Treatment of lower-risk myelodysplastic syndromes/neoplasms (MDS)

INTRODUCTION — 

Myelodysplastic syndromes/neoplasms (MDS) are 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).

Before beginning treatment, the patient with MDS is evaluated for the nature and severity of disease-related symptoms and comorbid conditions. Management is guided by the nature and severity of symptoms, laboratory abnormalities, pathologic features of the malignant cells, comorbidities, and patient preference.

Treatment of MDS is stratified according to the prognostic category, which is defined by the burden of myeloblasts, the number and degree of cytopenias, and the cytogenetic and molecular features of the malignant cells as either:

●Higher-risk MDS

●Lower-risk MDS

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

Related topics include:

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

●(See "Myelodysplastic syndromes/neoplasms (MDS): Overview of diagnosis and management".)

●(See "Myelodysplastic syndromes/neoplasms (MDS): Treatment of higher-risk MDS".)

PRETREATMENT EVALUATION — 

The patient with an MDS is assessed for clinical findings, comorbid conditions, and risk category.

Clinical and laboratory assessment — Clinical evaluation and laboratory studies should assess the nature of symptoms, number and severity of cytopenias, and comorbid conditions that may affect treatment.

The initial evaluation of MDS is described separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Overview of diagnosis and management", section on 'Evaluation'.)

●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 the potential for human immunodeficiency virus (HIV) infection. Prior transfusion history should be documented.

●Laboratory – We obtain the following laboratory studies to exclude other causes of cytopenias or dysplasia and because the results may influence the choice and dosing of 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).

•Thyroid function – Thyroid-stimulating hormone (TSH).

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

Bone marrow examination for MDS includes microscopy, flow cytometry, cytogenetics, and mutation analysis by myeloid gene panel or next-generation sequencing (NGS), as described separately. (See "Clinical manifestations, diagnosis, and classification 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, these studies should be obtained prior to selecting treatment because the results may influence the choice of therapy. (See 'Multiple cytopenias' below.)

Prognostic category — We stratify risk using the Revised International Prognostic Scoring System (IPSS-R). A mutation-based model, such as the International Prognostic Scoring System-Molecular (IPSS-M) is also acceptable.

Risk stratification functions as a default staging system for MDS. MDS prognostic models are discussed in greater detail separately. (See "Prognosis of myelodysplastic syndromes/neoplasms (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 3.5 points without TP53 mutation

Patients with IPSS-R ≥4 or mutated TP53 are classified as higher-risk MDS.

●IPSS-M online calculator

•Very low risk

•Low risk

•Moderate low risk

•Moderate high risk

We consider the original IPSS model to be outmoded because it does not incorporate molecular findings, it considers very limited clinical and cytogenetic findings, and it 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 syndromes/neoplasms (MDS) in adults", section on 'IPSS (Original IPSS)'.)

OVERVIEW — 

Management of lower-risk MDS is guided by the predominant symptoms and/or laboratory abnormalities that warrant treatment.

Findings that warrant treatment — We consider any of the following signs, symptoms, or laboratory abnormalities warrant treatment:

●Anemia – Symptoms related to anemia (eg, dyspnea, fatigue, weakness), hemoglobin <8 g/dL, or red blood cell transfusion dependence (RBC-TD).

●Thrombocytopenia – Platelets <20,000/microL or clinically significant bleeding or bruising with platelets <50,000/microL.

●Neutropenia – Recurrent and/or severe infections.

Management strategies — Treatment is individualized according to the predominant clinical findings. We encourage participation in a clinical trial when possible.

Outside of a clinical trial, management strategy is informed by the nature and severity of cytopenias, response to supportive care, medical fitness, and personal preference. The following are general approaches to managing a patient with lower-risk MDS.

●Supportive care – All patients should receive antibiotics for infections and transfusions for symptomatic or profound anemia or thrombocytopenia, as needed.

•Supportive care may be adequate for patients without symptoms or other findings that warrant treatment. (See 'Asymptomatic patients' below.)

•Supportive care can help relieve symptoms and/or prevent complications in patients who are receiving treatment for MDS.

Supportive care for patients with lower-risk MDS is described below. (See 'Supportive care' below.)

●Lower-intensity treatments – Lower-intensity treatments are generally well-tolerated and can ameliorate cytopenias, lessen symptoms, and improve quality of life (QOL). However, these approaches do not provide long-term disease control and have not been shown in prospective trials to extend survival.

As discussed in the sections below, treatment choice is informed by the predominant cytopenia(s):

•(See 'Isolated or predominant anemia' below.)

•(See 'Predominant thrombocytopenia' below.)

•(See 'Multiple cytopenias' below.)

●Intensive therapy – Allogeneic hematopoietic cell transplantation has the potential to cure MDS, but it is associated with substantial toxicity and the possibility of early death. Such risks are generally not warranted in patients with a good prognosis.

Intensive treatments may be suitable for selected medically fit, younger patients with Revised International Prognostic Scoring System (IPSS-R) intermediate-risk MDS, or those who have progressed through multiple therapies and remain heavily transfusion-dependent or experience life-threatening infections due to neutropenia. Intensive treatments are discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Treatment of higher-risk MDS".)

Our approach to the management of lower-risk MDS is similar to the guidelines of the United States National Comprehensive Cancer Network (NCCN), the European LeukemiaNet, and the European Society for Medical Oncology [1-3].

Goals of care — The primary goals for patients with lower-risk MDS are to control symptoms, reduce or eliminate transfusion needs, and improve QOL while minimizing treatment-related toxicity.

The patient and clinicians should establish goals of care at diagnosis and periodically revisit the goals during the illness.

Median survival for patients with lower-risk MDS is more than three years, and there is little likelihood of transformation to acute myeloid leukemia. More patients die from complications of bone marrow failure than from disease transformation [4]. Since treatments for lower-risk MDS generally do not provide long-term disease control, management is more focused on symptom relief and minimizing or eliminating transfusions than on achieving complete remission and/or cure.

ASYMPTOMATIC PATIENTS — 

Asymptomatic patients with lower-risk MDS should be followed for the development of symptoms and evidence of disease progression.

Clinical findings that warrant treatment are presented above. (See 'Findings that warrant treatment' above.)

Conventional treatments do not alter the natural history of asymptomatic lower-risk MDS, and deferring therapy avoids treatment-related adverse effects. Although intensive treatments, such as allogeneic hematopoietic cell transplantation, can potentially cure MDS, the substantial toxicity and potential early mortality associated with transplantation are not warranted in asymptomatic patients.

Asymptomatic patients should receive supportive care, as needed. For example, antibiotics should be given for bacterial infections, and transfusions may be warranted prior to surgery. (See "Perioperative blood management: Strategies to minimize transfusions".)

Ongoing monitoring of patients with lower-risk MDS is discussed below. (See 'Response monitoring and surveillance' below.)

ISOLATED OR PREDOMINANT ANEMIA — 

Symptomatic anemia refers to troublesome anemia-related symptoms (eg, dyspnea, fatigue, weakness), red blood cell transfusion-dependence (RBC-TD), or impending RBC-TD (eg, hemoglobin <8 g/dL).

Management of isolated or predominant symptomatic anemia without symptomatic neutropenia or thrombocytopenia is informed by the level of serum erythropoietin (EPO) (algorithm 1), as described in the sections that follow.

Patients with mild isolated anemia should be evaluated for concurrent iron deficiency. Elevated serum ferritin caused by MDS-associated inflammation can mask iron deficiency in some patients with lower-risk MDS. (See "Diagnosis of iron deficiency and iron deficiency anemia in adults".)

For patients with symptomatic anemia in association with symptomatic neutropenia (eg, recurrent or severe infections) and/or symptomatic thrombocytopenia (algorithm 1), management is discussed below. (See 'Multiple cytopenias' below.)

Erythropoietin ≤200 mU/mL — For isolated or predominant symptomatic anemia with serum EPO ≤200 mU/mL, we suggest an erythropoiesis-stimulating agent (ESA) rather than RBC transfusions alone (algorithm 1).

ESAs cause few adverse effects (AEs), were more effective than placebo for achieving RBC transfusion independence (RBC-TI) in randomized trials, and improved quality of life (QOL) in some studies. The selection of an ESA, toxicity, and outcomes of treatment are presented below. (See 'Erythopoiesis-stimulating agents' below.)

ESA therapy is acceptable for initial treatment of symptomatic anemia and serum EPO ≤200 mU/mL, including patients with MDS with del(5q), MDS with ring sideroblasts (MDS-RS) and/or mutated SF3B1, or patients with hypoplastic MDS.

Chronic transfusion therapy can be used as the sole method for managing anemia in patients with MDS, but repeated RBC transfusions can cause alloimmunization and iron overload, as discussed below. (See 'Red blood cells' below.)

We also consider initial treatment with luspatercept acceptable in this setting, based on results from the COMMANDS trial. The COMMANDS trial reported that luspatercept was more efficacious than epoetin alfa in RBC-TD and ESA-naive patients with lower-risk MDS; however, the superior efficacy of luspatercept was primarily in patients with MDS-RS [5]. We await validation of the COMMANDS trial before routinely administering luspatercept in this setting. We also await results from an ongoing trial (ELEMENT-MDS; NCT05949684) that randomly assigns luspatercept versus epoetin alfa to adults with lower-risk MDS who have symptomatic anemia, RBC-TI, and serum EPO ≤500 mU/mL. Treatment with luspatercept is described below. (See 'Luspatercept' below.)

Unless there is a contraindication (eg, uncontrolled hypertension), ESA therapy is appropriate for initial therapy in all patients with lower-risk MDS with isolated or predominant symptomatic anemia (algorithm 1). Targeted approaches are often used for patients with MDS with del(5q), MDS-RS/mutated SF3B1, or those who are likely to respond to immunosuppressive therapy, but an initial trial with an ESA is also acceptable if serum EPO is ≤200 mU/mL. Treatment of those distinctive clinicopathologic syndromes is described below. (See 'del(5q)' below and 'Ring sideroblasts/mutated SF3B1' below and 'Likely to respond to immunosuppression' below.)

Erythopoiesis-stimulating agents — Either recombinant epoetin alfa or darbepoetin alfa can be used to treat patients with lower-risk MDS and serum EPO ≤200 mU/mL.

●Administration – Epoetin alfa or darbepoetin alfa have similar efficacy and toxicity, and the choice is guided by availability and patient preference. We generally begin ESA treatment with either:

•Epoetin alfa – Recombinant human epoetin is given 40,000 to 60,000 units/week subcutaneously; this can be administered once per week or in divided doses (eg, two injections per week).

•Darbepoetin alfa – Darbepoetin alfa is given 150 to 300 mcg subcutaneously every other week. Some clinicians begin treatment with doses up to 500 mcg every two to three weeks.

Further details of ESA regimens (table 3) and additional aspects of care, including iron repletion, are provided separately. (See "Role of ESAs in adults with non-hematologic cancers", section on 'Indications and contraindications'.)

Clinical practice guidelines support treatment with ESAs for MDS. ESA use in MDS is endorsed by the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology (ESMO), and European LeukemiaNet [1-3,6,7].

Epoetin alfa is approved by the European Medicines Agency (EMA) for the treatment of anemia in patients with lower-risk MDS with serum EPO ≤200 mU/mL. The manufacturer of darbepoetin withdrew its request to the EMA for approval in anemia caused by MDS.

Despite their widespread use, neither epoetin alfa nor darbepoetin alfa is approved by the US Food and Drug Administration (FDA) for the treatment of anemia in patients with MDS.

●Toxicity – AEs are comparable with recombinant epoetin alfa and darbepoetin alfa.

Hypertension should be controlled before and during therapy with ESAs.

There is no evidence that ESAs increase thromboembolic risk in patients with MDS. A review of 5673 patients with MDS in a United States Medicare database reported no difference in thrombosis rates between patients treated with an ESA compared with those who did not receive an ESA in the prior 12 weeks [8]. Nevertheless, before beginning ESA therapy, the patient should be evaluated for a history of prior thromboembolism, heritable or acquired thrombophilic conditions, prolonged immobility, and other risk factors, as discussed separately. (See "Role of ESAs in adults with non-hematologic cancers", section on 'Thromboembolic complications'.)

There is no evidence that ESAs are associated with increased risk for transformation to acute myeloid leukemia (AML). Rates of progression are low with both ESAs and are comparable with rates in patients who receive supportive care alone [9-11].

Patients with lower-risk MDS are an exception to the general recommendation from ASH and ASCO to avoid ESAs for treating malignancy-associated anemia in patients who are not receiving concurrent myelosuppressive chemotherapy [6,7].

●Outcomes – ESAs reduce transfusion needs and ameliorate anemia in approximately one-half of patients with lower-risk MDS. There is evidence that ESAs can improve QOL, and some retrospective studies reported that ESAs are associated with improved overall survival (OS).

The efficacy and toxicity of epoetin alfa and darbepoetin alfa are comparable, but no randomized trial has directly compared them in patients with lower-risk MDS.

•A phase 3 trial reported that darbepoetin alfa was more effective than placebo for achieving RBC-TI in 147 patients with lower-risk MDS, hemoglobin ≤10 g/dL, low transfusion burden, and serum EPO ≤500 mU/mL [12]. Patients were randomly assigned (2:1) to 24 weeks of darbepoetin alfa 500 mcg subcutaneously or placebo every three weeks. Compared with placebo, darbepoetin reduced the percentage of patients who needed transfusions in weeks 5 to 24 (36 versus 59 percent) and improved erythroid response at 24 weeks (15 versus 0 percent). Erythroid response rates were 35 percent for patients treated with darbepoetin every two weeks in an unblinded portion of the study.

•An open-label randomized trial (EPOANE 3021) reported that epoetin alfa 450 international units/kg subcutaneously each week was superior to placebo for achieving an erythroid response among 130 patients with lower-risk MDS, symptomatic anemia, hemoglobin ≤10 g/dL, RBC-TD, and baseline EPO <500 mU/mL [13]. Epoetin alfa achieved 32 percent erythroid response at week 24, compared with 4 percent with placebo; there was no difference in progression rates to AML. Responses were only seen in patients with EPO <200 mU/mL.

•In a phase 3 trial of 110 patients with MDS, epoetin alfa achieved more erythroid responses (36 versus 10 percent) than transfusion support alone, but there was no difference in OS [14]. Epoetin alfa plus filgrastim achieved superior erythroid response compared with transfusions alone in a phase 3 trial in 60 patients [15]. At 12 weeks, 42 percent of patients who received filgrastim plus epoetin alfa had an erythroid response compared with none who received transfusions.

•A systematic review of 35 studies reported that ESA treatment was associated with clinical benefits and few safety concerns [9]. Responses were comparable with epoetin alfa and darbepoetin alfa, and erythroid responses ranged from 45 to 73 percent in ESA-naive patients and 25 to 75 percent in patients with prior ESA exposure. Some retrospective studies reported improved OS, some showed improved QOL, and there was no evidence of an increased progression to AML.

•In a retrospective study that compared 284 ESA-treated patients with 225 patients who received only supportive care, ESAs were associated with improved OS, predominantly in responding patients [16]. Five-year OS was 64 percent in patients treated with an ESA, compared with 39 percent with supportive care alone (hazard ratio [HR] 0.61 [95% CI 0.44-0.83]).

Erythropoietin >200 mU/mL — The management of isolated or predominant symptomatic anemia in patients with serum EPO >200 mU/mL is informed by the presence of specific clinicopathologic features.

●Patients with isolated/predominant anemia and none of the specific clinicopathologic features described below are treated like patients with multiple cytopenias. (See 'Multiple cytopenias' below.)

●del(5q). (See 'del(5q)' below.)

●MDS-RS/mutated SF3B1. (See 'Ring sideroblasts/mutated SF3B1' below.)

●Potential for responding to immunosuppressive therapy (IST) [17] (see 'Likely to respond to immunosuppression' below):

•HLA-DR15-positive disease

•Paroxysmal nocturnal hemoglobinuria (PNH)-positive cells present by flow cytometry

•Hypoplastic MDS

•<5 percent bone marrow blasts

•Shorter duration of RBC-TD

•Age <60 years

del(5q) — For symptomatic anemia in MDS with del(5q) and up to one other cytogenetic abnormality (except those involving chromosome 7), we suggest lenalidomide (algorithm 1).

The administration and toxicity of lenalidomide are presented below. (See 'Lenalidomide' below.)

MDS with del(5q) in patients with serum EPO ≤200 mU/mL can be treated with an ESA, as discussed above. (See 'Erythropoietin ≤200 mU/mL' above.)

Treatment with a hypomethylating agent (HMA; ie, azacitidine, decitabine) is also acceptable in this setting. (See 'Hypomethylating agents' below.)

No randomized trials have directly compared lenalidomide versus an HMA or lenalidomide versus an ESA for patients with del(5q). Although both lenalidomide and HMAs are superior to placebo for reducing RBC-TD in patients with lower-risk MDS, few patients with del(5q) were included in the studies of HMAs for MDS. (See 'Hypomethylating agents' below.)

Lenalidomide — Lenalidomide is an immunomodulatory drug that is effective for MDS with del(5q), but it also has activity for lower-risk MDS that lacks del(5q).

●Administration – The usual starting dose of lenalidomide for MDS is 10 mg daily for 21 days every 28 days. Dose adjustments are often required for cytopenias, reduced renal function, or other AEs [18].

●Toxicity – Lenalidomide is associated with potential embryo-fetal toxicity, thrombocytopenia, neutropenia, and increased risk of arterial and venous thrombosis and pulmonary embolism.

Lenalidomide is approved by the FDA and EMA for lower-risk MDS with del(5q). 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".)

●Outcomes – Approximately two-thirds of patients who have MDS with del(5q) experience a reduction in 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 [19,20].

•MDS with del(5q) – Lenalidomide was superior to placebo for achieving RBC-TI in lower-risk MDS with del(5q).

In a phase 3 trial, 205 patients with lower-risk MDS with del(5q) and RBC-TD 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, with each delivered in a 28-day cycle [21,22]. Rates of RBC-TI after 26 weeks were 57 percent with 10 mg daily lenalidomide, 37 percent with 5 mg daily lenalidomide, and 2 percent with placebo. Other outcomes included cytogenetic responses in 57, 23, and 0 percent, respectively, and the cumulative risk of transformation to AML after two years was 13, 17, and 17 percent. The median duration of response was >83 weeks with 10 mg lenalidomide and >41 weeks with 5 mg lenalidomide. Three-year OS for the entire trial population was 57 percent; median OS did not differ according to initial therapy. The most common grade ≥3 AEs were myelosuppression and venous thromboembolism; rates of these AEs were similar with both doses of lenalidomide.

A phase 2 study also reported rapid, sustained hematologic responses in two-thirds of 148 patients with del(5q), and one-half of evaluable patients had a complete cytogenetic response [23,24].

•MDS without del(5q) – In a phase 3 trial that included 239 patients with lower-risk RBC-TD non-del(5q) MDS, lenalidomide achieved a higher rate of RBC-TI for ≥8 weeks than placebo (27 versus 3 percent, respectively) [25]. The median duration of response was 31 weeks, the median time to response was 10 weeks, and 90 percent of patients responded in ≤16 weeks. Health-related QOL and treatment-related mortality were similar in both arms, but there was more grade ≥3 neutropenia and thrombocytopenia with lenalidomide.

A phase 2 study reported that one-quarter of patients who had MDS without del(5q) achieved RBC-TI with lenalidomide [26].

Ring sideroblasts/mutated SF3B1 — For symptomatic anemia in patients with MDS-RS/mutated SF3B1, we suggest luspatercept (algorithm 1).

The administration, toxicity, and outcomes with luspatercept are presented below. (See 'Luspatercept' below.)

Treatment with an HMA is also acceptable in this setting. (See 'Hypomethylating agents' below.)

No randomized trials have directly compared luspatercept versus an HMA for MDS-RS. Both luspatercept and HMAs are superior to placebo for reducing RBC-TD in patients with lower-risk MDS, but there were few patients with MDS-RS in the HMA studies. (See 'Hypomethylating agents' below.)

Luspatercept — Luspatercept is a recombinant fusion protein that binds to transforming growth factor (TGF)-beta ligands, which promotes erythroid maturation.

●Administration – Luspatercept is started at 1 mg/kg subcutaneously once every three weeks.

The dose can be increased to 1.33 mg/kg daily if the transfusion requirement does not decline by at least one-third after three treatments, and it can be increased again to 1.75 mg/kg if needed. Luspatercept should be discontinued if transfusion requirements do not decrease after two dose escalations (ie, 24 weeks).

Patients of childbearing potential should have a documented negative pregnancy test before starting therapy.

Luspatercept is approved by the FDA and EMA for adults with RBC-TD in lower-risk MDS.

●Toxicity – Toxicity includes bone pain, arthralgias, and other mild AEs. Luspatercept is associated with potential embryo-fetal toxicity.

●Outcomes – Luspatercept was superior to placebo for achieving RBC-TI in lower-risk MDS-RS with previous ESA exposure or high serum EPO levels.

Luspatercept is also acceptable for the initial treatment of RBC-TD in patients with symptomatic anemia and serum EPO ≤200 mU/microL. (See 'Erythropoietin ≤200 mU/mL' above.)

•A phase 3 trial (MEDALIST) included 229 patients with MDS-RS and <5 percent bone marrow blasts who were refractory or unlikely to respond to ESAs [27]. Luspatercept was superior to placebo for achieving RBC-TI for ≥12 weeks (28 versus 8 percent) and it was well-tolerated; toxicity was primarily mild fatigue, diarrhea, asthenia, nausea, and dizziness.

-Longer follow-up of the MEDALIST trial (median >26 months) reported continued benefits with luspatercept [28]. Compared with placebo, luspatercept achieved more ≥8-week RBC-TI (45 versus 16 percent), more ≥16-week RBC-TI (28 versus 7 percent; odds ratio [OR] 6 [95% CI 2.2-16.0]), more patients had ≥50 percent reduction in transfusions (50 versus 14 percent), and more patients experienced erythroid improvement (59 versus 17 percent). Benefits with luspatercept were seen in both patients with high- and low-transfusion burdens.

-While median OS was comparable between the luspatercept and placebo arms in the MEDALIST trial, patients who responded to luspatercept had longer survival than nonresponders [29]. Patients with ≥8-week RBC-TI to luspatercept achieved superior 40-month OS compared with nonresponders (HR 0.319 [95% CI 0.161-0.630]); survival was also superior for luspatercept responders who had RBC-TI ≥16 weeks or a mean increase of hemoglobin ≥1.5 g/dL during weeks 1 to 24.

•Analysis of the phase 3 COMMANDS trial reported that luspatercept was more effective than epoetin alfa in RBC-TD, ESA-naive patients with lower-risk MDS [5,30]. RBC-TI for ≥12 weeks was superior with luspatercept compared with epoetin alfa (60 versus 35 percent; OR 3.1 [95% CI 2.0-4.8]); luspatercept also achieved superior RBC-TI for ≥24 weeks. The improved efficacy for luspatercept occurred mainly in patients with MDS-RS; response rates were comparable between trial arms for patients without MDS-RS. Treatment-related grade ≥3 AEs were reported in 9 percent with luspatercept and 3 percent with epoetin alfa.

Likely to respond to immunosuppression — For patients with symptomatic anemia who have clinicopathologic features associated with a good probability of responding to IST, we suggest treatment with antithymocyte globulin (ATG) plus cyclosporine A.

Clinicopathologic features that are associated with a response to IST include [17]:

●HLA-DR15 positive disease

●PNH-positive cells present by flow cytometry

●Hypoplastic MDS

●<5 percent bone marrow blasts

●Shorter duration of RBC-TD

●Age <60 years

Patients with these features and symptomatic anemia together with symptomatic neutropenia and/or thrombocytopenia can also be treated with IST; an HMA is also acceptable in this setting. (See 'Multiple cytopenias' below.)

Neither ATG nor cyclosporine is approved by the FDA for the treatment of MDS.

No randomized trials have directly compared IST versus an HMA in this setting. Although both IST and HMAs are superior to placebo for reducing RBC-TD in patients with lower-risk MDS, the studies of HMAs included few patients with these features. (See 'Hypomethylating agents' below.)

ATG, with or without cyclosporine can improve blood counts and achieve RBC-TI in this setting, but it is uncertain if survival is improved compared with supportive care alone.

●A phase 3 trial of 88 patients compared ATG plus cyclosporine versus best supportive care [31]. ATG plus cyclosporine achieved higher rates of hematologic response by six months (29 versus 9 percent, respectively), but there was no difference in two-year OS (49 versus 66 percent) or two-year transformation-free survival (46 versus 55 percent). The most common grade ≥3 AEs 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 [32].

●Among 61 patients with RBC-TD MDS, 21 became RBC-TI a median of 10 weeks after receiving a four-day course of ATG plus steroids [33]. After treatment, 19 of the 21 responders had normal neutrophil and platelet counts. Response to ATG was associated with younger age and lower initial platelet count.

●Another study reported hematologic responses in one-third of 129 patients with lower-risk MDS [34]. ATG plus cyclosporine was more effective (48 percent) than either ATG alone (24 percent) or cyclosporine alone (8 percent).

None of the above syndromes — Patients with predominant anemia, serum EPO >200 mIU/mL, and none of the clinicopathologic syndromes described above are treated like patients with multiple cytopenias. (See 'Multiple cytopenias' below.)

PREDOMINANT THROMBOCYTOPENIA — 

For isolated or predominant symptomatic thrombocytopenia and bone marrow blasts <5 percent, we suggest a thrombopoietin receptor agonist (TPO-RA; eg, romiplostim or eltrombopag), based on the favorable balance of benefit and toxicity.

Symptomatic thrombocytopenia describes <20,000 platelets/microL or <50,000 platelets/microL with excessive bleeding or bruising.

Both romiplostim and eltrombopag can decrease bleeding and reduce platelet transfusions, but no prospective trial has directly compared these TPO-RAs in this setting. Neither romiplostim nor eltrombopag is approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of MDS. The selection and administration of a TPO-RA are described separately. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'TPO receptor agonists'.)

We limit TPO-RAs to patients with <5 percent blasts to avoid potentially exacerbating progression to acute myeloid leukemia (AML). There is controversy about whether TPO-RAs can accelerate progression to AML. A meta-analysis that evaluated trials of a TPO-RA versus placebo in MDS reported no difference in mortality or premature progression to AML [35].

●Romiplostim – Romiplostim is a "peptibody" that is given 1 to 10 mcg/kg by subcutaneous injection weekly, and it is associated with improved platelet counts in one-half of patients with lower-risk MDS. In patients with lower-risk MDS, better response to romiplostim was associated with baseline TPO levels <500 pg/mL and a limited history of platelet transfusions [36].

•A study reported improved platelet counts and a trend to fewer bleeding events with romiplostim compared with placebo in patients with lower-risk MDS, but conclusions are limited because the study was terminated early [37]. Among the 56 patients who completed the 58-week study, romiplostim decreased the number of platelet transfusions (relative risk [RR] 0.71 [95% CI 0.61-0.82]) in patients with baseline platelet counts <20,000/microL, and there was a trend toward fewer clinically significant bleeding events. The study was closed early by the data monitoring committee when interim analysis suggested an increased risk for progression to AML, but with a five-year follow-up, there was no difference in overall survival (OS) or progression to AML between treatment groups [38].

•Among 77 patients with lower-risk MDS and a median platelet count of 25,000/microL, romiplostim was associated with 42 percent platelet response with a median duration of 340 days; neutrophil and erythroid responses were observed in 4 and 9 percent of patients, respectively [39]. A transient rise in circulating blasts (>10 percent) was noted in 8 percent of patients; the increase in blasts was reversible with romiplostim interruption, but two patients progressed to AML. No association has been found between TPO level and response to romiplostim. In another study, romiplostim was associated with 55 percent platelet response in patients with lower-risk MDS and thrombocytopenia, but 15 percent had a transient rise in marrow and/or circulating peripheral blasts that reversed after drug discontinuation [40].

•Romiplostim was safe and associated with trends toward fewer bleeding events and higher platelet counts in patients treated with decitabine [41] and fewer dose reductions/delays due to thrombocytopenia in patients treated with lenalidomide [42].

●Eltrombopag – Eltrombopag is an orally available nonpeptide TPO-RA. Initial dosing of eltrombopag varies, but lower starting doses should be used in patients of Asian descent.

•Eltrombopag was associated with fewer bleeding episodes and better platelet response compared with placebo in a study of patients with lower-risk MDS [43]. Eltrombopag was associated with fewer bleeding events (14 versus 42 percent) but more grade ≥3 adverse effects (AEs; 46 versus 16 percent).

•Eltrombopag was well-tolerated, and it was associated with 44 percent hematologic response in a study of 25 patients; the dose was escalated from 50 mg/day to a maximum of 150 mg/day over a period of 16 weeks [44]. Six patients had disease progression that was not associated with an expansion of mutated clones.

•Among 28 patients who received eltrombopag in combination with a hypomethylating agent (HMA) after not responding to >4 cycles of HMA therapy, improved platelet counts were reported in 11 percent; median OS was 12 months, and 11 percent had progressive disease [45].

•In patients with higher-risk MDS, eltrombopag was associated with fewer clinically relevant thrombocytopenia-related events, but there was no difference in platelet transfusion independence or hematologic parameters [46].

MULTIPLE CYTOPENIAS — 

For patients with lower-risk MDS and multiple cytopenias (≥2 symptomatic cytopenias), we suggest treatment with a hypomethylating agent (HMA; ie, azacitidine or decitabine) (algorithm 1).

Both azacitidine and decitabine were superior to best supportive care or placebo for improving symptomatic anemia; some studies reported improved survival or quality of life (QOL). Studies that compared the efficacy and toxicity of azacitidine and decitabine are described below. (See 'Hypomethylating agents' below.)

●A trial of 191 patients with MDS (one-half with lower-risk disease and one-half with higher-risk MDS) randomly assigned azacitidine versus supportive care. Azacitidine achieved superior overall response rate (ORR; 23 versus 0 percent), longer median time to acute myeloid leukemia (AML) or death (21 versus 13 months), and improved QOL [47,48]. Median overall survival (OS) did not differ (20 versus 14 months), but this may be due to the trial design, which permitted crossover to azacitidine after four months of supportive care.

●A trial that randomly assigned 170 patients (one-third with lower-risk MDS, two-thirds with higher-risk MDS) to decitabine versus best supportive care reported that decitabine achieved superior ORR (17 versus 0 percent), but there was no survival benefit and a trend toward longer time to AML transformation or death (12 versus 8 months) was not statistically significant [49].

●A systematic review and meta-analysis of patients with MDS (mostly higher-risk disease) reported that compared with conventional care, azacitidine but not decitabine was associated with improved OS and time to AML transformation or death [50]. The review included 952 patients in four randomized trials that compared either azacitidine or decitabine versus conventional care. OS was superior for azacitidine (hazard ratio [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). Treatment with an HMA was associated with better ORR but more treatment-related mortality (relative risk [RR] 7.27 [95% CI 1.67-31.64]; three trials).

Hypomethylating agents — Azacitidine and decitabine have comparable efficacy and toxicity.

The selection of an HMA is guided by the route and schedule of administration and the preference of the patient and clinician. Some favor decitabine because it is given intravenously over fewer days and administration can use an indwelling intravenous access device, if present. Others favor azacitidine because it is given subcutaneously and requires less time in an infusion center.

We generally treat with at least six cycles of therapy, but treatment can continue indefinitely until there is a loss of response or unacceptable adverse effects (AEs).

●For patients who have a complete remission after six cycles, we offer the opportunity to continue treatment indefinitely or discontinue therapy and resume it later when relapse occurs.

●Patients with ≥5 percent blasts should continue treatment for as long as they are tolerating therapy. If they are experiencing AEs, we attempt judicious dose reduction or brief treatment delays rather than abandoning the treatment, especially if they are responding. For example, the treatment duration can be shortened (eg, from five to three days) or the length of treatment cycles can be extended (eg, from 28 to 35 days).

A phase 2 study reported comparable outcomes when 113 patients with lower-risk MDS or MDS/myeloproliferative neoplasm were randomly assigned to low-dose/truncated dosing schedules (3 days of treatment every 28 days) of the HMAs [51]. One-year OS (87 percent with decitabine versus 83 percent with azacitidine), one-year event-free survival (EFS; 74 and 55 percent), and red blood cell transfusion-independence (RBC-TI; 32 versus 16 percent) did not differ to a statistically significant degree. Both agents were well-tolerated.

Azacitidine

●Administration – Azacitidine is generally given at 75 mg/m²/day for 7 days, every 28 days for at least 6 courses.

More convenient dosing regimens have been reported. Examples include azacitidine 75 mg/m²/day subcutaneously or intravenously 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) [51-56]. In nonrandomized settings, response rates with these alternative protocols were comparable to the seven-day azacitidine schedule.

We generally assess response after four to six treatment cycles. Most patients respond within 6 months, but some may take up to 12 cycles of therapy [57]. The optimal duration of therapy has not been defined, but treatment should continue if a benefit persists and the medication is tolerated.

Azacitidine is approved by the US Food and Drug Administration (FDA) for the treatment of MDS. The European Medicines Agency (EMA) approved azacitidine for higher-risk MDS.

●Toxicity – Cytopenias are common. Some patients require growth factor support or dose adjustment (eg, for kidney insufficiency) [58]. Most patients have at least one hospitalization for neutropenic fever during treatment.

Response monitoring is described below. (See 'Response monitoring and surveillance' below.)

For patients who do not respond adequately to HMA therapy, further management is discussed below. (See 'Second-line therapy' below.)

Decitabine

●Administration – Decitabine is administered intravenously or subcutaneously with a variety of doses and schedules.

Examples include 20 mg/m²/day subcutaneously or intravenously for 3 or 5 days or 10 mg/m²/day for 10 consecutive days, with 4- to 6-week cycles. At least 4 cycles should be given. Treatment should continue if a benefit persists and decitabine continues to be tolerated. A trial that compared various decitabine protocols is discussed below.

Growth factor support and dose adjustment (eg, for renal insufficiency) may be necessary for some patients [58,59].

Intravenous decitabine is approved by the FDA for adults with MDS and by the EMA for the treatment of AML.

●Toxicity – Cytopenias are common.

●Outcomes

•A single-institution study reported that five-day intravenous administration was associated with the highest response rate in patients with higher-risk MDS or chronic myelomonocytic leukemia (CMML), but it is uncertain if this also applies to lower-risk MDS [60]. Patients were randomly given 20 mg/m² intravenously daily for 5 days, 20 mg/m² subcutaneously daily for 5 days, or 10 mg/m² intravenously daily for 10 days.

•A phase 2 study in 99 patients with MDS (one-half with lower-risk disease, one-half with higher-risk MDS) reported that an outpatient schedule of 20 mg/m² intravenously over one hour daily for five consecutive days every four weeks was associated with 32 percent ORR (including 17 percent complete remission [CR]) and cytogenetic response in one-half of evaluable patients [61]. Responses occurred by the end of the second cycle in 82 percent. 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.

•Rates of OS, transformation to AML, hematologic improvement, cytogenetic response, and toxicity were comparable among 65 patients with lower-risk MDS who were randomly assigned (2:1) to decitabine 20 mg/m²/day subcutaneously on days 1 to 3 every 28 days versus once weekly [62]. Overall, 70 percent of patients were alive at 500 days.

An oral preparation of fixed-dose decitabine-cedazuridine, 35 mg plus 100 mg, respectively (cedazuridine inhibits cytidine deaminase in the gut and liver), is available, but it is not well-studied for lower-risk MDS. The compound emulated the pharmacokinetic, pharmacodynamic, and safety profiles of intravenous decitabine [63].

Two studies evaluated decitabine-cedazuridine by mouth daily for 5 days every 28 days for patients with MDS or CMML.

●A study of 80 patients with MDS (35 with lower-risk disease) or CMML reported that one-half achieved RBC-TI and/or platelet-TI for ≥56 days, and 18 percent had a CR [64]. The median treatment duration was seven months.

●In another study, one-half of 133 patients with lower-risk MDS became RBC-TI, and 21 percent had a CR [64].

We await larger studies and more clinically meaningful endpoints (eg, OS) before we routinely use decitabine-cedazuridine to treat lower-risk MDS. The oral preparation of decitabine plus cedazuridine is approved by the FDA for the treatment of MDS [64].

RESPONSE MONITORING AND SURVEILLANCE — 

Patients with lower-risk MDS are followed to assess treatment response and to monitor for disease progression.

●Response monitoring – Outside of a clinical trial, we assess treatment response based on symptoms, blood counts, transfusion needs, and quality of life. The schedule is individualized based on the severity of symptoms and cytopenias and patient and clinician concerns.

We generally schedule visits every one to six months. Visits include clinical evaluation and a complete blood count/differential count. Bone marrow examinations are not needed unless cytopenias worsen or there are other indications of disease progression. Standardized response criteria have been developed for clinical trials, but they are not generally used for routine clinical care. (See "Myelodysplastic syndromes/neoplasms (MDS): Overview of diagnosis and management", section on 'Monitoring'.)

Most patients respond slowly to lower-intensity agents for MDS; a meaningful improvement may require four to six months of treatment. Management of patients with an inadequate response to initial therapy is discussed below. (See 'Second-line therapy' below.)

●Surveillance and health maintenance – Patients with lower-risk MDS generally have survival measured in years. In addition to monitoring the status of MDS, they may need routine health maintenance.

Patients should receive routine health screening (eg, 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'.)

SUPPORTIVE CARE — 

Supportive care is important for managing all patients with MDS, whether 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 (QOL). However, chronic transfusion therapy may cause alloimmunization, iron overload, and other complications.

Transfusion support

Red blood cells — Red blood cell (RBC) transfusions can provide prompt relief for symptomatic anemia and improve QOL, but they may be associated with fluid overload, transfusion reactions, and/or alloimmunization, and heavily transfused patients may develop iron overload.

Leukoreduced blood products should be used to decrease risks for platelet isosensitization, febrile transfusion reactions, cytomegalovirus (CMV) and other viral infections, and immunosuppression.

Whenever possible, CMV-negative or leukapheresis blood products should be used for recipients who are CMV negative. Administration of CMV-negative, irradiated blood products is of special importance for patients who are candidates for hematopoietic cell transplantation (HCT). (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion".)

●Transfusion threshold – Transfusions are used primarily to relieve anemia-related symptoms and to prevent complications, especially in patients with cardiovascular, pulmonary, or neurologic comorbidities.

The threshold for transfusion varies with age, symptoms, and medical comorbidities. Although there is no consensus, many centers transfuse asymptomatic patients with hemoglobin ≤8 g/dL [65]. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Thresholds for specific patient populations'.)

●Toxicity – Adverse effects (AEs) associated with chronic transfusion therapy include transfusion reactions, infections, alloimmunization, and iron overload, as discussed separately. (See "Approach to the patient with a suspected acute transfusion reaction".)

●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 nonhematologic consequences of iron overload in transfusion-dependent patients with MDS [66-68]. Iron overload may also be associated with inferior outcomes for patients who later undergo allogeneic HCT [69]. Iron chelation can improve cytopenias in a small subset of patients.

●Chelation therapy – There is no demonstrated clinical benefit from iron chelation in patients with MDS and no consensus chelation regimen.

We consider chelation therapy after transfusion of approximately 50 units of RBCs in a patient with lower-risk MDS and a long life expectancy, or if magnetic resonance imaging (MRI) or a liver biopsy suggests substantial liver iron overload. A decision to pursue chelation therapy is personalized and should weigh the expense, inconvenience, and AEs (eg, gastrointestinal symptoms, impaired kidney function) against potential benefits. The choice of chelation agent and regimen is discussed separately. (See "Iron chelation: Choice of agent, dosing, and adverse effects".)

A multicenter trial (TELESTO) that randomly assigned patients with lower-risk MDS to oral deferasirox versus placebo closed prematurely due to lagging patient enrollment; we judge that no conclusions can be drawn from this trial because of changes in trial design, study objectives, and patient accrual [70].

Platelets — Platelet transfusions are used to control or prevent bleeding in patients with quantitative or qualitative platelet abnormalities.

Prophylactic platelet transfusions are routinely given to patients with platelets <10,000/microL. Many clinicians administer platelet transfusions at a higher platelet count (eg, 20,000/microL) for patients with active bleeding, fever, severe infection, pulmonary compromise, coagulopathy, or neurologic events.

Aminocaproic acid or other antifibrinolytic agents may be considered for bleeding refractory to platelet transfusions or for those with profound, refractory thrombocytopenia [71].

Further discussion of platelet transfusion and other supportive care for bleeding is presented separately. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Leukemia, chemotherapy, and HSCT'.)

Infection management — Patients with lower-risk MDS are at increased risk for infections due to decreased neutrophils and/or granulocyte dysfunction.

Patients with an absolute neutrophil count (ANC) <500/microL are at risk for severe, potentially life-threatening infections. However, only 7 percent of patients with lower-risk MDS have ANC <1500/microL, and life-threatening infections are uncommon in the absence of treatment with drugs that worsen neutropenia [2]. Bacterial infections predominate in this setting (especially infections involving skin), but fungal, viral, and mycobacterial infections can occur, especially in patients treated with immunosuppressive agents [72].

Our approach to the management of neutropenia and infectious complications of MDS is consistent with those of the United States National Cancer Center Network (NCCN) and the European Society of Medical Oncology (ESMO).

Management of infections in patients with MDS includes:

●Neutropenic fever – Patients with ANC <500/microL and fever or other infectious findings must be evaluated urgently. Empiric antibacterial therapy should be administered immediately after blood cultures have been obtained (and before other investigations have been completed). Filgrastim (granulocyte-colony stimulating factor [G-CSF]) can be added to antimicrobial agents for neutropenic fever.

Management of febrile neutropenia is discussed separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

●Asymptomatic neutropenia

•G-CSF – There is no evidence that prophylaxis with G-CSF in the absence of an infection has an impact on survival or other outcomes in patients with MDS.

G-CSF can be considered in patients with recurrent or resistant infections.

•Prophylactic antibiotics – There is no demonstrated role for routine antimicrobial prophylaxis in patients with MDS, whether they are neutropenic.

Clinical judgment should inform a decision to use prophylactic antimicrobials in patients receiving treatments (eg, azacitidine, decitabine, lenalidomide) that can cause neutropenia and prior to invasive surgical or dental procedures.

●Vaccinations – Patients with MDS should be vaccinated to reduce the risk of certain infections.

Patients with MDS can receive killed or recombinant immunizations, but live vaccines should generally not be given to immunocompromised individuals.

Specific recommendations regarding immunizations for patients with cancer and other immunocompromised conditions (figure 1) are discussed separately. (See "Immunizations in adults with cancer".)

●Viral reactivation – Immunocompromised patients, including those with MDS, may experience reactivation of herpes simplex or varicella-zoster virus. Early institution of treatment with antivirals should be provided for patients suspected of herpes virus reactivation. (See "Treatment of herpes zoster".)

INADEQUATE RESPONSE TO INITIAL THERAPY — 

Patients who have an inadequate or unsustained response to initial therapy may require a change in treatment. Supportive care should continue, as needed, and we encourage participation in a clinical trial when possible.

Response to the agents used for lower-risk MDS is often slow, so it is important to provide an adequate trial of the initial therapy. We generally treat for at least four to six months, while monitoring symptoms and blood counts, before concluding that the initial treatment was ineffective.

If there is a significant worsening of cytopenias or increasing blast count, bone marrow examination should be performed to evaluate the patient for possible disease progression.

For patients who are responding adequately but are having intolerable treatment-related adverse effects (AEs), we try judicious dose reduction or brief treatment delays rather than abandoning the treatment.

Second-line therapy — We change therapy for patients who have an inadequate or unsustained response after an adequate period of initial therapy. We do not use a different drug within the same drug class (eg, decitabine following azacitidine therapy).

There is no optimal second-line regimen for all patients with lower-risk MDS. The choice is informed by prior treatment, predominant cytopenia(s), toxicity, comorbidities, convenience, and patient preference.

Survival in patients with lower-risk MDS who fail to respond to initial therapy may be poor [73].

Erythropoiesis-stimulating agent failure — For erythropoiesis-stimulating agent (ESA) failure, we suggest luspatercept, particularly in patients with MDS with ring sideroblasts (MDS-RS)/mutated SF3B1 rather than other agents, based on the balance of efficacy and toxicity.

We favor imetelstat if luspatercept is not suitable or available, but lenalidomide is also acceptable for second-line therapy. Some clinicians add granulocyte-colony stimulating factor (G-CSF) to the ESA regimen before changing agents. We generally do not use a hypomethylating agent (HMA) as second-line therapy for patients with isolated/predominant anemia.

No randomized trials have directly compared these agents for second-line therapy, but each has been proven superior to placebo for patients with MDS-associated anemia who did not respond adequately to an ESA.

●Luspatercept – Luspatercept is a recombinant protein that binds to transforming growth factor (TGF)-beta ligands and provides a favorable balance of benefit, toxicity, and convenience.

Luspatercept was superior to placebo for reducing red blood cell transfusion dependence (RBC-TD) in patients with MDS-RS/mutated SF3B1 [27,28,74], but it is also effective in patients without RS.

Administration and outcomes with luspatercept are described above. (See 'Luspatercept' above.)

●Imetelstat – Imetelstat is a lipid-conjugated oligonucleotide that acts as a competitive inhibitor of telomerase enzymatic activity.

Imetelstat reduced RBC-TD in patients with lower-risk MDS who were not responding or lost their response to an ESA [6].

•Administration – Imetelstat 7.1 mg/kg is infused intravenously over two hours every four weeks. Premedication should be given for infusion-related reactions.

Treatment should be interrupted for infusion-related reactions, and the infusion rate should be decreased. If severe infusion reactions recur despite premedication and reduced rate of infusion, treatment should be discontinued.

A complete blood count should be obtained prior to treatment initiation, weekly for the first two cycles, and then prior to each subsequent treatment. The dose should be reduced or delayed for thrombocytopenia or neutropenia.

Imetelstat is approved by the US Food and Drug Administration (FDA) for adults with lower-risk MDS who require ≥4 RBC units over eight weeks or who did not respond or lost response to an ESA. Imetelstat has received validation for marketing from the European Medicines Agency (EMA).

•Toxicity – Cytopenias are the most common AEs.

•Outcomes

-A phase 3 trial (IMerge) reported that imetelstat was superior to placebo for reducing RBC-TD in ESA-refractory patients with lower-risk MDS [75]. Patients were randomly assigned (2:1) to imetelstat 7.1 mg/kg (118 patients) versus placebo (60 patients) every four weeks until disease progression or unacceptable toxicity. With a median follow-up of 20 months, imetelstat achieved RBC-TI (transfusion independence) for ≥8 weeks in 40 percent, compared with 15 percent who received placebo. Imetelstat achieved continuous RBC-TI for ≥24 weeks in 28 percent of patients, compared with 3 percent with placebo. The median duration of response was approximately one year. Subset analysis reported ≥8 weeks TI in 45 percent of patients with RS and 32 percent without RS. Grade ≥3 cytopenias were more common with imetelstat (neutropenia 68 versus 3 percent; thrombocytopenia 62 versus 8 percent); there were no treatment-related deaths.

-An earlier phase 2 study reported similar efficacy, along with reductions of cytogenetically abnormal clones and mutational allele burden, suggesting that imetelstat may have disease-modifying activity [76].

●Lenalidomide – Lenalidomide is an immunomodulatory drug (IMiD) that is effective for MDS with del(5q), but it also has activity for lower-risk MDS that lacks del(5q).

Lenalidomide is approved by the FDA and EMA for lower-risk MDS with del(5q).

AEs include thrombocytopenia, neutropenia, increased risk of arterial and venous thrombosis and pulmonary embolism, and potential embryo-fetal toxicity.

Administration and outcomes with lenalidomide are described above. (See 'Lenalidomide' above.)

Hypomethylating agent failure — For patients who failed to respond adequately to either azacitidine or decitabine, the likelihood of a response to the other agent is low. Patients should continue to receive supportive care as needed.

Management of HMA failure varies with the nature and number of cytopenias:

●For isolated/predominant anemia, we follow the approach for symptomatic anemia. (See 'Isolated or predominant anemia' above.)

●For ≥2 cytopenias, options include lenalidomide, luspatercept, or imetelstat. For transplant-eligible patients, allogeneic hematopoietic cell transplantation (HCT) is acceptable, as discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Treatment of higher-risk MDS".)

After other agents — Treatment for patients with lower-risk MDS who received initial therapy with other agents is informed by prior therapy.

●Thrombopoietin receptor agonist (TPO-RA) - Patients who did not respond to a TPO-RA can be treated like multilineage cytopenias. (See 'Multiple cytopenias' above.)

●Luspatercept or lenalidomide – Treatment is like that for an inadequate response to an ESA. (See 'Erythropoiesis-stimulating agent failure' above.)

Third line or later — The choice of a third-line regimen is influenced by prior treatments, toxicities, and comorbidities, but treatments are increasingly unlikely to be effective.

Fit patients who remain symptomatic or cytopenic after two prior lines of therapy may seek intensive remission induction therapy and/or allogeneic HCT as discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Treatment of higher-risk MDS", section on 'Medically fit patients'.)

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 5^th to 6^th 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 10^th to 12^th 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)")

SUMMARY AND RECOMMENDATIONS

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

●Prognostic category – We favor the Revised International Prognostic Scoring System (IPSS-R) (table 1) (calculator 1) for classifying prognosis. Mutation-based models are also acceptable, while the original IPSS is outmoded. (See 'Prognostic category' above.)

●Goals of care – Goals are symptom control, reduced transfusions, and improved quality of life while minimizing toxicity. (See 'Goals of care' above.)

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

●Symptomatic MDS – Guided by the predominant cytopenia(s). The following findings warrant treatment (see 'Findings that warrant treatment' above):

•Anemia – Anemia-related dyspnea, fatigue, weakness; transfusion-dependence; or hemoglobin <8g/dL.

•Thrombocytopenia – Platelets <20,000/microL or significant bleeding/bruising with platelets <50,000/microL.

•Neutropenia – Recurrent and/or severe infections.

●Isolated/predominant anemia – Treatment is guided by serum erythropoietin (EPO).

•EPO ≤200 mU/mL – We suggest an erythropoiesis-stimulating agent (ESA) rather than red blood cell (RBC) transfusions alone (algorithm 1) (Grade 2B). (See 'Erythropoietin ≤200 mU/mL' above.)

ESAs are acceptable for all patients with symptomatic anemia and EPO ≤200 mU/mL, including the clinicopathologic syndromes described below. Luspatercept is also acceptable in this setting.

Epoetin alfa or darbepoetin alfa have similar efficacy and toxicity, and the choice is guided by patient preference. (See 'Erythopoiesis-stimulating agents' above.)

•EPO >200 mU/mL – Treatment is informed by the presence of specific clinicopathologic features (algorithm 1). For these syndromes, a hypomethylating agent (HMA) is also acceptable.

•MDS with del(5q) – We suggest lenalidomide (Grade 2B). (See 'del(5q)' above.)

-MDS with ring sideroblasts/mutated SF3B1 – We suggest luspatercept (Grade 2B). (See 'Ring sideroblasts/mutated SF3B1' above.)

-Likely to respond to immunosuppressive therapy – We suggest antithymocyte globulin plus cyclosporine A (Grade 2C). (See 'Likely to respond to immunosuppression' above.)

-None of the above syndromes – We treat like multiple cytopenias. (See 'Multiple cytopenias' above.)

●Isolated/predominant thrombocytopenia – For symptomatic thrombocytopenia and bone marrow blasts <5 percent, we suggest a thrombopoietin receptor agonist (TPO-RA; eg, romiplostim, eltrombopag) (algorithm 1) (Grade 2C). (See 'Predominant thrombocytopenia' above.)

We treat patients with thrombocytopenia and ≥5 percent blasts like multiple cytopenias. (See 'Multiple cytopenias' above.)

●Multiple cytopenias – For ≥2 symptomatic cytopenias, we suggest an HMA (azacitidine or decitabine) (algorithm 1) (Grade 2C). (See 'Multiple cytopenias' above.)

Azacitidine and decitabine have comparable efficacy and toxicity, and the choice is guided by patient preference. (See 'Hypomethylating agents' above.)

●Inadequate response – Treatment response is generally slow, so an adequate trial (eg, four to six months) should be given. (See 'Inadequate response to initial therapy' above.)

Bone marrow examination is performed for worsening cytopenias or increasing blasts.

For intolerable toxicity, we try judicious dose reduction or brief treatment delays before changing treatment.

●Second-line therapy – Guided by prior treatment, predominant cytopenia(s), toxicity, comorbidities, convenience, and patient preference.

•After an ESA – We suggest luspatercept (Grade 2C), but imetelstat or lenalidomide is acceptable. (See 'Erythropoiesis-stimulating agent failure' above.)

•After an HMA – Management varies with the cytopenias (see 'Hypomethylating agent failure' above):

-For isolated/predominant anemia, treat like symptomatic anemia. (See 'Erythropoietin >200 mU/mL' above.)

-For ≥2 cytopenias, options include lenalidomide, luspatercept, imetelstat, or allogeneic hematopoietic cell transplantation (for transplant-eligible patients).

•After other agents. (See 'After other agents' above.)

-After TPO-RA – We treat like multilineage cytopenias.

-After luspatercept or lenalidomide – We treat like ESA failure (described above).

ACKNOWLEDGMENTS

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.