Myelodysplastic Syndrome (MDS)

Practice Essentials

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders commonly found in the aging population. All are characterized by one or more peripheral blood cytopenias. Bone marrow is usually hypercellular, but rarely, a hypocellular marrow mimicking aplastic anemia may be seen. Bone marrow cells display aberrant morphology and maturation (dysmyelopoiesis), resulting in ineffective blood cell production.

MDS affects hematopoiesis at the stem cell level, as indicated by cytogenetic abnormalities, molecular mutations, and morphologic and physiologic abnormalities in maturation and differentiation of one or more of the hematopoietic cell lines.^{[1, 2, 3]}  See the image below.

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Blood film (1000× magnification) demonstrating a vacuolated blast in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woerm....

See Myelodysplastic Syndromes: Classification, Features, Diagnosis, and Treatment Options, a Critical Images slideshow, to help identify, classify, work up, and treat these disorders.

MDS may involve one, two, or all three myeloid hematopoiesis cell lineages—erythrocytic, granulocytic, megakaryocytic—depending on the subtype and stage of the disease. The heterogeneity of MDS reflects the fact that its course involves a series of cytogenetic events. In a subgroup of patients, the acquisition of additional genetic abnormalities results in the transformation of MDS into acute myeloid leukemia (AML). Thus, although MDS is clonal, it is considered a premalignant condition.

Patients with MDS may present with clinical manifestations of anemia, thrombocytopenia, and/or neutropenia (see Presentation). The workup in patients with possible MDS includes a complete blood count with differential, peripheral blood smear, and bone marrow studies (see Workup).

Standard care for MDS is constantly changing, but it typically includes supportive therapy, including transfusions, and may include bone marrow stimulation and cytotoxic chemotherapy or hypomethylating agents. Bone marrow transplantation has a limited role. (See Treatment.)

For discussion of MDS in children, see Pediatric Myelodysplastic Syndrome. 

For patient education information, see Myelodysplastic or Myeloproliferative Neoplasms (Leukemia Types).

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Pathophysiology

MDS develops when a clonal mutation predominates in the bone marrow, suppressing healthy stem cells. The clonal mutation may result from genetic predisposition or from hematopoietic stem cell injury caused by exposure to any of the following:

• Cytotoxic chemotherapy
• Radiation
• Viral infection
• Genotoxic chemicals (eg, benzene)

MDS can be classified as primary (de novo) or secondary to aggressive treatment of other cancers, with exposure to radiation, alkylating agents, or topoisomerase II inhibitors; it also occurs in heavily pretreated patients with autologous bone marrow transplants.

In the early stages of MDS, the main cause of cytopenias is increased apoptosis (programmed cell death). As the disease progresses and converts into leukemia, further gene mutation occurs, and a proliferation of leukemic cells overwhelms the healthy marrow.

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Etiology

Cytogenetically, patients with MDS or AML fall into three groups:

• Normal karyotype
• Balanced chromosomal abnormality causing the generation of fusion oncogenes
• Complex karyotypes (usually >3 abnormalities)

Patients with complex karyotypes constitute 30% of primary MDS cases (only 20% of de novo AML) and up to 50% of therapy-related MDS and AML cases. These patients have a worse prognosis and response to treatment.

Balanced translocation abnormalities lead to the generation of fusion oncogenes such as Bcr-Abl in chronic myelogenous leukemia (CML) and PML-Rar alpha in acute promyelocytic leukemia (APL). Unbalanced recurrent aberrations, most commonly -5, 5q-,-7, 7q-, +8, 11q-, 13q-, and 20q-, suggest that genes within these regions have a role in the pathogenesis of MDS or myeloproliferative disorder (MPD), which is based on loss of tumor suppressor genes or haploinsufficiency of genes necessary for normal myelopoiesis.

Approximately 80% of patients with MDS do not have an obvious exposure or cause for MDS. In these cases, the disorder is classified as primary or idiopathic MDS.

The World Health Organiztion (WHO) classifies secondary MDS as MDS or acute leukemia that develops years after known exposure to sources of chromosomal damage. Patients who survive cancer treatment with alkylating agents, with or without radiotherapy, have a high risk of developing MDS or secondary acute leukemia 5-7 years after the exposure. These drugs are associated with a high prevalence of chromosomal abnormalities in bone marrow—in particular, the -5, del(5q), -7, del(q) and complex karyotype.

Secondary MDS after treatment with a topoisomerase II inhibitors such as an anthracycline or etoposide occurs 1-3 years after exposure to these agents. The chromosomal abnormalities commonly involve the MLL gene (11q23).

MDS may also develop after exposure to certain chemicals (eg, benzene). Insecticides, weed killers, and fungicides are also possible causes of MDS and secondary leukemia.^[4] Viral infections have also been implicated. Less evidence supports genetic predisposition, but familial incidences have been described. Some of the congenital platelet disorders with RUNX1 and GATA2 mutations can predispose to MDS.

Although familial cases of myelodysplastic syndromes are rare, they are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general.^[5] The best-characterized familial MDS is familial platelet disorder with propensity to myeloid malignancy, which is caused by heterozygous germline RUNX1 mutations. The incidence of MDS/AML in affected pedigrees is over 40%, with a median age of onset of 33 years. Familial monosomy 7; unusually short telomeres in dyskeratosis congenita; and four pedigrees with inherited MDS caused by heterozygous mutations in GATA2 have been reported.^[6] These familial forms may occasionally be found in the course of screening family members of a patient with MDS as bone marrow transplant donors.

A study by Kristinsson et al found that chronic immune stimulation is a trigger for acute leukemia and MDS development. The underlying mechanisms may also be caused by a genetic predisposition or treatment for infections or autoimmune conditions.^[7]

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Epidemiology

The actual incidence of MDS in the United States is unknown. MDS was first considered a separate disease in 1976, and its occurrence was estimated at 1500 new cases every year. At that time, only patients with less than 5% blasts were considered to have this disorder. MDS was not classified as neoplastic and included in cancer registries until 2001.^[8] Current estimates of the incidence of MDS in the United States vary widely, from 10,000 to 30,000-55,000 new cases each year.^{[8, 9, 10, 11]} The higher figures have been questioned as possible overestimates resulting from inclusion of other hematopoietic conditions.^[12]

The incidence of MDS has appeared to be increasing. The apparent rise is believed to reflect the increase in the elderly population, but may also reflect improvements in recognition and criteria for the diagnosis.^[9]

Although MDS may occur in persons of any age, including children, MDS primarily affects elderly people, with the median onset in the seventh decade of life. Data from 2001 through 2003 of the first National Cancer Institute's Surveillance, Epidemiology & End Reports (SEER) indicate 86% of MDS cases were diagnosed in individuals who were 60 years of age or older (median age: 76y).

Other data from SEER also show that the estimated incidence of MDS increases significantly with age, ranging from 0.7 per 100,000 population during the fourth decade of life to 20.8-36.3/100,000 after age 70 years. There is a fivefold difference in risk between age 60 and ≥80 years.

At all ages, MDS is more common in males than in females. In SEER data from 2001-2003, the incidence rate was significantly higher in men than in women (4.5 vs 2.7 per 100,000 population).^[13]

MDS is found worldwide and is similar in characteristics throughout the world. Data based mainly on European numbers from Germany and Sweden were very similar to the US numbers.^[11]

A review of United Kingdom population-based data from September 2004 to August 2013 found marked variations in MDS incidence, depending on the standard population used to calculate rates. For example, using the 1996 world standard, the population with the greatest weighting towards younger groups, the incidence rate was 1.67 per 100,000 population; using the 2013 European Standard Population, which has the greatest weighting towards older ages, the rate was 4.4 per 100,000 population.^[14]

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Prognosis

In some patients, MDS is an indolent disease. Other patients develop significant cytopenias; the resulting complications (eg, bleeding and infections) account for almost all the mortality related to MDS. In the remainder of cases the disease follows an aggressive course and converts into an acute form of leukemia.

Risk classification systems to estimate prognosis in patients with MDS have been developed by the French-American-British (FAB) Cooperative Group, the World Health Organization (WHO), and the MDS Risk Analysis Workshop.

The FAB system classifies MDS into the following five subgroups, differentiating them from acute myeloid leukemia^[15] :

• Refractory anemia (RA)
• RA with ringed sideroblasts (RARS)
• RA with excess blasts (RAEB; 6-20% myeloblasts)
• RAEB in transition to AML (RAEB-T; 21-30% myeloblasts)
• Chronic myelomonocytic leukemia (CMML)

An underlying trilineage dysplastic change in the bone marrow cells is found in all subtypes.

RA and RARS are characterized by 5% or less myeloblasts in bone marrow. RARS is defined morphologically as having 15% erythroid cells with abnormal ringed sideroblasts (see the image below), reflecting an abnormal accumulation of iron in the mitochondria. Both RA and RARS have a prolonged clinical course and a low prevalence of progression to acute leukemia. In a review of United Kingdom population-based data, with followup of 2 to 11 years, progression to acute leukemia occurred in 5% of RARS cases, compared with 25% of RAEB cases.^[14]

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Bone marrow film (1000× magnification) demonstrating ring sideroblasts in Prussian blue staining in a refractory anemia with excess of blasts in trans....

RAEB and RAEB-T (see the image below) are characterized by greater than 5% myeloblasts. The higher the percentage of myeloblasts present, the shorter the clinical course and the closer the disease is to acute myelogenous leukemia.

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Blood film (1000× magnification) demonstrating a vacuolated blast in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woerm....

Transition from early to more advanced stages may occur, which indicates that these subtypes are merely stages of disease rather than distinct entities. Elderly patients with MDS who progress to acute leukemia are often considered to have a poor prognosis because their disease response to chemotherapy is worse than that of de novo acute myeloid leukemia patients.

The 1999 WHO classification proposed including all cases of RAEB-T in the category of acute leukemia because these patients have similar prognostic outcomes.^[16] However, the response to therapy is worse than in patients with de novo or more typical AML or acute nonlymphocytic leukemia.

The fifth type of MDS, CMML, is the most difficult to classify. This subtype can have any percentage of myeloblasts but manifests as a monocytosis of 1000/μL or more, a total white blood cell (WBC) count of less than 13,000/μL, and trilineage dysplasia.

CMML may be associated with splenomegaly. This subtype overlaps with myeloproliferative disease (MPD) and may have an intermediate clinical course. CMML must be differentiated from classic chronic myelocytic leukemia, which is characterized by a negative Ph chromosome.

The current WHO classification lists CMML within a group of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes, along with four other entities: atypical chronic myeloid leukemia (aCML), BCR-ABL1; juvenile myelomonocytic leukemia (JMML); MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T); and MDS/MPN, unclassifiable. WHO criteria for these forms of CMML include splenomegaly and a WBC count greater than 13,000/μL.^[17]

WHO Classification

The WHO classification scheme for MDS was published in 1999. Updates to the scheme were published in 2008 and 2016. The 2016 WHO classification of MDS is as follows^[17] :

• MDS with single-lineage dysplasia (MDS-SLD) – 1 or 2 blood cytopenias; in bone marrow, dysplasia in ≥ 10% of one cell line, < 5% blasts
• MDS with multilineage dysplasia (MDS-MLD) – 1-3 blood cytopenias, < 1 × 10⁹/L monocytes; in bone marrow, dysplasia in ≥ 10% of cells in ≥ 2 hematopoietic lineages < 15% ring sideroblasts (or < 5% ring sideroblasts if SF3B1 mutation present) < 5% blasts 
• MDS with ring sideroblasts (MDS-RS) –  Anemia, no blasts;  in bone marrow, ≥ 15% of erythroid precursors with ring sideroblasts or ≥ 5% ring sideroblasts if SF3B1 mutation is present
• MDS with isolated del(5q) –  Anemia, platelets normal or decreased; in bone marrow, unilineage erythroid dysplasia, isolated del(5q), < 5% blasts ± one other abnormality except -7/del(7q)
• MDS with excess blasts (MDS-EB) – 1-3 blood cytopenias, 0-3 dysplastic bone marrow lineages, and 5-9% blasts in bone marrow or 2-4% blasts in blood (MDS-EB1) or 10-19% blasts in bone marrow or 5-19% blasts in blood (MDS-EB2)
• Unclassifiable MDS – Cytopenias, ±1% blasts on at least 2 occcasions; in bone marrow, single-lineage dysplasia or no dysplasia but characteristic MDS cytogenetics, < 5% blasts

The WHO classification also includes provisional category of refractory cytopenia of childhood, with cytopenias and < 2% blasts in peripheral blood and, in bone marrow, dysplasia in 1–3 lineages and < 5% blasts.

International Prognostic Scoring System

To improve prognostic classification, the MDS Risk Analysis Workshop developed the Myelodysplastic Syndrome International Prognostic Scoring System (IPSS). The IPSS was published in 1997 and updated in 2012.^{[18, 19, 20]} The revised IPPS (IPSS-R)  score is calculated on the basis of five variables:

• Hemoglobin level
• Absolute neutrophil count
• Platelet count
• Percentage of bone marrow blasts
• Cytogenetic category

With the IPSS, patients were stratified into four risk groups: low, intermediate 1 and 2, and high. The IPSS-R score is used to stratify patients into five risk groups, as shown in Table 1, below:

Table 1. Revised International Prognostic Scoring System risk groups and prognosis^[19]

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Mean survival is 18-24 months or longer in patients with the following features:

• Single or mild cytopenias
• Normal chromosomes or a single chromosomal abnormality (except those involving chromosome 7)
• Fewer than 10% myeloblasts in the bone marrow

Mean survival is 6-12 months in patients with the following features:

• Pancytopenia requiring red blood cell or platelet transfusions
• Chromosome 7 abnormalities or multiple chromosomal abnormalities
• Greater than 10% myeloblasts

Personalized Prognostic Model

Using artificial intelligence, Razha and colleagues developed a personalized prognostic model for patients with MDS that is based on clinical and genomic data.^[21] Factors identified as having an impact on overall and leukemia-free survivals included the following:

• Chromosomal karyotype
• Platelet count
• Hemoglobin level
• Bone marrow blast percentage
• Age
• Other clinical variables
• Seven discrete gene mutations (ASXL1, EZH2, KRAS, NRAS, RAD21, SF3B1, and TP53)
• Number of mutations

Validation of the model confirmed that it outperformed established prognostic models in MDS. The new model was able to predict the probability of survival and of transformation of MDS into leukemia at different time points that are unique for a given patient, permitting the upstaging or downstaging of patients into more appropriate risk categories.^[21]

Molecular International Prognostic Scoring System

The International Working Group for the Prognosis of MDS, working under the auspices of the MDS Foundation, has created and validated the Molecular International Prognostic Scoring System for MDS (IPSS-M). This system uses information from 31 gene mutations, along with diagnostic and clinical parameters, to determine a personalized, patient-specific risk score.^[22]

The IPSS-M has six risk categories: very low, low, moderate low, moderate high, high, very high).  The score can be used for determining clinical trial eligibility criteria, correlative studies, and treatment recommendations. The IPSS-M calculator is available at https://mds-risk-model.com/

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History

The development of myelodysplastic syndrome (MDS) may be preceded by a few years by an unexplained macrocytic anemia with no evidence of megaloblastic anemia and a mild thrombocytopenia or neutropenia. Clinical symptoms that should prompt a workup for MDS are due to low peripheral blood counts, usually from the anemia but also from the thrombocytopenia or neutropenia.

Symptoms such as fatigue and malaise result from anemia. Signs and symptoms of chronic heart failure may develop in patients with underlying cardiac problems, depending on the degree of anemia.

Petechiae, ecchymoses, and nose and gum bleeding are common manifestations of a low platelet count. If underlying dysplastic changes were missed initially, thrombocytopenia as the presenting symptom may be mistaken for immune thrombocytopenia.

Fever, cough, dysuria, or shock may be manifestations of serious bacterial or fungal infections in patients with neutropenia.

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Physical Examination

On physical examination, patients with myelodysplastic syndrome (MDS) may have evidence of thrombocytopenia, anemia, and/or neutropenia. Thrombocytopenia typically manifests as petechiae or ecchymoses; epistaxis and gum bleeding suggest severe thrombocytopenia. Hemoptysis, hematuria, and blood in stools may occur.

Pallor of the skin and mucosal membranes or evidence of fatigue, tachycardia, or congestive heart failure may be manifestations of severe anemia.

An enlarged spleen may be found in persons with chronic myelomonocytic leukemia (CMML), often indicating an overlap syndrome with MDS. CMML must be differentiated from chronic myelogenous leukemia (CML). Patients with an enlarged spleen may have complications related to spontaneous rupture and intra-abdominal exsanguination.

The presence of fever and infections, such as pneumonias and urinary tract infections, may be due to the neutropenia associated with MDS.

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Approach Considerations

The workup in patients with possible myelodysplastic syndrome (MDS) includes a complete blood count with differential, peripheral blood smear, and bone marrow studies with cytogenetic studies. In addition to genetic testing for acquired mutations in genes associated with MDS, additional molecular and genetic testing for hereditary hematologic malignancy predisposition may be considered in some patients, particularly in younger ones.^[23]

Findings on these studies are used to stage the disease. Because MDS has heterogeneous clinical manifestations and varying clinical outcomes, staging is necessary to determine prognosis and guide the approach to therapy. 

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Complete Blood Count and Peripheral Blood Smear

Significant changes are found in the blood counts and morphology of patients with MDS. The peripheral blood count may show a single cytopenia (anemia, thrombocytopenia, or neutropenia) in the early phase or bicytopenia (2 deficient cell lines) or pancytopenia (3 deficient cell lines) in later stages.

Anemia varies in degree from mild to severe. It is usually macrocytic (mean cell volume of >100 fL) with red blood cells (RBCs) that are oval-shaped (macro-ovalocytes). It is usually dimorphic (2 or more populations), with a normal or a hypochromic microcytic population (RARS) coexisting with the macrocytes. Punctate basophilia is observed in RBCs.

Neutropenia may vary from mild to severe. Morphologic abnormalities are often observed in the granulocytes. These can include bilobed or unsegmented nuclei (pseudo–Pelger-Huet abnormality) or hypersegmentation on the nuclei (6-7 lobes) similar to megaloblastic diseases.

Granulation abnormalities vary from an absence of granules to abnormal distribution inside the cytoplasm (Dohle bodies).

Platelet counts are decreased (rarely increased). Abnormalities such as giant hypogranular platelets and megakaryocyte fragments are present.

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Bone Marrow Studies

In most cases, bone marrow changes include hypercellularity with trilineage dysplastic changes. A small number of patients may have a hypocellular marrow. This often overlaps with aplastic anemia. Increased marrow fibrosis may be confused with other myeloproliferative disorders. Dysplastic changes in RBC lineage (dyserythropoiesis) are characteristic. In the absence of vitamin B12 or folate deficiencies, the bone marrow usually exhibits asynchronous maturation of nuclei and cytoplasm similar to that described in megaloblastic anemias.

Other changes include binuclearity or multinuclearity in the erythroid cell precursor cells and the presence of ringed sideroblasts (iron accumulation in the mitochondria). Refractory anemia with ringed sideroblasts (RARS) is one of the MDS types in the French-American-British (FAB) Cooperative Group classification system. (See the image below.)

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Bone marrow film (1000× magnification) demonstrating ring sideroblasts in Prussian blue staining in a refractory anemia with excess of blasts in trans....

Dysplastic changes in white blood cell (WBC) lineage (dysmyelopoiesis) involve myeloid hyperplasia with an increased number of myeloblasts and an expanded myelocyte and metamyelocyte population (midstage bulge). This separates it from acute leukemia (leukemic hiatus or absence of mid stage). In the FAB classification, the percentage of myeloblasts separates RA (< 5%), RAEB (5-20%), RAEB in transformation (>20, < 30%), and acute myeloid leukemia (AML; >30%).

The 2008 update of the WHO classification considers single-lineage dysplasia as a valid criterion for diagnosis of MDS, and refractory cytopenia with unilineage dysplasia (RCUD) became an official entity in that classification. In 2004, WHO revised the percentage of blasts that defines AML from 30% to 20%; thus, the RAEB in transformation entity has become officially AML.

Morphologic abnormalities are evident in nuclear-cytoplasm dissociation in maturation and when the pseudo–Pelger forms are also present in bone marrow.

Dysthrombopoiesis in the platelet production cell lineage consists of micromegakaryocytes (dwarf forms) with poor nuclei lobulation and giant platelets budding off from their cytoplasm.

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Cytogenetic Studies

Cytogenetic techniques have evolved from individual chromosome identification by banding techniques to the new, more sensitive color-coded methods. Separating individual chromosomes is dependent on the ability to induce the cell into mitosis to identify abnormalities. The new technique uses fluorescent in situ hybridization (FISH) and color-coded chromosomes to enable observation of the intact cell without requiring mitosis.

Cytogenetic studies of the bone marrow cells indicate mutations into clonal cell lines, with abnormal chromosomes in 48-64% in different series. With higher-resolution techniques (eg, FISH), some practitioners claim a 79% rate of chromosomal abnormalities in patients with primary MDS.

Chromosomal abnormalities are clonal and include 5q-, monosomy 7 (-7) or 7q-, trisomy 8 (+8), and numerous other less frequent abnormalities. Multiple combinations may be present; this indicates a very poor prognosis. A single abnormality, except those involving chromosome 7, usually indicates good prognosis and survival.

The WHO classification is helpful in predicting subgroup differences in prognosis and response to treatment in patients with MDS. Refractory cytopenias are divided into those in which multi-lineage dysplasia is absent (RCMD-) or present (RCMD+) and those with ringed sideroblasts (RCMD+/+RS) or without ringed sideroblasts (RCMD/-RS).

A new subcategory includes patients with isolated deletion of chromosome 5q (5q-) and less than 5% blasts, called the 5q- syndrome.^[24] Identification of the syndrome or presence of this particular cytogenetic abnormality is useful because the majority of these patients will respond to treatment with lenalidomide (Revlimid).

Unclassified by the WHO are the group of patients with MDS whose conditions overlap with severe aplastic anemia and paroxysmal nocturnal hemoglobinuria. This group includes MDS patients with the FAB-RA subtype who may have a hypoplastic marrow, usually have a human leukocyte antigen (HLA)-DR15 phenotype, are young (< 60 years), may have cells deficient in CD55 and CD59, and respond to immunosuppressive treatment with anti-thymocyte globulin (ATG) or cyclosporin.^[25]

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Histologic Findings

The presence of dysplastic changes in the peripheral blood smear and trilineage dysplasia and hypercellular marrow in the absence of vitamin deficiency is diagnostic of MDS. The presence of typical chromosomal abnormalities supports the diagnosis and contributes to determining the prognosis of MDS. (See the following images.)

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Blood film (1000× magnification) demonstrating a vacuolated blast in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woerm....

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This bone marrow film (400× magnification) demonstrates an almost complete replacement of normal hematopoiesis by blasts in a refractory anemia with a....

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Bone marrow film (1000× magnification) demonstrating ring sideroblasts in Prussian blue staining in a refractory anemia with excess of blasts in trans....

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Bone marrow film (1000× magnification) demonstrating granular and clotlike positive reaction in periodic acid-Schiff staining in a refractory anemia w....

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Staging

In 1997, an international group of experts, the MDS Risk Analysis Workshop, developed the International Prognostic Scoring System (IPSS) for staging MDS.^[18] The IPSS was revised in 2012 to accommodate advances in defining cytogenetic abnormalities.^[19] The revised IPSS (IPSS-R) also includes a more detailed consideration of cytopenias. (See Tables 2-4, below.) An online calculator for determining an individual patient's R-IPSS score is available on the MDS Foundation Web site.

Table 2 Cytogenetic abnormalities assigned an IPSS-R value for scoring

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Table 3.Calculation of IPSS-R score

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Table 4. IPSS-R prognostic risk scores and categories

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Calculation of the IPSS-R score in 7012 patients with MDS resulted in the following risk categorizations^[19] :

• Very low: 19%
• Low: 38%
• Intermediate: 20%
• High: 13%
• Very high: 10%

Clinical outcome according to IPSS-R risk category in those patients is outlined in Table 5, below.

Table 5. Clinical outcome by IPSS-R risk category

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Classification of the subtypes or categories of MDS has changed from the FAB classification to the WHO classification. (See Table 6, below.)

Table 6. Categories of FAB classification versus WHO classification for myelodysplastic syndrome (MDS)

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FAB – French-American-British Cooperative Group; WHO – World Health Organization; RA – Refractory anemia; RARS – RA with ringed sideroblasts; RAEB – RA with excess blasts; RAEB-T – RAEB in transition to AML; AML – Acute myelogenous leukemia; CMML – Chronic myelomonocytic leukemia; RCMD – Refractory cytopenia with multilineage dysplasia; RCUD – Refractory cytopenia with unilineage dysplasia

CMML in the FAB classification requires an actual monocyte count of more than 1000/μL with trilineage dysplasia.

WHO classifies CMML into the following:

• Juvenile and proliferative CMML under MDS/myeloproliferative neoplasma (MPN have more than 13,000/μL monocytes plus splenomegaly.
• CMML under MDS is limited to monocytosis of less than 13,000/μL with trilineage dysplasia.

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Laboratory Studies

In addition to blood counts, peripheral blood smears, and bone marrow studies, the National Comprehensive Cancer Network (NCCN) recommends the following studies in patients with suspected MDS^[23] :

• Serum erythropoietin (prior to red blood cell [RBC] transfusion)
• RBC folate and serum vitamin B-12
• Serum ferritin, iron, and total iron-binding capacity (TIBC)
• Thyroid-stimulating hormone (TSH)
• Lactate dehydrogenase (LDH)
• HIV testing if clinically indicated

NCCN guidelines also recommend considering evaluation of copper deficiency in patients with GI malabsorption, severe malnutrition, gastric bypass surgery, or patients on zinc supplementation.

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Approach Considerations

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

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

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

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

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

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

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Supportive Care

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

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

Red blood cell transfusion

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

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This bone marrow film (400× magnification) demonstrates an almost complete replacement of normal hematopoiesis by blasts in a refractory anemia with a....

Iron chelation

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

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

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

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

Platelet transfusion

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

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

Treatment of neutropenia

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

Bone marrow stimulation

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

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

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

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

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

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

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

• References

Pharmacologic Therapy

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

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

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

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

Lenalidomide

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

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

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

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

Hypomethylating agents

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

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

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

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

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

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

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

Immunosuppressive therapy

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

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

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

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

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

Luspatercept

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

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

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

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

Imetelstat

On June 6, 2024, the FDA approved imetelstat (Rytelo), an oligonucleotide telomerase inhibitor, for adults with transfusion-dependent MDS who have not responded to, have lost response to, or are ineligible for ESAs. Approval was based on results from the multicenter, randomized, double-blind, placebo-controlled, Phase 3 (IMerge) trial (N = 178). Trial participants had a IPSS low- or intermediate-1 risk MDS and required 4 or more RBC units over an 8-week period during the 16 weeks prior to randomization. The proportion of patients who did not require RBC transfusion(s) during any consecutive 8-week (56 days) period was significantly higher in the imetelstat arm compared with the placebo arm (40% vs 15%; P = 0.0008).^[45]

Experimental agents

New drugs for MDS are being generated at a brisk pace as new clinical trials continue to make inroads on improving outcomes in quality of life and, ultimately, in overall survival. Synergy is being sought with new combinations of the active drugs and the less active drugs. As more is being learned about the biology of MDS through the molecular mechanisms and the ability to modify these molecular targets, research has opened new doors for the treatment of this once obscure and poor-outcome disease.^[46]

• References

Bone Marrow Transplantation

Bone marrow transplantation with a matched allogeneic or syngeneic donor is used in patients with poor prognoses or late-stage MDS who are aged 55 years or younger and have an available donor. Among selected patients with less advanced/low-risk MDS (< 5% marrow myeloblasts), a 3-year survival of 65-75% is achievable with HLA-matched related and unrelated donors. Because hematopoietic stem cell transplantation (HSCT) offers the potential for cure, the timing of the procedure may be important in this subgroup of patients.^{[47, 48]}

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

Because most patients with MDS are elderly and only a few young patients will have a matched donor, the use of bone marrow transplantation is limited. However, in our institution, with a haploidentical (half-match) donor, 2-step protocol, we have shown that expanding the donor pool to include patients' children as well as siblings increases the availability of donors for elderly patients and produces the same result as transplantation from full-match donors. Sandhu et al reported that umbilical cord blood transplantation after reduced-intensity conditioning regimens in patients aged ≥70 years with MDS and AML produced results comparable to those of HLA full-matched sibling donor transplantation in this age group.^[49]

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

Shaffer and colleagues developed a system that can be used to determine prognosis in patients undergoing HLA-matched and -mismatched allogeneic HSCT for MDS.^[50] In the system, the following risk factors are assigned 1 point:

• Blood blasts >3%
• Platelet count ≤50 × 10⁹/L at transplantation
• Karnofsky performance status < 90%
• Comprehensive cytogenetic risk score of poor or very poor
• Age 30 to 49 years

Risk factors assigned 2 points are as follows:

• Monosomal karyotype
• Age 50 years or older

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

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

Lindsley et al reported that the presence of specific genetic mutations may predict clinical outcomes in patients who undergo allogeneic HSCT for MDS.^[51] Their findings included the following:

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

• References

Surgical Care

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

• References

Guidelines Summary

Myelodysplastic Syndrome (MDS) Classification

In 2016, the World Health Organization (WHO) released a revision to its 2008 classification scheme for myelodysplastic syndrome (MDS).^{[52, 17]}  The National Comprehensive Cancer Network  (NCCN) has included the revised WHO classification system in its 2017 updated guidelines.^[23]

The two systems are compared in the table below..

Table. 2008 and 2016 World Health Organization (WHO) classifications of myelodysplastic syndromes

View Table

See Table

• References

Diagnosis

For the workup in patients with suspected MDS (eg, because of cytopenias), the NCCN recommends the following^[23] :

• History and physical examination
• Complete blood count (CBC) with differential
• Reticulocyte count
• Examination of peripheral blood smear
• Bone marrow aspiration with iron stain plus biopsy and cytogenetics by standard karyotyping; consider testing for fibrosis
• Serum erythropoietin (prior to red blood cell [RBC] transfusion)
• RBC folate, serum vitamin B12
• Serum ferritin, iron, total iron-binding capacity (TIBC)
• Documentation of transfusion history
• Thyroid-stimulating hormone (TSH)
• Lactate dehydrogenase (LDH)
• Genetic testing for somatic mutations (ie, acquired mutations) in genes associated with MDS is highly recommended
• Recommend additional molecular and genetic testing for hereditary hematologic malignancy predisposition in a subset of patients, particularly in younger patients
• HIV testing if clinically indicated
• Consider evaluation of copper deficiency in patients with GI malabsorption, severe malnutrition, gastric bypass surgery, or patients on zinc supplementation
• Consider distinction from congenital sideroblastic anemia (CSA)

ESMO recommendations are as follows^[53] :

• Diagnosis is based on blood count, marrow aspirate and marrow karyotype.
• Bone marrow biopsy is recommended at diagnosis.
• Molecular biology is useful for diagnosis if blood and marrow tests are inconclusive
• Flow cytometry of blood and marrow cells is useful for diagnosis in experienced hands.

The NCCN utilizes the WHO classification system for diagnosis and distinguishes subtypes on the basis of blood and bone marrow findings.^{[23, 52]}

MDS with single-lineage dysplasia (MDS-SLD) criteria are as follows:

• Blood: single cytopenia or bicytopenia
• Bone marrow: dysplasia in ≥ 10% of one cell line, < 5% blasts

MDS with ring sideroblasts (MDS-RS) criteria are as follows:

• Blood: anemia, no blasts
• Bone marrow: ≥ 15% of erythroid precursors with ring sideroblasts, or ≥ 5% blasts ring sideroblasts if SF3B1 mutation is present

MDS with multilineage dysplasia (MDS-MLD) criteria are as follows:

• Blood: cytopenia(s), < 1 × 10⁹/L monocytes
• Bone marrow: dysplasia in ≥ 10% of cells in ≥ 2 hematopoietic lineages; < 15% ring sideroblasts (or < 5% ring sideroblasts if SF3B1 mutation present), < 5% blasts

MDS with excess blasts-1 (MDS-EB-1) criteria are as follows:

• Blood: cytopenia(s) ≤2-4% blasts, < 1 × 10⁹/L monocytes
• Bone marrow: unilineage or multilineage dysplasia, no Auer rods, 5-9% blasts

MDS with excess blasts-2 (MDS-EB-2) criteria are as follows:

• Blood: cytopenia(s), 5-19% blasts, < 1 × 10⁹/L monocytes
• Bone marrow: unilineage or multilineage dysplasia, ±Auer rods, 10-19% blasts

Myelodysplastic syndrome–unclassified (MDS-U) criteria are as follows:

• Blood: cytopenias, ±1% blasts on at least 2 occasions
• Bone marrow: unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, < 5% blasts

Myelodysplastic syndrome associated with isolated del(5q) criteria are as follows:

• Blood: anemia, platelet levels normal or increased
• Bone marrow: unilineage erythroid dysplasia, isolated del(5q), < 5% blasts ± one other abnormality except -7/del(7q)

• References

Prognostic Scoring Systems

The following prognostic scoring systems are most commonly used:

• International Prognostic Scoring System (IPSS and IPSS-R)
• WHO Prognostic Scoring System (WPSS)
• Lower-Risk Prognostic Scoring System (LR-PSS)

NCCN guidelines prefer the IPSS-R, because it provides more accurate risk stratification than the IPSS or WPSS, but note that the LR-PSS may be useful in identifying patients with lower-risk disease who have a poorer prognosis and require earlier treatment..^[23]  The 2021 European Society for Medical Oncology (ESMO) guidelines consider the IPSS-R to be required for prognostic evaluation, but note that molecular analysis may add prognostic value, especially for TP53 mutations in del(5q) MDS and SF3B1 mutations in patients with < 5% blasts.^[53] The 2013 European LeukemiaNet (ELN) guidelines recommend that all patients be risk stratified using IPSS.^[54]

International Prognostic Scoring System

The IPSS has been the most widely used prognostic scoring system for MDS. First published in 1997, it was intended for use with the French-American-British (FAB) classification system which has since been largely supplanted by the World Health Organization (WHO) classification system. The following three factors are rated^[18] :

• The percentage of blasts in the bone marrow (scored on a scale from zero to 2)
• Karyotype (scored from zero to 1)
• Cytopenias (scored as zero or 0.5)

Each factor is given a score and totaled and the patient’s risk is classified according to the following:

• 0 = Low risk
• 0.5-1 = Intermediate risk - 1
• 1.5-2 = Intermediate risk - 2
• ≥2 = High risk

In 2012, a revised IPSS (IPSS-R) was released with five risk groups (very low, low, intermediate, high and very high). It refined the original model by incorporating more detailed cytogenetic prognostic categorization and cut-offs for hemoglobin levels, platelet counts and neutrophil count. The prognostic score is now weighted according to the severity of cytopenias in addition to the bone marrow blast percentage.^[19]

WHO Prognostic Scoring System (WPSS)

The WHO Prognostic Scoring System (WPSS) was developed in 2005 based on the 2001 WHO classifications and refined most recently in 2011.^{[55, 56]} In contrast to the IPSS and IPSS-R, which are applied only at the time of diagnosis, the WPSS is dynamic, and patients can be reassigned categories as their disease progresses. The WHO score is calculated on the basis of the following three factors^[56] : 

• WHO disorder classification (0-3)
• Karyotype (0-2)
• Presence or absence of severe anemia (0-1)

Based on the total score, risk classification is as follows:

• 0 = Very Low
• 1 = Low
• 2 = Intermediate
• 3-4 = High
• ≥5 = Very High

Lower-Risk Prognostic Scoring System (LR-PSS)

In 2008, researchers at MD Anderson Cancer Center developed the Lower-Risk Prognostic Scoring System (LR-PSS) to identify patients with very low or low risk with a poorer prognosis. The model is a refinement of IPSS and included the following factors that were independent predictors of survival outcomes^[57] :

• Unfavorable cytogenetics
• ≥60 years old
• Decreased hemoglobin level
• Decreased platelet count
• Higher percentage of bone marrow blasts

Each factor was given a weighted score and based on the total, patients were assigned to one of the following risk categories:

• References

Treatment

Guidelines for the management of MDS have been issued by the following organizations:

• National Comprehensive Cancer Network (NCCN)^[23]
• European LeukemiaNet (ELN)^[54]
• European Society for Medical Oncology (ESMO)^[53]
• British Society for Haematology (BSH)^[58]

The NCCN guidelines recommend supportive care as the standard of care for patients with lower-risk MDS. Supportive care includes the following^[23] :

• Clinical monitoring
• Psychosocial support
• Quality-of-life assessment
• Transfusion – Red blood cell (RBC) transfusions for symptomatic anemia, platelet transfusions for thrombocytopenic bleeding
• Consider aminocaproic acid or other antifibrinolytic agents for bleeding refractory to platelet transfusions or profound thrombocytopenia
• Antibiotics for bacterial infections; consider prophylaxis in patients with recurrent infections
• Iron chelation, after > 20-30 RBC transfusions, particularly in patients who have lower-risk MDS or are potential transplant candidates, with deferoxamine subcutaneously or deferasirox orally, except in patients with low creatinine clearance (< 40 mL/min)
• Erythropoietin for symptomatic anemia
• Consider  in neutropenic patients with recurrent or resistant infections.
• Consider treatment with a thrombopoietin-receptor agonist in patients with lower-risk MDS who have severe or life-threatening thrombocytopenia.

In lower-risk MDS, all four guidelines recommend lenalidomide for the treatment of symptomatic anemia in patients with del(5q) MDS.^{[23, 54, 53, 58]} However, the BHS guidelines consider erythropoiesis-stimulating agents (ESAs) first-line therapy, although responses are inferior to those seen in low-risk MDS lacking del(5q).^[58]

For treatment of symptomatic anemia in patients without del(5q), with or without other cytogenetic abnormalities and with ring sideroblasts < 15% (or ring sideroblasts < 5% with an SF3B1 mutation), NCCN recommendations are as follows^[23] :

• Serum erythropoietin (EPO) level  ≤500 mU/mL - Recombinant human EPO or darbepoetin
• Serum erythropoietin (EPO) level > 500 mU/mL - Immunosuppressive therapy with equine anti-thymocyte globulin (ATG), with or without cyclosporine, for patients likely to respond (generally, those ≤60 y and with ≤5% marrow blasts, or those with hypocellular marrows, PNH clone positivity, or STAT-3 mutant cytotoxic T-cell clones); for those unlikely to respond to immunosuppressive therapy, azacitadine is preferred

For patients with symptomatic anemia with no del(5q) with or without other cytogenetic abnormalities and with ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation), NCCN recommendations are as follows^[23] :

• Serum erythropoietin (EPO) level  ≤500 mU/mL - Recombinant human EPO or darbepoetin
• Serum erythropoietin (EPO) level > 500 mU/mL - Luspatercept-aamt

For patients with clinically relevant thrombocytopenia or neutropenia or increased marrow blasts, NCCN guidelines recommend azacitidine (preferred), decitabine, or immunosuppressive therapy in selected cases.^[23]

For patients with higher-risk MDS who are candidates for transplantation, NCCN guidelines recommend allogeneic hematopoietic stem cell transplantation, alone or preceded by treatment with azacitidine, decitabine, or high-intensity chemotherapy. For patients who are not candidates for transplantation, options are azacitidine (preferred, category 1), decitabine, or clinical trial enrollment.^[23]

The ESMO, ELN, and BSH guidelines offer similar recommendations.^{[54, 53, 58]}

In addition, BSH guidelines recommend transplantation for patients with lower-risk MDS and any of the following^[58] :

• Transfusion dependency (≥2 units of blood/month)
• Significant cytopenias (platelets < 30 × 109/L, neutrophils < 0.3 × 109/L)
• Adverse cytogenetics

Further BSH recommendations regarding transplantation include the following:

• Transplantation in lower-risk MDS should possibly be considered at an early stage before iron overload occurs, or after failure of ESA or lenalidomide treatment, in particular if TP53 mutation coexists with del(5q), or if fibrosis is present.
• In higher-risk MDS, upfront transplantation is recommended if bone marrow blasts are 5-10%, with hypomethylating agents given before transplantation if blasts are > 10%.
• Screen patients who are potential transplantation candidates for mutations of the TP53, RAS, JAK2, DNMT3A, TET2, ASXL1, and RUNX1 genes, which correlate with poorer outcomes.
• Selected older patients (> 70 years) with high-risk MDS who have good performance status and a low transplantation-specific comorbidity index should be presented as candidates for allogeneic transplantation.

• References

Medication Summary

Treatment of myelodysplastic syndrome (MDS) is based on the stage and mechanism of the disease that predominates the particular phase of the disease process. In the early phases, when increased bone marrow apoptosis results in ineffective hematopoiesis, retinoids and hematopoietic growth factors are indicated.

In late stages, with inevitable leukemic transformation, cytotoxic chemotherapy and bone marrow transplantation may be necessary. All of these modes of therapy are undergoing clinical trials to determine the overall benefit to quality of life and survival.

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

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

Patients with associated serious medical comorbidities should be treated with less aggressive agents such as azacitidine or arsenic trioxide (Trisenox), or they should be entered into a clinical trial. However, these are currently in the early experimental stages.

• References

Isotretinoin or 13 cis-retinoic acid (Claravis, Amnesteem, Absorica, Zenatane, Myorisan)

• Dosing, Interactions, etc.

Clinical Context:  This agent is the most active among retinoids. This form of therapy is not generally accepted as standard therapy.

• References

Class Summary

Retinoids are the most active agents in MDS. Vitamin D-3 also has activity but is not of clinically significant value.

• References

Epoetin alfa (Procrit, Epogen)

• Dosing, Interactions, etc.

Clinical Context:  Epoetin alfa is a glycoprotein that stimulates red blood cell (RBC) production by stimulating division and maturation of committed RBC precursor cells. It is effective in 20-26% of MDS patients when administered alone and in as many as 48% of patients when combined with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF).

• References

Darbepoetin (Aranesp)

• Dosing, Interactions, etc.

Clinical Context:  Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary growth factor that is produced in the kidney and stimulates development of erythroid progenitor cells in bone marrow. This agent's mechanism of action is similar to that of endogenous erythropoietin, which interacts with stem cells to increase red cell production.

Darbepoetin differs from epoetin alfa (recombinant human erythropoietin) in containing 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3. Darbepoetin has a longer half-life than epoetin alfa, and may be administered weekly or biweekly.

• References

Sargramostim (Leukine)

• Dosing, Interactions, etc.

Clinical Context:  This GM-CSF stimulates division and maturation of earlier myeloid and macrophage precursor cells. It has been reported to increase granulocytes in 48-91% of patients with MDS.

• References

Filgrastim (Neupogen, Granix)

• Dosing, Interactions, etc.

Clinical Context:  This G-CSF stimulates division and maturation of granulocytes, mostly neutrophils, in 75-100% of MDS patients and seems to enhance erythroid response when given in combination with erythropoietin.

• References

Class Summary

Ineffective blood cell production is due to excess cellular apoptosis (programmed cell death) caused by activation of the Fas-Fas ligand. Hematopoietic growth factors are capable of reversing this process to some extent.

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Azacitidine (Vidaza)

• Dosing, Interactions, etc.

Clinical Context:  Azacitidine is a pyrimidine nucleoside analogue of cytidine. It interferes with nucleic acid metabolism. It exerts antineoplastic effects by DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic bone marrow cells. Nonproliferative cells are largely insensitive to azacitidine. This agent is approved by the US Food and Drug Administration for treatment of all 5 MDS subtypes.

• References

Decitabine (Dacogen)

• Dosing, Interactions, etc.

Clinical Context:  Decitabine is a hypomethylating agent believed to exert antineoplastic effects by incorporating into DNA and inhibiting methyltransferase, resulting in hypomethylation. Hypomethylation in neoplastic cells may restore normal function to genes that are critical for cellular control of differentiation and proliferation.

Decitabine is indicated for treatment of MDSs, including previously treated and untreated, de novo, and secondary MDSs of all French-American-British (FAB) subtypes (ie, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia) and International Prognostic Scoring System (IPSS) groups intermediate-1 risk, intermediate-2 risk, and high risk.

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Class Summary

Demethylation agents are a ntineoplastics that exert anticancer effects by causing DNA demethylation or hypomethylation in abnormal hematopoietic bone marrow cells. These agents may restore normal function to the tumor suppressor genes responsible for regulating cell differentiation and growth.

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Lenalidomide (Revlimid)

• Dosing, Interactions, etc.

Clinical Context:  Lenalidomide is indicated for the transfusion-dependent MDS subtype of deletion 5q cytogenetic abnormality. This agent is structurally similar to thalidomide. It elicits immunomodulatory and antiangiogenic properties, inhibits proinflammatory cytokine secretion, and increases release of anti-inflammatory cytokines from peripheral blood mononuclear cells. The dose used in MDS is much lower than that used for multiple myeloma.

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Class Summary

Immunomodulators elicit immunomodulatory, antiangiogenic properties, and inhibit proinflammatory cytokines.

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Arsenic trioxide (Trisenox)

• Dosing, Interactions, etc.

Clinical Context:  May cause DNA fragmentation and damage or degrade the fusion protein PML-RAR alpha. Use only in patients that have relapsed or are refractory to retinoid or anthracycline chemotherapy.

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Class Summary

Agents in this class inhibit cell growth and proliferation.

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Luspatercept (Reblozyl)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for first-line treatment of anemia in patients with very low- to intermediate-risk MDS who may require regular RBC transfusions and are ESA-naïve. 

Additionally, it is indicated for anemia failing an ESA and requires at least 2 units of RBCs over 8 week in adults with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). 

 It is not a substitute for RBC transfusions in patients who require immediate correction of anemia.

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Class Summary

These agents promote erythroid maturation by antagonizing inhibitors of late-stage erythropoiesis.

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Imetelstat (Rytelo)

• Dosing, Interactions, etc.

Clinical Context:  Indicated for adults with transfusion-dependent, low- to intermediate-risk MDS who have not responded to, have lost response to, or are ineligible for ESAs. 

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Class Summary

Inhibit telomerase enzymatic activity and prevent telomere binding that may result in reduced telomere length, reduced malignant stem and progenitor cell proliferation, and apoptosis.

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