infections). The percentage of marrow cells that are blasts is particularly important. Blasts are very early (immature) cells that are produced by bone marrow stem cells. Blasts eventually mature into normal blood cells. In CMML, some of the blasts do not mature properly, so there may be too many blasts and not enough mature cells. For a diagnosis of CMML, a patient must have less than 20% blasts in the bone marrow. A patient who has more than 20% blasts in the bone marrow is considered to have acute leukemia.

Additional tests are done on the bone marrow to help the doctor diagnose CMML and exclude other blood diseases:

Immunocytochemistry: Cells from the bone marrow sample are treated with special antibodies that cause certain types of cells to change color. The color change can be seen only under a microscope. This testing is helpful in distinguishing CMML from other types of leukemia and from other diseases.

Flow cytometry: This technique is sometimes used to examine the cells from bone marrow and blood samples. It can be very helpful in diagnosing leukemia and lymphoma. A sample of cells is treated with special antibodies and passed in front of a laser beam. Each antibody sticks only to certain types of cells. If the sample contains those cells, the laser will cause them to give off light. The instrument detects the light, and a computer counts the cells. This test may not be needed for all patients.

Cytogenetics: This test involves looking at the chromosomes inside the cells. DNA in human cells is packed into chromosomes. Each cell should have 46 chromosomes (23 pairs). Chromosome abnormalities are fairly common in CMML. Sometimes pieces of chromosomes or even whole chromosomes are missing. CMML cells may also have extra copies of all or part of some chromosomes. Chromosome translocations may also be seen. This is where portions of chromosomes may trade places with each other. Chromosome testing can also help the doctors be sure that the problem isn’t a different chronic leukemia, called chronic myeloid leukemia or CML. The leukemia cells in CML often contain an abnormal chromosome caused by a certain translocation (translocation (9;22)). This is called the Philadelphia chromosome. If the Philadelphia chromosome is present, the diagnosis is CML, not CMML.

Cytogenetic testing can take several weeks because the bone marrow cells need time to grow in laboratory dishes before their chromosomes can be viewed under the microscope. The results of cytogenetic testing are written in a shorthand form that describes which chromosome changes are present. For example:

A minus sign (-) or the abbreviation del is used to mean a deletion. For example, if a copy of chromosome 7 is missing, it can be written as -7 or del(7). Often, only a part of the chromosome is lost. There are 2 parts to a chromosome, called p and q. Thus the loss of the q part of chromosome 5 is called 5q- or del(5q).

A plus sign is used when there is an extra copy of all or part of a chromosome. For example, +8 means that chromosome 8 has been duplicated and too many copies of it are found within the cell.

The letter t is used to indicate a translocation, which is when a piece of one chromosome breaks off and becomes part of another chromosome.

Molecular genetic studies: This is another type of test that can be used to find chromosome and gene abnormalities. An example of this is fluorescent in situ hybridization, more commonly called FISH. In FISH, specific gene sequences are stained with a fluorescent dye. These may correspond to a certain area of a chromosome or even a certain translocation. An advantage of FISH is that it doesn’t require actively dividing cells. This allows the testing to go a bit faster. FISH is very good for finding translocations; it can even find some that may be too small to be seen with usual cytogenetic testing. This test is not needed to make a diagnosis of CMML, but it may be used in some cases. It is sometimes used to look for certain gene or chromosome changes, such as the Philadelphia chromosome, which is associated with CML.

How is chronic myelomonocytic leukemia staged?

Doctors often group cancers into different stages based on the size of the tumor and how far the cancer has spread from the original site in the body. The stage of a cancer can help predict the outlook for a cancer. Often, the stage of a cancer is used to decide which treatment is needed.

Chronic myelomonocytic leukemia (CMML) is a disease of the bone marrow. It cannot be staged by looking at the size of a tumor like some other cancers. Instead, CMML is split into 2 groups based on cell counts in the blood and bone marrow:

CMML-1: blasts make up less than 5% of white cells in the blood and less than 10% of the cells in the bone marrow.

CMML-2: blasts make up 5% to 20% of the white cells in the blood, or they make up 10% to 20% of the cells in the bone marrow.

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