Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS

INTRODUCTION — Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematologic malignancies that manifest as cytopenias (anemia, neutropenia, and/or thrombocytopenia) and abnormal cellular maturation, with variable rates of bone marrow failure and progression to acute myeloid leukemia (AML). Patients with MDS often have symptomatic anemia, infections related to neutropenia, and/or bleeding associated with thrombocytopenia. Much of the morbidity and death with MDS is due to consequences of cytopenias rather than transformation to AML.

Cases of MDS are diagnosed and classified according to specific molecular and genetic abnormalities using a contemporary classification system, as described separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

All patients require attention to potential hematologic complications of MDS. Other aspects of management are guided by the prognostic category (ie, lower-risk MDS versus higher-risk MDS), defined using a molecular-based model, such as the Molecular International Prognostic Scoring System (IPSS-M), as described separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'Mutation-based models'.)

This topic reviews management of hematologic complications for patients with lower-risk MDS.

Other aspects of MDS management are discussed separately:

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

●(See "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

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

EVALUATION — Evaluation for hematologic complications of MDS and alternative causes of cytopenias.

Details of evaluation, diagnosis, and classification of MDS are presented separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●History – Symptoms related to cytopenias (eg, fatigue, dyspnea, infections, bleeding/bruising).

Assessment for other potential causes of cytopenias, including medications, blood loss, infections, hemolysis, renal insufficiency, nutritional deficiencies, thyroid dysfunction, autoimmune disorders, and other conditions that can contribute to cytopenias, should be evaluated.

●Physical examination – Examination should note findings related to anemia (eg, pallor, tachycardia, tachypnea), occult blood loss, bleeding or bruising, splenomegaly, and evidence of infections.

●Laboratory studies

•Hematology

-Complete blood count (CBC) with differential leukocyte count

-Review of the blood smear

-Reticulocyte count and reticulocyte production index (RPI) (calculator 1) to help distinguish impaired red blood cell (RBC) production versus blood loss or hemolysis

•Chemistries

-Basic metabolic panel, kidney function, and liver function tests, including lactate dehydrogenase (LDH).

-Iron studies, including serum iron, transferrin, ferritin.

-Serum erythropoietin (EPO).

-Other laboratory tests, including thyroid function tests, folate, vitamin B12, serum copper, and viral serologies (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV]), are guided by clinical and laboratory findings.

●Bone marrow examination – Bone marrow aspirate and biopsy are key components of the initial diagnosis and classification of MDS, as discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Bone marrow examination'.)

Repeat bone marrow examination may be useful if there is suspicion of transformation to acute myeloid leukemia or other conditions that may exacerbate cytopenias.

The extent of cytopenias are features in most prognostic models of MDS, as discussed separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

ANEMIA — Anemia is the most common cytopenia in patients with MDS. More than three-quarters of patients with MDS have anemia, one-half of whom have hemoglobin (Hb) <10 g/dL [1]. Patients with MDS tend to be older (ie, median age >65 years at presentation) and/or have comorbid medical problems, so factors other than MDS may contribute to anemia.

Anemia can manifest as fatigue, weakness, exercise intolerance, loss of appetite/weight loss, angina, dizziness, dyspnea, headache, cognitive impairment, or an altered sense of wellbeing. Clinical manifestations of anemia in adults are discussed separately. (See "Diagnostic approach to anemia in adults", section on 'Correlation with symptoms'.)

Management of anemia in patients with MDS is guided by the degree of anemia-associated symptoms and the serum level of erythropoietin (EPO).

In general, management of anemia is not determined by the MDS subtype. However, patients who have MDS with deletion of chromosome 5 (with or without one additional chromosomal abnormality, except -7/del[7q]) or MDS with ring sideroblasts/SF3B1 mutation may be candidates for distinctive treatments, as discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Chromosome 5q deletion' and "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'MDS with ring sideroblasts'.)

Management of asymptomatic patients — We do not treat anemia based on the level of Hb alone in asymptomatic patients, as there is no evidence that treating asymptomatic anemia affects outcomes of patients with MDS.

However, we transfuse red blood cells (RBCs) if bleeding or the rate of decline of Hb suggests that the patient will soon become symptomatic, especially if there are comorbid cardiac, pulmonary, or neurologic conditions. RBC transfusion for such patients is discussed below. (See 'Red blood cell transfusions' below.)

Symptomatic patients — We stratify anemia management in symptomatic patients based on the level of serum EPO.

Serum erythropoietin ≤500 mU/mL — For patients with serum EPO ≤500 mU/mL, we recommend treatment with an erythropoiesis-stimulating agent (ESA) rather than RBC transfusions alone.

ESAs were more effective than placebo for achieving transfusion independence and raising the level of Hb in two randomized trials, and they were associated with improved quality of life and prolonged survival in some observational studies. There is little toxicity associated with ESAs in this setting. RBC transfusions can be used as the sole treatment of anemia, but repeated RBC transfusions may cause complications from chronic transfusion therapy (eg, alloimmunization, iron overload), as discussed below. (See 'Red blood cell transfusions' below.)

Although patients with MDS with certain del(5q) abnormalities or MDS with ring sideroblasts/mutated SF3B1 are managed distinctly, a trial of an ESA is acceptable in such patients who have anemia-related symptoms and serum EPO ≤500 mU/mL. Other aspects of management of these MDS subtypes are discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Special patient populations'.)

Choice of erythropoiesis-stimulating agent — Treatment with either recombinant epoetin alfa or darbepoetin alfa is acceptable for lower-risk MDS with EPO ≤500 mU/mL, based on similar efficacy and adverse effects (AEs).

Patients should be evaluated for thromboembolic risk prior to ESA therapy, and hypertension should be controlled before and during treatment.

Some experts consider an ESA plus filgrastim (granulocyte-colony stimulating factor [G-CSF]) acceptable for initial treatment. The administration of ESA plus filgrastim is discussed below. (See 'Inadequate response to erythropoiesis-stimulating agent' below.)

Outcomes of treatment with an ESA, with or without G-CSF, are presented below. (See 'Outcomes' below.)

Administration and toxicity — Various doses and schedules of ESAs have been used for treatment of anemia in patients with MDS. We generally begin treatment with either:

●Administration

•Epoetin alfa – Recombinant human epoetin 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 – 150 to 300 mcg subcutaneously every other week; some experts begin treatment with doses up to 500 mcg every other week.

Further details of ESA regimens (table 1) and additional aspects of care, including iron repletion, are provided separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Clinical use of ESAs in cancer patients'.)

Epoetin alfa is approved by the European Medicines Agency (EMA) for treatment of anemia in patients with lower-risk MDS with a serum EPO level ≤200 mU/mL; the manufacturer withdrew its request to the EMA for approval of darbepoetin for treating anemia in MDS. Neither epoetin alfa nor darbepoetin alfa is approved by the US Food and Drug Administration (FDA) for treatment of anemia in patients with MDS, despite their widespread use.

Use of ESAs is recommended by international clinical practice guidelines based on the large body of evidence demonstrating their effectiveness in lower-risk MDS. ESA use in MDS is supported by the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO), and European LeukemiaNet [2-6]. It should be noted that patients with low- or intermediate-1-risk MDS are an exception to the general recommendation from ASH and ASCO to avoid ESAs for the treatment of anemia associated with malignancy in patients who are not receiving concurrent myelosuppressive chemotherapy [2,3]. (See 'Society guideline links' below.)

●Adverse effects – ESAs can exacerbate hypertension, but there is no persuasive evidence that they increase thromboembolic complications or mortality in patients with MDS (as has been shown in other settings) or increase the rate of progression to acute myeloid leukemia (AML).

•Exacerbation of hypertension – Hypertension should be controlled before and during therapy with ESAs.

•Thrombotic risk – 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 [7].

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 erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Issues related to thromboembolic risk'.)

•Progression to acute myeloid leukemia – There is no clear evidence that ESAs are associated with increased transformation to AML. Rates of progression are low with both epoetin alfa and darbepoetin alfa and are comparable with rates in patients who receive supportive care alone [8-10].

Response to erythropoiesis-stimulating agent therapy — We assess transfusion needs and Hb after six to eight weeks of ESA therapy.

We treat with an ESA for ≥16 weeks before concluding that therapy was ineffective. We do not continue treatment for >6 months if no response was observed by then.

Initially, transfusions may be needed to manage symptoms while awaiting an erythroid response, but we then adjust ESA administration to the lowest level that enables avoidance of further RBC transfusions. Median time to erythroid response is five weeks (range, four to nine weeks), and duration of response ranges from 8 to >48 months [8,11-17].

We judge erythroid response to ESAs as follows:

●Adequate response – Hb 10 to 12 g/dL, Hb rise by ≥1.5 gm/dL, and/or reduced transfusion requirements.

Hematologic responses to treatment should follow the revised International Working Group (IWG) 2018 criteria [18].

Further management of patients with an adequate response to ESA therapy is discussed below. (See 'Adequate response to erythropoiesis-stimulating agent' below.)

●Inadequate response – Not meeting the criteria for an adequate response (described above) after ≥16 weeks of ESA treatment.

Further management of patients with an inadequate response is discussed below. (See 'Inadequate response to erythropoiesis-stimulating agent' below.)

Adequate response to erythropoiesis-stimulating agent — For patients with an adequate response to ESA therapy, we continue treatment and adjust administration to minimize transfusions and maintain Hb 10 to 12 g/dL.

If the rise of Hb is sufficient to avoid transfusions or if it increases ≥1.5 g/dL in any two-week period, the dose of epoetin alfa can be reduced by 25 percent, or the dose of darbepoetin alfa can be reduced by 40 percent. Less frequent dosing is an acceptable alternative to dose reduction.

For patients who subsequently lose their response to ESA treatment, we manage as per an inadequate initial response. (See 'Inadequate response to erythropoiesis-stimulating agent' below.)

Inadequate response to erythropoiesis-stimulating agent — For patients with an inadequate response (ie, Hb rise <1.5 g/dL or no improvement in transfusion frequency) after ≥16 weeks of treatment, some experts add filgrastim to the ESA.

Some experts consider adding lenalidomide to ESA therapy as an acceptable alternative approach. While some patients may favor lenalidomide because it is an oral agent, this approach may exacerbate thromboembolic risk and/or other cytopenias (ie, neutropenia or thrombocytopenia).

Only small studies have reported effects of adding G-CSF to ESA therapy after an inadequate response to an ESA alone:

●Addition of G-CSF to epoetin alfa was associated with a better response in patients who did not initially respond adequately or who had only a transient response to epoetin alone [19]. Among 27 patients who did not respond adequately to epoetin alfa, 22 percent had an erythroid response when G-CSF 1 mcg/kg per day was added.

●Among 30 patients who had an inadequate response to epoetin beta alone, addition of G-CSF 300 mcg subcutaneously twice weekly was associated with an erythroid response in 44 percent [20].

We monitor the response to ESA plus G-CSF as described above. (See 'Response to erythropoiesis-stimulating agent therapy' above.)

Outcomes — ESAs can reduce transfusion needs and ameliorate anemia in approximately one-half of patients with lower-risk MDS, and there is some evidence that these agents can improve overall survival (OS) and quality of life (QOL). The benefits and AEs associated with epoetin alfa and darbepoetin alfa do not differ significantly, but no randomized trials have directly compared them for patients with MDS and symptomatic anemia.

Numerous studies report erythroid responses in one-quarter to three-quarters of patients in this setting, but reports vary widely. Differences in outcomes among studies are due, in part, to various inclusion criteria, treatment regimens, and response criteria [8].

●Systematic review

•A systematic review of 35 studies reported that ESA treatment was associated with clinical benefits and very few safety concerns [8]. There was consistent improvement in erythroid response across studies, regardless of prior ESA treatment; responses ranged from 45 to 73 percent in ESA-naïve patients and 25 to 75 percent in patients with prior ESA exposure. There was no clear difference in responses to epoetin alfa and darbepoetin alfa. Several of the studies reported improved OS, some showed improved QOL, and there was no evidence of an increased rate of progression to AML.

●Randomized trials of erythropoiesis-stimulating agents versus placebo or transfusion support

•A phase 3 trial reported that darbepoetin alfa was more effective than placebo for achieving transfusion independence among 147 patients with lower-risk MDS, hemoglobin ≤10 g/dL, low transfusion burden, and serum EPO ≤500 mU/mL [21]. 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).

•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, Hb ≤10 g/dL, transfusion dependence (≤4 RBC units within eight weeks of randomization), and baseline EPO <500 mU/mL [22]. Epoetin alfa achieved 32 percent erythroid response at week 24, compared with 4 percent with placebo; there was no difference in rates of progression to AML. Responses were only seen in patients with EPO <200 mU/mL.

•Compared with transfusion support alone, epoetin alfa alone achieved more erythroid responses (36 versus 10 percent), but no difference in OS, in a phase 3 trial of 110 patients with MDS [19].

•Epoetin alfa plus G-CSF achieved superior erythroid response compared with transfusions alone in a phase 3 trial in 60 patients [23]. At 12 weeks, 42 percent of patients who received G-CSF plus epoetin alfa had an erythroid response compared with none who received transfusions.

●Other outcomes

•Survival – Some studies reported that ESA treatment was associated with improved OS.

-ESA treatment was associated with improved OS in a retrospective study that compared 284 patients treated with an ESA with 225 patients who received only supportive care [17]. 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]).

-Subset analysis of a prospective study reported that OS was superior in ESA-responsive patients compared with nonresponders (six versus two years, respectively) [19]. A retrospective study reported that treatment with an ESA plus G-CSF was associated with improved survival compared with supportive care alone (HR 0.61 [95% CI 0.44-0.83]) [9].

-Mortality was 2 percent after 48 weeks of darbepoetin therapy in one phase 3 trial, but none of the fatal events were considered treatment related [21]. In another phase 3 trial, darbepoetin alfa was associated with higher mortality at 52 weeks (8 versus 2 percent) than placebo, but none of the deaths were attributed to the ESA [22]. Epoetin alfa did not achieve higher OS at 6 or 12 months than standard care in another phase 3 trial, but there was a trend toward higher OS at last follow-up (28 versus 16 percent at a median of nearly six years follow-up) [19].

•Quality of life – Some studies have reported improved QOL with ESA treatment.

-There was no significant difference in QOL with darbepoetin alfa compared with placebo, but differences may have been obscured because patients in the control arm were transfused to maintain Hb >8 g/dL [21].

-Another phase 3 trial reported no difference in QOL (measured by Functional Assessment of Cancer Therapy [FACT]-Anemia score) between epoetin alfa plus G-CSF compared with transfusion support alone [23].

-Various single-arm studies reported improved QOL in association with ESA therapy [13,15,24-27].

•Initial treatment with erythropoiesis-stimulating agent plus granulocyte-colony stimulating factor

-A meta-analysis reported that initial treatment with G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) added to standard-dose epoetin alfa (a dose of 30,000 to 40,000 units weekly) was associated with inferior responses compared with higher-dose epoetin alfa alone (ie, 60,000 to 80,000 units weekly) [28]. Higher-dose epoetin alfa was associated with higher erythroid response (65 percent) compared with either standard-dose epoetin alfa plus G-/GM-CSF (51 percent) or standard-dose epoetin alfa alone (49 percent). In the subset of patients who were transfusion dependent, addition of G-CSF/GM-CSF was not associated with lower rates of transfusion.

-There was no significant difference in erythroid response between patients treated with an ESA plus G-CSF (58 percent) compared with an ESA alone (66 percent) in a retrospective analysis of 403 patients [17]. The frequency of AML progression was similar in both cohorts.

-Other studies reported similar rates of erythroid response among patients treated with an ESA, whether with or without G-CSF [9,24,29].

Serum erythropoietin >500 mU/mL — For symptomatic patients with EPO >500 mU/mL, we stratify treatment according to the likelihood of a response to immunosuppression (based on clinical and pathologic features).

Assess likelihood of response to immunosuppressive therapy — We estimate the likelihood that a patient will respond to immunosuppressive therapy (IST) using the following criteria [30,31]:

●Age ≤60 years and <5 percent marrow blasts

or

●Hypocellular marrow, paroxysmal nocturnal hemoglobinuria clone positivity, or a STAT3 mutant cytotoxic T cell clone

Likely to respond to immunosuppressive therapy — For patients with EPO >500 mU/mL who are more likely to respond to immunosuppression, we suggest IST using horse antithymocyte globulin, with or without cyclosporin A, and with or without eltrombopag.

No studies have compared various IST regimens for patients with MDS. The suggestion for adding the thrombopoietin mimetic, eltrombopag, is based on studies of adults with severe aplastic anemia [32]. Addition of eltrombopag to IST in severe aplastic anemia was associated with improved hematologic response and overall response rate (ORR) compared with a historical cohort; there was no increase in clonal evolution. Another study reported similar rates of two-year OS, complete response (CR), and time to response when IST (antithymocyte globulin, methylprednisolone, cyclosporin A, and G-CSF) was administered with or without addition of eltrombopag [33].

Details of administration, AEs, and outcomes with IST in patients with severe aplastic anemia are discussed separately. (See "Treatment of aplastic anemia in adults", section on 'Triple IST (hATG, CsA, EPAG)'.)

Eltrombopag is not approved by the FDA or the EMA for use in patients with MDS.

Unlikely to respond to immunosuppressive therapy — For patients who are less likely to respond to IST, we treat the underlying MDS according to the MDS prognostic category and disease subtype, as described separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Symptomatic MDS' and "Treatment of high or very high risk myelodysplastic syndromes".)

Treatments

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

●Transfusion threshold – Transfusions should be used primarily to relieve symptoms related to anemia and to prevent complications in patients who have significant 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 Hb ≤8 g/dL [34]. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Thresholds for specific patient populations'.)

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

CMV-negative or leukapheresis blood products should be used, whenever possible, for recipients who are CMV negative. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)

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", section on 'Irradiation'.)

●Toxicity – AEs associated with chronic transfusion include:

•Transfusion reactions

•Infections

•Alloimmunization

•Iron overload

AEs associated with RBC transfusions are discussed in detail separately. (See "Approach to the patient with a suspected acute transfusion reaction".)

●Iron overload – Chronic transfusion therapy may be associated with iron overload and resultant organ toxicity, but this is predominantly a problem for patients who have received >50 units of RBCs and who have longer life expectancy.

•Evaluation – We generally measure serum ferritin before or early in chronic transfusion therapy and monitor ferritin periodically in a patient who has received >20 units of RBC transfusion.

Assessment of iron stores with magnetic resonance imaging (MRI) or a liver biopsy is discussed separately. (See "Management of thalassemia", section on 'Assessment of iron stores and initiation of chelation therapy'.)

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

We consider iron chelation therapy after transfusion of approximately 50 units of RBCs in a patient with lower-risk MDS and long life expectancy, or if 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 chelators: 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 [35].

Erythropoiesis-stimulating agents — Administration, toxicity, and outcomes with ESA therapy for patients with MDS and symptomatic anemia are presented above. (See 'Serum erythropoietin ≤500 mU/mL' above.)

Other agents — Other agents have been associated with improvements in anemia in selected patients with MDS, including those with MDS with del(5q) and MDS with ring sideroblasts/SF3B1 mutation.

Lenalidomide — Lenalidomide can reduce transfusion needs in patients with MDS with del(5q) and in a subset of patients with non-(del5q), lower-risk MDS.

Lenalidomide is approved by the FDA and the EMA for treatment of transfusion-dependent MDS with del(5q).

Lenalidomide may cause thrombocytopenia and neutropenia, increase risk of arterial and venous thrombosis/pulmonary embolism, and is associated with embryo-fetal toxicity.

Lenalidomide has been given with ESAs for patients with lower-risk MDS.

●An open-label trial randomly assigned 195 evaluable patients with lower-risk, non-del(5q) MDS to lenalidomide plus an ESA versus lenalidomide alone [36]. After four cycles of treatment, the combination achieved a higher rate of major erythroid response compared with lenalidomide alone (28 versus 12 percent, respectively), and the median duration of response was 24 months compared with 13 months.

●One-quarter of 23 patients with non-del(5q) MDS who did not have an erythroid response to lenalidomide alone responded to combined treatment with lenalidomide plus an ESA [37].

Treatment, AEs, and outcomes with lenalidomide are discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Lenalidomide'.)

Luspatercept — Luspatercept is a transforming growth factor (TGF)-beta antagonist that can reduce transfusion dependence in patients with MDS with ring sideroblasts/SF3B1 mutation. Luspatercept was superior to an ESA for front-line treatment of transfusion-dependent patients with lower-risk MDS in a phase 3 trial; most of the benefit was seen in patients with MDS with ring sideroblasts [38].

Luspatercept is approved by the EMA for treatment of transfusion-dependent anemia in adults with lower-risk MDS with ring sideroblasts/SF3B1 mutation who had an unsatisfactory response to or are ineligible for ESA therapy.

Luspatercept is approved by the FDA for treatment of transfusion-dependent anemia in adults with lower-risk MDS, including ESA-naïve patients.

Treatment with luspatercept is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Luspatercept'.)

Imetelstat — Imetelstat is an antisense oligonucleotide telomerase inhibitor that can reduce transfusion dependence in selected patients with lower-risk MDS, as discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Imetelstat'.)

Imetelstat is not approved by the FDA or the EMA for treatment of MDS.

NEUTROPENIA — Patients with lower-risk MDS are at increased risk for infections due to reduced numbers of neutrophils and/or granulocyte dysfunction (eg, impaired chemotaxis and microbial killing).

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 [5]. Bacterial infections predominate in this setting (especially those involving skin), but fungal, viral, and mycobacterial infections can occur, especially in patients treated with immunosuppressive agents [39]. Risk factors for infections in hospitalized patients with MDS include higher-risk MDS, ANC <500/microL, and chronic obstructive pulmonary disease [40].

Our approach to 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). (See 'Society guideline links' below.)

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). Granulocyte-colony stimulating factor (G-CSF) can be added to antimicrobial agents in the setting of neutropenic fever.

Evaluation of febrile neutropenia and empiric antibiotic therapy are discussed separately. (See "Diagnostic approach to the adult cancer patient with neutropenic fever" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

●Asymptomatic neutropenia

•Granulocyte-colony stimulating factor – Filgrastim, pegylated filgrastim, and biosimilars can improve neutropenia, but there is no evidence that routine prophylactic administration 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 or not.

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".)

●Suspected 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".)

THROMBOCYTOPENIA — Patients with MDS are at increased risk for bleeding due to thrombocytopenia, qualitative platelet disorders, and/or disorders of coagulation. Management of bleeding is guided by the underlying cause, as described separately. (See "Approach to the adult with a suspected bleeding disorder".)

Platelets <50,000/microL are seen in one-third of patients with lower-risk MDS [5].

Our approach to managing bleeding in the patient with MDS is similar to those of the American Society for Clinical Oncology (ASCO) (table 2) and the Association for the Advancement of Blood and Biotherapies (AABB) [41,42].

Platelet transfusion — Platelet transfusions are the mainstay of bleeding management in bleeding patients with either quantitative or qualitative (ie, functional) 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 [43].

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'.)

Refractory bleeding — For patients with platelets ≤20,000/microL and clinical bleeding who do not respond to platelet transfusions or aminocaproic acid, we suggest treatment with a thrombopoietin (TPO) mimetic (ie, romiplostim or eltrombopag).

We generally limit TPO mimetic administration to patients with lower-risk MDS and <5 percent blasts to avoid potentially exacerbating progression to acute myeloid leukemia (AML). Although there is controversy about whether TPO mimetics can accelerate progression to AML, a meta-analysis that evaluated trials of a TPO versus placebo found no clear evidence of a difference in mortality or premature progression to AML [44].

Either romiplostim or eltrombopag can decrease bleeding, reduce platelet transfusions, and aid timely administration of MDS treatments, but no prospective trial has directly compared these TPO mimetics in this setting.

Neither romiplostim nor eltrombopag is approved by the US Food and Drug Administration or the European Medicines Agency for use with MDS.

Details of administration and adverse effects (AEs) with TPO mimetics are presented separately. (See "Clinical applications of thrombopoietic growth factors".)

●Romiplostim – Romiplostim is a "peptibody" that is administered 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 [45].

•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 [46]. 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-years follow-up, there was no difference in overall survival (OS) or progression to AML between treatment groups [47].

•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 [48]. 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 [49].

•Romiplostim was safe and associated with trends toward fewer bleeding events and higher platelet counts in patients treated with decitabine [50] and with fewer dose reductions/delays due to thrombocytopenia in patients treated with lenalidomide [51].

●Eltrombopag – Eltrombopag is an orally available nonpeptide TPO receptor agonist. 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 [52]. Eltrombopag was associated with fewer bleeding events (14 versus 42 percent) but more grade ≥3 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 [53]. Six patients had disease progression that was not associated with expansion of mutated clones, and no patient progressed to AML while on study.

•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 [54].

•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 [55].

TRANSFORMATION TO ACUTE MYELOID LEUKEMIA — Patients with MDS have variable rates of transformation to acute myeloid leukemia (AML) that are closely associated with the MDS prognostic category (table 3).

The categorization and distinction between MDS and AML differ between the two contemporary systems for diagnosis and classification of hematologic malignancies [56,57], as discussed separately. (See "Classification of hematopoietic neoplasms", section on 'Myeloid neoplasms'.)

The decision of when and with what to treat a patient with AML-directed therapy is individualized and is discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults" and "Acute myeloid leukemia: Management of medically unfit adults".)

MONITORING — Patients with MDS should be followed to monitor hematologic parameters, clinical manifestations, and disease progression. The schedule and protocol for follow-up should be individualized based on the severity of cytopenias, degree of symptoms, and concerns on the part of the patient and clinician.

Patients with hematologic complications of lower-risk MDS are followed with clinical evaluation and complete blood count with differential leukocyte count. We assess symptoms, transfusion needs, trends of blood counts, and quality of life every two to six months, according to clinical judgment.

Outside of a clinical study, we do not perform routine bone marrow examinations unless there is evidence of worsening cytopenias or other indications of disease progression.

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: Autologous 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 – Management of hematologic complications is needed for all patients with myelodysplastic syndromes/neoplasms (MDS). Most morbidity and deaths in patients with lower-risk MDS are related to cytopenias rather than progression to acute myeloid leukemia (AML).

Diagnosis, classification, and risk stratification of MDS are discussed separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)" and "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)

●Evaluation – Clinical and laboratory evaluation is discussed above. (See 'Evaluation' above.)

●Asymptomatic anemia – We do not treat anemia based on the level of hemoglobin (Hb) alone (ie, without anemia-associated symptoms). However, we transfuse red blood cells (RBCs) if bleeding, hemolysis, or declining Hb suggests that the patient will soon become symptomatic, especially in those with comorbid conditions. (See 'Management of asymptomatic patients' above.)

●Symptomatic anemia – We stratify management of anemia in symptomatic patients based on the level of serum erythropoietin (EPO). (See 'Symptomatic patients' above.)

●Serum erythropoietin ≤500 mU/mL – For symptomatic patients with serum EPO ≤500 mU/mL, we recommend epoetin alfa or darbepoetin alfa rather than RBC transfusions alone (Grade 1B). (See 'Serum erythropoietin ≤500 mU/mL' above.)

Treatment with either agent is acceptable, based on similar efficacy and adverse effects (AEs). Dosing (table 1) and AEs are discussed above. (See 'Administration and toxicity' above.)

Consequences of chronic RBC transfusion therapy are discussed above. (See 'Red blood cell transfusions' above.)

•Response assessment – We assess response after six to eight weeks of erythropoiesis-stimulating agent (ESA) therapy and treat for ≥16 weeks before concluding therapy is ineffective; treatment is discontinued if no response is observed after six months.

We consider reduced transfusion requirements, Hb 10 to 12 g/dL, or Hb rise by ≥1.5 gm/dL an adequate response. (See 'Response to erythropoiesis-stimulating agent therapy' above.)

-Adequate response – Continue treatment and adjust the dose or treatment interval to minimize transfusions and maintain Hb 10 to 12 g/dL. (See 'Adequate response to erythropoiesis-stimulating agent' above.)

-Inadequate response – For an inadequate response after ≥16 weeks of treatment, we suggest adding granulocyte-colony stimulating factor (G-CSF) to the ESA (Grade 2C). (See 'Inadequate response to erythropoiesis-stimulating agent' above.)

Management of patients with an inadequate response ESA plus G-CSF is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

●Erythropoietin >500 mU/mL – Management is guided by the likelihood of responding to immunosuppressive therapy (IST), as described above. (See 'Assess likelihood of response to immunosuppressive therapy' above.)

•Likely to respond to immunosuppressive therapy – We suggest IST using horse antithymocyte globulin, with or without cyclosporin A, and with or without eltrombopag (Grade 2C). (See 'Likely to respond to immunosuppressive therapy' above.)

•Unlikely to respond – Management is guided by MDS prognostic score. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)".)

●Neutropenia – There is no evidence that routine prophylactic G-CSF or antibiotics benefit asymptomatic patients with lower-risk MDS. (See 'Neutropenia' above.)

●Thrombocytopenia

•Platelet transfusions – Transfusions are the mainstay of managing bleeding in patients with severe thrombocytopenia. (See 'Platelet transfusion' above.)

•Refractory bleeding – For thrombocytopenic patients with continued bleeding after platelet transfusions and antifibrinolytic agents or with severe thrombocytopenia refractory to platelet transfusion, we suggest romiplostim or eltrombopag (Grade 2C). Either agent can reduce bleeding and improve platelet counts, and there is no persuasive evidence of increased progression to AML. (See 'Refractory bleeding' 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.