Myelodysplastic syndromes (MDS)

INTRODUCTION — The myelodysplastic syndromes (MDS, myelodysplasia) are not one specific disease, but include a series of blood disorders, all characterized by chronic deficiencies of certain components of the blood and abnormal growth of blood cells. MDS can cause infections, bleeding, anemia (low level of red blood cells), and can progress to acute leukemia, which is often difficult to treat. MDS may occur on its own or years after exposure to chemotherapy. The risk of developing MDS increases with age and is very rare in childhood.

SIGNS AND SYMPTOMS — MDS usually causes a low number of red blood cells, white blood cells, and/or platelets. Each cell type performs a number of functions, including the following: Red blood cells carry oxygen throughout the body White blood cells help to protect the body from infection Platelets helps blood to clot normally

Anemia is almost always present in MDS and is generally associated with a slow regrowth of red blood cells. A low total white blood cell count is found in approximately 50 percent of patients with MDS at the time of diagnosis, which increases a person's risk of developing infections.

A low platelet count is found in roughly 25 percent of people with MDS. An increase in the platelet count is less common, but occurs in association with a specific abnormality in chromosome 5, called the 5q-syndrome. Abnormalities of the immune system may be found in patients with MDS in a minority of cases. There is usually an excess of bone marrow blast cells in MDS; often bone marrow cells are deformed and have abnormal growth and maturation.

A microscopic study of blood and bone marrow cells is necessary to diagnose MDS.

TYPES OF MYELODYSPLASTIC SYNDROME — MDS is classified according to the type and number of red blood cells. Refractory anemia (RA) causes a lack of red blood cells and is resistant (refractory) to standard treatment; RA occurs in approximately 21 percent of MDS patients. Refractory anemia with ringed sideroblasts (RARS) causes a lack of red blood cells, along with the presence of "ringed" deposits of iron in bone marrow cells under a microscope. RARS is also resistant (refractory) to standard treatment and occurs in approximately 17 percent of MDS patients. Refractory anemia with excess blasts (RAEB): a lack of red blood cells, and a bone marrow examination which shows a slight excess of bone marrow blast (leukemic) cells under a microscope and is resistant (refractory) to standard treatment; RAEB occurs in approximately 37 percent of MDS patients. Refractory anemia with excess blasts in transformation (RAEB-t) causes a lack of red blood cells, which shows a greater excess of bone marrow blast cells (greater than in RAEB) under a microscope and is resistant (refractory) to standard treatment. There may be little difference between RAEB-t and acute myeloid leukemia. RAEB-t occurs in approximately 13 percent of MDS patients. Chronic myelomonocytic leukemia (CMML) is a type of chronic leukemia with an excessive number of monocytes (a type of white blood cell); CMML occurs in approximately 12 percent of MDS patients. Most people with CMML have an elevated white blood cell count.

Some cases of MDS are not readily categorized. This is particularly true for people with treatment-related MDS. In such cases, the terms "unclassifiable MDS" or "refractory anemia with dysplasia" have been used.

TREATMENT — Treatment of patients with MDS includes four major goals: Control of symptoms - this goal is easily achieved Improving quality of life and minimizing the side effects of therapy - this goal is frequently achievable Decreasing progression to acute leukemia - we are currently unable to achieve this goal Improving overall survival - with good medical care and judicious use of growth factors we can have an impact here

Practice guidelines of the National Comprehensive Cancer Network (NCCN) suggest that treatment should be based upon three features (show table 3): Age of the patient Performance status, a measure of how well a patient can perform normal daily tasks Risk category, as defined by the IPSS system

High versus low intensity treatment — The NCCN has characterized treatment as being either of "high" or "low" intensity, as follows: High intensity treatment requires hospitalization and includes intensive combination chemotherapy with or without bone marrow transplantation. Low intensity treatment includes outpatient treatments, such as hematopoietic growth factors, differentiation-inducing agents, biologic response modifiers, and low intensity chemotherapy.

Treatment recommendations — MDS treatment guidelines include the following (show table 3): Patients less than 61 years of age who have minimal disease symptoms and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.3 to 1.8 years) are generally treated with high intensity therapies. Patients in the low or intermediate-1 category (expected survival 5 to 12 years) are generally treated with low intensity therapy. Patients >60 years of age with good performance status (expected survival 0.4 to 5 years), are generally treated with low intensity therapy, although selected patients may be candidates for high intensity therapies. For patients with a limited life expectancy, supportive care or low intensity therapies are recommended. Supportive care includes transfusion of red cells or platelets, antibiotics, and hematopoietic growth factors.

Due to the advanced age of most patients with MDS, the chronic nature of the disease and its symptoms, supportive care is an important part of treatment for all patients.

Virtually all of the treatments discussed below are still considered to be experimental. Comparative clinical trials with the critical involvement of MDS patients are still needed in order to determine the relative value of each of the treatments described below.

Hematopoietic growth factors — The hematopoietic growth factors, recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) do not improve survival or prevent infection in people with MDS. Recombinant human erythropoietin (EPO) promotes the growth of red cells, and decreases the need for red cell transfusions in 20 percent of MDS patients.

Combination therapy, using G-CSF along with EPO, may be more effective than EPO alone, especially in those with low serum levels of EPO and low transfusion requirements.

Immunosuppressive drugs — In some patients with MDS, the immune system may encourage a decreased production of blood cells. This may be especially true in people with a reduced number of cells in the bone marrow.

Some of these patients, particularly those who are younger, with normal blood cells, reduced cell content of the marrow, and early disease, respond to immunosuppressive therapies, which weaken the immune system. Examples of immunosuppressive therapies include antithymocyte globulin (ATG) and cyclosporine.

Most everyone who is treated with ATG develops serum sickness, which causes hives, swelling, and fever. This reaction can be reduced by giving steroids along with the ATG.

Thalidomide and its derivatives — Responses to thalidomide occur in 20 percent of patients with MDS, but side effects such as fatigue and constipation can be formidable.

Second generation thalidomide-like drugs (eg, Revlimid, lenalidomide) may be more active and more tolerable for treatment of anemia. In early studies, this agent has been particularly effective in patients with abnormalities of chromosome 5 (called the 5q minus syndrome).

Low and intermediate dose chemotherapy — Low doses of chemotherapy have been used in selected patients with MDS. This approach is a good option in older patients (show table 3).

Cytarabine has been the most widely studied drug, although rates of complete remission are below 20 percent. The drug 5-azacytidine has shown activity in MDS, and may lengthen survival, although the improvement is modest. 5-aza-2-deoxycytidine may be more effective than 5-azacytidine.

High intensity chemotherapy — Aggressive chemotherapy has generally not been as effective in people with MDS as in people with acute leukemia. In one study, patients <60 years of age with a good performance status underwent aggressive chemotherapy followed by bone marrow transplantation [2]. Survival of these patients was comparable to, or better than, that of patients treated with only supportive care and nonintensive treatment approaches.

Ongoing studies are evaluating new drugs (eg, clofarabine combined with cytarabine). Such chemotherapy programs entail a significant risk, especially in people with other serious medical conditions, such as the elderly. This risk would only be justified if the new agents appeared much more effective than the older treatment programs.

Inhibitors of tumor necrosis factor-alpha — Some of the diminished production of blood cells is thought to be due to an excess production of tumor necrosis factor (TNF)-alpha, a protein which usually has anticancer activity, but, in excess, can cause a deficiency of red blood cells and some of the necessary components in the blood. Clinical trials are ongoing using etanercept, a protein that binds to TNF-alpha and prevents it from having harmful effects.

STEM CELL TRANSPLANTATION — In the past, patients over age 50 were not considered for hematopoeitic stem cell transplantation (also called bone marrow transplantation), mostly due to the risk of transplant-related complications. Improvements in technique and supportive care have allowed the upper age limit for BMT to expand to people age 60 or more. However, approximately 75 percent of patients with MDS are older than 60 at diagnosis, so conventional BMT can only be offered to a minority of individuals. (See "Patient information: Overview of bone marrow transplantation").

One study from Seattle evaluated the outcome after BMT in 50 patients between the ages of 55 and 66 [3], and found that survival in all categories was inversely related to their IPSS risk score. For example, a person in this age group with a high risk score was less likely to survive than a person with a low risk score. Thus, age alone might not be the only determining factor in the decision to undergo BMT.

However, patients who are less than 60 years with the most favorable IPSS scores have median survivals of 5 to 12 years with standard (supportive) care only. This group also has the highest success rate following BMT, although the median survival is approximately five years, which takes into account those patients "cured" of MDS as well as those dying early as a result of the transplantation procedure itself. Thus, survival following transplantation may be lower than that achieved with supportive care alone. Accordingly, the decision to undergo transplantation is difficult.

Patients with MDS who are under the age of 60 and who have a tissue-matched sibling donor of bone marrow should be considered for a BMT. The decision to have BMT depends upon a number of criteria, including the IPSS score and the risk of disease progression and the overall health of the patient. Although there is a significant chance of cure after BMT in low and intermediate risk patients (approximately 60 and 40 percent, respectively), transplant-related deaths and the relapse rate at five years are also high (as high as 40 percent).

One study described the outcome after BMT in 93 patients with MDS [4,5]. After four years, 41 percent of patients were alive and free of disease, 28 percent had relapsed, and 43 percent died of transplant-related complications. As expected, those patients who had the best overall result were younger (<40 years). A 1998 update of this study included 251 patients with MDS; 60, 36, and 28 percent of patients in the low and intermediate-1, intermediate-2, and high risk groups, respectively, were disease free after five years [6]. Based upon this data, BMT is recommended for patients with intermediate-1, intermediate-2, and high risk MDS, but not for patients with low risk disease.

The use of tissue-matched unrelated donors for patients with MDS has been limited. One study found that age was a factor with unrelated bone marrow transplants; younger patients had better survival than older patients.

Use of reduced intensity treatment before transplantation, also called "mini-transplants", have allowed some patients with MDS, who would not otherwise be eligible, to receive a transplant with a lower incidence of transplant-related complications. This is an area of intense research interest.

Children — BMT is the treatment of choice for children with MDS. BMT allows for long term survival for a high percentage of those with tissue-matched sibling donors.

Progression to acute leukemia prior to BMT — If a patient's MDS evolves into acute leukemia prior to a bone marrow transplantation procedure, many physicians choose to perform the transplant immediately, rather than administering pretransplant chemotherapy. Pre-BMT chemotherapy can increase a patient's risk of developing complications such as infections, especially fungal disease, and organ damage.

Other considerations — Patients with MDS are chronically immunosuppressed and are at risk for a variety of infections. They are also at high risk for a relapse of MDS following effective treatment. The risk of relapse may be as high as 40 percent at five years.

Recommendations for BMT — The above studies indicate that a subset of patients with MDS can be cured following BMT. This is in contrast to all other treatments, none of which has provided a significant chance for cure.

BMT should be considered for people with MDS who are under the age of 60 who have a tissue-matched sibling donor. The decision to undergo BMT depends upon a number of criteria, including the IPSS score, the risk of disease progression, underlying infections, and the overall health of the patient.

Although there is a significant chance of cure after BMT in low and intermediate risk patients (approximately 60 and 40 percent, respectively), transplant-related death is also high (as much as 40 percent). In addition, even five years after successful BMT, the risk of relapse of MDS is about 40 percent. Patients and their physicians should balance these competing issues and compare the outcomes of BMT and supportive care only.

TREATMENT-RELATED MDS — Treatment-related MDS (t-MDS) is an extremely serious complication of chemotherapy, and is usually fatal even with standard treatment. In one study, survival was strongly dependent upon the chemotherapy used immediately prior to BMT. Five-year survival after BMT for patients with treatment-related MDS is lower than that of patients with spontaneously-occurring MDS.

PROGNOSIS

IPSS Prognostic model — A prognostic system (model) was devised, called the International prognostic scoring system (IPSS), which considers variables such as age, type of blood abnormality present, as well as studies of the genetic makeup of the abnormal cells. The IPSS system is helpful to determine the prognosis of patients. Based on these criteria, four risk groups for survival and likelihood of progression to acute leukemia were defined: low, intermediate-1, intermediate-2, and high risk groups (show table 2): Overall median survival was longer for those in the low risk category compared to those in the intermediate and high risk categories. These were 5.7, 3.5, 1.2, and 0.4 years for patients with low, intermediate-1, intermediate-2, and high risk, respectively. The time for 25 percent of the patients to develop acute leukemia was longer for those in the low risk category than those in the intermediate and high risk categories: 9.4, 3.3, 1.1, and 0.2 years, for patients with low, intermediate-1, intermediate-2, and high risk, respectively. Survival of high risk patients was independent of age, being approximately 0.3 to 0.5 years for all age groups. Survival of low risk patients was strongly dependent on age: 11.8, 4.8, and 3.9 years in patients 60, >60, and >70 years of age, respectively.

The survival times noted above are averages; there is considerable variation from patient to patient, especially in the low-risk group.

Using the classification system, patients with RAEB and RAEB-t have relatively poor outcomes, with median survivals ranging from 5 to 12 months. In contrast, those with RA and RARS had median survivals of approximately three to six years.

The proportion of individuals whose disease progressed to acute myeloid leukemia (AML) varies similarly; 40 to 50 percent of patients with RAEB and RAEB-t progress to AML, compared to 5 to 15 percent of patients with RA and RARS (show table 1). RAEB-t usually progresses to AML faster than the other subgroups.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus)
The Leukemia & Lymphoma Society

(www.leukemia-lymphoma.org)
National Marrow Donor Program

(www.marrow.org)
Aplastic Anemia and MDS International Foundation, Inc.

(www.aamds.org)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)


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3. Deeg, HJ, Shulman, HM, Anderson, JE, et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 2000; 95:1188.
4. Anderson, JE, Appelbaum, FR, Fisher, LD, et al. Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome. Blood 1993; 82:677.
5. Appelbaum, FR, Barrall, J, Storb, R, et al. Bone marrow transplantation for patients with myelodysplasia. Pretreatment variables and outcome. Ann Intern Med 1990; 112:590.
6. Appelbaum, FR, Anderson, J. Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 1998; 12 Suppl 1:S25.