CREST syndrome

Definition

Myelodysplastic syndrome (MDS) is a disease that affects the production of all three major types of human blood cells. Patients with MDS have a lack of red blood cells, white blood cells, and platelets. The disorder occurs because the blood cells do not develop into mature cells, but rather stay in an immature stage within the bone marrow.

Description

Overview

To understand MDS, a basic knowledge of blood cells is needed. Blood cells are used by the body for many important functions. For this reason, the spongy tissue inside large bones (the bone marrow) stores a supply of blood cells in case the body needs them. Specialized cells known as stem cells are stored here. Stem cells have the ability to develop into immature blast cells and eventually become different types of mature blood cells. The three main types of blood cells produced in the bone marrow are: red blood cells (to carry oxygen); white blood cells (to prevent and fight infection); and platelets (needed for blood clotting). When the body needs a specific type of blood cell, the bone marrow uses its stockpile of stem cells to produce the appropriate mature cell. Although several changes and stages are required during blood cell development, the process is carefully controlled and occurs rapidly to meet the body's demands.

In patients with MDS, blood cells fail to mature. They remain in various immature blast cell stages. Because the cells do not mature, they also do not leave the bone marrow. Eventually, the marrow becomes filled with blasts until there is no room for normal cells to develop. In addition, many of the cells that do mature cannot function correctly. MDS therefore causes a shortage of functional blood cells of all types.

Subtypes of MDS

There are five different subtypes of MDS that are classified according to the number and appearance of the blast cells in the bone marrow. It is important for doctors to know which type of MDS a patient has, because each subtype affects patients differently and requires specific treatment. The five subtypes of MDS are:

• Refractory anemia (RA). Less than 5% blasts. RA is characterized by an abnormal appearance of red cell blasts.
• Refractory anemia with ring sideroblasts (RAS). Less than 15% blasts. RAS is similar to RA but has additional abnormalities in the red cells.
• Refractory anemia with excess blasts (RAEB). 5-20% blasts. RAEB is characterized by abnormal white and platelet blast cells. This form of MDS may transform into acute myelogenous leukemia.
• Refractory anemia with excess blasts in transformation (RAEB-t). 21-30% blasts. RAEB is characterized by a bone marrow appearance similar to that seen in acute myelogenous leukemia, except that RAEB-t has slightly fewer blast cells. This form of MDS is most likely to become leukemic.
• Chronic myelomonocytic leukemia (CMML). 5-20% blasts. This form of leukemia is characterized by too many mature white cells (monocytes) in the blood. CMML is also considered a type of MDS because the bone marrow contains excess white cell blasts together with abnormal forms of red cell and platelet blasts.

Progression

MDS used to be called preleukemia because the blast cells can resemble certain leukemic cells or eventually become leukemic. Only about one-third of myelodysplastic cases, however, actually lead to leukemia. For this reason, most doctors today seldom use preleukemia as a name for the condition. The types of MDS most likely to turn into leukemia are RAEB and RAEB-t.

Incidence

Approximately 5,000 new cases of MDS are diagnosed each year in the United States. Most of these belong to the RA or RAS subtypes. Most MDS cases occur in the elderly; it is quite rare to have MDS before age 50. An estimated 0.1% of persons 65 years old have MDS; the median age for people with this disease is 70. In older patients, MDS is more common in males than in females.

Causes & symptoms

Causes of MDS

There is no clear cause for the majority of MDS cases, which are called primary myelodysplastic syndromes. In some cases, however, MDS results from earlier cancer treatments, such as radiation and/or chemotherapy. This type of MDS is called secondary or treatment-related myelodysplastic syndrome. It is often seen in patients under the age of 30. The time span between cancer therapy and the development of MDS is usually three to six years, with a range of 1.5 to 13 years.

Other possible causative agents for MDS include exposure to radiation, cigarette smoke, and such toxic chemicals as benzene. Children with preexisting chromosomal abnormalities such as those found in Down syndrome may also have a higher risk of developing MDS. MDS does not appear to run in families, nor can it be spread to other individuals.

Symptoms of MDS

MDS symptoms are related to the type of blood cells that the body is lacking. The earliest symptoms are usually due to anemia, which results from a shortage of mature red blood cells. Anemia causes patients to feel tired, weak, and out of breath, because there is a lack of cells transporting oxygen throughout the body. MDS may also lead to a shortage of white blood cells and cause immune system problems. These patients are more likely to get infections. Another symptom of MDS is abnormal bruising and bleeding (e.g., heavy periods, blood in the stool, bleeding gums, and nosebleeds). Excessive bleeding results from a low level of platelets. These symptoms can occur in any combination, depending on a given patient's specific subtype of MDS. For example, an enlargement of the spleen or lymph nodes is a characteristic symptom of CMML.

Diagnosis

Blood tests

The diagnosis of MDS requires a complete analysis of the patient's blood and bone marrow. This analysis is done by a doctor that specializes in blood diseases (a hematologist). But because the early symptoms of MDS are usually fatigue and difficulty breathing, patients with MDS often go first to their general practitioner. To test for anemia, the doctor takes a blood sample and sends it to a laboratory for analysis. A complete blood count (CBC) must be done first to determine the number of each blood cell type within the sample. Low numbers of red blood cells, white blood cells, or platelets are signs that the patient has MDS. In these cases, the hematologist also studies the blood cells under the microscope to find out if any of the cells are abnormal. This analysis is called a blood film report, and will usually show abnormal red blood cells in MDS patients.

Bone marrow biopsy

A bone marrow biopsy is required to confirm the diagnosis of MDS and determine the correct MDS subtype. This procedure involves using a needle to take a sample of marrow from inside the bone. The area on the skin where the needle is inserted is numbed or anesthetized, and sometimes the patient is also sedated. Patients may experience some discomfort, but the procedure is over fairly quickly. Marrow samples are usually taken from the back of the hip bone (the iliac crest) or from the breast bone (the sternum). A sample of the marrow, known as an aspirate, and a small piece of bone are both removed with the needle.

A hematologist or a specialist in diseases (a pathologist) will carefully examine the bone marrow samples through a microscope. Microscope examination allows the doctor to determine the number and type of blasts within the marrow in order to identify the MDS subtype. Cells from the bone marrow biopsy may also be used for cytogenetic testing, which analyzes the cells' chromosomes. Certain chromosomal abnormalities in bone marrow cells are common in MDS. In fact, 40-70% of MDS patients have changes within their bone marrow chromosomes as a result of the disease. The pattern of these changes can be used to predict how a patient will respond to treatment. Thus, the full set of information provided by a bone marrow biopsy ultimately allows the doctor to design the most effective treatment plan.

Treatment

Supportive care

Treatment for MDS is tailored to the patient's age, general health, and specific MDS subtype. Although treatment tends to vary for each patient, most treatment strategies are designed to control the symptoms of MDS. This approach is called supportive care; it aims to improve the patient's quality of life. Supportive care for MDS patients commonly includes red blood cell transfusions to relieve anemia symptoms. Vitamins may also be prescribed to increase red blood cell production. Platelet transfusions can also provide a way to control excessive bleeding. In patients with low white cell counts, antibiotics can be prescribed to combat infections.

Corrective treatment

A variety of therapies are directed at providing MDS patients with a cure, although many of these approaches are still considered experimental. These strategies often require the patients to be in fairly good health and are therefore more likely to be used for younger patients. For example, bone marrow transplantation (BMT) has been found to be a successful treatment for MDS patients under the age of 50 (and some over 50 in good health). Following BMT, many patients are able to achieve long-term, disease-free survival. Unfortunately, most MDS patients cannot receive a bone marrow transplant because of their age, or because they do not have a suitable donor.

Chemotherapy has also been used to treat some MDS patients; however, the disease often recurs after a period of time. This type of therapy uses cell-killing (cytotoxic) drugs that are either taken orally or injected into the body. These drugs are standard chemotherapy agents, including cytarabine (ARA-C), idarubicin, daunorubicin (Cerubidine), 6-thioguanine (Lanvis), and mitoxantrone. The drugs primarily kill rapidly growing cells in the bone marrow and blood, but may also destroy healthy cells that are growing. For this reason, chemotherapy is generally not used until the MDS becomes aggressive. Chemotherapy is most successful in patients with the RAEB, RAEB-t and CMML subtypes of MDS.

Biological therapy agents are also being developed to treat MDS. One group of these agents, called growth factors, are natural protein substances that the body normally uses to control blood cell production. Growth factors have also been made in the laboratory and can be given to MDS patients. These substances stimulate the patient's bone marrow to produce healthy blood cells and platelets. Growth factors that stimulate white cell production are G-CSF (granulocyte colony stimulating factor, sold under the trade name Neupogen) and GM-CSF (granulocyte-macrophage colony stimulating factor, sold under the trade names Leukine or Prokine). In order to increase red blood cell production another growth factor, erythropoietin (EPO, Epogen), is used.

Alternative treatment

There are no alternative therapies that successfully treat MDS, as medical attention is required for this disease. A well-balanced diet and adequate rest, however, are helpful in managing the symptoms of anemia.

Prognosis

The prognosis for MDS patients depends on the subtype of their disease. Patients with the more common, lower-risk RA and RAS rarely develop leukemia and may live with the disease for some years, depending on when it is detected. The higher-risk subtypes--RAEB, RAEB-t, and CMML--progress more rapidly, and require intensive therapy to control the disease.

Managing MDS requires frequent doctor appointments to monitor disease progression and evaluate the patient's response to treatment. Fortunately for many patients, recent advances in therapy have significantly enhanced their ability to cope with MDS. Experimental drugs and a better understanding of the disease are likely to improve the quality of life for MDS patients.

Prevention

MDS is usually impossible to prevent, although avoiding exposure to radiation and benzene may decrease the risk of developing the disorder. Secondary complications of MDS such as bruising and bleeding may be prevented by being careful about daily activities and avoiding the use of aspirin-like products that thin the blood. Infections can also be prevented by practicing good hygiene and avoiding crowds or people with virus infections. A well-balanced diet is needed for the body to make red blood cells and avoid anemia.

Key Terms

Acute myelogenous leukemia

A cancerous disease that involves high numbers (above 30%) of white cell blasts in the bone marrow. When MDS cases transform into acute leukemia, they usually belong to this type.

Anemia

A lack of red blood cells in the body that causes tiredness, shortness of breath, and weakness.

Blasts

Immature blood cells.

Bone marrow transplant

A form of therapy whereby patients are exposed to high doses of chemotherapy and/or radiation therapy to destroy all of their bone marrow. The destroyed marrow is then replaced with healthy bone marrow from another person.

Chemotherapy

The use of cell-killing drugs to destroy cancerous or rapidly dividing cells.

Chromosomes

The strands of DNA within a cell's nucleus that encode genetic information. Certain chromosomal abnormalities within bone marrow and blood cells are a sign of MDS.

Cytogenetics

An analysis of chromosomes that is used to diagnose specific types of MDS.

Growth factors

Natural protein substances made by the body that stimulate cell growth.

Leukemia

A cancerous disease that occurs when too many blood cells are produced and cannot function properly.

Monocyte

A white blood cell that works to fight infections.

Platelets

Small disk-shaped blood cells produced in the bone marrow. Platelets help to seal off cuts by forming clots that stop bleeding.

Red blood cells (RBCs)

Cells produced in the bone marrow that carry oxygen to all parts of the body in the blood circulation.

Stem cells

Cells that are able to develop into any type of mature blood cell.

White blood cells (WBCs)

Cells of the immune system that fight off invading germs and disease agents. WBCs are made in the bone marrow and lymph nodes.

Further Reading

For Your Information

Books

• Castro-Malaspina, Hugo, and Richard J. O'Reilly. "Aplastic Anemia and Myelodysplastic Syndromes." In Harrison's Principles of Internal Medicine, 14th ed., edited by Anthony S. Fauci, et al. New York: McGraw-Hill, 1998.
• Nomura, Takeo, and Yataro Yoshida. Myelodysplastic Syndromes: Advances in Research and Treatment. Amsterdam: Elsevier Science, 1995.

  Organizations

• Aplastic Anemia Foundation of America. P.O. Box 613, Annapolis, MD 21404. (800)747-2820. http://www.aplastic.org.
• Leukemia Society of America. 600 Third Avenue, New York, NY 10016. (800)955-4LSA. http://www.leukemia.org.
• Myelodysplastic Syndromes Foundation. 464 Main Street, P.O. Box 477, Crosswicks, NJ 08515. (800)MDS-0839. http://www.mds-foundation.org.

Gale Encyclopedia of Medicine. Gale Research, 1999.