CMML - Definiton .. Causes .. Symptoms ... Risk Factors ... Complications

Highlights

*  Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic   leukemia (JMML) are

uncommon blood cancers that are classified by the World Health Organization (WHO) as “mixed elodysplastic/myeloproliferative diseases.”

* CMML and JMML each start with one or more acquired changes (mutations) to the DNA of a single cell

called a “monocyte” (a type of blood cell).

* For CMML, the median age at diagnosis ranges from 65 to 75 years.

Common CMML symptoms include weakness, fatigue, unexplained bruising and/or bleeding, infection and enlarged liver and/or spleen.

Most CMML patients are treated with drug therapy. Allogeneic stem cell transplantation is a potential

curative option for a small number of patients.

The safety and effectiveness of new therapies for CMML are being researched in clinical

 

Introduction

Chronic myelomonocytic leukemia (CMML) is an uncommon blood cancer that has characteristics of two other types of blood cancers called  myelodysplastic syndromes” (MDS) and “myeloproliferative disorders” (MPDs). For this reason the

World Health Organization (WHO) has classified CMML as “mixed myelodysplastic/myeloproliferative diseases.” This is a relatively new (2001) classification that is expected to lead to greater

understanding of this disease and to the development of more effective treatments. CMML was 

Chronic Myelomonocytic Leukemia (CMML)

CMML is a clonal disorder, which means that it begins with one or more changes (mutations) to the DNA

Monocytes represent about 5 to 10 percent of the cells in normal human blood. These cells and other white cells called “neutrophils” are the two major microbe-eating and microbe-killing cells in the blood. When monocytes leave the blood and enter the tissue, they are converted to macrophages. The

macrophage is the monocyte-in-action: it can combat infection in the tissues, ingest dead cells and assist other cells, such as lymphocytes, in carrying out their immune functions.

The WHO classification categorizes CMML into two subtypes based on the percentage of blast cells (also referred to as “blasts”) found in the blood and marrow:

• CMML-1—Less than 5 percent blasts in the blood and less than 10 percent blasts in the marrow

• CMML-2—5 to 19 percent blasts in the blood and 10 to 19 percent blasts in the marrow.

In most healthy individuals, blast cells represent less than 5 percent of developing marrow cells.

CMML Incidence

CMML affects approximately 3 out of 100,000 individuals in the United States each year. The median age at diagnosis ranges from 65 to 75 years. Seventy-five percent of patients are older than 60 years at the time of diagnosis. CMML has been reported in a small number of older children and younger adults. There are approximately twice as many male CMML patients as female CMML patients.

Signs and Symptoms of CMML

Signs and symptoms may include

• Weakness and fatigue due to “anemia” (a decrease below normal in the number of red cells and, consequently, in the hemoglobin concentration of the blood)

• Petechiae (pinhead-sized sites of bleeding in the skin), bruising and bleeding due to “thrombocytopenia” (low platelet counts)

• Infections due to “leukopenia” (a below-normal concentration of white cells)

• Enlargement of the spleen and/or liver

• Feeling of fullness below the ribs due to spleen enlargement.of a single cell that multiplies uncontrollably. In CMML the change affects the normal development of a type of white cell called a “monocyte.”  Monocytes arise from immature blood-forming cells called “myeloblasts” and “myelocytes.” In CMML, the myeloblasts and myelocytes accumulate in the marrow and in other organs, and interfere with the normal production of monocytes and other types of blood cells, including red blood cells (which carry oxygen to all the tissues of the body) and platelets (which form plugs to help stop bleeding after an injury).

Diagnosis of CMML

Patients who are eventually diagnosed with CMML may seek medical attention at first because of physical weakness, infection or unexplained bleeding. A diagnosis of CMML usually cannot be confirmed with one lab test result that shows abnormal blood counts. The diagnosis can only be confirmed after a patient has been monitored for a period of time with repeat lab tests to rule out

other forms of myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPDs).

Generally, the tests used in the diagnosis of CMML include additional blood tests and bone marrow

 

• A persistent elevated monocyte count in the blood (greater than  1,000/microliter [1,000/μl] of

blood)

• Less than 20 percent blasts in the blood or the marrow

• Signs of abnormalities in one or more of the types of precursor cells that develop into red cells, certain types of white cells or platelets.

Other diagnostic tests for CMML may include

• X-rays and/or computed tomography (CT) scans of the abdomen and pelvis to detect the

enlargement of the spleen and liver

• Cytogenetic tests that confirm the absence of the Philadelphia (Ph) chromosome or the

• Blood and urine tests to detect elevated “lysozyme” levels. Lysozyme is an enzyme that functions as an antibacterial agent and is found in saliva, tears and some immune cells such as monocytes

• Blood tests to detect elevated levels of proteins such as “lactate dehydrogenase” (LDH) and “beta 2-microglobulin.” LDH levels may become elevated when there is tissue damage in the body. Beta 2-microglobulin levels may increase as a result of increased production or destruction of white cells,

BCR-ABL gene associated with chronic myelogenous leukemia (CML)due to inflammation or to certain types of cancer.

Genetic Mutations.

Twenty to 40 percent of CMML patients have chromosomal abnormalities.  About 1 to 4 percent of CMML patients have an abnormality called a “translocation” (a piece of one chromosome breaks off and attaches to another chromosome, which can lead to the development of

an “oncogene” (cancer-causing gene). In CMML the translocation involves the

Other chromosomal abnormalities associated with CMML, which may be tested for only in a research setting, include

• Monosomy 7 and trisomy 8, which are the most common chromosomal abnormalities in CMML

patients.

• Mutation of a specific gene within the gene family known as

“RAS,” such as the K-RAS or N-RAS genes. RAS genes and the proteins they encode regulate cell growth. When a mutation of a RAS gene occurs, cells multiply uncontrollably. This type of mutation occurs in about 35 percent of CMMLpatients.

Treatment of CMML

For most CMML patients, the disease is treatable, but not curable, with currently available therapies.

Patients are advised to

• Seek treatment from a physician who is experienced in treating CMML or from a physician who is in consultation with a center or physician who has experience treating this disease

• Discuss the most appropriate treatment for their situation with their physician.

The type of treatment depends on various patient factors, including the

• Nature and extent of symptoms

• Need for rapid disease control

• Eligibility for stem cell transplantation

• Overall health and quality of life.

Drug Therapy for CMML.

etoposide (VePesid

There is no one standard treatment for CMML. Treatment for previously untreated or relapsed CMML patients may include standard-dose or low-dose cytarabine (Cytosar-U®),®) and hydroxyurea (Hydrea®). Treatment with these agents has been useful for a small number of patients.

Azacitidine (Vidaza

The small number (about 1 to 4 percent) of CMML patients who have the

myelogenous leukemia (CML) and some other diseases.

Outcomes for CMML Patients

CMML is a difficult disease to treat. The recent WHO reclassification of CMML is expected to lead to a greater understanding of this disease and to the development of more effective treatments. All patients are advised to discuss survival information with their physicians. Keep in mind that outcome data can

show how other people with CMML responded to treatment, but cannot foretell how any one person will respond.

Many factors influence patient survival. Unfortunately, lasting remissions are not common. The reported median survival of individuals diagnosed with CMML is from 12 to 24 months after the initiation of treatment. In general, statistics may underestimate survival to a small degree since they may not reflect

 

Factors that may indicate a less favorable outcome include

• Severe anemia

• High blast percentage

• High total leukocyte (white cell) count

• High LDH level

• Larger spleen size.

Approximately 20 percent of CMML patients have disease that progresses to acute myelogenous leukemia (AML).

the most recent advance in treatment.®) and decitabine (Dacogen®), approved for treating MDS, are also approved for treating CMML patients. However, the effectiveness of azacitidine and decitabine for CMML treatment requires further study.PDGFR-β and TEL gene mutation are treated with the drug imatinib (Gleevec®). This treatment usually results in a return to normal blood counts, cytogenetic remissions, and, occasionally, molecular remissions for these CMML patients. Gleevec is an oral medication that is approved to treat chronicPDGFR-β and TEL genes. Patients that have the PDGFR-β and TEL gene mutation may respond favorably to treatment with the drug imatinib (Gleevec®).

aspiration and biopsy to check forpreviously classified as myelodysplastic syndromes (MDS) subtypes or atypical chronic myeloid disorders.

trials.