All About Myelodysplastic Syndromes (MDS)

Eric T. Shinohara, MD, MSCI
Updated by: Christina Bach, MBE, MSW, LCSW, OSW-C
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: April 15, 2016

What is Myelodysplastic Syndrome (MDS)?

MDS is a diverse group of diseases that are characterized by the abnormal or ineffective production of blood cells. It is a disease of the blood cells and bone marrow. These syndromes are considered to be malignant stem cell disorders. Stem cells are immature cells, found in the bone marrow, that gradually mature to form the various components of blood. There are three main cell lines that make up your blood:

  • Red blood cells (also known as erythrocytes), which carry inhaled oxygen from the lungs to other organs, and carry carbon dioxide from the organs to the lungs to be exhaled.
  • Platelets (also known as thrombocytes), which form clots.
  • White blood cells (also known as leukocytes), which are comprised of granulocytes, lymphocytes, and monocytes, each of which has a different role in the immune system. There are 2 types of lymphocytes, called B and T lymphocytes.

In MDS, the stem cells do not mature properly and create immature versions of these cells in the blood, which are called blasts. MDS can potentially transform into a more aggressive cancer, such as acute leukemia.

Am I at risk for myelodysplastic syndrome?

The exact incidence of MDS is not known, however, estimates suggest that there are approximately 13,000 new cases of MDS in the United States annually. It occurs more frequently in the elderly, with the average age at diagnosis being 72. Statistics from 2008 to 2012 estimate the risk of developing MDS grows from 6 in every 100,000 people during ages 60-64, to 65.6 in every 100,000 people in those 85 and above.

Previous treatment with certain chemotherapy medications can increase the risk of developing MDS. These medications include (but are not limited to): mechlorethamine, procarbazine, chlorambucil, etoposide, teniposide, cyclophosphamide, ifosfamide, and doxorubicin. This risk is increased if radiation was used in combination with these chemotherapy medications. However, the number of people who develop this "secondary" or treatment related MDS, given the number of people who receive those chemotherapy medications, is very small.

Some genetic abnormalities can increase the risk of developing MDS. These include, Shwachman-Diamond syndrome, Diamond Blackfan anemia, familial platelet disorder, Fanconi anemia, and severe congenital neutropenia. Certain chemical exposures, such as pesticides, solvents (such as benzene), petroleum, and tobacco smoke can also increase the risk of developing MDS.

Though rare, MDS can occur in children, with an average age of 6 at diagnosis. There are two types of MDS that occur in children; juvenile myelomonocytic leukemia and monosomy-7 syndrome, both of which present in a similar fashion. Children with either of these diseases can present with an increased white blood cell count with a decreased red blood cell and platelet count. The spleen may be enlarged and the skin may be involved as well. There may also be an increase in antibody production (polyclonal gammopathy).

How can I prevent MDS?

There are not any specific interventions that can prevent MDS. Many of the risk factors can not be avoided, such as aging. Generally, if someone has a cancer requiring chemotherapy or radiation, it is difficult to avoid using these agents without compromising the treatment of the cancer. One way to lessen the risk of developing MDS is to avoid exposure to known carcinogenic substances such as pesticides, solvents, and tobacco smoke.

What screening tests are available?

There is not a specific test for MDS. Routine blood work can be used as a screen to check the red and white blood cell counts, and the platelet count. These tests can help with the diagnosis of MDS and prompt further, more invasive testing, such as a bone marrow biopsy.

What are the signs of MDS?

People with MDS often have no symptoms, which can make the disease difficult to detect. Often, people feel fine and the only signs of an abnormality are seen on laboratory testing. When people do have symptoms, it is most commonly related to a low red blood cell count (anemia). Sixty percent of people will be anemic at presentation and 26% will have bruising or other signs of a low platelet count. Less than 5% of people will have a low white blood cell count or platelet count without anemia.

Symptoms of anemia include, pale skin or mucous membranes (i.e. gums), generalized fatigue, chest pain, and dizziness. People may also develop symptoms related to a decrease in the platelet or white blood cell count, such as infections (decreased white blood cell count), and easy bruising or bleeding (low platelet count). Another sign of a low platelet count is petechiae; these are small red or purple spots under the skin that are caused by bleeding. Infections are due to both low white blood cell counts as well as dysfunction of the white blood cells. Bacterial infections are most common and they may respond slowly to antibiotics.

Other problems with the immune system can also occur in people with MDS. Studies have suggested that about 15% of people with MDS have autoimmune related symptoms (where the body’s immune system attacks normal tissues). This can include damage to normal blood vessels (vasculitis), heart (pericarditis), skin, eyes (iritis), muscles (myositis), nerves (peripheral neuropathy) and red blood cells (pure red blood cell aplasia). Occasionally autoimmune diseases such as Raynaud's phenomenon and Sjogren’s disease have been associated with MDS, but it does not appear that one causes the other. Generally, the autoimmune syndrome will resolve with immunosuppressant medications, but treatment with these agents may increase the risk for infection.

Other symptoms, which tend to develop late in the course of MDS, can include fevers and weight loss. Remember, all of these symptoms can be related to a variety of causes, so it is important to see your healthcare provider for a full evaluation if you are experiencing these symptoms.

How is MDS diagnosed?

People with MDS often have mild symptoms (or no symptoms) and laboratory tests are many times the first sign that something is wrong. These include:

  • Complete Blood Count (CBC):

A CBC counts the number of red blood cells, platelets and white blood cells. The amount of hemoglobin, the substance that carries oxygen in red blood cells, and a breakdown of the various types of white blood cells can also be checked with a CBC. Decreased white blood cell counts can be seen (leucopenia) and specifically, the cells which fight bacterial infection (neutrophils), can be decreased in up to 50% of patients with MDS.

  • Peripheral Blood Smear

A small sample of blood can be smeared on a slide and examined both to help count cells, as well as examine them for defects.

Anemia is commonly seen in MDS. The body’s normal response to anemia is to form new blood cells (by increasing the production of immature red blood cell knows as reticulocytes) and this response may be poor in people with MDS. Reticulocytes can be counted to see if the body is responding appropriate to the low red blood cell count. Red blood cells may appear normal in MDS on a peripheral smear, but often times they have defects including bizarre shapes, reflecting defective production of the red blood cells. In 8% of patients, the defects in the red blood cell shape appear similar to those seen in alpha thalasemia, another disease that affects red blood cells. Defects in red blood cell development may also be detected in bone marrow biopsies, which can aid in diagnosis.

Defects in the appearance of the white blood cells can also be seen on a peripheral blood smear. These defects cause white blood cells to not function well, impacting immune system function and increasing the risk of developing an infection.

  • Bone Marrow Biopsy

In MDS, the bone marrow usually demonstrates a larger number of cells than normally seen (called hypercellular marrow). This increase in cells can be in one cell line or multiple cell lines. For example an increase in the number of megakaryocytes, which will go on to form platelets in the blood, can be seen. Approximately 25% of people with MDS will have low platelets on a CBC. This can occur because though there is an increase in the number of megakaryocytes, many will die prior to maturing into platelets. Only about 8% of people with MDS present with an increased platelet count. Occasionally it is possible to see a decrease in the number of cells in the bone marrow (called hypocellular marrow).

There are a number of specific terms that pathologists use to describe findings seen on a blood smear or bone marrow biopsy:

  • Auer Rods: are comprised of granules that accumulate in a rod like pattern that can be seen in white blood cell blasts. They are most commonly associated with Acute Myeloid Leukemia (AML) and their presence suggests a leukemic process rather than MDS.
  • Blasts: are defined as immature blood cells
  • Monocytes: a normal component of the immune system that can ingest (phagocytize) substances which are foreign to the body. They can go on to form macrophages when they exit the blood, which also play an important role in ingesting foreign substances (such as bacteria). Elevated monocyte counts can indicate a number of disease states including MDS.
  • Sideroblasts and Ringed Sideroblasts: When a stain for iron is used on bone marrow biopsy specimens, deposits of iron may be seen in red blood cells and these deposits are called sideroblasts. If a large amount of iron is seen, then they are called ringed sideroblasts. This usually occurs due to a defect in the formation of hemoglobin, which is located in red blood cells.

A number of special studies can be done to help with the diagnosis of MDS:

  • Iron Staining: for detecting sideroblasts (described above).
  • Periodic Acid Schiff (PAS) Staining: a stain to detect defects in red blood cell maturation
  • Peroxidase/Sudan Black: can be used to help determine if a blast is part of the white blood cell line.
  • Esterase Stain: Can be used to detect abnormal white blood cells.
  • Cytogenetic Studies: Examination of the chromosomes to check for genetic defects.
  • Iron, B12 and folate levels: This are essential building blocks for red blood cells and determining if your body has adequate levels of these are important in people who are anemic.
  • Serum erythropoietin (EPO) levels: EPO stimulates the bone marrow to produce more red blood cells. Low levels of EPO may be a contributing factor for anemia.

The FAB and WHO Classifications of MDS

After diagnostic tests are complete, the healthcare team will have a better understanding of the subtype of MDS present. The first classification of different subtypes of MDS was proposed by the FAB (French-American-British Group) in 1976 and was revised in 1982. In 2001, and again in 2008, the WHO (World Health Organization) utilized the FAB as a framework to further refine MDS classifications to what we use today. The WHO classification categorizes the subtypes of MDS based on the results of both blood tests and bone marrow biopsy results.

2008 WHO Classification of MDS

  • Refractory cytopenia with unilineage dysplasia(RCUD): Accounts for about 5-10% of MDS cases. These people have low counts of one cell type, but normal counts of the other 2. Refractory anemia (RA) is the most common, but refractory neutropenia and refractory thrombocytopenia are also possible. Less than 5% of blast cells are found in the bone marrow.
  • Refractory anemia with ring sideroblasts (RARS): Accounts for 10-15% of MDS cases. People who have all the findings of RA, but who have greater than 15% ringed sideroblasts seen in the bone marrow (instead of a limited number of sideroblasts as seen in RA).
  • Refractory anemia with multilineage dysplasia (RCMD): Accounts for about 40% of MDS cases. People, who have less than 5% of their bone marrow involved with blasts, but, who have decreased or dysfunctional of two or more cell lines, (for example platelets and red blood cells) are considered to have RCMD.
  • Refractory anemia with excess blasts (RAEB-1): People who have bone marrow that contains 5-9% blasts and less than 5% blasts in the blood, are considered to have RAEB. This condition can progress to acute myeloid leukemia.
  • Refractory anemia with excess blasts-2 (RAEB-2): In RAEB2, there are more blasts present in the bone marrow, between 10-20%, and from 5-19% of blasts in the blood. RAEB2 has a higher risk of progressing to leukemia than RAEB1.
  • MDS associated with isolated del(5q): 5q refers to a missing part of chromosome number 5 associated with this type of MDS. This type of MDS tends to be more common in women and anemia is very common (80% of people will have anemia), while other blood cell lines tend to be in the normal range. This type of MDS less frequently transforms into acute leukemia (16%).
  • MDS, unclassifiable: This category incorporates people who don’t fit in any other classification due to the blast counts or abnormal cells, despite having a genetic finding that is only seen in MDS or leukemia. This classification is quite rare.

CMML is a type of blood cancer that had been part of the FAB classification. The WHO classification includes CMML in another category called myelodysplastic/myeloproliferative neoplasms.

MDS is also classified as primary or secondary. Primary is more common and is used when the cause is not known. Secondary MDS occurs due to damage caused by chemotherapy or radiation therapy. This may also be called treatment associated MDS and it can be more difficult to treat.

The International Working Group for the Prognosis of MDS (IWG-PM) has also developed a tool to help clinicians estimate prognosis and risk of MDS progression to acute leukemia. This tool includes measures of hemoglobin levels, absolute neutrophil count (ANC), platelets, bone marrow blast percentage, and cytogenetic category to produce a score and category that can help estimate clinical outcomes and treatment planning. Additionally, the age at diagnosis and how generally healthy the person is at the time of diagnosis are taken into account when selecting a therapy.

IWG-PM International Prognostic Scoring System (IPSS-R)

PSS-R Cytogenetic risk groups

Cytogenetic prognostic subgroups

Cytogenetic abnormalities

Very good

-Y, del(11q)

Good

Normal, del(5q), del(12p), del(20q), double including del(5q)

Intermediate

del(7q), +8, +19, i(17q), any other single or double independent clones

Poor

-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities

Very poor

Complex: >3 abnormalities

IPSS-R Prognostic Score Values

Prognostic variable

0

0.5

1

1.5

2

3

4

Cytogenetics

Very Good

Good

Intermediate

Poor

Very Poor

BM Blast %

<2

>2-<5%

5-10%

>10%

Hemoglobin

>10

8-<10

<8

Platelets

>100

50-<100

<50

ANC

>0.8

<0.8

IPSS-R Prognostic Risk Categories/Scores

RISK CATEGORY

RISK SCORE

Very Low

<1.5

Low

>1.5 - 3

Intermediate

>3 - 4.5

High

>4.5 - 6

Very High

>6

What are the treatments for MDS?

Treatment decisions for MDS are centered on a variety of factors but two goals remain clear:

  • Symptom management related to decreased blood counts.
  • Decrease the risk of progression of this disease to acute leukemia and improve overall survival.

Given that most people present with MDS at an older age and that MDS is a chronic disease, supportive care is extremely important to limit symptoms of MDS and maintain a high quality of life. These treatments include:

  • Red blood cell transfusions: some people with MDS require frequent transfusions of red blood cells to limit symptoms of anemia.
    • Iron chelation therapy: frequent transfusions can cause large amounts of iron to build up in the person’s body, which can cause damage to various organs including the liver, pancreas and heart. This therapy can be used to bind up the iron such that it can be passed out via the urine when numerous transfusions are required.
  • Growth factors: Several types of growth factors can be used to maintain the various cell lines. GCSF, GM-CSF, epoetin alfa and darbepoetin can be used to help maintain red blood cell counts without transfusion.
  • Lenalidomide: A derivative of thalidomide. It has been found to work very well in people with 5q-syndrome, though it also appears to work in some people with other types of MDS.
  • Antithymocyte globulin (ATG), sometimes used in combination with cyclosporine. ATG is an immune suppressant that has been shown to be useful in the treatment of certain subtypes of MDS in people under the age of 60.
  • Chemotherapy: There are a variety of chemotherapy options available for the treatment of MDS and the intensity of the chemotherapy treatment depends on the goals of therapy, the patient’s health and their IPSS score.
    • Low Intensity Chemotherapy: medications in this group include azacitidine and decitabine. These medications may decrease the risk of MDS transforming into leukemia and in some patients may improve survival.
    • High Intensity Chemotherapy: This is similar to the chemotherapy used in the treatment of acute leukemia (AML). In addition to using the same medications used in the low intensity regimens, other chemotherapies like cytarabine, daunorubicin and mitoxantrone may be used.
  • Stem Cell Transplant: Allogeneic stem cell transplants (where the bone marrow comes from a donor) can be used to treat MDS. This is the only potential cure for people with MDS and is generally used for people in good health, who are younger than 60, and who have a matched donor.
    • Even after transplant, MDS can relapse. Donor leucocyte infusions (DLI) in combination with azacitdine chemotherapy can be used in the treatment of relapsed MDS post-transplant depending on cytogenetics, comorbidities and age.

Clinical Trials

Clinical trials are extremely important in furthering our knowledge of this disease. It is though clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your healthcare provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

Follow-Up Care and Testing

MDS is a chronic disease. This means that it requires long term monitoring and treatment. After a diagnosis of MDS, you will have regular blood testing to gauge the status of your disease. The exact timing of how often you may need testing is unique to each patient. You should report any change or increase in symptoms to your healthcare team immediately.

Fear of progression or transformation to AML, relationships challenges, the financial impact of long term cancer treatment, employment issues and coping strategies are common emotional and practical issues experienced by MDS survivors. Your healthcare team can identify resources for support and management of these practical and emotional challenges faced during and after cancer.

Cancer survivorship is a relatively new focus of oncology care. With some 15 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship – or in many cases of MDS, to live "with" the cancer. What should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after (or with) cancer and helping you communicate knowledgeably with your healthcare providers. Create a survivorship care plan today on OncoLink.

Resources for more information

Aplastic Anemia and MDS International Foundation

Provides disease and treatment information and support resources.
http://www.aamds.org/

MDS Foundation

Provides disease and treatment information for healthcare professionals and patients/caregivers.
http://www.mds-foundation.org/what-is-mds/

Leukemia and Lymphoma Society

Provides disease information and support resources.
http://www.lls.org/

Leukemia Research Foundation

Provides disease information and a glossary of medical terms related to leukemia.
http://www.leukemia-research.org

References

SEER Statistics, MDS, http://seer.cancer.gov/faststats/selections.php?#Output

NCCN Guidelines, Myelodysplastic Syndromes (registration required): http://www.nccn.org/professionals/physician_gls/f_guidelines.asp

Alessandrino, E. P., Della Porta, M. G., Malcovati, L., Jackson, C. H., Pascutto, C., Bacigalupo, A., ... & Guidi, S. (2013). Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome. American Journal of Hematology, 88(7), 581-588.

Bowen, D. T., Gore, S. D., Haferlach, T., Le Beau, M. M., & Niemeyer, C. (2013). Myelodysplastic Syndromes. Springer.

Duléry, R., Mohty, M., Duhamel, A., Robin, M., Beguin, Y., Michallet, M., ... & Bulabois, C. E. (2014). Antithymocyte globulin before allogeneic stem cell transplantation for progressive myelodysplastic syndrome: a study from the French Society of Bone Marrow Transplantation and Cellular Therapy. Biology of Blood and Marrow Transplantation, 20(5), 646-654.

Garcia?Manero, G. (2014). Myelodysplastic syndromes: 2014 update on diagnosis, risk?stratification, and management. American Journal of Hematology, 89(1), 97-108.

Robin, M., Porcher, R., Adès, L., Raffoux, E., Michallet, M., François, S., ... & Bay, J. O. (2015). HLA-matched allogeneic stem cell transplantation improves outcome of higher risk myelodysplastic syndrome A prospective study on behalf of SFGM-TC and GFM. Leukemia, 29(7), 1496-1501.

Schroeder, T., Rachlis, E., Bug, G., Stelljes, M., Klein, S., Steckel, N. K., ... & Dienst, A. (2015). Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions—a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biology of Blood and Marrow Transplantation, 21(4), 653-660.

van de Loosdrecht, A. A., & Westers, T. M. (2013). Cutting edge: flow cytometry in myelodysplastic syndromes. Journal of the National Comprehensive Cancer Network, 11(7), 892-902.

Vardiman, J. (2012). The classification of MDS: from FAB to WHO and beyond. Leukemia Research, 36(12), 1453-1458.

West, A. H., Godley, L. A., & Churpek, J. E. (2014). Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for translational investigations. Annals of the New York Academy of Sciences, 1310(1), 111-118.


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