INTRODUCTION — The myelodysplastic syndromes (MDS) comprise a range of hematologic malignancies that are characterized by isolated or multiple cytopenias (anemia, neutropenia, and/or thrombocytopenia) accompanied by abnormal cellular maturation. As a result, patients with MDS are at risk for symptomatic anemia, infections, bleeding, and variable rates of bone marrow failure and progression to acute myeloid leukemia (AML). Much of the morbidity and most deaths from MDS are due to the consequences of the cytopenias rather than transformation to AML. Cytopenias and associated complications may be managed by supportive therapy alone or together with definitive therapy for the underlying MDS.
This topic will review management of hematologic complications of MDS.
Clinical manifestations, diagnosis, and treatment of MDS are presented separately.
●(See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)
●(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".)
MDS WITH DEL(5q) ABNORMALITIES — MDS associated with a del(5q) cytogenetic abnormality has distinctive clinical features and responsiveness to immunomodulatory drugs (eg, lenalidomide). Our approach to management of MDS with del(5q) abnormalities is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Lenalidomide'.)
ANEMIA
Evaluation of anemia — Anemia is present in more than three-quarters of patients with MDS, half of whom have hemoglobin <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 other factors, besides MDS, may contribute to anemia.
Anemia can be 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'.)
Patients should be evaluated for other factors that may contribute to anemia in the setting of MDS, including blood loss, hemolysis, renal insufficiency, medications, nutritional deficiencies, thyroid dysfunction, autoimmune disorders, and anemia of chronic disease. Evaluation should include a history and physical examination; complete blood count (CBC) with differential; review of the peripheral blood smear; reticulocyte count; and investigation for occult blood loss. Calculation of the reticulocyte production index (RPI) (calculator 1) is useful for distinguishing between impaired red blood cell (RBC) production versus blood loss or hemolysis.
Other laboratory studies that may be useful to identify factors that exacerbate anemia in the patient with MDS include renal and thyroid function tests and measurement of serum iron, transferrin, ferritin, folate, vitamin B12, copper, and erythropoietin (EPO). Depending on the severity of anemia and associated findings, evaluation may require a repeat bone marrow examination. Interpretation of findings from the evaluation of anemia is discussed separately. (See "Diagnostic approach to anemia in adults".)
The degree of anemia is an important laboratory feature in most prognostic models of MDS, as discussed separately. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults".)
Selection of therapy — Selection of therapy for anemia is influenced by the severity of symptoms, underlying cause(s), and comorbid medical conditions. We suggest using the revised International Prognostic Scoring System (IPSS-R) (table 1) to determine the MDS prognostic category, because the likelihood of response to recombinant erythropoiesis-stimulating agents (ESA) is influenced by the MDS prognostic category. (See "Prognosis of myelodysplastic neoplasms/syndromes (MDS) in adults", section on 'IPSS-R (IPSS-Revised)'.)
Anemia may be improved or exacerbated by treatment of the underlying MDS. The approach to treatment of MDS is discussed separately. (See "Overview of the treatment of myelodysplastic syndromes".)
Management of MDS with del(5q) is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Chromosome 5q deletion'.)
Symptomatic — For symptomatic patients, our approach to treatment of anemia is influenced by the MDS prognostic category, level of RBC production based on RPI (calculator 1), and serum EPO level:
●Low/very low/intermediate risk MDS (ie, IPSS-R ≤4.5 points) (table 1) – Anemia may improve or may be exacerbated by treatment of the underlying MDS. The approach to treatment for lower-risk MDS is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)".)
•Impaired RBC production (ie, RPI <2) and serum EPO ≤500 mU/mL – We suggest initial treatment with an ESA rather than chronic transfusion therapy or treatment with an ESA plus a myeloid growth factor. In this setting, treatment with an ESA generally offers the most favorable balance of benefits and toxicity; in comparison, the alternative approaches are associated with more substantial complications or toxicity. It should be noted that the risk for thrombosis is increased in certain patients who are treated with ESAs, as described below. (See 'Erythropoiesis-stimulating agents' below.)
•Adequate RBC production (ie, RPI ≥2) or serum EPO >500 mU/mL – We consider RBC transfusions or a trial of an ESA (alone or together with a myeloid growth factor) to be acceptable approaches. It is especially important to seek causes of blood loss or hemolysis in the setting of adequate RBC production. Transfusions can rapidly improve symptoms, but chronic transfusion therapy is associated with risks of alloimmunization and other adverse effects. ESA therapy alone is unlikely to be beneficial in this setting, while an ESA plus a myeloid growth factor has a low likelihood of improving an erythroid response but is associated with added toxicity and expense. (See 'Red blood cell transfusions' below and 'Add a myeloid cytokine' below.)
●High/very high risk MDS (ie, IPSS-R >4.5 points) (table 1) – For patients with adverse prognosis MDS, we suggest chronic transfusion therapy, together with definitive therapy of the underlying disease, as an initial approach, because ESA therapy (alone or together with a myeloid growth factor) is less likely to be beneficial. Other contributing factors (eg, bleeding, hemolysis) should be corrected. Although transfusions can rapidly improve symptoms, chronic transfusion therapy is associated with risks of alloimmunization and other adverse effects, as discussed below. (See 'Red blood cell transfusions' below.)
Anemia may improve or may be exacerbated by treatment of the underlying MDS. The approach to treatment for higher-risk MDS is discussed separately. (See "Treatment of high or very high risk myelodysplastic syndromes".)
Asymptomatic — For asymptomatic patients, we generally do not treat on the basis of a specific value for hemoglobin (Hb) or hematocrit (Hct). However, we do intervene if ongoing bleeding, hemolysis, or the rate of decline of Hb/Hct suggests that the patient will soon become symptomatic, especially if there are comorbid cardiac, pulmonary, or neurologic conditions. Decisions regarding transfusion support in this setting are discussed separately. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Thresholds for specific patient populations'.)
Anemia may respond or may be exacerbated by treatment of the underlying MDS, as discussed separately. (See "Overview of the treatment of myelodysplastic syndromes".)
Monitoring of MDS is discussed below. (See 'Monitoring' below.)
Treatment
Erythropoiesis-stimulating agents — Erythropoiesis-stimulating agents (ESAs), such as epoetin alfa or darbepoetin alfa, can improve anemia associated with MDS, reduce the need for RBC transfusion, and improve the quality of life, but they may increase the risk for thrombotic events in some patients. The likelihood of a response to ESA therapy is influenced by the MDS prognostic category, level of baseline serum EPO, and degree of transfusion dependence [1]. Our approach to selection of patients for ESA therapy is described above. (See 'Selection of therapy' above.)
ESA administration
●Selection of an ESA – The choice of epoetin alfa versus darbepoetin alfa is influenced by clinician and patient preference, as neither agent provides a superior balance of benefit and risk [2].
Details of ESA regimens 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'.)
●Thrombotic risk – The risk for thrombosis in patients with MDS appears to be no higher than in age-matched patients without MDS. However, prior to beginning an ESA:
•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'.)
•Hypertension should be controlled before and during therapy with ESAs.
●Dose adjustment – We suggest treating with an ESA for at least 6 to 12 weeks before concluding that the therapy is ineffective, but we do not continue for more than six months if no response is observed. Transfusions may be needed initially 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.
As examples, if the rise of Hb is sufficient to avoid transfusions or increases >1 g/dL in any given 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.
Management of patients with an ineffective response to ESA therapy is discussed below. (See 'Ineffective response' below.)
●Response to ESAs – Rates of erythroid response to an ESA alone range from 14 to 73 percent and may be as high as 45 to 73 percent in ESA-naive patients with MDS [2-4]. Both epoetin alfa and darbepoetin alfa can reduce the incidence of RBC transfusions and there is a trend toward more favorable response rates with higher doses of both agents [2,5,6]. Median time to erythroid response is 5 weeks (range, 4 to 9 weeks) and duration of response ranges from 8 to >48 months [2,6-12].
A systematic review and network meta-analysis of 35 studies identified no clear difference in efficacy or safety between epoetin alfa and darbepoetin alfa [2]. In responding patients, ESAs consistently raised and sustained levels of Hb and some of the studies reported that treatment was associated with improved quality of life. Rates of progression to acute myeloid leukemia (AML) are low with both epoetin alfa and darbepoetin alfa and are comparable to AML progression with supportive care alone [2,5,13].
Use of ESAs for treatment of symptomatic anemia in patients with MDS is an unlabeled or investigational use according to the US Food and Drug Administration. However, use of ESAs in MDS is supported by the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) [14-16]. 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 [14,15]. (See 'Society guideline links' below.)
Ineffective response — For patients with an inadequate response to ≥12 weeks of treatment with an ESA, we initially either increase the ESA dose and/or shorten the interval between treatments. There is no demonstrated benefit in crossing-over from epoetin alfa to darbepoetin alfa or vice versa. (See 'Increase ESA dose or frequency' below.)
For patients who decline an alteration of ESA dose or frequency and for those in whom there is concern about excessive thrombosis risk, we either add a myeloid cytokine to the ESA or we choose treatment based on the morphologic or cytogenetic features of the MDS cells. (See 'Add a myeloid cytokine' below and 'Guided by morphologic/cytogenetic features' below.)
Increase ESA dose or frequency — We generally begin by increasing the ESA dose and/or shortening the treatment interval. Examples include increasing epoetin alfa to 60,000 to 80,000 U/week or administering darbepoetin alfa 500 mcg every two weeks.
For patients who have an inadequate response to ESA dose/schedule adjustment we either add a myeloid cytokine to the ESA or we choose treatment based on the morphologic or cytogenetic features of the MDS cells. (See 'Add a myeloid cytokine' below and 'Guided by morphologic/cytogenetic features' below.)
Add a myeloid cytokine — Addition of G-CSF or GM-CSF to an ESA may improve the likelihood of an erythroid response, but it can be associated with additional adverse effects (eg, bone pain and fevers) and expense [17].
A meta-analysis and a large retrospective study suggested that an ESA plus either G-CSF or GM-CSF did not yield higher erythroid response rates than high dose ESA alone [12,18], but a prospective study reported that addition of G-CSF to darbepoetin alfa improved response rates after failure of ESA alone [7]. (See 'Erythropoiesis-stimulating agents' above.)
Guided by morphologic/cytogenetic features — For patients who do not respond to increasing the dose or frequency of the ESA and/or adding a myeloid cytokine, we choose therapy based on morphologic and cytogenetic features of the MDS cells, as follows:
●MDS with ring sideroblasts – For patients with lower-risk MDS with ring sideroblasts, treatment with luspatercept was superior to placebo for achieving transfusion-independence in patients with lower-risk MDS with ring sideroblasts [19], as discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Luspatercept'.)
●MDS with del(5q) – For patients with MDS with del(5q), single-agent lenalidomide reduced RBC transfusion needs in two-thirds and improved quality of life [20-22]. Lenalidomide may be associated with significant thrombocytopenia and neutropenia, increased risk of arterial and venous thrombosis and pulmonary embolism, and embryo-fetal toxicity. Lenalidomide is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of MDS with del(5q). Treatment with lenalidomide for MDS with del(5q) is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Lenalidomide'.)
●Non-del(5q) MDS – For patients with MDS who do not have del(5q), other treatment options include:
•Lenalidomide plus an ESA – An open-label trial randomly assigned 195 evaluable patients with lower-risk, non-del(5q) MDS to either lenalidomide plus an ESA versus lenalidomide alone [23]. 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. In a separate study, 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 [24].
•Lenalidomide (single agent) – Treatment with single-agent lenalidomide achieved transfusion-independence in more than one-quarter of patients in a phase 3, placebo-controlled trial of 239 patients with non-(del5q) lower-risk MDS [25]. Treatment of patients with non-(del5q) MDS is an off-label use of lenalidomide. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Lenalidomide'.)
•Hypomethylating agents – A shortened course of azacitidine or decitabine (eg, 3 or 5 days of treatment every 28 days) may be beneficial for patients who did not respond adequately to an ESA [26,27]. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Hypomethylating agents'.)
•Immunosuppressive therapy – For patients with a good probability of responding to immunosuppressive therapy (eg, age <60 years, ≤5 percent blasts, hypocellular bone marrow, paroxysmal nocturnal hemoglobinuria [PNH]-positive clones), treatment with anti-thymocyte globulin (ATG) plus cyclosporine can produce hematologic responses. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Immunosuppressive therapy'.)
•CC-486 – CC-486 is an oral hypomethylating agent that reduced transfusion-dependence in a phase 3 trial that included 216 patients with lower-risk MDS [28]. Compared with placebo, transfusion-independence was more common with CC-486 (31 versus 11 percent, respectively) and of longer duration (11 versus 5 months). However, there were more early deaths (16 versus 6 patients) associated with CC-486, primarily related to infections.
We await confirmatory studies before routinely offering CC-486 in this setting.
•Imetelstat – More than one-third of patients who had an inadequate response to an ESA alone achieved transfusion-independence when treated with the investigational agent imetelstat [29]. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Imetelstat'.)
Red blood cell transfusions — RBC transfusions can provide prompt relief for symptomatic patients and improve health-related quality of life but may be associated with fluid overload, transfusion reactions, and/or alloimmunization. Iron overload may occur in heavily transfused patients who have a longer life expectancy.
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 indications for transfusion vary with patient age, symptoms, and medical comorbidities. There is no agreed-upon trigger value for RBC transfusion, but many centers suggest transfusion for asymptomatic patients with hemoglobin ≤8 g/dL. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)
We suggest use of leukoreduced transfusion products to decrease risks for platelet isosensitization, febrile transfusion reactions, cytomegalovirus (CMV) and other viral infections, and immunosuppression. Although graft-versus-host disease is unusual in patients with MDS receiving transfusions, many centers routinely irradiate blood products for such patients. Administration of CMV-negative, irradiated blood products is of special importance for patients who are candidates for hematopoietic cell transplantation. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction' and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Irradiation'.)
Risks of RBC transfusion include transfusion reactions (eg, hemolytic, febrile, non-hemolytic, lung injury), transfusion-associated circulatory overload (TACO), virus transmission (eg, hepatitis, human immunodeficiency virus [HIV]), increased thrombotic risks, and alloimmunization. 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. We generally measure serum ferritin before or early in the course of chronic transfusion therapy. We consider monitoring ferritin periodically in a patient who has received >20 units of RBC transfusion. 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 magnetic resonance imaging (MRI) or a liver biopsy suggests substantial liver iron overload. Assessment of iron stores and chelation therapy for iron overload are discussed separately. (See "Management of thalassemia", section on 'Assessment of iron stores and initiation of chelation therapy'.)
No controlled prospective studies have demonstrated a benefit from iron chelation in MDS, and there is no consensus regarding an optimal chelation regimen. A multicenter trial (TELESTO) that randomly assigned patients to oral deferasirox versus placebo closed prematurely due to lagging patient enrollment [30]. The primary objective of the trial was event-free survival (a composite of various measures of organ dysfunction, hospitalization, and complications), which modestly favored the chelation arm. However, because of changes in the trial design, study objectives, patient accrual, and the diverse components of the primary objective, we judge that no conclusions about the value of chelation can be drawn from this study.
Chelation therapy is expensive, cumbersome, and may be associated with significant adverse effects (eg, gastrointestinal symptoms, impaired kidney function) that should be weighed against potential benefits. The choice of chelation agent and regimen is influenced by clinician experience, patient preference, and cost, as discussed separately. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)
INFECTIONS — Infections are a major cause of morbidity and mortality in patients with MDS. The increased risk for infections is related to neutropenia and/or granulocyte dysfunction (eg, impaired chemotaxis and microbial killing). Bacterial infections predominate, especially those involving the skin. Fungal, viral, and mycobacterial infections are less common but may be exacerbated by concurrent administration of immunosuppressive agents.
Prophylaxis and treatment of infectious complications in neutropenic patients are presented separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Overview of neutropenic fever syndromes" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies".)
Evaluation — Evaluation of a patient with fever or other suspected findings of an infection should include history and physical examination, complete blood cell count with differential, and other laboratory studies.
The neutropenic patient (ie, absolute neutrophil count <500/microL) must be evaluated urgently and should receive empiric antibacterial therapy immediately after blood cultures have been obtained and before other investigations have been completed. The diagnostic approach and empiric therapy for the patient with febrile neutropenia are discussed separately. (See "Diagnostic approach to the adult cancer patient with neutropenic fever".)
Evaluation of the non-neutropenic patient with MDS suspected of having an infection is informed by findings from clinical evaluation and screening laboratory studies. It should be recognized that a patient who is not neutropenic may still be immunocompromised (on the basis of qualitative, functional leukocyte or humoral abnormalities). Evaluation should include:
●History and physical examination.
●Chemistry studies, including electrolytes, renal function tests, transaminases, bilirubin, amylase.
●Gram stain and culture of urine, sputum, or other sites and blood cultures, based on clinical judgment.
●Chest radiograph – For a patient with unexplained pulmonary infiltrates and/or persistent fever, opportunistic infections should be considered. If the chest radiograph is negative, computed tomography (CT) of the chest should be considered. Pathogens associated with immunocompromised individuals and evaluation of an immunocompromised patient with fever and a pulmonary infiltrate are discussed separately. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)
●Other tests should be performed, guided by clinical judgment. As an example, lumbar puncture should be performed in patients who have a change in mental status.
Treatment — The management of infections in patients with MDS depends on the patient's risk factors for life-threatening infections (eg, neutropenia, recent therapy) and whether they appear septic or toxic at presentation.
●Patients who are septic and/or have an absolute neutrophil count <500 cells/microL should be treated on an emergency basis with empiric, intravenous broad spectrum coverage. If an organism is later identified, the spectrum of therapy can be narrowed to cover the identified pathogen. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)
●Patients who are not septic and have an absolute neutrophil count ≥500 cells/microL can often be treated with antibiotics directed at the most likely pathogen, given the presenting signs and symptoms. As an example, patients with signs and/or symptoms of a sinobronchial infection can often be treated with conventional antibiotics used in the general population. Most patients respond to such treatment, but some patients develop chronic sinusitis that may require referral to an ear, nose, and throat specialist. (See "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment".)
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 "Epidemiology, clinical manifestations, and diagnosis of herpes zoster" and "Treatment of herpes zoster in the immunocompetent host".)
Prevention — Given the high rate of infection and associated morbidity and mortality among patients with MDS, attempts have been made to decrease the rate of infection by using vaccines, prophylactic antimicrobials, and myeloid growth factors.
Vaccination — 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 are summarized (figure 1) and discussed in greater detail separately. (See "Immunizations in adults with cancer".)
Antimicrobials — There is no demonstrated role for routine, prophylactic treatment with antimicrobials for patients with MDS.
No randomized trials have evaluated the use of prophylactic antimicrobials in this population. Prophylactic antimicrobials have no proven benefit in patients with MDS who are not undergoing active treatment. For patients who are receiving treatment for the underlying MDS, clinical judgment can inform a decision to use prophylactic antimicrobials based on the treatment regimen and its associated immunodeficiencies. (See "Overview of the treatment of myelodysplastic syndromes".)
Myeloid growth factors — There is no demonstrated role for routine, prophylactic treatment with myeloid growth factors in patients with MDS.
The response of patients with MDS to treatment with granulocyte colony-stimulating factors (G-CSF) [31-33] or granulocyte-macrophage colony-stimulating factors (GM-CSF) [34-40] in efficacy trials, including randomized trials, has been disappointing. United States National Cancer Center Network (NCCN) treatment guidelines do not recommend its routine use in patients with MDS [16]. (See 'Society guideline links' below.)
Myeloid growth factors may have utility in combination with an erythropoiesis-stimulating agent to enhance an inadequate erythroid response, as described above. (See 'Add a myeloid cytokine' above.)
BLEEDING — Bleeding in a patient with MDS may be due to thrombocytopenia, qualitative platelet disorders, or disorders of coagulation. Management of bleeding in this setting is guided by the underlying cause(s). Evaluation of patients with bleeding disorders is described separately. (See "Approach to the adult with a suspected bleeding disorder".)
Platelet transfusion — Platelet transfusions are the mainstay of bleeding management in bleeding patients with either quantitative or qualitative (ie, functional) platelet abnormalities.
We suggest prophylactic platelet transfusion for <10,000/microL in asymptomatic patients, but at higher counts in patients with active bleeding or with clinical problems such as fever, severe infection, pulmonary compromise, coagulopathy, or neurologic events suggesting central nervous system impairment [41]. Aminocaproic acid or other antifibrinolytic agents may be considered for bleeding refractory to platelet transfusions or for those with profound, refractory thrombocytopenia [42]. 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'.)
Our approach is similar to those of the 2017 American Society for Clinical Oncology (ASCO) (table 2) and the 2015 practice guideline from the AABB (Association for the Advancement of Blood and Biotherapies; formerly the American Association of Blood Banks) [43,44].
Thrombopoietin mimetics — Thrombopoietin mimetics should not be used routinely for patients with thrombocytopenia associated with MDS, as they may increase the risk of progression to acute myeloid leukemia (AML) in some patients with MDS.
Although romiplostim may transiently improve platelet counts, there is controversy regarding its potential to increase blast cell counts and accelerate progression to AML, particularly in MDS with excess blasts [45-50]. For patients with lower-risk MDS without excess blasts who have persistent bleeding due to thrombocytopenia who do not respond to transfusions or aminocaproic acid, we consider romiplostim or another thrombopoietin mimetic an acceptable option.
A randomized, double-blind, placebo-controlled trial of romiplostim was discontinued early by an independent data monitoring committee due to increases in peripheral blast cell counts [48]. The trial randomly assigned 250 patients with lower-risk MDS and thrombocytopenia (median platelet count 19,000/microL) to placebo versus romiplostim (750 mcg weekly); only 56 patients completed the 58-week study. Overall, romiplostim was associated with a nonsignificant trend toward fewer clinically significant bleeding events and it 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. However, there was a trend toward a higher rate of AML in patients treated with romiplostim (6 versus 2 percent; hazard ratio [HR] 2.51; 95% CI 0.55-11.47). In addition, two patients treated with romiplostim developed grade 3 bone marrow fibrosis.
Thrombopoietin mimetics have not been approved by the US Food and Drug Administration for use in MDS. Use of these agents in other clinical settings (eg, chronic immune thrombocytopenia [ITP]) is described separately. (See "Second-line and subsequent therapies for immune thrombocytopenia (ITP) in adults", section on 'TPO receptor agonists'.)
TRANSFORMATION TO AML — Patients with MDS have a variable rate of transformation to acute myeloid leukemia (AML) that is closely associated with the IPSS-R prognostic score (table 1). Indeed, the distinction between MDS and AML is itself arbitrary, as the World Health Organization classification describes patients with <20 percent bone marrow blasts as having MDS, while those with ≥20 percent blasts are considered to have AML [51]. The decision of when and with what to treat a patient with AML-directed therapy is individualized, and is discussed separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults" and "Acute myeloid leukemia: Management of medically-unfit adults".)
MONITORING — Patients with MDS should be followed longitudinally to monitor hematologic parameters and associated clinical findings, assess the response to therapy, and monitor for 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. As examples, for patients with lower-risk MDS, this may entail clinical evaluation and complete blood count (CBC) and differential count every one to six months. For patients with higher-risk MDS, visits with clinical and laboratory evaluation will likely be more frequent. Outside of a clinical trial, we assess the response to therapy based on reduction of symptoms, improvement of blood counts, reduced transfusion needs, and improved quality of life.
There is generally no role for routine bone marrow examinations, unless there is evidence of worsening cytopenias or other indications of disease progression.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myelodysplastic syndromes".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Myelodysplastic syndromes (MDS) (The Basics)" and "Patient education: 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
●Patients with myelodysplastic syndromes (MDS) are at risk for complications, including anemia, infections, and bleeding, as well as progression to acute myeloid leukemia (AML). Much of the morbidity and most deaths from MDS are due to the consequences of the cytopenias rather than transformation to AML. Supportive care is a central component of the management of all patients with MDS and may be administered with or without treatment for the underlying MDS.
●MDS with del(5q) cytogenetic abnormalities has clinical and therapeutic features that distinguish it from other categories of MDS. Our approach to management of MDS with 5q minus is discussed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Lenalidomide'.)
●Anemia is present in most patients with MDS and may manifest as fatigue, weakness, exercise intolerance, or other symptoms. In addition to MDS, other factors may contribute to anemia, including blood loss, hemolysis, renal insufficiency, effects of medications, nutritional deficiencies, anemia of chronic disease, and other disorders. Evaluation should include assessment of reticulocyte production (calculator 1) to distinguish between impaired red blood cell (RBC) production versus other causes. (See 'Evaluation of anemia' above.)
●Selection of treatment for anemia is informed by the nature and severity of symptoms, underlying cause(s), and comorbid medical conditions. Our approach to management of anemia recognizes that the response of MDS to recombinant erythropoiesis-stimulating agents (ESA) is influenced by the prognostic category of MDS and the level of reticulocyte production. We suggest using the revised International Prognostic Scoring System (IPSS-R) (table 1) score to stratify patients according to prognostic score. (See 'Selection of therapy' above.)
●For symptomatic patients with MDS, selection of treatment is influenced by the IPSS-R score, level of RBC production based on reticulocyte production index (RPI) (calculator 1), and serum erythropoietin (EPO) level (see 'Symptomatic' above):
•Low/very low/intermediate risk MDS (ie, IPSS-R ≤4.5 points) – Treatment selection is informed by RPI and EPO levels:
-Impaired RBC production (ie, RPI <2) and serum EPO ≤500 mU/mL – We suggest initial treatment with an ESA rather than chronic transfusion therapy or treatment with an ESA plus a myeloid growth factor (Grade 2B), based on the more favorable balance of benefits and toxicity; however, the risk of thrombosis is increased in certain patients, as described above. (See 'Erythropoiesis-stimulating agents' above.)
-Adequate RBC production (ie, RPI ≥2) or serum EPO >500 mU/mL – We consider RBC transfusions or a trial of an ESA (alone or together with a myeloid growth factor) to be acceptable approaches. It is especially important to seek causes of blood loss or hemolysis in the setting of adequate RBC production. RBC transfusions can rapidly improve symptoms, but chronic transfusion therapy may be associated with alloimmunization and other adverse events, while ESA therapy (alone or plus a myeloid growth factor) is less likely to be beneficial in this setting. (See 'Red blood cell transfusions' above and 'Add a myeloid cytokine' above.)
•High/very high risk MDS (ie, IPSS-R >4.5 points) – For patients with adverse prognosis MDS, we suggest chronic transfusion therapy, along with definitive treatment of the disease, because ESA therapy (alone or together with a myeloid growth factor) is unlikely to achieve a meaningful erythroid response. Other contributing factors (eg, bleeding, hemolysis) should be corrected. Transfusions can rapidly improve symptoms, but chronic transfusion therapy is associated with risks of alloimmunization and other adverse effects, as discussed above. (See 'Red blood cell transfusions' above.)
●For asymptomatic patients, we generally do not treat on the basis of a specific threshold value for hemoglobin (Hb) or hematocrit (Hct). However, we do intervene if ongoing bleeding, hemolysis, or the rate of decline of Hb/Hct suggests that the patient will soon become symptomatic, especially if there are comorbid cardiac, pulmonary, or neurologic conditions. (See 'Asymptomatic' above.)
●Patients with MDS have a high incidence of infection, and infections are a principal cause of death. Bacterial infections predominate, but fungal, viral, and mycobacterial infections can occur, especially in patients receiving immunosuppressive agents. Suggestions regarding evaluation, treatment, and prevention strategies for infections are discussed above. (See 'Infections' above.)
●Bleeding in a patient with MDS may be due to thrombocytopenia, qualitative (ie, functional) platelet abnormalities, or disorders of coagulation. Management of bleeding in this setting is guided by the underlying cause and is discussed above. (See 'Bleeding' above.)
●Patients with MDS have a variable rate of transformation to AML, although most patients who die do so not as a consequence of transformation, but due to bone marrow failure associated with MDS. The treatment of AML is discussed in more detail separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults" and "Acute myeloid leukemia: Management of medically-unfit adults".)
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.
