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Higher-Risk Myelodysplastic Syndromes: Lacking Treatment Advances in Over a Decade
Other options like allogeneic stem cell transplantation (ASCT) have the potential to cure HR-MDS, but many patients may not be eligible because they may be too frail or sick to tolerate the procedure or may not have a suitable donor.15-16 Due to age or comorbidities, only 6% to 14% of people living with HR-MDS undergo ASCT. Even patients who are eligible to receive ASCT have relatively poor outcomes, as transplant-related mortality ranges from 20% to 37%.17-18
In the event that neither chemotherapy nor ASCT are options, supportive care alternatives, such as transfusions or blood cell growth factors can help manage symptoms, but have no efficacy against the disease itself.15,19
A significant need remains for targeted therapies for those living with HR-MDS.
For over a decade, there has been little advancement in treatment options for people living with HR-MDS despite poor patient outcomes.
Continued research is critical to potentially bring a targeted therapeutic option to HR-MDS patients, to not only improve OS, but also to manage symptoms and preserve quality of life. Though there has been little progress in HR-MDS treatment options over the last decade, late-stage clinical studies are actively investigating novel agents in combination with HMAs to improve efficacy and patient outcomes while maintaining safety and tolerability. Due to its aggressive nature and poor survival rates, people living with HR-MDS urgently require new treatment options that are more effective at inducing remission and slowing or preventing disease progression to ultimately improve the survival and quality of life of patients living with this disease.
Author Disclosure: Dr. Watts has received consultancy fees from Takeda/Millennium Pharmaceuticals, Genentech, Jazz Pharmaceuticals, and Rafael Pharmaceuticals.
Acknowledgements: The author would like to acknowledge W2O Group for their writing support, which was funded by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Sponsored by Takeda Oncology.
- American Cancer Society. What Are Myelodysplastic Syndromes? https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html. Accessed April 3, 2020.
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- MDS Foundation. Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes Risk Assessment Calculator. https://www.mds-foundation.org/ipss-r-calculator/. Accessed April 3, 2020.
- Greenberg, P. L., Tuechler, H., Schanz, J., Sanz, G., Garcia-Manero, G., Solé, F., … Haase, D. (2012). Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood, 120(12), 2454—2465. doi:10.1182/blood-2012-03-420489.
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- Kumar C. C. (2011). Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia. Genes & cancer, 2(2), 95—107. doi:10.1177/1947601911408076
- American Cancer Society. Facts & Figures 2020 Reports Largest One-year Drop in Cancer Mortality. https://www.cancer.org/latest-news/facts-and-figures-2020.html. Accessed April 3, 2020.
- Clinical Advances in Hematology & Oncology. Hypomethylating Agents in Myelodysplastic Syndromes. https://www.hematologyandoncology.net/archives/february-2011/hypomethylating-agents-in-myelodysplastic-syndromes/. Accessed April 3, 2020.
- American Cancer Society. General Approach to Treatment of Myelodysplastic Syndromes. https://www.cancer.org/cancer/myelodysplastic-syndrome/treating/general-approach.html. Accessed April 3, 2020.
- American Cancer Society. Stem Cell Transplant for Myelodysplastic Syndrome. https://www.cancer.org/cancer/myelodysplastic-syndrome/treating/stem-cell-transplant.html. Accessed April 3, 2020.
- Della Porta, M.G., Alessandrino, E.P., Bacigalupo, A., van Lint, M.T., Malcovati, L., … Rambaldi, A. Predictive Factors for the Outcome of Allogeneic Transplantation in Patients with MDS Stratified According to the Revised IPSS-R. Blood 2014; 123 (15): 2333—2342. doi: https://doi.org/10.1182/blood-2013-12-542720.
- Lozano, S., Olavarria, E., Iacobelli, S., van Biezen, A., Beelen, D.W., … Robin, M. The EBMT Score Predicts Transplant Related Mortality and Overall Survival after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes. Blood 2015; 126 (23): 3223. doi: https://doi.org/10.1182/blood.V126.23.3223.3223
- Malcovati, L., Hellström-Lindberg, E., Bowen, D., Adès, L., Cermak, J., Del Cañizo, C., …Cazzola, M. European Leukemia Net (2013). Diagnosis and Treatment of Primary Myelodysplastic Syndromes in Adults: Recommendations from the European LeukemiaNet. Blood, 122(17), 2943—2964. doi:10.1182/blood-2013-03-492884
What to know about higher-risk myelodysplastic syndromes (HR-MDS) [Infographic]
(BPT) - Sponsored by Takeda Oncology
MDS is a rare cancer that is not commonly discussed, and is often referred to as a disorder or condition.
In recognition of MDS World Awareness Day, here are three key things to know about MDS:What is MDS?
MDS is a rare form of bone marrow cancer.1 There are 14,000 cases of MDS reported every year in the U.S., ranging in prognosis from very low- to very high-risk.2 Approximately 43% of new cases are higher-risk, meaning patients are at an increased risk for poor outcomes.3Why is it important that MDS should be widely considered a cancer?
MDS can be difficult to identify because symptoms are often vague, and patients are typically 70 years or older.4 MDS can be classified as higher-risk disease, which is often fatal. HR-MDS can transform into another aggressive cancer, acute myeloid leukemia (AML), which also has extremely poor survival outcomes.1 Greater recognition of MDS as a cancer could lead to greater urgency to treat patients.Are there any treatment options available for HR-MDS?
Stem cell transplants are the only potential curative option, but the vast majority of people are too frail or sick to undergo transplant.5 A specific type of chemotherapy — hypomethylating agents (HMAs) — is approved to treat HR-MDS, but, alone, provides limited benefit.6 There have been no novel advances in treatment for HR-MDS in over 10 years.7-8
1 American Cancer Society. https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html. Accessed August 27, 2020.
2 National Cancer Institute. https://seer.cancer.gov/csr/1975_2016/browse_csr.php?sectionSEL=30&pageSEL=sect_30_table.02. Accessed August 27, 2020.
3 Greenberg, P. L., Tuechler, H., Schanz, J., Sanz, G., Garcia-Manero, G., Sol�, F., … Haase, D. (2012). Blood, 120(12), 2454–2465. doi.org/10.1182/blood-2012-03-420489. Accessed August 27, 2020.
4 American Cancer Society. https://www.cancer.org/cancer/myelodysplastic-syndrome/detection-diagnosis-staging/signs-symptoms.html. Accessed August 27, 2020.
5 American Cancer Society. https://www.cancer.org/cancer/myelodysplastic-syndrome/treating/general-approach.html. Accessed June 8, 2020.
6 Gil-Perez, A., Montalban-Bravo, G. (2019). Therapeutic Advances in Hematology, 10, 2040620719847059. doi.org/10.1177/2040620719847059. Accessed August 27, 2020.
7 Gotza, K.S., Muller-Thomas, C., Peschel, C. (2009). Cancer Management and Research, 1, 119-130. doi.org/10.2147/cmr.s4721. Accessed August 27, 2020.
8 National Comprehensive Cancer Network. https://www.nccn.org/patients/guidelines/content/PDF/mds-patient.pdf. Accessed August 27, 2020.
Myelodysplastic Syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. MDS is often referred to as a “bone marrow failure disorder”. MDS is primarily a disease of the elderly (most patients are older than age 65), but MDS can affect younger patients as well. To help you better understand MDS, it might be helpful to first consider some basics about bone marrow and blood. The bone marrow functions as a factory that manufactures three kinds of blood cells: red blood cells, white blood cells, and platelets. Healthy bone marrow produces immature blood cells — called stem cells, progenitor cells, or blasts — that normally develop into mature, fully functional red blood cells, white blood cells, and platelets. In MDS, these stem cells may not mature and may accumulate in the bone marrow or they may have a shortened life span, resulting in fewer than normal mature blood cells in the circulation.
Low blood cell counts, referred to as cytopenias, are a hallmark feature of MDS and are responsible for some of the symptoms that MDS patients experience — infection, anemia, spontaneous bleeding, or easy bruising. Anemia (low red blood cell counts), neutropenia (low white blood cell counts), and thrombocytopenia (low platelet counts) are the major types of blood cell cytopenias, and are discussed below. In addition to reduced numbers of blood cells, the mature blood cells circulating in the blood may not function properly because of dysplasia. The formal definition of dysplasia is the abnormal shape and appearance, or morphology, of a cell. The prefix myelo- is from the Greek and it means marrow; so myelodysplasia refers to the abnormal shape and appearance — or morphology — of the mature blood cells. Syndromes comes from the Greek and means a set of symptoms that occur together.
Failure of the bone marrow to produce mature healthy cells is a gradual process, and therefore MDS is not necessarily a terminal disease. Some patients do succumb to the direct effects of the disease: reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. In addition, for roughly 30% of the patients diagnosed with MDS, this type of bone marrow failure syndrome will progress to acute myeloid leukemia (AML).
To read more about the effects of MDS on blood cells, click here to view our complete handbook.
WHAT CAUSES MDS?
With a few exceptions, the exact causes of MDS are unknown. 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. If the external factor cannot be identified, then the disease is referred to as “primary MDS”.
Radiation and chemotherapy for cancer are among the known triggers for the development of MDS. Patients who take chemotherapy drugs or who receive radiation therapy for potentially curable cancers, such as breast or testicular cancers, Hodgkin’s disease and non-Hodgkin’s lymphoma, are at risk of developing MDS for up to 10 years following treatment. MDS that develops after use of cancer chemotherapy or radiation is called “secondary MDS” and is usually associated with multiple chromosome abnormalities in cells in the bone marrow. This type of MDS often develops rapidly into AML.
Long term exposure to certain environmental or industrial chemicals, such as benzene, can also trigger MDS. While benzene use is now highly regulated, it is not clear which other chemicals may predispose individuals to MDS, although certain occupations have been labeled “at risk” for the development of MDS or AML (e.g., painters, coal miners, embalmers). There are no known food or agricultural products that cause MDS. While alcohol consumed on a daily basis may lower red blood cell and platelet counts, alcohol does not cause MDS. There is insufficient data available to determine if smoking increases the risk of developing MDS. However, it is known that the risk of developing AML is 1.6 times greater for smokers than for non-smokers.
Patients and their families often worry that MDS might be contagious. No evidence exists to suggest that a virus causes MDS; thus, MDS cannot be transmitted to loved ones.
MDS is not inherited. In fact, it is a very rare occasion when family members, including siblings, are diagnosed with MDS.
WHAT ARE THE SYMPTOMS OF MDS?
In the early stages of MDS patients may experience no symptoms at all. A routine blood test may reveal a reduced red cell count, or low hematocrit, sometimes along with reduced white cell and/or reduced platelet counts. On occasion, the white cell and platelet counts may be low while the hematocrit remains normal. However, some patients, particularly those with blood cell counts well below normal, experience definite symptoms. These symptoms, described below, depend on which blood cell type is involved as well as the level of the cell count.
LOW RED CELL COUNT (ANEMIA)
The majority of individuals are anemic when they are initially diagnosed with MDS. Anemia is characterized by a persistently low hematocrit (a measure of the body’s red blood cells) or persistently low levels of hemoglobin (the blood protein that carries oxygen to the body’s tissues). Anemic patients generally experience fatigue and report that they are tired much of the time and have no energy. Anemia varies in its severity. In mild anemia, patients may feel well or just slightly fatigued. In moderate anemia, almost all patients experience some fatigue, which may be accompanied by heart
palpitations, shortness of breath, and pale skin. In severe anemia, almost all patients appear pale and report chronic overwhelming fatigue and shortness of breath. Because severe anemia reduces blood flow to the heart, older patients may be more likely to experience cardiovascular symptoms, including chest pain. Although chronic anemia is seldom life threatening, it can drastically reduce a patient’s quality of life.
LOW WHITE CELL COUNT (NEUTROPENIA)
A reduced white cell count lowers the body’s resistance to bacterial infection. Patients with neutropenia may be susceptible to skin infections, sinus infections (symptoms include nasal congestion), lung infections (symptoms include cough, shortness of breath), or urinary tract infections (symptoms include painful and frequent urination). Fever may accompany these infections.
LOW PLATELET COUNT (THROMBOCYTOPENIA)
Patients with thrombocytopenia have an increased tendency to bruise and bleed even after minor bumps and scrapes. Nosebleeds are common and patients often experience bleeding of the gums, particularly after dental work. Before having dental work, consultation with your hematologist, who may prescribe the prophylactic use of antibiotics, is recommended since infection and bleeding pose a risk for most MDS patients.
What can I do to help?
There are many ways that you can support those diagnosed with MDS. You can learn more about MDS from our website, and by reading materials such as our Building Blocks of Hope program.
You can also support the MDS Foundation in our efforts. You can learn more about the Foundation here, and can click here to make a tax-deductible donation.
For more information, feel free to contact us directly.
What is MDS
MDS are a group of a progressive bone marrow diseases characterized by failure of the bone marrow to generate normal blood cells. The bone marrow is the organ in the human body that makes blood cells that are essential for critical physiologic functions. These cells include platelets (also called thrombocytes) that make your blood clot, red blood cells (erythrocytes) that carry oxygen in your blood, and most of the white blood cells in our bodies that fight infection. For these cells to carry out their functions, they must be produced in adequate numbers and must be functioning normally. In patients with MDS, the blood cells that are produced are too few in number and they are dysfunctional.
Blood cells are formed from stem cells in the bone marrow. The diagram below illustrates this process and it shows which kinds of blood cells are ultimately affected in MDS.
As the diagram shows, MDS is a disease associated with cells in the myeloid lineage. When myeloid cells look abnormal under the microscope, they are called dysplastic. Thus, the name of the disease: myelodysplastic. Because MDS patients have too few or improperly functioning blood cells, their blood does not clot properly and they are at higher risk for life-threatening infections than people who don’t have MDS. In addition, about 1/3rd of patients who have MDS are at risk for developing a blood cancer called acute myeloid leukemia (AML).
MDS is diagnosed in least 10,000 people each year in the United States, and approximately 60,000 people are living with the disease in the US today. Most cases of MDS occur in people age 70 or older. About 90% of MDS patients have what is called de novo MDS, meaning the disease arises with no apparent cause. Approximately 10% of patients get MDS because of prior treatment for cancer, e.g., with chemotherapy or radiation, and are therefore said to have therapy-related MDS. A very small proportion of patients have MDS as a result of an inherited genetic condition affecting their bone marrow, such as Fanconi anemia. These patients are typically children, and the types of MDS that children get are generally different from the MDS that adults get. There are also some other bone marrow diseases, called MDS/MPD (where MPD means myeloproliferative disorders), that look a little bit like MDS but have some unique characteristics of their own. More research is required to understand the nature of MDS/MPD and how best to treat them.
MDS can be divided into high risk and low risk disease, where higher risk MDS is associated with a greater chance of death or transformation to AML. The only way to cure MDS is through a stem cell transplant. Stem cells can be obtained from many sources, including bone marrow, blood, or umbilical cord blood. Unfortunately, stem cell transplants are not possible for all MDS patients because sometimes it is difficult to find a stem cell donor, and not all patients are healthy enough to undergo the procedure. There are other drugs available to treat MDS, and although some may prolong survival by a small amount, many simply treat the symptoms of MDS and none have the potential to cure the disease. Therefore, it is very important that more research be done to develop a cure for MDS.
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ON THIS PAGE: You will learn about how doctors describe MDS. This is called subtype and classification. Use the menu to see other pages.
MDS is classified into several different subtypes based on the following features:
Blood cell counts
Percentage of blasts in the bone marrow
Risk that it will turn into AML
It is also classified as either primary MDS or secondary MDS. And, MDS is given a stage called an IPSS-R score. These classifications help doctors plan treatment and predict a patient’s prognosis, which is the chance of recovery. Each is described below in more detail.
WHO system for MDS subtypes
The World Health Organization (WHO) developed a classification system for MDS to standardize the definitions of the different subtypes. The 7 subtypes of MDS in this system include:
Refractory anemia (RA). The primary sign of RA is anemia. White blood cell counts and platelet counts are healthy. There are less than 5% blasts found in the bone marrow. This subtype of MDS does not often turn into AML.
Refractory anemia with ringed sideroblasts (RARS). People with this subtype of MDS have anemia, similar to those with RA, except more than 15% of the red blood cells are sideroblasts. A sideroblast is a red blood cell in which the iron in the cell appears to be in a ring around the center of the cell where the genes are found, called the nucleus. The white blood cell and platelet counts are usually healthy. People diagnosed with RARS have a low risk of developing AML.
Refractory cytopenia with multilineage dysplasia (RCMD). In this subtype, people have less than 5% blasts and less than 15% ringed sideroblasts in the bone marrow. The other bone marrow cells look abnormal when viewed under the microscope. At least 2 of the blood cell counts are low. RCMD may eventually turn into AML.
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS). This subtype is similar to RARS, in which people have anemia and more than 15% sideroblasts. The other bone marrow cells also look abnormal when viewed with a microscope. In addition, at least 2 types of blood cell counts are low. RCMD-RS may eventually turn into AML.
Refractory anemia with excess blasts (RAEB). People with RAEB can have decreases in all or some of their blood cell counts. There are less than 5% blast cells in the blood and 5% to 20% blasts in the bone marrow. People with more than 20% blasts in the bone marrow are diagnosed with AML. People with RAEB may also have lower white blood cell and platelet counts. About 40% of people diagnosed with RAEB eventually develop AML.
Myelodysplastic syndrome, unclassified (MDS-U). People diagnosed with this subtype have decreased numbers of white blood cells, red blood cells, or platelets, but do not have the specific signs of the other MDS subtypes.
MDS associated with isolated del(5q). People with this subtype have anemia and fewer than 5% blasts, and genetic material is missing from chromosome 5.
CMML and JMML. In addition to the 7 MDS subtypes above, chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are types of blood cancers that the WHO classifies as “mixed myelodysplastic/myeloproliferative diseases.” Unlike other types of MDS in which blood counts are low, white blood cell counts are higher in these subtypes. Both CMML and JMML begin after a change, or mutation, happens in a type of blood cell called a monocyte. CMML generally occurs in people ages 65 to 75. JMML is most common in children younger than 6. Treatment is similar to MDS and can include chemotherapy and/or stem cell transplantation (see Types of Treatment).
In addition to subtype, MDS is called either primary or secondary MDS. Primary MDS is much more common than secondary MDS. About 80% of people with MDS have primary MDS.
In primary MDS, no apparent risk factors can be found. This may also be called de novo MDS.
Secondary MDS occurs because of damage to the DNA from chemotherapy or radiation therapy previously given to treat another medical condition. MDS can develop 2 to 10 years after such treatment. Secondary MDS is often associated with more complex chromosomal abnormalities.
The revised International Prognostic Scoring System (IPSS-R) is another classification system used by doctors to help predict a person’s risk of developing AML and overall survival. The IPSS-R looks at factors such as the percentage of blasts found in the bone marrow, type and extent of chromosomal changes, and levels of hemoglobin found in red blood cells, platelets, and a type of white blood cell called neutrophils.
Poor prognostic factors include:
Certain types and higher numbers of chromosomal changes
Higher percentage of blasts in the bone marrow
Low levels of hemoglobin, platelets, and neutrophils
The total IPSS-R score places people with MDS into 5 distinct groups:
Very low risk
Very high risk
People with MDS who have a lower IPSS-R score have the best outlook for survival and need less aggressive treatment. For patients with lower IPSS-R scores, overall survival rates tend to be lower when they need red blood cell transfusions. A red blood cell transfusion is a procedure in which blood or blood cells from 1 person are given to another person. A person diagnosed with a high-risk subtype of MDS and whose IPSS-R score is high usually needs more intensive treatment.
Recurrent MDS is MDS that has come back after a period of remission, or absence of symptoms, also called “no evidence of disease” or NED. If the MDS does return, there will be another round of tests to learn about the extent of the recurrence. These tests and scans are often similar to those done at the time of the original diagnosis.
Information about the subtype and classification will help the doctor recommend a specific treatment plan. The next section in this guide is Types of Treatment. Use the menu to choose a different section to read in this guide.