Myelodysplastic syndromes (MDS) are a group of cancers that prevent your bone marrow from producing enough healthy blood cells. MDS are not necessarily terminal diseases, but they are not easily curable either. Depending on how progressive your MDS is, you may not immediately need aggressive treatment. In some cases, MDS progress into a form of leukemia. A bone marrow transplant is the only treatment that has potential to cure MDS, though it is a risky procedure and not appropriate for everyone.^1,2

MDS encompass a group of varied but related diseases. The kind you develop depends on both genetic as well as epigenetic phenomena that remain poorly characterized to date. Depending on the type of MDS you have, you may develop deficiencies in red blood cells, white blood cells, and/or platelets. Your symptoms will depend on which type of blood cell(s) your bone marrow is not producing correctly. Extreme tiredness, shortness of breath, easy bleeding, or frequent infections are common, though it is also not unusual for some patients not to experience symptoms, especially in the early stages of MDS.²

There are as many as 170,000 people living with MDS in the United States, where an average of 33‒55 people are diagnosed every day. While MDS can affect people of all ages, 75% of patients with MDS are older than 60 years. One in three patients with MDS eventually develop another blood disorder called acute myeloid leukemia (AML). Regrettably, the development of AML in the setting of pre-existing MDS is difficult to treat. The average survival is approximately five months for high-risk MDS patients and up to six years for lower-risk patients who do not receive a bone marrow transplant.^3,4 Allogeneic bone marrow transplant has the potential to significantly prolong overall survival in select patients, but quality of life is frequently compromised.

In this protocol, you will learn how MDS develop and which factors increase risk. You will also learn how MDS are typically diagnosed and treated. You will discover several emerging treatment strategies currently being pursued in research settings and learn how to find ongoing clinical trials in which you may be able to participate. In addition, you will learn about various dietary and lifestyle considerations, as well as natural interventions, that may be supportive in cases of MDS.

In 1900, physicians first began describing patients with what are now regarded as telltale signs of MDS: severe shortages in different types of blood cells, cells that do not fully mature or that develop abnormally, and bone marrow that is overcrowded with cells that never leave to enter the bloodstream.⁵ MDS were first noted in the medical literature in the 1930s, where they were described as pre-leukemic conditions. Historically, these disorders have been referred to as refractory anemia, oligoblastic anemia, myelodysplastic anemia, preleukemia, and smoldering leukemia. MDS were not regarded as separate, distinct disorders until 1976.^6,7

MDS were first classified in a 1982 publication by the French-American-British group.^5,7 This system developed subgroups based on the condition of blood and bone marrow, as well as the presence of specific abnormalities. During the 1990s, the importance of other clinical variables was recognized. In particular, chromosome analysis largely contributed to improved clinical outcomes.⁵

In 1997, patient cohorts were gathered from the United States, Europe, and Japan and reviewed thoroughly to create the database for the International Prognostic Scoring System (IPSS).^5,7 This was the first widely used classification system for MDS. Based on the blood cell counts, percentages of bone marrow cells, and genetic risk profile, the IPSS was used to divide patients into risk categories. This helped identify probabilities of survival and risk of disease progression.⁵

Blood Cells and Genes

Blood consists of fluid, which is mainly water, and a combination of three main cell types: platelets that clot to control bleeding, red blood cells that deliver oxygen throughout the body, and white blood cells, which are part of the immune system.² Blood cells grow and develop within bone marrow, the spongey tissue inside the center of most bones. Immature cells with the ability to turn into mature, functional cells are called stem cells. Immature blood cells are referred to as hematopoietic stem cells, which develop into young blood cells called blasts. Blasts mature into platelets, red blood cells, and white blood cells before leaving the bone marrow and entering the bloodstream.

All cells in the body contain genes, which are instructions for how cells function and build new cells.² Genes are stored in the form of deoxyribonucleic acid (DNA) and organized into long strands called chromosomes. Changes in genes, which are referred to as mutations, have the possibility of turning normal cells into cancer cells.

Blood stem cells are direct precursors for the maturation and function of mature blood cells.^2,8 With MDS, blood stem cells do not generate enough new blood cells and make blood cells that are defective. These cells have abnormal size, shape, and appearance, which is called dysplasia. They do not mature into normal, healthy blood cells; often do not leave the bone marrow; and may die early either in the bone marrow or shortly after entering the bloodstream. This results in having low numbers of one or more types of blood cells in the bloodstream, referred to as cytopenia.

Most symptoms of MDS are due to a lack of healthy platelets, red blood cells, or white blood cells.^2,8 Anemia occurs due to a shortage of healthy red blood cells and can cause fatigue, weakness, dizziness, shortness of breath, and pale skin. With low amounts of white blood cells, referred to as neutropenia, patients may experience frequent or severe infections. Having low numbers of platelets, which is called thrombocytopenia, can cause bruising, bleeding, and make it more difficult for wounds to heal.

In some patients, MDS are slow-developing conditions and some patients do not experience symptoms early in the course of the disease.^2,8 In other patients, defective blood stem cells and blasts can accumulate and overcrowd the bone marrow. In certain patients, MDS may progress into a fast-growing cancer called acute myeloid leukemia (AML).^2,8 In the past, MDS were considered “pre-leukemic” conditions, but evidence clearly indicates that not all patients with MDS necessarily develop AML, which occurs roughly about one-third of the time.

Causes for MDS are generally unknown, and little is known about what contributing factors may cause the gene mutations that lead to disease. However, although research is ongoing, evidence suggests several potential risk factors.

Environmental and Therapeutic Exposure

Studies have shown that chemotherapies, particularly a class called alkylating agents, and radiation therapy used to treat previous cancers could possibly lead to MDS.^9-12 Occupational exposure to certain other chemicals, like benzene^13,14 or pesticides,^15-17 have also been associated with higher risk for MDS.

Modifiable Lifestyle Considerations

In a review¹⁸ of available small studies, smoking^13,19-22 and alcohol^21,23 use were each evaluated as potential risk factors for MDS in four studies. Body mass index (BMI)^21,24 and anemia were each evaluated in two studies. A BMI of 30 kg/m² or greater more than doubled risk of MDS in a study of both men and women in the United States.²¹ History of autoimmune diseases, certain infectious diseases, anemia, and use of anti-tuberculosis drugs were associated with increased risk of MDS as well. Conversely, vigorous physical activity and tea and dietary isoflavone intake were associated with lower MDS risk.¹⁸

MDS are commonly organized into subtypes using a classification system developed by the World Health Organization (WHO) and National Comprehensive Cancer Network (NCCN) guidelines.^8,25 The 2017 WHO Revision contains additional subtypes in a category for myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN).^8,26 Factors used to determine MDS and MDS/MPN subtypes include the types of cytopenias and/or dysplasias, amount of blasts in the blood and bone marrow, type of gene mutations found in the bone marrow, and presence of defective red blood cells that contain too much iron, called sideroblasts.

*To be interpreted with the help of a clinician skilled in the management of MDS. ^αA type of white blood cell. ^ßType of abnormal presence found in defective blasts. ^dType of gene mutation. ^†Over 5% for patients with SF3B1 gene mutations. ^†5% or more for patients with SF3B1 gene mutations.
GM-CSF, granulocyte-macrophage colony-stimulating factor; MDS, myelodysplastic syndromes; MPN, myeloproliferative overlap neoplasms; NCCN, the National Comprehensive Cancer Network; WHO, World Health Organization

Tests for MDS involve a complete medical history and physical exam to review symptoms and when they began. Sometimes MDS tests are completed to review unsuspected results from blood tests done for other reasons.^2,8 If a person is suspected to have a MDS, tests should be conducted to examine his or her blood and bone marrow for evidence of MDS or a different health condition.^2,8,27

Complete Blood Count and Differential

A complete blood count (CBC) measures the number of white blood cells, red blood cells, and platelets. A CBC for MDS includes a differential to measure specific types of white blood cells, like neutrophils, monocytes, and lymphocytes.^2,8,27

Reticulocyte Count

Reticulocytes are immature red blood cells. Measuring the number of reticulocytes in the bloodstream reflects on how quickly reticulocytes are being made and released from healthy bone marrow and can also help determine the cause of anemia.^2,8,27

Blood Smear

By examining a drop of blood on a microscope slide, blood cells are assessed for size, shape, and maturity to look for abnormalities, or dysplasias. This process also can help count different types of blood cells and check for blast cells in the bloodstream, which are normally only in the bone marrow.^2,8,27

Serum EPO

Erythropoietin (EPO) is a hormone made by the kidneys that stimulates bone marrow to make more red blood cells when blood oxygen levels are low. Measuring EPO can help determine the cause of anemia. A low EPO level can itself cause anemia and may be a sign of a different health condition. In patients with known MDS, low EPO levels can worsen anemia.^2,28

Iron, Ferritin, Folate, and Vitamin B12

Checking for shortages of certain substances can help determine the cause of anemia. Iron is needed to make hemoglobin, the protein in red blood cells that carries oxygen. Ferritin represents the amount of iron stored in the body. Folate and vitamin B12 are nutrients needed to make red blood cells. Low levels of these can cause anemia and shortages in folate or vitamin B12 can also cause red blood cell dysplasia.⁸

Thyroid Hormones

Hormones made by the thyroid help control energy usage and can also affect other body functions. High thyroid-stimulating hormone (TSH) levels may indicate an underactive thyroid, which can cause anemia.²⁹

Copper

Copper is a mineral that supports many bodily processes, and low levels can cause low numbers of red blood cells, white blood cells, and have been associated with dysplasia. Copper deficiency could potentially be confused for MDS. Because copper plays a role in mobilizing iron from the liver to tissues throughout the body, copper deficiency can cause iron to accumulate in the liver and not reach other tissues. This can lead to problems with blood cell formation in the bone marrow secondary to lack of iron availability.³⁰ The abnormalities in blood cell production may be mistaken for MDS. Most commonly, copper deficiency manifests as low red blood cell and white blood cell counts. Low copper levels can be detected via blood testing.³⁰ Measuring copper levels is not a standard test for MDS, but it is sometimes needed to rule out other causes of dysplasia.^31-35

HIV Testing

Human immunodeficiency virus (HIV), which can cause cytopenia and dysplasia, may need to be ruled out in certain cases.^2,27

Flow Cytometry

Flow cytometry is a technique that can be used to measure different characteristics of cells, including their size, count, and type. In some cases of MDS, flow cytometry is used to identify specific types of cells in blood or bone marrow by analyzing proteins on the surface of the cells.^36-41

Bone Marrow Biopsy and Aspiration

To confirm a diagnosis of MDS, a small piece of solid bone and a bone marrow sample are biopsied for testing, typically from the hip bone. At the same time, a bone marrow aspiration collects bone marrow from inside the bone. These tests provide specific information on cytopenias, dysplasias, and blast cells from the bone marrow. Whereas in healthy bone marrow less than 5% of the cells are blasts, samples from patients with MDS can show blasts in up to 19% of cells. With AML, more than 20% blasts can be measured in the bone marrow. The samples are also dyed to test for ring sideroblasts, dysfunctional red blood cells that have too much iron.^42-46

Genetic Tests

Bone marrow and sometimes blood are examined by cytogenetic testing under a microscope to see the chromosomes inside cells. The chromosomes are detailed into an outline, called a karyotype. Sometimes fluorescence in situ hybridization (FISH)^47,48 is also used to study chromosomes. Chromosomes with missing or misplaced parts may provide valuable disease state information. In MDS, it is common to have abnormal chromosomes, though not all patients do.^41,49-57

Molecular Testing

More sensitive than karyotyping or FISH, molecular testing in blood and bone marrow detects small defects in genes, known as mutations. Often, a patient with a normal karyotype can have detectable mutations at the molecular level.^58-62 Recurrent gene mutations that occur commonly in MDS can be looked for specifically using DNA sequencing.^61,63

PDGFRβ Gene Mutation

Changes to the platelet-derived growth factor receptor beta (PDGFRβ) gene occur in a subtype of MDS called chronic myelomonocytic leukemia (CMML). Knowing if cells have a PDGFRβ gene mutation helps guide treatment decisions for some patients.^53,57,64-66

Prognostic Factors

Prognostics predict patterns and outcomes of disease. Certain factors related to blood counts, bone marrow assessment, and karyotype/molecular profile affect the predicted outcome of MDS and help classify the severity of the diseases. An important aspect that affects the prognosis of MDS is the risk of progressing to AML. Other prognostic factors include MDS subtype, number and severity of cytopenias, amount of blasts in the bone marrow, and type and number of chromosome changes.^8,58,67,68

Prognostic Scoring and Grouping

Prognostic scoring uses points to rate the severity of MDS in individual patients based on their prognostic factors. Two common scoring systems are the Revised International Prognostic Scoring System (IPSS-R) and the WHO classification-based Prognostic Scoring System (WPSS).^69-71

Prognostic factors have different scores based on their severity. When the scores for individual prognostic factors are added together, they provide an overall risk score. A lower total score means a better outlook. The risk score describes how slow or fast MDS will likely grow and progress to AML if not treated. Risk scores are used to assign risk groups that guide decisions on treatment.^8,69-72

*To be interpreted with the help of a clinician skilled in the management of MDS.
IPSS-R, Revised International Prognostic Score System; MDS, myelodysplastic syndromes; WPSS, World Health Organization classification-based Prognostic Scoring System

Determining Low Risk vs. High Risk

It is important to note that risk groups are based on averages from large groups of patients, so some cases of MDS fare better or worse than predicted. For example, factors like age, general health, ability to do daily activities, and the presence of other health conditions can affect risk, although these are not currently accounted for in available scoring systems. Also, risk groups can only help predict the likely course of untreated MDS over time, but cannot provide an estimate as to how patients will respond to treatment or how long an individual will live.^8,69-72

Risk groups measured with each scoring system are often separated into two categories: lower-risk and higher-risk MDS. Generally, lower-risk MDS are likely to progress more slowly over time, not cause many or severe symptoms, and involve less intensive treatment. Higher-risk MDS are more likely to progress faster or develop into AML, cause more symptoms, and involve more intensive treatment.^8,69-72

*To be interpreted with the help of a clinician skilled in the management of MDS.
IPSS-R, Revised International Prognostic Score System; MDS, myelodysplastic syndromes; WPSS, World Health Organization classification-based Prognostic Scoring System

MDS treatments may include supportive care, drug therapy, and stem cell transplantation. Supportive care might involve blood transfusions, medications to increase the production of red blood cells, and antibiotics.

Chemotherapy

Chemotherapy uses different intravenous and oral drugs to kill abnormal cells or stop new ones from being made. The drugs used for MDS work in various ways and two or more agents may be used in a combination regimen. These medications can also affect normal cells, so they are given in varying cycles of treatment days followed by rest.

Low-intensity chemotherapy describes agents that are less likely to cause severe side effects. High-intensity chemotherapy is typically reserved to treat AML or before a hematopoietic cell transplant (HCT) for MDS. Two low-intensity chemotherapies are approved to treat MDS: azacitidine^73-76 and decitabine.^77-81 These drugs are in a class known as hypomethylating agents. They modify gene expression in abnormal cells and stunt their growth, which in turn activates genes for growth of normal, healthy cells in the bone marrow.^82-85 Common side effects of hypomethylating agents are low white blood cell, platelet, or red blood cell counts and fever.

Immunosuppressive Therapy

With some types of MDS, the immune system attacks bone marrow tissue. Anti-thymocyte globulin (ATG) [equine] and cyclosporine are immunosuppressive drugs used for MDS. They suppress parts of the immune system to prevent damage to bone marrow.^86-89

Cyclosporine inhibits an enzyme called calcineurin, preventing it from activating T cells and thereby restraining the immune system. Side effects might include increased blood pressure and elevated potassium levels. Vaccinations may be less effective in people taking cyclosporine, and it is important to avoid live attenuated vaccines while taking cyclosporine.

ATG is an antibody that stifles the immune system by eliminating certain types of white blood cells from the bloodstream. It may cause fever, chills, rash, low platelet or white blood cell counts, and joint pain. In certain situations, ATG and cyclosporine are used in combination.⁸

Immunomodulator

Lenalidomide is approved to treat MDS with cells that are missing part of chromosome 5, or del(5q). It supports the immune system by preventing the release of proteins that signal for inflammation and promoting development of T cells. This in turn helps bone marrow make normal cells and kill abnormal cells.^90-100 Lenalidomide may be useful in some patients without del(5q) as well.101 In treating MDS, some of the common side effects of lenalidomide are low platelet and white blood cell counts, itching or rash, joint pain, and fever.

Targeted Therapy

Targeted therapies, like imatinib mesylate, are drugs that target unique features of cancer cells, and thus may be less likely to affect normal cells. A tyrosine kinase inhibitor (TKI), imatinib targets proteins that help cancer cells grow and is used especially in CMML expressing PDGFRβ gene mutations.8,64-66 Examples of common side effects include swelling, nausea and vomiting, muscle cramps, and musculoskeletal pain.

Allogeneic Hematopoietic Cell Transplant

An allogeneic hematopoietic cell transplant (HCT) destroys bone marrow cells with chemotherapy and replaces them with new blood stem cells, or hematopoietic stem cells, from a donor. The goal of HCT is to cure the cancer by allowing healthy blood stem cells to grow and form new bone marrow and blood cells. This process, called engraftment, takes about 2 to 4 weeks.^102-106 The transplanted cells also give rise to new healthy T cells that can recognize and attack remaining malignant cells. This is known as the graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect.¹⁰⁷ A donor lymphocyte infusion may be used to donate lymphocytes, a type of white blood cell, to stimulate the GVL effect to treat MDS that reoccur or progress after an HCT.¹⁰⁸

*To be interpreted with the help of a clinician skilled in the management of MDS.
ATG, Anti-thymocyte globulin, equine; MDS, myelodysplastic syndromes. IV, intravenous

Treatment Approaches

Treatment options are guided by many factors, including MDS risk groups, patient symptoms, presence of chromosome abnormalities, serum EPO levels, and features that might indicate likelihood of response to certain medications.⁸

*To be interpreted with the help of a clinician skilled in the management of MDS.
ATG, Anti-thymocyte globulin, equine; EPO, erythropoietin; G-CSF, granulocyte colony stimulating factor; HCT, hematopoietic cell transplant; MDS, myelodysplastic syndromes.

Lower-risk MDS with anemia. Initial treatment for lower-risk MDS with anemia should consider the level of serum EPO in the blood and chromosome changes in the MDS cells, like del(5q).^2,28 If MDS cells have a del(5q) chromosome change, with or without other chromosome abnormalities, lenalidomide treatment may be recommended. However, lenalidomide should not be given if patients have an abnormal chromosome 7, complex karyotype, or very low number of neutrophils or platelets.^8,90-100

For patients with MDS and anemia, but without del(5q), serum EPO levels guide treatment. Epoetin alfa and darbepoetin alfa are erythropoietin-stimulating agents (ESAs) given for serum EPO levels ≤ 500 mU/mL. ESAs are sometimes given with G-CSF in order to stimulate growth of white blood cells.^2,28 If tests show serum EPO > 500 mU/mL and factors indicate a high chance that MDS will respond to immunosuppressive therapy (IST), then ATG with cyclosporine may be helpful.86-89 If MDS are not likely to respond to IST, then patients usually receive azacitidine or decitabine.⁸

Lower-risk MDS without anemia. Azacitidine^73-76 or decitabine^82-85 are both low-intensity chemotherapy drugs used for lower-risk MDS without anemia. For some patients, if features of the MDS cells and other factors indicate that they are likely to respond to IST, treatment using ATG with or without cyclosporine is available.^86-89

Higher-risk MDS. Patients with higher-risk MDS should be evaluated for treatment with an allogeneic HCT and high-intensity chemotherapy. While high-intensity treatments can improve survival and slow or stop MDS progression to AML, side effects can be severe and not all patients can tolerate therapy. In some instances, an HCT is performed right away. In other instances, patients receive azacitidine, decitabine, or high-intensity chemotherapy first.^102-106

If an allogeneic HCT is not a good option, azacitidine may help improve blood cell counts, lower risk for progression to AML, and can increase survival time. Similarly, decitabine can lower the chance that MDS will progress to AML.⁸

Treatment of anemia. With MDS, anemia will be treated if it is causing symptoms. While ruling out and/or treating other possible causes of anemia, patients may receive iron, folate, or vitamin B12, red blood cell transfusions, and other supportive care. If a del(5q) mutation is present without an abnormal chromosome 7 or very low neutrophil or platelet counts, lenalidomide serves as an option.^2,8

If no relevant chromosome abnormalities are present, patients should receive epoetin alfa or darbepoetin alfa for serum EPO levels ≤ 500 mU/mL. If 15% or more of the bone marrow is ring sideroblast, then G-CSF is typically given alongside the ESA.^109-116

*To be interpreted with the help of a clinician skilled in the management of MDS.
EPO, erythropoietin; G-CSF, granulocyte colony stimulating factor; MDS, myelodysplastic syndromes

Following are several clinical developments in the MDS “pipeline.” None of the following products are currently approved for MDS. While this is not an exhausted list, these represent some important advancements in MDS research.

Clinical Trials

New treatment approaches for MDS are currently being developed and researched. Especially for certain patients who do not meet the criteria for some treatments or do not see benefit when using current therapies, clinical trials may provide suitable options and should be considered when available. The Leukemia & Lymphoma Society (LLS) provides assistance for patients through the Clinical Trial Support Center (https://www.lls.org/treatment/types-of-treatment/clinical-trials).

Venetoclax

Venetoclax (Venclexta) is a highly selective, oral inhibitor of the B-cell lymphoma 2 (Bcl-2) protein which interferes with cell death. Venetoclax helps restore the process of cancer cell death. This represents a newly available approach for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). It can also be used in combination with the hypomethylating agents, azacitidine or decitabine, or with cytarabine for patients 75 years or older with AML or those who have comorbidities that prevent the use of intensive induction chemotherapy.¹¹⁷

Guadecitabine

Guadecitabine is a next-generation hypomethylating agent (HMA) that is resistant to the enzyme that breaks down typical HMAs. It is administered under the skin and thought to release more gradually to provide longer exposure to the drug. Long-term phase II studies for MDS have been completed and an ongoing phase III study is currently underway.^118,119

Immune Checkpoint Inhibition

A form of cancer immunotherapy, checkpoint inhibitors (CPIs) are agents that target and deactivate key controllers of the immune system called “checkpoints.” Checkpoint controllers weaken the immune system’s response to various cancers, so suppressing checkpoints allows the body’s immune system to mount a better response to cancer.^118,120,121 More so, evidence suggests previous exposure to common MDS HMAs, like azacitidine, can induce certain immune checkpoints.¹²⁰

Targeted Therapies

Many efforts are focusing on drug therapies that target genes common to MDS. TP53^118,122,123 and isocitrate dehydrogenase (IDH) mutations,^118,124 for instance, are just two examples of many aberrations associated with aggressive MDS and AML diseases. Mutations like these can result in poor clinical course and poor response to medications, so developing agents to target them is key. The IDH2 inhibitor enasidenib (Idhifa) was approved for treating AML after a phase I/II trial that included 30 patients with previous MDS.^118,125

Targeting Innate Immunity

Toll-like receptors (TLRs) are a family of receptors involved in immune responses. With MDS, high levels of TLR2 are often expressed in the bone marrow, especially after treatment with HMAs, and disrupt the development of blood cells. When the experimental anti-TLR2 drug, tomaralimab, was given to 22 low-risk MDS patients in a phase I/II trial, it produced either complete or partial reduction of MDS in 50% of patients and little dose-limiting toxicity was observed.^118,126

Amifostine

Used as a protectant, amifostine (Ethyol) binds excess chemotherapies in the body to protect patients from their harmful side effects.^127,128 Due to its ability to stimulate growth of blood stem cells from healthy bone marrow and ameliorate cytopenias, amifostine is sometimes used as a single agent in the treatment of MDS.^129-131

Sucrosomial Iron

MDS often cause certain types of red blood cell shortages that require supportive care with therapeutic iron administered through IV lines. IV iron, however, can cause gastrointestinal upset in up to 50% of patients and requires accessing a vein for administration by a trained clinician.¹³² Sucrosomial iron is a form of iron supplementation developed in Italy that is taken orally. Absorbed differently than other oral iron supplements, it has shown efficacy in MDS with less gastrointestinal side effects.^132,133 When 92 patients with MDS and refractory anemia were followed for a median of 22 months while taking 28 mg sucrosomial iron daily, patients experienced high rates of incremental improvements. The regimens also included 400 mg vitamin B12 and 7.5 mg calcium levofolinate by mouth daily.^132,134 Preliminary data suggest that oral sucrosomial iron may be as effective as IV iron in patients with MDS.¹³²

The integrative interventions below may complement conventional MDS treatments for some people. Patients should always consult clinicians skilled in the management of MDS before starting a new regimen with any agent.

Vitamin K

Evidence suggests vitamin K may selectively clear abnormal blast cells in MDS.^138,139 Menatetrenone (MK-4), a vitamin K compound, was given at 15 mg three times daily by mouth to nine patients with MDS for 16 weeks. Five patients in the vitamin K group experienced resolution of cytopenias, compared to one patient in the no menatetrenone group. Three major responses were observed in white blood cells, while increases in red blood cells and platelet count occurred in two patients each.¹⁴⁰

A different multicenter phase II trial was conducted to investigate use of MK-4 alone versus MK-4 plus an active vitamin D3 metabolite for low-risk MDS with anemia, cytopenia, and multiple dysplasias. Out of 38 patients who received MK-4 (45 mg by mouth daily for 16 weeks), four saw improvements in anemia and one in thrombocytopenia. When 20 of the patients who did not respond to vitamin K alone took this in combination with 0.75 mcg of the vitamin D3 metabolite daily, six had improvements in cytopenias indicating that combination therapy may be helpful.¹⁴¹

Japanese researchers reported a case in 1999 in which an 80-year-old woman with MDS and refractory anemia was successfully treated with 45 mg daily of MK-4. Before treatment, the woman was heavily dependent on blood transfusions. Her blood cell counts gradually improved during 14 months of treatment with MK-4, to the extent that she no longer needed transfusions. Remarkably, her blood cell counts deteriorated again when she discontinued the MK-4 supplementation but recovered once more when she reinstated MK-4 supplementation. The researchers suggested that MK-4 may help restore hematopoiesis in certain MDS cases.

In preclinical research published in 2019, a team of researchers out of Germany and France found that drugs that block the effects of vitamin K, like the anticoagulant drug warfarin (Coumadin), altered the physiology of the bone marrow microenvironment and reduced functional hematopoietic stem cells 8-fold. Vitamin K-antagonist drugs were not found to be directly toxic to hematopoietic stem cells, but they modified the function of some key proteins in the bone marrow microenvironment—an effect to which the scientists attributed the decrease in functional hematopoietic stem cells. In an accompanying analysis of patient records, the researchers also found that use of vitamin K antagonists was more common in people who had been diagnosed with a MDS than in healthy people. However, the researchers stressed that their findings did not establish a causal link between vitamin K antagonists and MDS in humans, and that further research should be done to explore this connection.¹⁴²

Importantly, people taking warfarin to prevent blood clots should not initiate vitamin K supplementation without first talking with their physician. Vitamin K, especially in high doses, may interfere with the efficacy of warfarin.

Vitamin D

Vitamin D can modulate different types of immune responses.¹⁴³ Low levels of vitamin D3 have been associated with shorter survival after azacitidine treatment in patients with MDS. A study at a hospital in Spain analyzed vitamin D3 levels in 58 patients with MDS between 2006 and 2014. The estimated probability of surviving 2 years was 40% in patients with vitamin D3 levels over 13 ng/mL compared with 14% in those with lower levels.¹⁴⁴ Unfortunately, participants’ vitamin D levels in this study were all below 50 ng/mL, which many experts consider a lower bound for the target healthy vitamin D range (50–80 ng/mL). More studies are needed to prospectively evaluate higher vitamin D levels and/or vitamin D supplementation in the context of MDS outcomes.

One study on the effects of vitamin D3 metabolites for MDS followed 19 patients for an average of more than 26 months. Five patients received 266 mcg calcifediol (25-hydroxyvitamin D3) three times weekly by mouth and 14 patients received calcitriol 0.25 to 0.75 mcg once daily by mouth. Eleven patients saw improvements in transfusion requirements and in counts for platelets, white blood cells, and red blood cells. Two patients experienced complete normalization of all blood cells.¹⁴⁵

Maitake Mushroom

Preclinical research has shown that Maitake-derived beta-glucan may stimulate the growth of blood cells in bone marrow, increase the number of white blood cells in the bloodstream, and protect cells from potentially harmful molecules called reactive oxygen species (ROS).^146-148 In a phase II clinical trial, 18 patients with MDS were given 3 mg/kg Maitake by mouth twice daily for 12 weeks. The treatment was well tolerated and increased the function of endogenous neutrophils and monocytes, which are types of white blood cells. These results suggest Maitake may have immunomodulatory potential and may enhance immune responses against bacterial infections for patients with MDS. However, there were small decreases in neutrophil count and hemoglobin levels among people taking the Maitake extract, although the changes were so small as to be deemed not clinically meaningful.¹⁴⁸

Green Tea

The polyphenols epigallocatechin gallate (EGCG), epicatechin gallate, epigallocatechin, and epicatechin are well-known active plant compounds in green tea.¹⁴⁹ Some epidemiology data suggest consuming green tea may protect against MDS. One study matched 208 patients with MDS to 208 control patients at a hospital based in China, accounting for gender, age, and residential locality. Compared with non-tea drinkers, regular tea consumption was associated with a decreased risk of developing MDS. This held true for those who consumed tea >20 years, ≥2 cups daily, and dried tealeaves ≥750 grams per annum and was associated across gender, good and intermediate/poor genetic risk groups, and lower versus higher risk groups.¹⁵⁰ However, a large Japanese cohort study of 45,937 men and 49,870 women age 40‒69 years failed to find an association between tea consumption and risk of MDS.¹⁵¹ Further study is necessary to elucidate the role of tea consumption on MDS.

Ginger

6-shogaol is derived from the main active compound in ginger root, 6-gingerol, which also gives ginger its distinctive flavor. Shogaols from ginger display several liver-protective effects and can induce Nrf2, which controls genes for several liver-protective enzymes.¹⁵² Serum ferritin is often elevated in patients with MDS, and some research suggests ferritin levels are a potential prognostic factor. In a 6-month study measuring serum ferritin, six patients with low-risk MDS were given 1 gel capsule daily of 20 mg ginger extract, standardized at 20% 6-shogaol. Three patients experienced decreases in serum ferritin, despite having increased baseline levels, and one also had improved liver markers. Due to decreases in serum ferritin levels during the initial study, two of the three patients repeated the study for another six months. No ill effects from 6-shogaol were reported by patients.¹⁵³

Coenzyme Q10

Coenzyme Q10 (CoQ10) occurs naturally in the body, mostly in the heart, liver, kidneys, and pancreas, and is used to support healthy cellular membranes and serum. Lower levels of CoQ10 reportedly occur with age, use of certain drugs, and cancer. It is thought to restore mitochondrial energy production that is impaired in patients with MDS. In 29 patients with MDS, 1,200 mg CoQ10 was given daily by mouth for a minimum of 16 weeks. Of the seven patients who responded to treatment, three had major responses in all three types of blood cells, including one patient who continued CoQ10 for 17 months before having a delayed response. Another patient’s red blood cell and platelet counts normalized, amongst other patients corrected cytopenias and improvements in quality of life. Two patients even experienced cellular genetic responses.^154,155

Curcumin

Curcumin is the active ingredient in turmeric. By influencing various pathways, for example those regulated by growth factors or Nrf2, curcumin has a wide range of anti-inflammatory, antioxidant, and chemopreventive benefits.^156,157 Supplemental curcumin has been shown in preclinical studies to sensitize MDS tissue samples to treatment with arsenic trioxide and has displayed synergy when used in combination with azacitidine.^158,159

Luteolin

Nuclear factor erythroid 2-related factor 2 (NRF2) can play a pivotal role in protecting some types of cancer cells from certain chemotherapies. Luteolin, a common dietary flavonoid, inactivates NRF2.^160,161 A study of 137 tissue samples from patients with MDS showed that patients with high-risk MDS often have greater levels of NRF2 in bone marrow than those with low-risk MDS. Furthermore, it showed that when 2 μM of luteolin was applied to the samples it enhanced the efficacy of a chemotherapy called cytarabine when given together. This suggests luteolin combined with conventional chemotherapy to target NRF2 could provide new therapy options in high-risk MDS.¹⁶⁰ In another study of tissue samples from four patients, luteolin appeared to directly clear MDS-derived cells.¹⁶¹

Withaferin A

Withaferin A is an active substance from the Indian herb, Withania somnifera, commonly known as Indian winter cherry. Widely distributed across South Asian field, it is a traditional medicine used to treat inflammatory diseases, autoimmune diseases, and malignant tumors.¹⁶² Withaferin A showed that it might also suppress the growth of MDS cells in one study, when it was applied to tissue samples obtained from a patient with MDS.¹⁶² Another study used animal and human tissue samples to investigate how Withaferin A is able to do this. It found that Withaferin A had potential direct toxicity to MDS cells, but did not significantly affect normal human bone marrow cells.¹⁶³

Copper

Copper is an essential element for all living organisms, but the daily copper requirement in humans is very low so deficiencies are not common. Nevertheless, copper shortages can cause blood abnormalities that can mimic MDS.^30,164

Copper deficiencies can result from tube feeding, gastric bypass surgery, celiac disease, intestinal surgery, and other malabsorptive conditions. Copper deficiency can also arise as a consequence of excessive zinc intake, use of the chelating drug penicillamine, or from chronic use of prescription and over-the-counter proton pump inhibitors for heartburn or gastric reflux.^30,165