Myelodysplastic Syndromes

-"Understanding Myelodysplastic Syndromes: A Patient Handbook", Peter Kouides, MD, and John M, Bennett, MD, published by the Myelodysplastic Syndromes Foundation.

What is MDS?
What Causes MDS?
What are the Symptoms of MDS?
How Severe is My MDS?
What Tests are Used to Diagnose MDS?
How is MDS Treated?

What is MDS?

MDS, or myelodysplastic syndromes, is a group of bone marrow diseases. Normal bone marrow produces three different cell types that help make up the blood - red blood cells, white blood cells, and platelets. In MDS the bone marrow is "injured", that is, loses its ability to produce normal cells of one or more of these types. The diseased cells are called myelodysplastic cells.

MDS is primarily a disease of the aging, most patients being over 65. MDS does not necessarily shorten life expectancy. The bone marrow’s failure to produce normal cells is a gradual process, and the elderly often succumb to other diseases before MDS takes its toll. It is possible, however, that in time the bone marrow will fail completely, making patients unable to fight infection or prevent bleeding. There is also the ever present risk of MDS progressing into acute myeloid leukemia (AML), which does not respond well to chemotherapy. AML is a bone marrow malignancy where the marrow is replaced by a population of extremely immature or primitive "blast" or stem cells. Therefore, there is a severe shortage of normal cells. But the majority of patients, roughly 70%, never develop leukemia. In other words, MDS shortens life in some patients but not in others. Eventually 70 to 75% of patients with MDS succumb to either complications or progression to AML.

What Causes MDS?

The exact causes are unknown. Smoking increases the risk of AML (1.6 times normal). There are no known food products that cause MDS. Alcohol consumed on a daily basis may lower red blood cell and platelet counts but does not cause MDS. Some evidence suggests that certain people are born with a tendency to develop MDS. This tendency can be thought of as a "switch" that is triggered by an external factor. Radiation and chemotherapy are among the known triggers. Patients taking chemotherapy drugs for potentially curable cancers such as Hodgkins’s disease and lymphoma are at risk of developing MDS for up to ten years following treatment. Unfortunately, it is not clear which chemicals, aside from benzene, are implicated. We distinguish between primary MDS (no known cause) and secondary MDS (strong association with a leukemogenic agent). The latter usually have multiple chromosome abnormalities in the bone marrow and evolve to AML rapidly. Patients and their families often worry that MDS might be contagious. There is no evidence to suggest that MDS is caused by A virus. In other words, it cannot be transmitted to loved ones. On rare occasions there may be cases of MDS in siblings. There is no need for routine screening of blood counts in families.

What Are The Symptoms of MDS?

Many patients in the early stages of MDS experience no symptoms at all. A routine blood test will reveal a reduced red cell count, or hematocrit, sometimes along with reduced white cell and/or platelet counts. On occasion the white cell and platelet counts maybe low while the hematocrit remains normal. The counts are not low enough to produce symptoms.

Other patients experience definite symptoms. These symptoms depend on which blood cell type is involved, as well as the level to which the cell count drops.

Low Red Cell Count (Anemia)

Anemic patients experience fatigue and related symptoms. In mild anemia (hematocrit 30 to 35%) the patient may feel well or just slightly fatigued. In moderate anemia (hematocrit 25 to 30%) almost all patients experience some fatigue, which may be accompanied by heart palpitations, shortness of breath, and pale skin. In severe anemia (hematocrit less than 25%) almost all patients suffer severe fatigue and shortness of breath; they also appear pale. Because severe anemia reduces blood flow to the heart, older patients may suffer chest pains (angina) or have a heart attack.

Low White Cell Count (Neutropenia)

A reduced white cell count lowers resistance to bacterial infection. In addition to fever, patients with neutropenia may be susceptible to skin infections, sinus infections (nasal congestion), lung infections (cough, shortness of breath), or urinary infections (painful and frequent urination).

Low Platelet Count (Thrombocytopenia)

Patients with thrombocytopenia have an increased tendency to bruise, even after minor scrapes and bumps. Bruises can be dramatic, some as large as the palm of the hand. Nosebleeds are common. Patients often experience bleeding of the gums, particularly after dental work.

How Severe is My MDS?

The French-American-British (FAB) Classification

In the early 1980's physicians from France, the U.S., and Great Britain developed a classification system to evaluate the potential risks of the disorders collectively known as MDS. The FAB classification is helpful because it gauges the aggressiveness of these disorders. A central criterion for the classification is the percentage of blasts, or primitive leukemic cells, in the bone marrow. There are five FAB categories of disease:

  1. Refractory anemia.Patients are not responsive, that is, refractory, to iron or vitamins. There maybe mild to moderate neutropenia and thrombopenia: less than 5% blasts are seen in the bone marrow. Median survival is about 4 years and less than 10% progress to AML.
  2. Refractory anemia with ringed sideroblasts. Sideroblasts are red blood cells containing granules of iron. Ringed sideroblasts are abnormal. In patients with this disorder, less than 5% of marrow cells are blasts and median survival is 55 months with less than 5% progressing to AML.
  3. Refractory anemia with excess blasts. Five to 20% of marrow cells are blasts, and 1 to 5% blasts may circulate in the blood. Median survival is about 2 years and 20 to 30% progress to AML.
  4. Refractory anemia with excess blasts in transformation. Twenty to 30% of the marrow cells are blasts, and more than 5% blasts circulate in the blood. Median survival is about 6 months and 75% progress to AML.
  5. Chronic myelomonocytic leukemia. The marrow findings are similar to other subtypes of MDS except for an increase in monocytes in the blood and marrow. The marrow contains 1 to 20% blasts. The total white cell count may be elevated and chronic granulocytic leukemia must be ruled out. Median survival is about 3 years.

The International Prognostic Scoring System (IPSS)

A more recently developed system grading the severity of MDS is the International Prognostic Scoring System. IPSS "scores" a patient’s disease in terms of its risk, that is, shortened life expectancy and the chances of transformation to AML. The score is the sum of three factors: the percentage of blasts appearing in the bone marrow; the cytogenetic finding, a test that looks for chromosomal abnormalities in the bone marrow blood cells; and the blood cell count.

What Tests Are Used to Diagnose MDS?

Initially, a complete blood cell count is done. This requires blood drawn from the arm. The blood is also tested for erythropoietin, a protein produced in the kidneys that helps red blood cells develop. If it is confirmed that a patient has a low hematocrit, possibly along with a low white cell and/or platelet count, a bone marrow examination is performed. The bone marrow is examined to define the percentage of blasts and abnormally mature cells (dysplastic cells). A sample is stained to determine iron content. A chromosomal analysis is also performed to discover any abnormalities (such as a missing or extra chromosome). The cytogenetic findings can be particularly helpful in judging how aggressive a patient’s condition is and in planning treatment (see Checklist). Periodic bone marrow exams help determine whether MDS has transformed to AML.

Both of these conditions can be associated with "dysplastic" - appearing cells and anemia.

Checklist of Test Results for Your Hematologist

  What is my hematocrit? Normal 36-50%
  What is my white cell count? Normal 3,500 - 10,000
  What is my platelet count? Normal 150,000 - 450,000
  What is my serum erythropoietin level? Normal 10-20
  What is the percent of blasts in my bone marrow? Normal <2% blasts
  What is my cytogenetic finding? Good: Normal cytogenetics or 5 q- or 20q or Y-.

Intermediate: Any other cytogenetic abnormality.

Poor: >3 or more abnormalities or monsomy 7: 5q- means a partial loss of the long arm of chromosome 5; -7 is a complete loss of one of the two "7" chromosomes (usually there are 46). +8 means an extra #8 chromosome (Trisomy 8)

  What is the FAB classification of my MDS?    
  Is there any chance that instead of MDS, I have vitamin B12 or folate deficiency?    

The Bone Marrow Examination

This procedure can be performed in the physician’s office. It usually takes about twenty minutes. The patient reclines on the examining table, on either his side or his stomach, preferably whichever way is most comfortable. A mild sedative or narcotic may be administered. The physician feels for the bony protrusion on the right or left side of the hip, the so-called posterior iliac crest. (This is the usual site for the procedure; bone marrow exams are never performed on the spine). The physician swabs the skin with iodine and places a sterile towel and drape over the area to reduce the risk of bacterial infection.

A needle, smaller than one used to draw blood from the arm, is slowly inserted under the skin to inject the anesthetic Lidocaine. The patient may feel a twinge of pain. Soon a dime-sized area of the skin is numb. Now a longer, slightly larger needle is used to inject anesthetic into the bone itself. It is common for patients to experience a twinge of pain when the second needle is inserted. Once the needle makes contact with the bone itself, the patient should only feel slight pressure, as though a thumb were pressing against the skin.

After about five minutes the bone covering, or periosteum. Should be well anesthetized. Now the patient is asked if he feels anything. If so, more Lidocaine is injected into the area. If not, the physician proceeds with a third, larger needle, which is inserted into the bone marrow itself. There are no pain fibers (nerve endings) in the marrow, so this stage should be painless. While asking the patient to take several slow, deep breaths, the physician attaches a syringe to the end of the needle and then quickly pulls out, or aspirates, the marrow, removing about a tablespoon. Typically the patient experiences a shocklike sensation, but just for a fraction of a second. Often a second aspiration is done to obtain additional marrow for cytogenetic testing.

Finally, a fourth, wider needle is inserted to obtain a section of bone for biopsy. The needle is "cored" several millimeters into the bone, at which time the patient should feel nothing more than a dull pressure. When the physician loosens the bone and removes it, the patient experiences a jerking sensation. The bone marrow exam is over.

The Risks of a Bone Marrow Exam

The exam carries three risks: infection, bruising, and bleeding, and discomfort. Anytime a needle is inserted through the skin there is the possibility of infection. However, infection is highly unlikely if antiseptic conditions are maintained.

After the examination, some patients develop a sizable bruise or a swelling of blood (hematoma) under the skin, particularly those whose platelet count is low. If the platelet count is below 50,000 per microliter, the physician should apply at least five minutes of pressure over the needle site.

Discomfort is a common fear of patients who face a bone marrow examination. It might help reduce fear to point out that a bone marrow examination is similar to a tooth being pulled out. In each case, the bone is "pricked". If this is properly done, there should be little pain other than the twinge of the needle going under the skin.

Some patients want to know why they can’t simply receive general anesthesia before a bone marrow examination. General anesthesia, which carries risks, is not necessary doing this procedure. However, patients have the right to request additional medication if they are concerned that Lidocaine will not be adequate. Patients undergoing a bone marrow exam are advised to come to the doctor’s office with someone who can drive them home.

How is MDS Treated?

Treatment for MDS depends on two main factors: the degree to which blood cell counts are reduced, and the risk of progression to AML.

Induction Chemotherapy

In the high-risk group and the intermediate-risk group II, there is a high rate of progression to AML. These patients should consider receiving intravenous chemotherapy. Relatively strong doses of chemotherapy are given to "induce" control of the disease. One temporary side effect of inductive chemotherapy is further failure of the bone marrow. Initially, chemotherapy kills the bone marrow cells that normally produce platelet and red and white blood cells. This phase lasts several weeks, during which the patient remains hospitalized, receiving red cell and platelet transfusions along with antibiotics to fight infection. Because chemotherapy kills dividing cells elsewhere in the body, not just in the bone marrow, patients experience hair loss, mouth sores, and often diarrhea.

If induction chemotherapy manages to control the myelodysplastic cells, then relatively normal cells should grow. Within several weeks there will be enough red cells and platelet produced in the marrow to require fewer transfusions. Meanwhile, the white cell count should also rise, lessening the risk of infection.

Unfortunately, the chance of controlling MDS with induction chemotherapy is only about 30%. Even in successful cases, the disease often returns within twelve months. Thus aggressive chemotherapy is given to a minority of MDS patients.

Red Cell Transfusion

Patients in the low-risk group or intermediate-risk group 1 may not be producing enough red blood cells, in which case they are given supportive treatment in the form of transfusions. If patients are quite anemic (hematocrit consistently less than 25%) they will receive periodic transfusions, typically two units every two to six weeks. In older patients, there is some risk of shortness of breath from excess fluid received during transfusion. This can often be avoided or minimized by intravenous administration of the diuretic Lasix.

Iron is carried by red blood cells. After ten or twenty transfusions, a patient may accumulate so much iron that it ends up being deposited on the heart and liver, shortening life expectancy. Some patients are given a medication called Deferral to lower their iron level. Deferral has to be administered through a pump device under the skin. The device is usually worn at night for about eight hours. Another risk of red cell transfusion is the transmittal of viruses. Fortunately, tests can be performed to detect certain viruses, making the risk of transmittal very low. For instance, the chance of contracting HIV is 1 in 500,000 transfusions; of contracting hepatitis C, 1 in 100,000; and of contracting hepatitis B, 1 in 60,000. Much higher are the risks run by avoiding transfusion treatment when it is needed.

Alternatives to Red Cell Transfusion

The ideal treatment for anemia is to prevent or improve it so that blood transfusions are unnecessary. The following treatments offer limited success.

Erythropoietin (EPO). This protein, produced in the kidneys, helps red blood cells develop. In about a quarter of MDS patients, erythropoietin, injected under the skin three to seven times a week, is effective in raising the red cell count and hence preventing the need for transfusions. Erythropoietin is particularly helpful if the serum EPO level is below 200 IU. For most patients, however, erythropoietin treatment is not worth the expense of roughly $200 a week.

Pyridoxine. This is Vitamin B6. If the bone marrow stain shows deposits of iron in the red cells indicating sideroblastic anemia, then the patient should try taking 100 mg of pyridoxine twice a day. About 5% of patients show improvement in their red cell count with this therapy. Higher doses of pyridoxine can produce side effects such as tingling of the fingers.

Deferral. This treatment, as mentioned, is given for iron overload caused by red cell transfusions. Some patients with anemia who are not receiving transfusions show improvement on this medication.

Growth Factors

Granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) are proteins that the body makes to promote white cell production. For patients with a low white cell count who have had at least one infection, it is worth trying growth-factor medication. In 75% of patients who take either G-CSF (Neupogen) or GM-CSF(Leukine), the white cell count rises, reducing the chances of further infection. Both medications are administered under the skin between one and seven times a week. Neither has been proven to prolong survival. Neupogen and Leukine are well tolerated and do not cause major side effects, though patients occasionally report rashes and bone pain.

Platelet Transfusions

Platelet transfusions are rarely given unless the platelet count is below 10,000 per microliter. As a rule, patients become resistant to these products within a few months. At present, there is no growth-factor medication for patients receiving periodic platelet transfusions. Fortunately, ongoing studies with growth factors such as Interleukin-11 and -6 look promising. In particular, thrombopoietin may prove effective in raising the platelet count.

Vitamin Therapy

Vitamins have been an active area of MDS research over the past two decades. In test tubes, myelodysplastic cells often normalize when exposed to vitamins such as D3 and A (retinoic acid). Overall, however, clinical trials have been disappointing. Presently a major area of research is devoted to combining vitamins with low doses of chemotherapy and/or growth factors such as erythropoietin and GM-CSF. It may be worth asking your specialist about any ongoing studies.

Bone Marrow Transplantation

Bone marrow transplantation is becoming more effective as therapy, particularly for AML. The ultimate goal of transplantation is to cure patients by completely eliminating their myelodysplastic cells. To date, about 500 MDS patients have undergone bone marrow transplantation. Almost all have been under the age of 40. In patients over the age of 55, the risks of transplantation clearly outweigh the benefits, given the high risk that the donated marrow (graft) will reject the patient (host). Because MDS is a disease of the elderly, bone marrow transplantation doesn’t represent a viable option for most patients.

In addition to being young enough, candidates for transplants must have a sibling who is the same transplantation type. That is, there must be an HLA match between the two. HLA type - not to be confused with blood type - is determined through a blood test. Unfortunately, children and parents of the patient do not qualify as HLA matches.

Even in younger patients, bone marrow transplantation is a high-risk procedure. Within the first year there is a 30 to 50% chance of dying from transplant complications, either graft vs. host disease, or damage to the liver or lungs. Patients who survive these complications, however, have a good chance of being cured. There is clearly no right answer to the question of whether patients under the age of 55 who have an HLA match should undergo transplantation. For people without other major medical problems, certainly the risks of life-threatening transplant complications are lower than the risks of delaying, or not receiving, a transplant.

Conclusion

An important part of the Hippocratic oath is this: First, do no harm. MDS is a puzzling, life-threatening set of disorders for which there are no easy cures or quick remedies. Treatment consists largely of supportive care. Relatively aggressive therapies such as chemotherapy and bone marrow transplantation can sometimes do more harm than good. But not all patients die from MDS. It is incumbent upon both patient and physician to be cautious in considering the level and type of treatment provided. Whatever path is ultimately chosen, above all it should reflect the patient’s preferences.

For further information contact:

The MDS Foundation

P.O. Box 477

464 Main Street

Crosswicks, NJ 08515

Tel:1-800-MDS-0839

Fax:609-298-0590