Myelodysplastic Syndrome (MDS) Treatment & Management

Updated: Aug 31, 2023
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, MBA, FACP  more...
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Approach Considerations

The standard care for patients with myelodysplastic syndrome (MDS) and decreased blood counts is constantly changing. Supportive therapy, including transfusions of the cells that are deficient (ie, red blood cells [RBCs], platelets), and treatment of infections are the main components of care. [26]

The approach to therapy is based on the revised International Prognostic Scoring System (IPSS-R) score, the patient's age and co-morbidities, and the patient's expectations and personal goals. The more toxic and aggressive forms of therapy, such as stem cell transplantation and aggressive chemotherapy, are reserved for younger and fit patients with high-risk disease.

Lenalidomide is approved by the US Food and Drug Administraiton (FDA) for the treatment of lower-risk, transfusion-dependent MDS patients who harbor a del(5q) cytogenic abnormality. Cytotoxic chemotherapy is used in patients with MDS who have increasing myeloblasts and those who have progressed to acute leukemia. The usual combination treatment is cytarabine plus an anthracycline, which yields a limited response rate of 30-40%.

Treatment with hypomethylating agents (ie, azacytidine, decitabine) is considered standard therapy for both low-risk MDS cases without 5q-, as well as intermediate and high-risk MDS. This approach is especially useful in elderly patients, who experience high rates of morbidity and mortality with cytotoxic chemotherapy. 

Patients with MDS should be under the care of a hematologist. Because most treatments for MDS are not standard and are considered experimental, referral to a tertiary care center with bone marrow transplantation capabilities is often necessary.

Although treatment of symptoms improves quality of life in MDS, these measures are temporary. More long-term measures are necessary to stimulate the patient's bone marrow production of mature blood cells. Practitioners are encouraged to refer patients for participation in clinical trials at academic centers and the MDS Centers of Excellence.


Supportive Care

Supportive care includes transfusion of red blood cells (RBCs) or platelets. The goal is to replace cells that are prematurely undergoing apoptosis in the patient's bone marrow.

Decrease transfusion-related complications by using leukocyte-depleted blood products, which have been shown to decrease nonhemolytic febrile reactions, prevent alloimmunization and platelet refractoriness, and prevent cytomegalovirus transmission. Additionally, this practice has been shown to achieve better quality control of blood products compared with bedside filtering and to be cost effective.

Red blood cell transfusion

Patients with moderate-to-severe anemia require RBC replacement (see the image below). Transfusing packed RBCs for severe or symptomatic anemia benefits the patient temporarily, only for the life span of the transfused RBCs (2-4 wk). Patients with congestive heart failure may not tolerate the same degree of anemia as young patients with normal cardiac function, and slow or small-volume (eg, packed RBCs) transfusions with judicious use of diuretics should be considered. For bone marrow transplantation candidates who are cytomegalovirus (CMV) negative, CMV-negative or leukopheresed) blood products are recommended whenever possible. [23]

This bone marrow film (400× magnification) demonst This bone marrow film (400× magnification) demonstrates an almost complete replacement of normal hematopoiesis by blasts in a refractory anemia with an excess of blasts in transformation. Note the signs of abnormal maturation such as vacuolation, double nucleus, and macrocytosis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Iron chelation

Patients with low-risk or intermediate-1–risk MDS typically have long-term survival and may receive multiple RBC transfusions. These patients may develop transfusion-induced iron overload and can incur significant damage of the liver, heart, pancreas, and other tissues. In addition, some evidence suggests that iron overload in the bone marrow adds to the cellular early apoptosis contributed by the microenvironment. [27]

Current guidelines recommend starting iron chelation therapy in those patients who have received 20-25 units of packed RBCs or who have a serum ferritin level of > 1000 μg/L. [28]

Deferoxamine (Desferal) is difficult to administer in elderly patients because it has to be given subcutaneously by pump over 12 hours daily to be effective. It is often given at the same time as the RBC transfusion, although in fact that is ineffective.

Deferasirox (Exjade) is an FDA-approved dispersible tablet that is dissolved in 7 oz of water and taken by mouth once daily. It is excreted in stools rather than urine, and it is 100-fold more active as a chelator of iron. Patients who cannot tolerate side effects such as diarrhea may require dose modification.

Platelet transfusion

Platelet transfusion is beneficial to stop active bleeding in thrombocytopenic patients, but the life span of transfused platelets is only 3-7 days. Avoid repeated and frequent platelet transfusions on the basis of low platelet counts (< 20,000/µL) in patients who are not experiencing clinical bleeding.

Long-term measures to prevent skin and mucosal bleeding may be achieved by administering oral antithrombolytic agents such as prophylactic oral epsilon-aminocaproic acid (Amicar) to avoid alloimmunization.

Treatment of neutropenia

Treat infections and neutropenia. Some patients may require granulocyte transfusions, but the risk of alloimmunization is high, as is the risk of developing refractoriness to future transfusion therapy. Life-threatening infections, especially of fungal etiologies, require administration of granulocytes and antifungal agents. Prophylactic antibiotics and antifungal agents may be considered in extrememly high risk patients with severe neutropenia. [29]

Bone marrow stimulation

Hematopoietic growth factors can stimulate bone marrow cell production and decrease excess bone marrow cell apoptosis. These erythropoiesis-stimulating agents (ESAs) include the recombinant human erythropoietin (EPO) agents epoetin alfa and darbepoetin alfa. [30]

National Comprehensive Cancer Network (NCCN) guidelines recommend the use of ESAs for treatment of symptomatic anemia in patients in the R-IPSS very low risk, low risk, or intermediate risk category whose tumor lacks the 5q31 deletion and whose level of endogenous EPO is ≤500 mU/mL. [23] These patients should receive epoetin alfa, 40,000–60,000 U subcutaneously (SC), 1–3 times weekly; or darbepoetin alfa, 150–300 μg SC weekly.

During ESA treatment, iron supplementation should be considered for patients with a transferrin saturation < 20%. If the patient responds to ESA treatment, an attempt should be made to reduce the ESA dose (or the frequency of administration) to the lowest able to maintain the hemoglobin level between 10 and 12 g/dL.

In cases of the presence of ringed sideroblasts or an absence of response, the addition of granulocyte colony-stimulating factor (G-CSF; filgrastim, filgrastim-sndz, or tbo-filgrastim), 1–2 μg/kg 1–3 times per week should be considered. The combination of ESAs and G-CSF should be considered only for patients who are not heavily transfusion dependent (fewer than 2 RBC units per month), have serum erythropoietin levels < 500 mU/mL, and are not responding to ESAs alone. For patients with a serum EPO ≤500 mU/mL and ring sideroblasts < 15% who have no response to an ESA alone, the NCCN suggests. adding lenalidomide plus or minus G-CSF. [23]  

Of MDS patients with neutropenia, 75% respond to G-CSF. [31] Of MDS patients with anemia and neutropenia, 75% respond to a combination of an ESA and G-CSF for their neutropenia, with a 50% increase in erythroid response. The addition of low doses of G-CSF synergistically enhances the erythroid response to ESAs—in particular, patients who have refractory anemia with ringed sideroblasts (RARS).

A re-analysis that used the World Health Organization classification demonstrated a significantly better response in RARS (75%) than in refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS; 9%). This may reflect G-CSF's ability to strongly inhibit cytochrome c release and hence mitochondria-mediated apoptosis in RARS erythroblasts.

Thrombopoietin receptor agonists (TPO-RA) such as romiplostim and eltrombopag have been approved to treat immune thrombocytopenia. Their use in MDS is limited in current practice owing to the increase in the blast percentage seen with the use of eltrombopag in some studies.


Pharmacologic Therapy

Cytotoxic chemotherapy is used in patients with MDS with increasing myeloblasts and those who have progressed to acute leukemia. The usual combination treatment is a cytarabine-anthracycline combination, which yields a response rate of 30-40% (high complication rate and morbidity in elderly patients).

Drug combinations using hematopoietic growth factors and drugs such as topotecan (Hycamtin), are yielding better response rates with lower morbidity. Aggressive chemotherapy may be indicated in small populations of elderly patients with good performance status and no associated serious medical comorbidity.

Isotretinoin or 13 cis-retinoic acid (Accutane) is the most active retinoid. In a randomized placebo-controlled trial in 70 MDS patients treated with low-dose isotretinoin (20 mg/m2/d), 1-year survival among patients with refractory anemia was 77%, compared with 36% in the placebo group. [32] That is statistically significant, although this form of therapy is not generally accepted. The author limits this treatment to patients who are not transfusion dependent.

A more recent study found that elderly MDS patients (n=63) with unfavorable features for response to erythropoietin alone had a 60% erythroid response rate to combination treatment with erythropoietin, isotretinoin, and vitamin D. Long-term follow-up showed a median erythroid response duration of 17 months, with 20% of patients still in response after 6 years of therapy—a longer duration than has been documented in most studies of treatment with erythropoietin alone. [33]


Lenalidomide is a 4-amino-glutarimide thalidomide analogue that is more potent than thalidomide but lacks its neurotoxicity and teratogenic effects. It is active in patients with MDS categorized as low risk or intermediate risk–1 according to the International Prognostic Scoring System (IPSS).

Lenalidomide is the drug of choice in MDS with 5q deletion syndrome. In particular, patients with the karyotype characterized by deletion 5q31 show the best response. List et al reported an erythroid response in 76% of these patients, with 67% no longer requiring transfusions; 73% of their 148 patients had a cytogenetic response, 45% had a complete cytogenetic remission, and 36% achieving a normal bone marrow histologically. [34]

In an earlier study by List et al, erythroid responses occurred in 57% of MDS patients with a normal karyotype, in 68% of those in the IPSS low-risk category, and 50% of those in the intermediate–1 risk category. [35]

Although the best responses have been observed in MDS patients with isolated 5q deletion, responses may also be elicited in patients with 5q deletion and other chromosomal abnormalities. However, treatment should be limited to patients without the p53 mutation. Thus, assessment of an additional molecular marker may be necessary before committing to this treatment in those patients.

Hypomethylating agents

Epigenetic modulation of gene function is a very powerful cellular mechanism. DNA methylation leads to silencing of suppressor genes, increasing the risk for transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine are the two hypomethylating agents currently used in the treatment of MDS. Azacitidine and decitabine may reduce hypermethylation and induce re-expression of key tumor suppressor genes in MDS. [36]

Azacitidine and decitabine are approved by the US Food and Drug Administration for treatment of all 5 MDS subtypes. They are considered standard therapy for both low-risk cases without 5q-, as well as intermediate and high-risk MDS. Although the two drugs were thought to be similar, only azacytidine has additional RNA and DNA activity compared with decitabine.

In a pivotal trial that included patients in all stages of MDS, patients treated with azacitidine showed a 37% response (7% complete response, 16% partial response) versus a 5% response in the control arm, with an improved median time to transformation or death (21 mo for azacitidine vs 13 mo for controls) and transformation to leukemia (15% for azacitidine vs 38% for controls). [37]

In 2020 the FDA approved the oral combination of decitabine and cedazuridine (Inqovi) for adult patients with MDS. [38] Cedazuridine binds to and inhibits cytidine deaminase, a key enzyme in the catabolism of decitabine, preventing its breakdown and increasing its bioavailability and efficacy. As an oral therapy, the combination allows outpatient therapy, freeing patients from the need to come in to a healthcare facility to receive intravenous treatment. [39] Indications for its use include previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk IPSS groups. [38]

Approval of Inqovi was based on the results of two open-label, randomized, crossover trials that showed similar drug concentrations between intravenous decitabine and Inqovi and found that approximately half of the treated patients who were formerly dependent on transfusions no longer required transfusions during an 8-week period. The safety profile of Inqovi was also similar to intravenous decitabine. [38]

Compared with supportive care, both azacytidine and decitabine show an overall response (60% with azacytidine vs 5% with decitabine) and a longer time to progression to AML or death, and improvement of quality of life but no overall survival advantage. In a phase III trial involving 358 patients with an IPSS classification of intermediate-2 or high risk, treatment with azacytidine (75 mg/m2/d for 7 d q28d) significantly increased survival. At 2 years, 50.8% of patients in the azacitidine group were alive compared with 26.2% in the patients who received conventional care. [40]

After sequencing 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients, Bejar et al reported that response to hypomethylating agents was most likely to occur in patients with TET2 mutations and wild-type ASXL1, a pattern found in 10% of the MDS cases in their study. However, these authors note that their study did not identify any mutations that reliably and strongly predicted primary resistance to treatment, and thus their findings provide no genetic rationale for denying treatment with hypomethylating agents to any patients with MDS. [41]

Immunosuppressive therapy

Some cases of MDS have an autoimmune process underlying the pancytopenia and respond to immunosuppressive therapy (IST). However, identifying these cases is problematic.

A portion of these cases represent an overlap between aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and MDS. These patients are usually younger and may have hypoplastic bone marrow with dysplasia and cytogenetic abnormalities (separate from AA). In addition, they may have a small clone of PNH cells, but these typically constitute less than 3% of cells and require a special sensitive flow cytometry to be detected. Indeed, as little as 0.126% of granulocytes and 0.001% of erythrocytes (PNH-type cells) are positive.

A feature of some of these cases is HLA-A allele–lacking leukocytes (HLA-LLs). These are derived from hematopoietic stem cells that develop copy number–neutral loss of heterozygosity of the HLA haplotype owing to uniparental disomy of the short arm of chromosome 6 (6pUPD).

Patients with MDS who have a thrombopoietin (TPO) level ≥320 pg/mL (TPO high patients) exhibit a high progression-free survival rate and good response to IST, similar to cases of AA. The small number of cases reported and the limited access to the special tests required make it difficult to place these into perspective for general clinical use.

Trials of IST in MDS have used cyclosporine (56%); rabbit (27%) or horse (35%) anti-thymocyte globulin (ATG); alemtuzumab; and recently, sirolimus. At the author's institution, a combination of ATG and cyclosporine is used in AA. Studies of this combination in MDS have reported response rates of only 16-30%, however, which is problematic, especially in view of the small number of patients studied. [42] Responses have mostly been observed in notably lower-risk MDS and patients with HLA-DR15 positivity. Consequently, this form of therapy is considered experimental and should be performed in the setting of clinical trials.


Patients with lower-risk MDS and anemia in whom therapy with an erythropoietin-stimulating agent (ESA) is not effective generally become dependent on RBC transfusions. Luspatercept-aamt is a recombinant fusion protein that promotes RBC maturation by binding several endogenous transforming growth factor (TGF)–β superfamily ligands, thereby diminishing Smad2/3 signaling. Indications for luspatercept are as follows:

  • First-line treatment of anemia in patients with very low–risk to intermediate-risk MDS who may require regular RBC transfusions and are ESA-naïve
  • Second-line treatment of anemia refractory to ESA therapy and requiring transfusion of at least 2 units of RBCs over 8 weeks, in adults with very low–risk to intermediate-risk MDS with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) 

Initial approval of luspatercept was for second-line treatment, based on the MEDALIST trial, a randomized, multicenter, double-blind, placebo-controlled study in 229 transfusion-dependent patients with very low– to intermediate-risk MDS-RS or MDS-RS-T. By 24 weeks, 38% of patients in the luspatercept arm had achieved the study's main endpoint of transfusion independence for 8 weeks or longer, compared with 13.2% of those in the placebo group (P< 0.001). [43]  

Approval as first-line treatment was supported by the phase 3 open-label COMMANDS trial. Interim analysis showed luspatercept improved the rate at which RBC transfusion independence and increased hemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. [44]  

Experimental agents

New drugs for MDS are being generated at a brisk pace as new clinical trials continue to make inroads on improving outcomes in quality of life and, ultimately, in overall survival. Synergy is being sought with new combinations of the active drugs and the less active drugs. As more is being learned about the biology of MDS through the molecular mechanisms and the ability to modify these molecular targets, research has opened new doors for the treatment of this once obscure and poor-outcome disease. [45]


Bone Marrow Transplantation

Bone marrow transplantation with a matched allogeneic or syngeneic donor is used in patients with poor prognoses or late-stage MDS who are aged 55 years or younger and have an available donor. Among selected patients with less advanced/low-risk MDS (< 5% marrow myeloblasts), a 3-year survival of 65-75% is achievable with HLA-matched related and unrelated donors. Because hematopoietic stem cell transplantation (HSCT) offers the potential for cure, the timing of the procedure may be important in this subgroup of patients. [46, 47]

Compared with patients with de novo acute myeloid leukemia transplanted in first remission, patients with MDS experience higher mortality rates associated with the procedure (21-30% vs 10%), lower disease-free survival rates, and higher relapse rates (70% vs 40%). Among patients with more advanced/high-risk disease (≥5% marrow myeloblasts and high IPSS scores), the probability of posttransplant relapse ranges from 10-40%; as a result, relapse-free survival is inferior in this group.

Because most patients with MDS are elderly and only a few young patients will have a matched donor, the use of bone marrow transplantation is limited. However, in our institution, with a haploidentical (half-match) donor, 2-step protocol, we have shown that expanding the donor pool to include patients' children as well as siblings increases the availability of donors for elderly patients and produces the same result as transplantation from full-match donors. Sandhu et al reported that umbilical cord blood transplantation after reduced-intensity conditioning regimens in patients aged ≥70 years with MDS and AML produced results comparable to those of HLA full-matched sibling donor transplantation in this age group. [48]

The use of nonmyeloablative (mini) bone marrow transplantation and reduced-intensity conditioning regimens has been used in elderly patients as old as 75 years with some success. This approach is still considered experimental and should be performed only in a clinical trial setting.

Shaffer and colleagues developed a system that can be used to determine prognosis in patients undergoing HLA-matched and -mismatched allogeneic HSCT for MDS. [49] In the system, the following risk factors are assigned 1 point:

  • Blood blasts >3%
  • Platelet count ≤50 × 10 9/L at transplantation
  • Karnofsky performance status < 90%
  • Comprehensive cytogenetic risk score of poor or very poor
  • Age 30 to 49 years

Risk factors assigned 2 points are as follows:

  • Monosomal karyotype
  • Age 50 years or older

Increasing score proved predictive of increased relapse (P < 0.001) and treatment-related mortality (P < 0.001) in HLA-matched patients and predictive of relapse (P < 0.001) in the HLA-mismatched cohort. The 3-year overall survival rates after transplantation, by point score, were as follows:

  • Low (0-1 point): 71% (95% confidence index [CI], 58-85%)
  • Intermediate (2-3 points): 49% (95% CI, 42-56%)
  • High (4-5 points): 41% (95% CI, 31-51%)
  • Very high (≥6 points): 25% (95% CI, 4-46%)

Lindsley et al reported that the presence of specific genetic mutations may predict clinical outcomes in patients who undergo allogeneic HSCT for MDS. [50] Their findings included the following:

  • TP53 mutations were associated with shorter survival and a shorter time to relapse.
  • RAS pathway mutations (in patients 40 years of age or older who did not have TP53 mutations) were associated with shorter survival, due to a high risk of relapse; however, the increased risk of relapse was evident only in patients who received reduced-intensity conditioning.
  • JAK2 mutations were associated with shorter survival due to a high risk of death without relapse.
  • Young adults with compound heterozygous mutations in the Shwachman-Diamond syndrome–associated SBDS gene with concurrent TP53 mutations had a poor prognosis.

Surgical Care

In the past, splenectomy was performed in patients with an enlarged spleen to treat the cytopenias or transfusion refractoriness. With current therapy, splenectomy is not indicated; indeed, it could be disastrous in this condition.