Your activity: 267 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email:

Treatment of lower-risk myelodysplastic syndromes (MDS)

Treatment of lower-risk myelodysplastic syndromes (MDS)
Mikkael A Sekeres, MD, MS
Uwe Platzbecker, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 30, 2022.

INTRODUCTION — Myelodysplastic neoplasms/syndromes (MDS) are heterogeneous malignant hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cytopenias, abnormal cellular maturation with dysplastic features, and variable risk for progression to acute myeloid leukemia (AML).

Treatment of MDS is stratified according to the prognostic category (higher-risk versus lower-risk); patients who are considered to have lower-risk MDS are described below. (See 'Classification as lower-risk MDS' below.)

Management of patients with lower-risk MDS is influenced by the nature and severity of symptoms, pathologic features, and patient preferences.

This topic discusses management of patients with lower-risk MDS.

Related topics include:

(See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)

(See "Overview of the treatment of myelodysplastic syndromes".)

(See "Management of the hematologic complications of myelodysplastic syndromes".)

(See "Treatment of high or very high risk myelodysplastic syndromes".)


Classification as lower-risk MDS — We favor classifying prognosis for patients with MDS using either the Revised International Prognostic Scoring System (IPSS-R) or a mutation-based model, such as the International Prognostic Scoring System - Molecular (IPSS-M).

MDS prognostic models are discussed in greater detail separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

Using IPSS-R or IPSS-M, the following categories correspond to lower-risk MDS:

IPSS-R (table 1) (calculator 1)

Very low risk (≤1.5 points)

Low risk (>1.5 to 3.0 points)

Intermediate risk (>3 to 4.5 points) without TP53 mutation

IPSS-M online calculator (

Very low risk

Low risk

Moderate low risk

We generally consider the original IPSS model to be outmoded because it does not incorporate molecular findings, considers very limited clinical and cytogenetic findings, and lacks the prognostic accuracy of IPSS-R and molecular models. Nevertheless, patients classified as low-risk or Intermediate-1 according to the original IPSS can be considered to have lower-risk MDS (table 2). (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'IPSS (Original IPSS)'.)

Clinical and laboratory assessment — Clinical evaluation and laboratory studies should assess the nature of symptoms, severity of cytopenias, and comorbid conditions that may affect treatment. Details of the initial evaluation of MDS are described separately. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Medical fitness'.)

Clinical – The medical history should review factors that may cause or exacerbate cytopenias. Examples include nutritional status, alcohol and drug use, medications, exposure to toxic chemicals, prior treatment with cytotoxic agents or radiation therapy, autoimmune conditions, and potential for human immunodeficiency virus (HIV) infection. Prior transfusion history should be documented.

Laboratory – We obtain the following laboratory studies prior to treatment:

Hematology – Complete blood count (CBC) with differential count, reticulocyte count, and review of the blood smear

Serum chemistries – Electrolytes, renal and liver function tests (including lactate dehydrogenase [LDH])

Iron and related studies – Serum iron, total iron-binding capacity, ferritin, vitamin B12, folate (serum or red blood cell)

Erythropoietin – Serum erythropoietin (EPO)

Bone marrow examination – Bone marrow examination is required for the diagnosis, classification, and risk stratification of MDS.

Bone marrow examination should include microscopy, flow cytometry, cytogenetics, and mutation analysis (by myeloid gene panel or next-generation sequencing [NGS]), as described separately. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Bone marrow examination'.)

If chromosome analysis, fluorescence in situ hybridization (FISH), or mutation analysis were not performed on the diagnostic bone marrow, we suggest obtaining these studies prior to selecting treatment, because the results may influence the choice of therapy. (See 'Multiple cytopenias' below.)

Medical fitness — Medical fitness is judged by the patient's functional status, rather than age, per se.

Evaluation – Medical fitness is judged according to the patient’s performance status, physiologic fitness, and cognitive function. For some individuals, it may be useful to obtain geriatric consultation and/or perform a more comprehensive functional assessment, as discussed separately. (See "Comprehensive geriatric assessment for patients with cancer".)

We estimate performance status (PS) according to the ECOG scale (table 3). Physiologic fitness can be judged using the Modified Charlson comorbidity index (CCI) (table 4). Details of evaluation and classification of fitness are described in greater detail separately. (See "Acute myeloid leukemia: Management of medically-unfit adults", section on 'Pretreatment evaluation'.)

Categories – There are no clear distinctions between various categories of medical fitness, but we classify patients according to ECOG PS and/or CCI as follows:

Medically-fit – Medically-fit patients can tolerate intensive treatments; fitness is reflected in ECOG PS 0 to 2 and CCI 0 to 2.  

Medically-unfit, but not frail – This category includes a broad range of physical function. Some patients have only modest, recent, or transient impairment of functional status, while others have substantial comorbid illnesses, cognitive impairment, or other conditions that may affect their ability to tolerate treatment. The level of fitness is reflected by ECOG PS 3 or CCI 3.

Frail – Debility or comorbid conditions that do not permit treatment aimed at modifying the disease course, as reflected by both the following: ECOG PS ≥3 and CCI ≥3.

Goals of care — The primary goals for patients with lower-risk MDS are to control symptoms, improve the quality of life, and reduce or eliminate transfusion needs, while minimizing treatment-related toxicity. Median survival is often greater than three years, and there is a low probability of transformation to acute myeloid leukemia (AML); more patients die from complications of bone marrow failure than from transformation to AML [1]. Consequently, management should focus more on symptom relief than on achieving complete remission and/or potential cure.

Together, the patient and clinicians should establish goals of care based on medical fitness and personal values. Goals of care should be revisited periodically during the course of the illness.

ASYMPTOMATIC PATIENTS — Asymptomatic MDS refers to patients who have adequate levels of hemoglobin, platelets, and neutrophils, and no symptoms attributable to cytopenias (algorithm 1), as defined below. (See 'Definition of symptomatic MDS' below.)

For asymptomatic patients, we suggest monitoring rather than immediate treatment. There is no evidence that early treatment of asymptomatic lower-risk MDS improves long-term survival, and deferral of treatment precludes potential treatment-related adverse events. In some settings, patients with asymptomatic lower-risk MDS may benefit from supportive care. As examples, antibiotics should be given for bacterial infections and transfusions may be warranted prior to surgery. (See "Perioperative blood management: Strategies to minimize transfusions".)

Monitoring should focus on observing for symptoms or complications of cytopenias and evidence of disease progression. We suggest clinical evaluation, complete blood count (CBC) and differential, and other laboratory studies (as clinically warranted) every one to six months. However, the schedule and protocol for monitoring is influenced by the severity and trajectory of cytopenias and by concerns on the part of the clinician and patient. Routine, periodic bone marrow examination is not suggested as a component of routine follow-up visits. However, if the patient has significant declines in blood counts or an increasing percentage of blasts, we suggest repeat evaluation, including bone marrow examination, to evaluate for disease progression. (See 'Pretreatment evaluation' above.)

In addition, patients should receive routine health screening (eg, screening for other cancers), disease prevention (eg, immunizations), counseling regarding healthy behaviors (eg, smoking cessation, weight management), and age- and sex-specific health practices. An example of long-term care for a patient with a hematologic condition is provided separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Health maintenance'.)


Definition of symptomatic MDS — We consider patients with any of the following to have symptomatic MDS:

Anemia – Symptoms related to anemia (eg, dyspnea, fatigue, weakness) or hemoglobin (Hb) <10g/dL

Thrombocytopenia – Platelets <20,000/microL or excessive bleeding or bruising with platelets <50,000/microL

Neutropenia – Recurrent and/or severe infections

Management strategies — There is no optimal management strategy for all patients with symptomatic lower-risk MDS and we suggest participation in a clinical trial, when possible.

Outside of a clinical trial, choice of a management strategy is informed by the nature and severity of cytopenias, responsiveness to supportive care, medical fitness, and personal values:

Supportive care – For some symptomatic patients, supportive care alone (eg, antibiotics for infections, transfusions for symptomatic anemia or thrombocytopenia) can adequately relieve symptoms and/or prevent complications. Supportive care should continue as needed, regardless of whether other treatments are implemented. (See 'Supportive care' below.)

Lower-intensity treatments – For most symptomatic patients who have ongoing transfusion requirements (eg, ≥1 unit of packed red blood cells per month), progressive cytopenias (eg, Hb <9.0 g/dL or platelet count <50,000/microL), or a declining quality of life, we suggest treatment with a lower intensity therapy rather than supportive care alone or more intensive therapies. Lower intensity agents offer the most favorable balance of outcomes and toxicity in this setting. They are generally well-tolerated and can ameliorate cytopenias, lessen symptoms, improve the quality of life, and may extend survival, but will generally not achieve long-term disease control. Selection of a lower intensity agent is described below. (See 'Choosing a lower intensity approach' below.)

Intensive therapy – Some patients (especially younger, medically-fit individuals, with intermediate-risk MDS) may instead choose intensive therapy because they value the potential for a prompt response, long-term disease control, or possible cure more than the substantial risks of toxicity and death. (See 'Intensive therapies' below.)

Special populations of patients with lower-risk MDS are discussed below. (See 'Special patient populations' below.)

Our approach to management is similar to guidelines of the US National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet [2,3].

Choosing a lower intensity approach — Treatment with a lower intensity agent is the preferred management strategy for most patients with symptomatic lower-risk MDS, as discussed separately. (See 'Management strategies' above.)

Lower intensity agents are generally well-tolerated and can ameliorate cytopenias, lessen symptoms, and improve quality of life, but they do not generally achieve long-term disease control or prolong survival in patients with lower-risk MDS. The choice of agent is influenced by whether the patient has an isolated cytopenia versus multilineage cytopenias. They can be administered in the outpatient setting and are generally well-tolerated, but the toxicity profile, comorbid illnesses, cost, availability, convenience of administration, and patient preference may influence selection.

No individual lower intensity agent has proven superior for all patients with lower-risk MDS, and few studies have directly compared them. Compared with supportive care alone, azacitidine and decitabine (often referred to as hypomethylating agents [HMA]) provide superior symptom relief. Outcomes with other lower intensity agents are less well-defined.

Anemia alone — For isolated or predominant anemia that is either symptomatic, transfusion-dependent, or for hemoglobin (Hb) <10 g/dL, we select treatment based on the level of serum erythropoietin (EPO) (algorithm 1):

EPO ≤500 mU/mL – We generally treat with an erythropoiesis-stimulating agent (ESA) for at least three months. (See "Management of the hematologic complications of myelodysplastic syndromes", section on 'Erythropoiesis-stimulating agents'.)

EPO >500 mU/mL – We treat as for multiple cytopenias; we do not treat with an ESA as it is unlikely to be beneficial in this setting. (See 'Multiple cytopenias' below.)

Thrombocytopenia alone — For isolated or predominant thrombocytopenia (ie, <20,000/microL or <50,000/microL with troublesome bleeding or bruising), we suggest initial treatment with a thrombopoietin receptor agonist (TPO-RA), based on the favorable balance of benefit and toxicity. However, we avoid using TPO-RAs for patients who have ≥5 percent bone marrow blasts, because of concerns that they may accelerate proliferation of leukemic blasts or marrow fibrosis. Treatment with TPO-RAs is described separately. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'TPO receptor agonists'.)

Multiple cytopenias — For patients with two or three symptomatic cytopenias, treatment choice is informed by the presence of certain pathologic and/or clinical features (algorithm 1).

For patients with specific pathologic and clinical features, initial treatment may be with an appropriate targeted agent/specialized approach (described below) or with azacitidine, decitabine, or lenalidomide. Only limited studies have compared these approaches, and choice of agent may be influenced by availability, toxicity profile, cost, convenience, and personal preference.

Pathologic and clinical features that are amenable to a targeted agent/specialized approach include:

del(5q) – For patients with del(5q), with or without one other cytogenetic abnormality (except those involving chromosome 7), treatment with lenalidomide is an acceptable choice. (See 'Lenalidomide' below.)

Ring sideroblasts – For patients with MDS with ≥15 percent ring sideroblasts or >5 percent ring sideroblasts if an SF3B1 mutation is present, and <5 percent bone marrow blasts, treatment with luspatercept is an acceptable choice. (See 'Luspatercept' below.)

IDH mutation – For patients with a mutation of isocitrate dehydrogenase (IDH)1 or IDH2, treatment with ivosidenib or enasidenib, respectively, is acceptable, but these agents are not approved in this setting. (See 'IDH inhibitors' below.)

Likely responsive to immune suppressive therapy (IST) – For patients with a good probability of responding to IST, treatment with anti-thymocyte globulin (ATG) plus cyclosporine A is an acceptable option. Features associated with a higher likelihood of responding to IST include age <60 years with ≤5 percent blasts, hypocellular bone marrow, paroxysmal nocturnal hemoglobinuria (PNH)-positive clones, or STAT3-mutant T cell clones. (See 'Immunosuppressive therapy' below.)

For patients with none of the above features, we suggest initial treatment with azacitidine, decitabine, or lenalidomide. None of these lower intensity agents is optimal for all patients and only limited studies have compared their efficacy. Treatment selection is influenced by expected toxicities, comorbid illnesses, cost, availability, convenience of administration, and patient preference, as described below. (See 'Lower intensity agents' below.)

Monitoring response to treatment is described below. (See 'Monitoring' below.)

For patients who do not respond adequately, further management is discussed below. (See 'Second-line and later treatment' below.)

Management of patients with IPSS-R intermediate-risk MDS, therapy-related MDS, and certain clinicopathologic findings is described below. (See 'Special patient populations' below.)


Erythropoiesis-stimulating agents (ESA) — Treatment with ESAs to improve anemia associated with MDS is generally more effective in patients with serum erythropoietin (EPO) levels <500 mU/mL. Most experts begin treatment with an ESA alone, but some suggest adding a myeloid growth factor (eg, granulocyte colony-stimulating factor [G-CSF]) when initiating therapy. Doses and regimens of ESAs for MDS-associated anemia are discussed separately. (See "Management of the hematologic complications of myelodysplastic syndromes", section on 'Treatment'.)

Hypomethylating agents — Azacitidine and decitabine are often referred to as hypomethylating agents (HMA) because they can inhibit DNA methyltransferase, but it is unclear if this activity accounts for their mechanism of action in MDS. Neither agent is conclusively superior for treatment of MDS. Both achieve a hematologic response in approximately one-third of patients and can reduce the risk of leukemic transformation, but neither has been shown to prolong survival in patients with lower-risk MDS [4].

Both azacitidine and decitabine are approved by the US Food and Drug Administration (FDA) for treatment of MDS. Some clinicians prefer decitabine because it is given intravenously (IV) over fewer days. Other clinicians prefer azacitidine because it can be administered subcutaneously as an outpatient and requires less time in an infusion center. For patients who did not respond adequately to one HMA, there is little likelihood of response to the other.

Studies that compared azacitidine and decitabine in lower-risk MDS do not conclusively demonstrate superiority for either of the HMAs:

A phase 2 trial randomly assigned 113 patients with lower-risk MDS or MDS/myeloproliferative neoplasm (MPN) to truncated dosing schedules (ie, 3-day course every 28 days) of decitabine (73 patients) versus a 3-day course of azacitidine (40 patients) [5]. With median follow-up of 20 months, survival with decitabine and azacitidine did not differ significantly: median event-free survival (EFS) 20 versus 13 months, respectively; one-year overall survival (OS) 87 versus 83 percent; and median OS was not reached for either arm. Other outcomes favored decitabine: overall response (OR; 70 and 49 percent, respectively), transfusion-independence (32 versus 16 percent), and cytogenetic response (61 versus 25 percent). Both drugs were well tolerated, with the six-week mortality rate of 0 percent.

A systematic review and meta-analysis of MDS patients, most of whom had higher-risk disease, reported that, compared with conventional care, azacitidine but not decitabine improved OS and time to acute myeloid leukemia (AML) transformation or death [4]. This review included data from 952 patients enrolled in four randomized trials that compared either azacitidine or decitabine versus conventional care; in three of the studies the control arm was supportive care, but in one of the azacitidine trials the control arm was best supportive care, low dose cytarabine, or intensive treatment. OS was superior for azacitidine (HR 0.67; 95% CI 0.54-0.83; two trials, 549 patients), but not for decitabine (HR 0.88, 95% CI 0.66-1.17; one trial, 233 patients). Collectively, treatment with an HMA achieved superior rates of OR, complete response (CR), partial response (PR), and hematologic improvement, but was associated with substantially more toxicity. There was no difference in early mortality (at three months) between an HMA and conventional care, but treatment with an HMA was associated with higher overall treatment-related mortality (relative risk [RR] 7.27, 95% CI 1.67-31.64; three trials).

Azacitidine — Azacitidine (5-azacytidine) is a pyrimidine nucleoside analog of cytidine that can inhibit DNA methyltransferase, induce cell differentiation, and has direct cytotoxicity on abnormal bone marrow hematopoietic cells [6-10]. For patients with lower-risk MDS, rates of OR are approximately 30 to 40 percent [11-14].

Azacitidine is generally administered subcutaneously at a dose of 75 mg/m2/day for 7 days, every 28 days for at least 6 courses. We generally assess response after two to four treatment cycles. Most patients respond within six months, but some may take up to 12 cycles of therapy [15]. Some patients may require growth factor support or dose adjustment (eg, with renal insufficiency) [16]. Most patients have at least one hospitalization for neutropenic fever during treatment. The optimal duration of therapy has not been defined, but treatment should continue for as long as a benefit persists and the medication is tolerated.

More convenient dosing regimens have been reported, in which azacitidine 75 mg/m2/day was given subcutaneously or IV for 3, 5, or 10 consecutive days, or for 7 days with a 2-day "drug holiday" over the weekend (all with 28-day cycles) [5,17-21]. In non-randomized settings, response rates were comparable to the 7-day azacitidine schedule.

One trial randomly assigned 191 patients (54 percent with lower-risk MDS) to azacitidine (7-day schedule) versus supportive care. Azacitidine achieved a superior rate of CR plus PR (23 versus 0 percent), longer median time to leukemic transformation or death (21 versus 13 months), and improved quality of life (QoL) [11,22]. Median OS did not differ (20 versus 14 months), but this may reflect a confounding effect of the trial design, which permitted cross over to azacitidine after four months of supportive care.

Azacitidine is approved by the FDA and the European Medicines Agency (EMA) for treatment of MDS [23,24].

Studies of azacitidine in the setting of higher-risk MDS are presented separately. (See "Treatment of high or very high risk myelodysplastic syndromes".)

Decitabine — Decitabine (5-aza-2'-deoxycytidine) is a pyrimidine nucleoside analog of cytidine that, like azacitidine, inhibits DNA methylation, induces cell differentiation, and is clinically effective for patients with MDS [6-8,25-35]. Decitabine can achieve hematologic and cytogenetic responses in approximately one-half and one-third of patients, respectively [30,31].

Decitabine is administered IV or subcutaneously with a variety of doses and schedules. Examples include 20 mg/m2/day subcutaneously or IV for 5 days or 10 mg/m2/day for 10 consecutive days, all with 4- to 6-week cycles. Growth factor support and dose adjustment (eg, for renal insufficiency) may be necessary for some patients [16,36]. A randomized study that compared protocols reported that the five-day IV schedule was associated with the highest response rate [37]. At least four cycles (six weeks each) should be given, and treatment should continue for as long as a benefit persists and decitabine is tolerated.

Informative studies include:

A multicenter trial that randomly assigned 170 patients (one-third were lower-risk MDS) to either decitabine versus best supportive care reported that decitabine achieved superior OR (17 versus 0 percent) and a trend toward longer time to AML transformation or death (12 versus 8 months), but no survival benefit [29].

A multicenter phase 2 trial (the ADOPT trial) evaluated an outpatient schedule of decitabine (20 mg/m2 IV over one hour daily for five consecutive days every four weeks) in 99 patients with MDS [38]. Rates of OR and CR were 32 and 17 percent, respectively, and a cytogenetic response was seen in 17 of 33 evaluable patients. In 82 percent of patients, responses were seen by the end of the second cycle. Cytopenias were common, and treatment was delayed in one-third of cycles. Hospitalization was needed for 19 percent of treatment cycles and two-thirds of patients were hospitalized at some point in the study.

Among 65 patients with lower-risk MDS who were randomly assigned to decitabine 20 mg/m2/day subcutaneously on days 1 to 3 every 28 days (43 patients) versus once weekly (22 patients), rates of OS, transformation to AML, overall improvement, hematologic improvement, cytogenetic response, and toxicity were comparable [39]. Overall, 70 percent of patients were alive at 500 days.

An oral preparation of decitabine-cedazuridine (an inhibitor of cytidine deaminase in the gut and liver) emulated the pharmacokinetic (PK), pharmacodynamic, and safety profiles of IV decitabine, based on a phase 1 study of 43 evaluable patients [40]. Two studies evaluated a fixed-dose preparation (35 mg decitabine plus 100 mg cedazuridine by mouth, daily for 5 days every 28 days) for patients with MDS or chronic myelomonocytic leukemia; in both studies, either the first or second cycle of therapy substituted IV decitabine 20 mg/m2 for the oral agent to enable PK comparison [41]:

In the first study, 35 of the 80 patients had lower-risk MDS (Int-1); the median treatment duration was 7 months and median follow-up was 24 months [41]. Among all patients in this study, the CR rate was 18 percent (9 month median duration of response) and 49 percent of patients with baseline transfusion needs converted to red blood cell- and/or platelet-transfusion independence for ≥56 days.

In the second study, 59 of 133 patients had MDS Int-1; median follow-up was 13 months [41]. For all patients in this study, 21 percent achieved CR and 53 percent become transfusion-independent. The PK and safety profiles of the oral agent were similar to IV decitabine.

Larger studies and longer-term data will be needed to determine if clinically meaningful endpoints (eg, OS) for MDS are similar to those with IV decitabine or azacitidine.

IV decitabine is approved by the FDA for treatment of adults with MDS [36] and by the EMA for treatment of AML [42]. The oral preparation of decitabine plus cedazuridine is approved by the FDA for treatment of MDS [41].

Lenalidomide — Lenalidomide is an immunomodulatory drug (IMiD) that is effective for lower-risk MDS; it is particularly efficacious for MDS with del(5q), but it also has activity for lower-risk MDS that lacks del(5q). Lenalidomide reduces transfusion needs in two-thirds of patients with del(5q) but does not delay progression to AML; it reduces transfusion needs for approximately one-quarter of patients without del(5q) [43-45].

Lenalidomide is approved by the FDA and the EMA for treatment of lower-risk MDS with del(5q) [46,47]. In the United States, lenalidomide is available under a special restricted distribution program (RevAssist) and the FDA label includes boxed warnings about embryo-fetal toxicity, significant thrombocytopenia and neutropenia, and increased risk of arterial and venous thrombosis and pulmonary embolism (with thromboembolic events being more common when lenalidomide is used in combination with steroids to treat multiple myeloma). (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs' and "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)

The recommended starting dose of lenalidomide is 10 mg daily for 21 days every month, but dose adjustments are frequently required due to cytopenias, reduced renal function, or other toxicity [48]. Approximately two-thirds of patients with MDS with del(5q) experience a reduction in red blood cell (RBC) transfusion needs; responses are usually seen within four months and last a median of approximately two years. Most patients will experience neutropenia or thrombocytopenia, but such myelosuppression may be associated with a higher likelihood of response [49,50].

Informative studies regarding lenalidomide for MDS include:

MDS with del(5q) – A phase 3 trial reported that lenalidomide was superior to placebo for achieving RBC transfusion-independence [51,52]. In this trial, 205 patients with transfusion-dependent, lower-risk MDS with del(5q) were randomly assigned to low dose lenalidomide (10 mg daily on days 1 to 21), lower dose lenalidomide (5 mg daily on days 1 to 28), or placebo, each delivered in a 28-day cycle. For low dose lenalidomide, lower dose lenalidomide, and placebo, the rates of transfusion-independence for ≥26 weeks were 57, 37, and 2 percent, respectively; rates of cytogenetic response (CR plus PR) were 57, 23, and 0 percent; and two-year cumulative risk of transformation to AML were 13, 17, and 17 percent. Collectively, three-year OS was 57 percent and median OS did not differ according to initial therapy. For low and lower dose lenalidomide, median response duration was >83 weeks and >41 weeks, respectively. The most common severe (≥grade 3) adverse events were myelosuppression and venous thromboembolism; rates were similar for both doses of lenalidomide.

A phase 2 study also reported rapid, sustained hematologic responses in two-thirds of 148 patients with del(5q) and cytogenetic CR in one-half of evaluable patients [53,54].

MDS without del(5q) – In a phase 3 trial that included 239 patients with lower-risk, transfusion-dependent non-del(5q) MDS, compared to placebo, lenalidomide achieved a higher rate of transfusion-independence for ≥8 weeks (27 versus 3 percent) [55]. The median duration of response was 31 weeks (95% CI 21-59), median time to response 10 weeks, and 90 percent responded within 16 weeks of treatment. Health-related QoL and treatment-related mortality were similar in both arms, but there was more severe (grade ≥3) neutropenia and thrombocytopenia with lenalidomide treatment.

A phase 2 study also reported that one-quarter of patients without del(5q) achieved transfusion-independence with lenalidomide [56].

IDH inhibitors — Mutant isocitrate dehydrogenase (IDH)-1 or IDH2 are susceptible to inhibition by ivosidenib and enasidenib, respectively. Neither agent is approved for treatment of MDS, but both agents are approved by the FDA for treatment of AML with IDH mutations detected by an FDA-approved diagnostic test. Treatment with IDH inhibitors is discussed separately. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Targeted agents'.)

Luspatercept — Luspatercept is an erythroid maturation agent that can improve anemia in MDS by enhancing late-stage erythropoiesis. Luspatercept reduces aberrant Smad2/3 signaling by binding ("trapping") transforming growth factor (TGF) beta superfamily ligands [57]. It is most effective in MDS with ring sideroblasts. Luspatercept is approved by the FDA for treatment of anemia associated with MDS with ring sideroblasts or MDS with ring sideroblasts and thrombocytosis [58].

Luspatercept was superior to placebo for achieving transfusion-independence in patients with lower-risk MDS with ring sideroblasts. A phase 3 trial (MEDALIST) included 229 patients with ≥15 percent ring sideroblasts (or ≥5 percent ring sideroblasts if an SF3B1 mutation was present) and with <5 percent bone marrow blasts, who were refractory or unlikely to respond to ESAs [59]. Luspatercept was superior to placebo for achieving RBC transfusion-independence (TI) for ≥8 weeks (38 versus 13 percent) and TI for ≥12 weeks (28 versus 8 percent). Luspatercept was well-tolerated, and toxicity was primarily mild fatigue, diarrhea, asthenia, nausea, and dizziness. Longer-term follow-up (median >26 months) indicates that benefits of luspatercept continued to increase over time [60]. Compared with placebo, luspatercept achieved more ≥8-week TI (45 versus 16 percent), ≥16-week TI (28 versus 7 percent; odds ratio 6.0 [95% CI 2.2-16.0]), ≥50 percent reduction in transfusion requirements (50 versus 14 percent), and erythroid improvement (59 versus 17 percent, per IWG 2006 criteria [61]); the median duration of ≥8-week TI was 30 weeks with luspatercept and 17 weeks for placebo. Improvements were seen both in patients with high- and low-transfusion burdens and there were no new toxicity signals.

A phase 2 study reported similar benefits and toxicity with luspatercept [62].

Imetelstat — Imetelstat is an antisense oligonucleotide inhibitor of telomerase that may reduce the rate of transfusion-dependence in patients with lower-risk MDS, especially those who lack a del(5q) abnormality and have not previously received an HMA or lenalidomide.

Treatment with imetelstat was associated with 37 percent transfusion-independence (TI) for 8 weeks and 23 percent TI for 24 weeks, among 57 heavily transfusion-dependent (TD) patients (median, seven units RBC per eight weeks) with lower-risk MDS who were ineligible or relapsed/refractory to an ESA [63]. The median duration of TI was 65 weeks, and nearly two-thirds of patients had a rise of hemoglobin ≥3 g/dL. Among the subset of 38 patients who lacked a del(5q) abnormality and had not previously been treated with an HMA or lenalidomide, imetelstat was associated with 42 percent 8-week TI, 29 percent 24-week TI, and an 86-week median duration of TI. Imetelstat also demonstrated evidence of disease-modifying activity, with reductions of cytogenetically abnormal clones and mutational allele burden among the subset of patients who were studied. The most common adverse events were cytopenias, which were typically reversible within four weeks.

The FDA has granted a fast-track designation to imetelstat for the treatment of adult patients with relapsed or refractory myelofibrosis (MF), but it is not approved for either MF or MDS.

Immunosuppressive therapy — Immunosuppressive agents such as antithymocyte globulin (ATG) and cyclosporine can produce hematologic responses in a subset of patients with MDS [64-78]. Although clinical responses may be seen with these agents, they are not approved for treatment of MDS and they do not appear to improve OS rates compared to supportive care only.

ATG alone or, more commonly, in combination with cyclosporine and steroids, can be effective for patients with multiple cytopenias. Clinical and pathologic features that are associated with response to immunosuppressive agents include [79] (see 'Hypoplastic MDS or PNH+' below):

HLA-DR15 positive disease

PNH-positive cells present by flow cytometry

Hypoplastic MDS (see 'Hypoplastic MDS or PNH+' below)

<5 percent bone marrow blasts

Shorter duration of red cell transfusion-dependence

Age <60 years

Informative studies using immunosuppressive therapy for lower-risk MDS include the following:

A multicenter phase 3 trial of 88 patients compared ATG plus cyclosporine versus best supportive care [80]. ATG plus cyclosporine resulted in significantly higher rates of hematologic response by six months (29 versus 9 percent, respectively), but no difference in OS (49 versus 66 percent) or transformation-free survival (46 versus 55 percent) at two years. Responses were more likely to be seen with hypoplastic MDS and in those with low blast counts. The most common severe (grade ≥3) toxicities were thrombocytopenia (53 percent), anemia (47 percent), leukopenia (33 percent), and neutropenia (38 percent). A subsequent phase 2 trial showed a similar response rate in 27 patients (33 percent), most of whom had multiple cytopenias [81].

In a non-randomized study, 21 of 61 red cell transfusion-dependent patients with refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), or refractory anemia with excess blasts (RAEB) became transfusion-independent at a median time of 10 weeks after receiving a four-day course of ATG plus steroids [65]. After treatment, 19 of the 21 responders had normal neutrophil and platelet counts. On multivariate analysis, predictors of response to ATG included younger age and lower initial platelet count.

One trial reported hematologic responses in one-third of 129 patients with lower-risk MDS who were treated with ATG alone, cyclosporine alone, or the combination [64]. The combination was more effective (48 percent) than either ATG alone (24 percent) or cyclosporine alone (8 percent).

SUPPORTIVE CARE — Supportive care (eg, antibiotics for infections, transfusions for symptomatic cytopenias, iron chelation therapy, psychosocial support) is important for management for all patients with MDS, whether or not they receive other treatments.

For some patients with lower-risk MDS, supportive care alone may be sufficient to lessen symptoms and improve the quality of life. However, recurrent transfusions may cause alloimmunization, iron overload, and other complications. Transfusion, erythropoiesis-stimulating agents (ESA), and other supportive care for cytopenias in MDS are discussed separately. (See "Management of the hematologic complications of myelodysplastic syndromes".)

Antibiotics – Antibiotics should be given for infections, but prophylactic antibiotics are generally not helpful and may select for antibiotic resistance. Management and prevention of infections in the patient with MDS are discussed separately. (See "Management of the hematologic complications of myelodysplastic syndromes", section on 'Infections'.)

Transfusion support – Transfusion support for symptomatic anemia and thrombocytopenia are discussed separately. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult" and "Platelet transfusion: Indications, ordering, and associated risks".)

Iron overload – While iron overload in patients with lower-risk MDS has been associated with adverse outcomes, the benefit of reducing iron levels through chelation remains controversial.

Cardiac events (eg, arrhythmias, heart failure), liver dysfunction and fibrosis, and increased risk for infections are among the most common non-hematologic consequences of iron overload transfusion-dependent patients with MDS [82-84]. Iron overload may also be associated with inferior outcomes for patients who later undergo allogeneic hematopoietic cell transplantation (HCT) [85].

Patients Iron chelation can improve cytopenias in a small subset of patients.

Despite differences from country to country, guidelines suggest consideration of chelation therapy for patients with low-risk MDS who show a serum ferritin threshold of 1000 to 15000 ng/mL and have received 20 to 25 transfusions [86,87]. Nevertheless, iron chelation for patients with MDS is controversial [2,88,89]. The decision to initiate iron chelation should be made on a patient-by-patient level. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

INTENSIVE THERAPIES — Intensive therapies for lower-risk MDS include intensive remission induction therapy (as is used for acute myeloid leukemia), with or without allogeneic hematopoietic cell transplantation. These intensive approaches can alter the natural history of MDS but are associated with substantial morbidity and mortality. We generally administer intensive therapies to patients with lower-risk MDS only in the context of a clinical trial, and only in patients with excess blasts. Treatment with intensive therapies for MDS is discussed separately. (See "Treatment of high or very high risk myelodysplastic syndromes".)

MONITORING — Patients with lower-risk MDS should be followed longitudinally to assess response to therapy and to monitor for disease progression. The schedule and protocol for follow-up should be individualized based on the severity of symptoms and cytopenias and concerns on the part of the patient and clinician.

Outside of a clinical trial, we assess the response to therapy based on reduction of symptoms, improvement of blood counts, reduced transfusion needs, and improved quality of life. We generally schedule follow-up visits every one to six months, which include clinical evaluation and complete blood count (CBC) and differential count. In lower-risk MDS, there is no role for routine bone marrow examinations unless there is evidence of worsening cytopenias or other indications of disease progression. For patients enrolled in a clinical trial, standardized response criteria have been developed that use bone marrow and peripheral blood analysis to allow better comparisons between published studies. (See "Overview of the treatment of myelodysplastic syndromes", section on 'Response assessment and monitoring'.)

Most patients respond slowly to lower intensity agents for MDS, and a meaningful improvement may require three or more months of treatment. In general, patients should remain on therapy for as long as they are deriving benefit and not experiencing significant adverse effects. For patients who experience significant adverse effects, we suggest judicious dose reduction or brief treatment delays rather than abandoning the treatment, especially if there is evidence of a response to that treatment. Otherwise, we try to avoid dose reductions or interruptions.

For patients who do not respond adequately to initial therapy, we treat as discussed below. (See 'Second-line and later treatment' below.)

SPECIAL PATIENT POPULATIONS — Treatment of most patients with lower-risk MDS is guided by the treatment strategy outlined above. (See 'Management strategies' above.)

However, certain patient populations may need distinctive aspects of management, as described in the following sections.

Intermediate-risk IPSS-R — Patients who are classified as having revised international prognostic scoring system (IPSS-R) intermediate MDS (table 1) (calculator 1) can be managed as either lower-risk or higher-risk MDS. (See 'Classification as lower-risk MDS' above.)

There is no consensus regarding the optimal treatment for such patients. Options include approaches used for patients with lower-risk MDS (ie, supportive care with or without lower intensity agents) versus intensive therapies that are used for patients with higher-risk MDS, particularly in the setting of excess blasts. Treatment decisions should reflect the individual's values and goals and an individual interpretation of what constitutes a reasonable balance of risk, quality of life, and survival. Intensive therapy may be chosen by some (eg, younger, medically-fit) who place greater value on long-term survival than on the risk of treatment-related mortality and morbidity. For patients who want to focus on quality rather than quantity of remaining years, supportive care with or without lower intensity agents may be selected.

Treatment with lower intensity and higher intensity approaches are discussed above and separately. (See 'Choosing a lower intensity approach' above and "Treatment of high or very high risk myelodysplastic syndromes".)

Therapy-related MDS — People who were previously treated with cytotoxic chemotherapy or radiation therapy are at risk of developing therapy-related myeloid neoplasms (t-MN), which constitute a distinct category within the World Health Organization (WHO) classification of myeloid malignancies [90]. Therapy-related acute myeloid leukemia (t-AML), myelodysplastic syndromes (t-MDS), and myelodysplastic syndromes/myeloproliferative neoplasms (t-MDS/MPN) lie along a continuum of disease but typically have high-risk features and worse outcomes than the corresponding de novo AML, MDS, or MDS/MPN. Evaluation, diagnosis, and management of t-MNs are discussed separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and "Therapy-related myeloid neoplasms: Management and prognosis".)

Chromosome 5q deletion — Approximately 5 percent of patients with MDS present with deletion (del) of all or part of chromosome 5q. In the WHO classification system of MDS, this is identified by isolated del(5q), or del(5q) plus one other abnormality (with the exception of -7/del(7q)) (table 5) [90]. Affected patients are typically older women who present with refractory macrocytic anemia and normal or elevated platelet counts and lack significant neutropenia. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on '5q- syndrome/MDS with an isolated del(5q)'.)

Patients with del(5q) have high response rates to treatment with lenalidomide, and we recommend lenalidomide for symptomatic patients with lower-risk MDS, either as initial treatment or following therapy with an ESA, as discussed above. For symptomatic patients who are ineligible or intolerant of lenalidomide, we suggest treatment described for other patients with lower-risk MDS. (See 'Lenalidomide' above and 'Multiple cytopenias' above.)

MDS with ring sideroblasts — Patients with MDS with ring sideroblasts generally have a more indolent disease course and are often responsive to the biologic agent, luspatercept. (See 'Luspatercept' above.)

This syndrome is defined as ≥15 percent ring sideroblasts or >5 percent ring sideroblasts if an SF3B1 mutation is present, and <5 percent bone marrow blasts [90]. Treatment of symptomatic patients should begin with an ESA followed by luspatercept once an ESA is determined to be ineffective. Both agents are generally well-tolerated and the rates of achieving transfusion-independence appear to be comparable [59]. We generally stratify initial treatment based on the serum level of erythropoietin, as described above. (See 'Multiple cytopenias' above.)

Hypoplastic MDS or PNH+ — A subset of patients with MDS have relatively hypoplastic bone marrow and/or a subset of paroxysmal nocturnal hemoglobinuria-positive (PNH+) cells. These patients are generally younger and have a better overall prognosis than those with normocellular or hypercellular marrows and are less likely to transform into AML [64,91,92]. They are believed to have immune-mediated hematopoietic suppression, perhaps secondary to an alteration in T cell function [93-96]. A population of PNH+ cells in MDS may serve as a marker for immune-mediated bone marrow failure, and may also predict for hematologic improvement after treatment with immunosuppressive therapy (IST) [97-99]. Patients with hypoplastic MDS/PNH+ cells may be incorrectly diagnosed as having idiopathic aplastic anemia or PNH. These patients should not be treated with the monoclonal antibody eculizumab; monoclonal antibodies like eculizumab are unlikely to be effective for patients with MDS because of the characteristically small populations of PNH+ cells. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis' and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

Patients who are younger, have normal cytogenetics, marrow hypoplasia, early stage disease, a shorter duration of red cell transfusion dependence, presence of PNH+ cells, HLA-DR15, or STAT3-mutant T cell clones are more likely to respond to IST, as described above. (See 'Immunosuppressive therapy' above.)

MDS/MPN — The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include disorders where both dysplastic and proliferative features coexist. These include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (BCR-ABL negative), juvenile myelomonocytic leukemia, and MDS/MPN, unclassifiable [100]. Data are limited regarding the treatment of patients with MDS/MPN. Clinical trials have either excluded such patients or the limited number of patients included with MDS/MPN makes it difficult to know whether the findings overall apply to this subgroup. The treatment of patients with CMML is discussed in more detail separately. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

SECOND-LINE AND LATER TREATMENT — For patients who do not respond adequately to initial therapy, who experience intolerable treatment-related adverse effects or complications, or for whom initial therapy is no longer effective, we select subsequent management based on prior therapy. Supportive care should continue, as needed, and we encourage participation in a clinical trial when possible. There is no consensus about the optimal approach for second-line therapy, and survival (particularly following therapy with a hypomethylating agent) may be poor [101].

For patients who experience significant adverse effects, we suggest judicious dose reduction or brief treatment delays rather than abandoning the treatment, especially if there is evidence of a response to that treatment, as described above. (See 'Monitoring' above.)

If there is not a significant improvement in symptoms, blood counts, or quality of life after an adequate trial (eg, three to six months), we suggest treatment with a different regimen according to the prior therapy. If there is evidence of a significant worsening of cytopenias, increasing blast count, or other indications of disease progression, we suggest a repeat bone marrow examination to reassess disease status.

The choice of a second-line regimen is influenced by prior therapy, the predominant cytopenia(s), expected toxicities, comorbid illnesses, availability, convenience of administration, patient preference, and medical fitness. Eligibility for intensive approaches such as intensive remission induction therapy and/or allogeneic hematopoietic cell transplantation (HCT) is discussed separately. (See "Treatment of high or very high risk myelodysplastic syndromes", section on 'Patients suitable for intensive treatment'.)

Selection of a second-line or later therapy may be informed by prior treatment, as follows:

Erythropoiesis-stimulating agent (ESA) – For patients with a modest or no response to an adequate trial of an ESA alone, addition of a myeloid growth factor can be considered (eg, granulocyte colony stimulating factor [G-CSF]) (algorithm 1) as described separately. (See "Management of the hematologic complications of myelodysplastic syndromes", section on 'Add a myeloid cytokine'.)

For patients who do not respond sufficiently to an adequate dose and duration of an ESA, we suggest treatment with luspatercept for MDS with ring sideroblasts; for others, we treat with lenalidomide, a hypomethylating agent, or immunosuppressive therapy, as for multilineage cytopenias (algorithm 1). (See 'Multiple cytopenias' above.)

Thrombopoietin receptor agonist (TPO-RA) – For patients with no response to an adequate trial of a TPO-RA, we suggest treatment as for multilineage cytopenias (algorithm 1). (See 'Multiple cytopenias' above.)

Azacitidine or decitabine – For patients who were previously treated with azacitidine or decitabine, we suggest second-line treatment with lenalidomide, luspatercept, intensive therapy, or immunosuppressive therapy (for those with a high likelihood of response to immunosuppression), depending on the predominating cytopenia. We suggest not treating with the other hypomethylating agent (HMA), because the likelihood of a response is low. Patients with a high likelihood of responding to immunosuppressive therapy are described above. (See 'Multiple cytopenias' above.)

Other lower intensity agents – For patients who were not previously treated with an HMA, we suggest treatment with either azacitidine or decitabine. (See 'Hypomethylating agents' above.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1)(new graphic), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myelodysplastic syndromes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) (The Basics)" and "Patient education: Allogeneic bone marrow transplant (The Basics)")

Beyond the Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")


Description – Myelodysplastic neoplasms/syndromes (MDS) are diverse hematologic malignancies characterized by clonal hematopoiesis, cytopenias, abnormal cellular maturation, and variable rates of transformation to acute myeloid leukemia (AML).

Lower-risk MDS – We classify prognosis using either the Revised International Prognostic Scoring System (IPSS-R) (table 1) (calculator 1) or a mutation-based model, such as the International Prognostic Scoring System - Molecular (IPSS-M), as described above. (See 'Classification as lower-risk MDS' above.)

Goals of care – For patients with lower-risk MDS, goals are symptom control, reduced transfusion needs, and improved quality of life (QoL), while minimizing treatment-related toxicity. (See 'Goals of care' above.)

Management – Management is guided by symptoms, pathologic features, and patient preference.

Asymptomatic patients – Asymptomatic patients are generally monitored for development of symptoms, complications of cytopenias, and disease progression. (See 'Asymptomatic patients' above.)

Symptomatic patients – For symptomatic patients, we choose treatment based on the nature/severity of cytopenias, responsiveness to supportive care, medical fitness, and personal values (algorithm 1) (see 'Symptomatic MDS' above):

-Supportive care – Transfusions, antibiotics, and other care can alleviate symptoms and prevent complications. (See 'Supportive care' above.)

-Choice of treatment – For ongoing transfusion requirements, progressive cytopenias, or a declining QoL, we suggest treatment with a lower intensity therapy, rather than supportive care alone or more intensive therapies (Grade 2B). (See 'Choosing a lower intensity approach' above.)

Some younger, fit patients may instead choose intensive therapy. (See 'Intensive therapies' above.)

Lower-intensity agents – Choice of a lower-intensity agent is influenced by an isolated cytopenia versus multilineage cytopenias (algorithm 1), toxicity, comorbidities, cost, availability, convenience, and patient preference (see 'Choosing a lower intensity approach' above):

Anemia alone – We select treatment based on serum erythropoietin (EPO) level (algorithm 1) (see 'Anemia alone' above):

-EPO ≤500 mU/mL – Treat with an erythropoiesis-stimulating agent (ESA) for 3 months. (See "Management of the hematologic complications of myelodysplastic syndromes", section on 'Erythropoiesis-stimulating agents'.)

-EPO >500 mU/mL – Treat as for multiple cytopenias; we do not treat with an ESA, as these patients are unlikely to respond. (See 'Multiple cytopenias' above.)

Thrombocytopenia alone – For isolated or predominant thrombocytopenia, we treat with a thrombopoietin receptor agonist (TPO-RA). For blasts >10 percent, we treat as for multiple cytopenias. (See 'Thrombocytopenia alone' above.)

Multiple cytopenias – Treatment choice is informed by disease features, toxicity, cost, convenience, and personal preference. (See 'Multiple cytopenias' above.)

-For certain subsets of MDS, we use targeted agents/specialized therapies, such as lenalidomide for del(5q), IDH inhibitors for IDH mutations, luspatercept for MDS with ring sideroblasts, and immune suppressive therapy (IST) for patients with a higher likelihood of responding to IST are acceptable options, as are azacitidine, decitabine, or lenalidomide. (See 'Multiple cytopenias' above.)

-For others, we treat with azacitidine, decitabine, or lenalidomide. (See 'Lower intensity agents' above.)

Inadequate response – For inadequate response or intolerable adverse effects/complications, choice of second line of therapy is described above. (See 'Second-line and later treatment' above.)


The UpToDate editorial staff acknowledges Elihu H Estey, MD, who contributed as an author for this topic review.

The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

  1. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454.
  2. Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 2013; 122:2943.
  3. (Accessed on January 14, 2020).
  4. Gurion R, Vidal L, Gafter-Gvili A, et al. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome--a systematic review and meta-analysis. Haematologica 2010; 95:303.
  5. Jabbour E, Short NJ, Montalban-Bravo G, et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood 2017; 130:1514.
  6. Fandy TE, Carraway H, Gore SD. DNA demethylating agents and histone deacetylase inhibitors in hematologic malignancies. Cancer J 2007; 13:40.
  7. Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res 2009; 15:3938.
  8. Quintás-Cardama A, Santos FP, Garcia-Manero G. Therapy with azanucleosides for myelodysplastic syndromes. Nat Rev Clin Oncol 2010; 7:433.
  9. Boultwood J, Wainscoat JS. Gene silencing by DNA methylation in haematological malignancies. Br J Haematol 2007; 138:3.
  10. Kihslinger JE, Godley LA. The use of hypomethylating agents in the treatment of hematologic malignancies. Leuk Lymphoma 2007; 48:1676.
  11. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20:2429.
  12. Musto P, Maurillo L, Spagnoli A, et al. Azacitidine for the treatment of lower risk myelodysplastic syndromes : a retrospective study of 74 patients enrolled in an Italian named patient program. Cancer 2010; 116:1485.
  13. van der Helm LH, Alhan C, Wijermans PW, et al. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. Br J Haematol 2011; 155:599.
  14. Sanchez-Garcia J, Falantes J, Medina Perez A, et al. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma 2018; 59:1095.
  15. Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 2011; 117:2697.
  16. Batty GN, Kantarjian H, Issa JP, et al. Feasibility of therapy with hypomethylating agents in patients with renal insufficiency. Clin Lymphoma Myeloma Leuk 2010; 10:205.
  17. Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 2009; 27:1850.
  18. Grövdal M, Karimi M, Khan R, et al. Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy. Br J Haematol 2010; 150:293.
  19. Filì C, Malagola M, Follo MY, et al. Prospective phase II Study on 5-days azacitidine for treatment of symptomatic and/or erythropoietin unresponsive patients with low/INT-1-risk myelodysplastic syndromes. Clin Cancer Res 2013; 19:3297.
  20. Grinblatt DL, Sekeres MA, Komrokji RS, et al. Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA registry. Leuk Lymphoma 2015; 56:887.
  21. Martin MG, Walgren RA, Procknow E, et al. A phase II study of 5-day intravenous azacitidine in patients with myelodysplastic syndromes. Am J Hematol 2009; 84:560.
  22. Kornblith AB, Herndon JE 2nd, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol 2002; 20:2441.
  23. (Accessed on January 16, 2020).
  24. (Accessed on January 16, 2020).
  25. Shen L, Kantarjian H, Guo Y, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol 2010; 28:605.
  26. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980; 20:85.
  27. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood 2002; 100:2957.
  28. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003; 349:2042.
  29. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106:1794.
  30. Wijermans P, Lübbert M, Verhoef G, et al. Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000; 18:956.
  31. Lübbert M, Wijermans P, Kunzmann R, et al. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Br J Haematol 2001; 114:349.
  32. Rüter B, Wijermans PW, Lübbert M. Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2'-deoxycytidine retreatment in high-risk myelodysplasia patients. Cancer 2006; 106:1744.
  33. Oki Y, Jelinek J, Shen L, et al. Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia. Blood 2008; 111:2382.
  34. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer 2008; 112:2341.
  35. Ravandi F, Issa JP, Garcia-Manero G, et al. Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer 2009; 115:5746.
  36. (Accessed on January 16, 2020).
  37. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109:52.
  38. Steensma DP, Baer MR, Slack JL, et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol 2009; 27:3842.
  39. Garcia-Manero G, Jabbour E, Borthakur G, et al. Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes. J Clin Oncol 2013; 31:2548.
  40. Savona MR, Odenike O, Amrein PC, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol 2019; 6:e194.
  41. (Accessed on July 29, 2020).
  42. (Accessed on January 16, 2020).
  43. Kuendgen A, Lauseker M, List AF, et al. Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis. Leukemia 2013; 27:1072.
  44. Revicki DA, Brandenburg NA, Muus P, et al. Health-related quality of life outcomes of lenalidomide in transfusion-dependent patients with Low- or Intermediate-1-risk myelodysplastic syndromes with a chromosome 5q deletion: results from a randomized clinical trial. Leuk Res 2013; 37:259.
  45. Oliva EN, Latagliata R, Laganà C, et al. Lenalidomide in International Prognostic Scoring System Low and Intermediate-1 risk myelodysplastic syndromes with del(5q): an Italian phase II trial of health-related quality of life, safety and efficacy. Leuk Lymphoma 2013; 54:2458.
  46. (Accessed on January 15, 2020).
  47. (Accessed on January 16, 2020).
  48. Sekeres MA, Swern AS, Giagounidis A, et al. The impact of lenalidomide exposure on response and outcomes in patients with lower-risk myelodysplastic syndromes and del(5q). Blood Cancer J 2018; 8:90.
  49. Sekeres MA, Maciejewski JP, Giagounidis AA, et al. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2008; 26:5943.
  50. Sekeres MA, List AF. Active treatment strategies improving outcomes in patients with myelodysplastic syndromes with the deletion 5q abnormality. Clinical Leukemia 2008; 2:28.
  51. Fenaux P, Giagounidis A, Selleslag D, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 2011; 118:3765.
  52. Giagounidis A, Mufti GJ, Mittelman M, et al. Outcomes in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the MDS-004 study. Eur J Haematol 2014; 93:429.
  53. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355:1456.
  54. List AF, Bennett JM, Sekeres MA, et al. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS. Leukemia 2014; 28:1033.
  55. Santini V, Almeida A, Giagounidis A, et al. Randomized Phase III Study of Lenalidomide Versus Placebo in RBC Transfusion-Dependent Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents. J Clin Oncol 2016; 34:2988.
  56. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008; 111:86.
  57. Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med 2014; 20:408.
  58. (Accessed on April 07, 2020).
  59. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med 2020; 382:140.
  60. Zeidan AM, Platzbecker U, Garcia-Manero G, et al. Longer-term benefit of luspatercept in transfusion-dependent lower-risk myelodysplastic syndromes with ring sideroblasts. Blood 2022; 140:2170.
  61. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108:419.
  62. Platzbecker U, Germing U, Götze KS, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol 2017; 18:1338.
  63. Steensma DP, Fenaux P, Van Eygen K, et al. Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study. J Clin Oncol 2021; 39:48.
  64. Sloand EM, Wu CO, Greenberg P, et al. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 2008; 26:2505.
  65. Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002; 137:156.
  66. Killick SB, Mufti G, Cavenagh JD, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with 'low-risk' myelodysplasia. Br J Haematol 2003; 120:679.
  67. Steensma DP, Dispenzieri A, Moore SB, et al. Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood 2003; 101:2156.
  68. Jonásova A, Neuwirtová R, Cermák J, et al. Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol 1998; 100:304.
  69. Molldrem JJ, Jiang YZ, Stetler-Stevenson M, et al. Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles. Br J Haematol 1998; 102:1314.
  70. Tichelli A, Gratwohl A, Wuersch A, et al. Antilymphocyte globulin for myelodysplastic syndrome. Br J Haematol 1988; 68:139.
  71. Molldrem JJ, Caples M, Mavroudis D, et al. Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol 1997; 99:699.
  72. Aivado M, Rong A, Stadler M, et al. Favourable response to antithymocyte or antilymphocyte globulin in low-risk myelodysplastic syndrome patients with a 'non-clonal' pattern of X-chromosome inactivation in bone marrow cells. Eur J Haematol 2002; 68:210.
  73. Yazji S, Giles FJ, Tsimberidou AM, et al. Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia 2003; 17:2101.
  74. Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 2004; 18:460.
  75. Lim ZY, Killick S, Germing U, et al. Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 2007; 21:1436.
  76. Asano Y, Maeda M, Uchida N, et al. Immunosuppressive therapy for patients with refractory anemia. Ann Hematol 2001; 80:634.
  77. Broliden PA, Dahl IM, Hast R, et al. Antithymocyte globulin and cyclosporine A as combination therapy for low-risk non-sideroblastic myelodysplastic syndromes. Haematologica 2006; 91:667.
  78. Olnes MJ, Sloand EM. Targeting immune dysregulation in myelodysplastic syndromes. JAMA 2011; 305:814.
  79. Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 2002; 100:1570.
  80. Passweg JR, Giagounidis AA, Simcock M, et al. Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care--SAKK 33/99. J Clin Oncol 2011; 29:303.
  81. Komrokji RS, Mailloux AW, Chen DT, et al. A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction. Haematologica 2014; 99:1176.
  82. Brunner AM, Blonquist TM, Hobbs GS, et al. Risk and timing of cardiovascular death among patients with myelodysplastic syndromes. Blood Adv 2017; 1:2032.
  83. Roy NB, Myerson S, Schuh AH, et al. Cardiac iron overload in transfusion-dependent patients with myelodysplastic syndromes. Br J Haematol 2011; 154:521.
  84. Girmenia C, Candoni A, Delia M, et al. Infection control in patients with myelodysplastic syndromes who are candidates for active treatment: Expert panel consensus-based recommendations. Blood Rev 2019; 34:16.
  85. Wermke M, Eckoldt J, Götze KS, et al. Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): a prospective, multicentre, observational trial. Lancet Haematol 2018; 5:e201.
  86. Gattermann N, Rachmilewitz EA. Iron overload in MDS-pathophysiology, diagnosis, and complications. Ann Hematol 2011; 90:1.
  87. Moukalled NM, El Rassi FA, Temraz SN, Taher AT. Iron overload in patients with myelodysplastic syndromes: An updated overview. Cancer 2018; 124:3979.
  88. Steensma DP, Gattermann N. When is iron overload deleterious, and when and how should iron chelation therapy be administered in myelodysplastic syndromes? Best Pract Res Clin Haematol 2013; 26:431.
  89. Zeidan AM, Griffiths EA. To chelate or not to chelate in MDS: That is the question! Blood Rev 2018; 32:368.
  90. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  91. Marisavljevic D, Cemerikic V, Rolovic Z, et al. Hypocellular myelodysplastic syndromes: clinical and biological significance. Med Oncol 2005; 22:169.
  92. Huang TC, Ko BS, Tang JL, et al. Comparison of hypoplastic myelodysplastic syndrome (MDS) with normo-/hypercellular MDS by International Prognostic Scoring System, cytogenetic and genetic studies. Leukemia 2008; 22:544.
  93. Kochenderfer JN, Kobayashi S, Wieder ED, et al. Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression. Blood 2002; 100:3639.
  94. Zeng W, Maciejewski JP, Chen G, et al. Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol 2002; 119:803.
  95. Wlodarski MW, Gondek LP, Nearman ZP, et al. Molecular strategies for detection and quantitation of clonal cytotoxic T-cell responses in aplastic anemia and myelodysplastic syndrome. Blood 2006; 108:2632.
  96. de Vries AC, Langerak AW, Verhaaf B, et al. T-cell receptor Vbeta CDR3 oligoclonality frequently occurs in childhood refractory cytopenia (MDS-RC) and severe aplastic anemia. Leukemia 2008; 22:1170.
  97. Wang H, Chuhjo T, Yasue S, et al. Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. Blood 2002; 100:3897.
  98. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999; 131:401.
  99. Ishiyama K, Chuhjo T, Wang H, et al. Polyclonal hematopoiesis maintained in patients with bone marrow failure harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. Blood 2003; 102:1211.
  100. World Health Organization classification of tumours of haematopoietic and lymphoid tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  101. Jabbour EJ, Garcia-Manero G, Strati P, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium. Cancer 2015; 121:876.
Topic 4542 Version 61.0