Myelodysplastic syndromes (MDS) are disorders of the bone marrow, which produces platelets (for blood clotting) and red and white blood cells. This leads to low platelets (thrombocytopenia), anemia and typically low white blood cells. MDS progresses to acute myeloid leukemia (AML) due to accumulation of genetic abnormalities,1 and is considered a pre-AML condition. People who are at greatest risk for MDS are those over 60 years old, with 80-90% of diagnoses fitting into this age group.2
In most MDS patients, death results typically from complications of bone marrow failure, including chronic anemia, infections, or severe bleeding.3 Bleeding and infections are the most common causes of death.4 Approximately one-third of adult MDS patients progress to acute myeloid leukemia (AML), with a median survival of 6–12 months.5 Despite existing approaches, the three-year survival rates in MDS patients is just 45%.6 Said another way, irrespective of which treatment or combination of treatments are used, 55% of all MDS patients die within three years of diagnosis. Thus, the establishment of new strategies for promoting health in people with MDS is an important issue.
There is no cure for MDS. Treatment typically focuses on reducing or preventing complications of the disease and complications caused by the MDS treatments.
Symptoms of MDS
Early in the disease process, people may not experience any symptoms. As it progresses, however, it can cause:
- Shortness of breath
- Paleness due to anemia
- Easy bruising or bleeding from low platelets
- Small red spots, called petechaie, under the skin.
- Frequent infections
What Causes MDS?
Often the cause of MDS is not known. However, many cases are caused by previous cancer treatments (eg, for breast cancer, lymphomas) and environmental pollutants.
When MDS is caused by previous chemotherapy or radiation therapy it is called therapy-related (or treatment-related) myelodysplastic syndrome (t-MDS).7 Like t-MDS, therapy-related acute myeloid leukemia (t-AML), also occurs. Therapy-related MDS tends to be a more aggressive form of MDS and progressive faster into AML than MDS not caused by previous cancer treatments. Since MDS frequently develoops into AML, and they are on a spectrum of bone marrow diseases and cancers, they are frequently discussed together in research papers as one entity. t-AML and t-MDS account for 10–20% of all cases of AML.8
Cases of t-MDS/t-AML caused by alkylating agents (eg, cyclophosphamide, chlorambucil, cisplatin) and/or radiation therapy occur approximately 5-10 years after the initial treatments. Patients who are exposed to topoisomerase II inhibitors (eg, etoposide, doxorubicin) tend develop leukemia within one year of starting the initial treatment (eg, chemotherapy or radiation therapy).
Learn more about cancer treatments and the risk of causing t-MDS/t-AML and the history of chemotherapy and radiotherapy.
MDS Caused by Environmental Toxins
Established genetic factors alone explain only approximately 5% of all cancers, the remainder can be attributed to environmental carcinogens such as benzene, petroleum products, insecticides, tobacco smoke, pollutants, chemotherapy drugs, radiation either from treatment for previous cancers or from flying in airplanes (eg, pilots, flight crew), and infectious agents that act in conjunction with both genetic and acquired susceptibility.9,10 There are more than 100 known carcinogens (chemical, physical, and biological).11
The treatment options available to patients with MDS are largely based upon the patient's age and prognosis as determined by the International Prognostic Scoring System (IPSS).12 The IPSS categories are Low Risk, Intermediate Risk-1, Intermediate Risk-2 and High Risk.
The US National Comprehensive Cancer Network MDS recommendations are that therapies for the patients with low-risk with clinically significant cytopenias (low blood counts) should be stratified into several groups, for example lenalidomide for del(5q), a genetic abnormality; and erythropoietin (Epo), a hormone that stimulates red blood cell production) for patients with low serum Epo.13 DNA-hypomethylating agents as azacitidine or decitabine are also recommended for non-responders to these treatments. However, these therapeutic effects are not satisfactory for every patient and other options for MDS are still required.14
Since the median age of patients is 60–70 years, bone marrow transplantation can be performed only in a small population of these patients.15 Although not approved by the FDA for the treamtent of MDS, the most commonly used agents are erythroid-stimulating agents (ESA), which increase the body's own production of red blood cells.16
Lenalidomide (Rivlimib®), a thalidomide derivative, is FDA approved for MDS patients. While lenalidomide appears effective at initiating transfusion-independence in 26% to 67% of patients, it also causes thrombocytopenia in 25% of patients and neutropenia in 30% of patients in one study.17, 18
Azacitidine (Vidaza®) is a DNA methyltransferase inhibitor FDA approved for all IPSS categories and all FAB MDS subtypes. While azacitidine effected complete remission in 7% of patients and partial remission in 16% of patients studied, it also caused granulocytopenia in 43% and thrombocytopenia in 52% of patients.19, 20
Decitabine (Dacogen®) differs from azacitidine only in the hydroxyl group on the sugar moiety. It too is FDA approved for all FAB MDS subtypes. Its efficacy and side effects profile appear to be similar to azacitidine. In the Phase III clinical trial used for Dacogen approval in the United States, the drug increase the time it either took patients to progress to AML or until they died by 5.2 months in patients with intermediate-2/high-risk disease, 3.2 months in those with de novo (newly diagnosed) disease, and 5 months in patients who had never previously undergone treatment.21, 22 When the patients were looked at a a whole group, however, there was no statistically significant increase in life or delay in progression to AML. In Februrary 2012, FDA oncologists reviewed an application to approve Dacogen for the treatment of AML and recommended against approving it because data do not support that the drug is effective at treating AML patients.23
High-dose chemotherapy achieves an acceptable response rate, but the high incidence of treatment-related death and the short duration of complete remission mean that there is no survival benefit.24, 25 Granulocyte colony stimulating factor (GCSF) may be useful in neutropenic patients with recurrent or resistant infections, but there are no data to support chronic use, or use for routine infection prophylaxis.26, 27
Iron chelation may be used in patients with elevated ferritin, which can occur secondary to blood transfusions. This practice is controversial.28 Although increased ferritin levels are associated with inferior survival,29 it is not clear that reduction in ferritin leads to improved survival.
About Myelodysplastic Syndrome
Benzene Causes Cancer
Chemotherapy and Radiation in Oncology
Tables Summarizing Safety and Efficacy of MK4 for Oncology Support