Myelodysplastic Syndromes (MDSs)

Definition, Etiology, Pathogenesis

Myelodysplastic syndromes (MDSs) are clonal hematologic disorders characterized by peripheral blood cytopenia, dysplasia (classically defined as >10% in ≥1 hematopoietic lineage based on bone marrow morphology), ineffective hematopoiesis, and risk of transformation to acute myeloid leukemia (AML). MDS can be preceded by the acquisition of somatic mutations that drive clonal expansion in the absence of abnormal counts or dysplasia, referred to as clonal hematopoiesis of indeterminate potential (CHIP), which is a precursor state for hematologic neoplasms and can be analogous to monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis. However, CHIP and its spectrum are of emerging interest due to associations with increased risk of cardiovascular disease.

Risk factors for MDS include exposure to chemicals (eg, benzene, toluene) and heavy metals; tobacco smoke; ionizing radiation and radiation therapy; and chemotherapy/cytotoxic agents. MDS that develops in patients who have undergone prior systemic chemotherapy or radiation is typically termed secondary or therapy-related MDS. The median age of onset is between 60 and 75 years of age, with an incidence of ~2/100,000 population per year. The incidence is increasing, in part due to increasing population age, earlier disease recognition, and advancements in molecular testing modalities.

Clinical Features And Natural History

Patients may present with signs and symptoms related to low blood counts, symptomatic anemia, and recurrent infections—in the context of neutropenia—or with bruises, ecchymosis, or bleeding in cases with thrombocytopenia. MDS can also be detected on routine blood tests in asymptomatic individuals. Additionally, patients may have constitutional symptoms such as fever, chills, night sweats, weight loss, changes in appetite, and severe fatigue. Hepatosplenomegaly can be seen in some cases as well, due to increased extramedullary hematopoiesis.

MDSs are classified using various prognostic scoring systems such as the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), molecular IPSS (IPSS-M), or the World Health Organization (WHO) classification–based Prognostic Scoring System (WPSS). These models combine biochemical data, patient characteristics, and cytogenetic and molecular profiles to estimate survival and risk of transformation to AML. Newer diagnostic models, including the WHO and European Leukemia Network (ELN) criteria from 2022, are using molecular profiles to define disease characteristics that may assist with management decisions. This is especially important given the significant overlap between MDSs and AML pathobiology in high-risk patients.

Diagnosis

Diagnostic Tests

1. Complete blood count (CBC): Single or multilineage cytopenias are common; pancytopenia (ie, decrease in all 3 cell lineages: leukocyte count, hemoglobin, and platelet count) can be seen in many cases. Anemia is typically macrocytic or occasionally normocytic with an increase in red cell distribution width (RDW). Leukopenia with neutropenia (~50% of cases) and severe thrombocytopenia (~25% of cases) can also be seen. Thrombocytosis is possible in patients with abnormalities of 5q–. Circulating blasts may be present. Review of peripheral blood smears may show hypogranular or bilobed neutrophils, polychromasia, dimorphic populations (occasionally in the setting of transfusion dependence as well), poikilocytosis, anisocytosis, thrombocytopenia, and occasional megathrombocytes (giant platelets). Inappropriately low reticulocyte counts are common due to poor bone marrow function and dyserythropoiesis.

2. Bone marrow examination is mandatory for the diagnosis of MDS. Typically bone marrow is hypercellular for the patient’s age. In ~10% of cases, MDS may be hypoplastic with decreased cellularity and may resemble aplastic anemia; in such cases, a paroxysmal nocturnal hemoglobinuria (PNH) clone may be observed. Single or multilineage dysplasia, dyserythropoiesis with the appearance of ringed sideroblasts (iron-laden mitochondria visible as perinuclear granules with Prussian iron stain), dysplastic granulocytes, and increased monocytes and myeloid precursors can be seen. Historically the classification of high-grade disease was based on the number of myeloblasts and characterized as MDS with excessive blasts type 1 (MDS-EB-1) (5%-9%) or type 2 (MDS-EB-2) (10%-19%). Auer rods can occasionally be seen in MDS-EB-2, with their presence raising concern for overt transformation to AML. Current classification paradigms rely on molecular and cytogenetic details in addition to morphologic features and blast count.

3. Cytogenetic testing: Normal cytogenetic findings or common abnormalities such as loss of the Y chromosome do not exclude the diagnosis of MDS. Fluorescence in situ hybridization (FISH) may be used for selected specific mutations, such as del(5q), which is seen in elderly female patients. Other abnormal karyotypes, including del(7) or del(17p), are diagnostic for MDS in the absence of cytopenias or dysplasia.

4. Molecular studies: Molecular studies from bone marrow or peripheral blood are becoming increasingly important in the diagnosis, prognostication, and management of MDSs. Patients with suspected MDS should have testing using next-generation sequencing, which can be used to detect epigenetic driver mutations or splicing mutations that are associated with poor risk and progression to AML.

The mutations of interest include DNMT3A, TET2, and ASXL1. Additionally, mutations such as NPM1 and FLT3-ITD/TKD are associated with high-risk disease. The presence of a TP53 mutation results in loss of the p53 tumor suppressor protein and confers resistance to conventional chemotherapy.

BCR-ABL1 testing is done to exclude chronic myelogenous leukemia in cases with a proliferative marrow and leukocytosis. JAK2 V617F testing can help exclude myeloproliferative neoplasms, which can mimic or overlap with MDSs.

5. Other laboratory studies: Elevated serum iron, serum ferritin, fetal hemoglobin (HbF), and endogenous erythropoietin levels may be measured, as they can either indicate disease or predict response to therapy. For example, lower erythropoietin levels (<500 U/L) are predictors of better response to erythropoietin-stimulating agents (ESAs).

Differential Diagnosis

Megaloblastic anemia, aplastic anemias, nutritional causes of leukopenia with neutropenia (eg, copper deficiency), medication use (eg, hydroxyurea), immune thrombocytopenia, acute leukemia, myelofibrosis, or metastatic disease involving bone marrow should be considered as alternative diagnoses. In patients with cytopenia and no documented features of MDS or with dysplasia not accompanied by cytopenia, the diagnosis of idiopathic dysplasia of undetermined significance (IDUS) or idiopathic cytopenia of uncertain significance (ICUS), respectively, is made. If a clonal mutation is identified with present cytopenias but not meeting the criteria for MDS, this is termed clonal cytopenia of uncertain significance (CCUS). These conditions, in addition to CHIP, may progress to MDS.

Treatment

Treatment, conducted in specialized centers, depends on the patient’s performance status and age as well as on the risk category according to the IPSS, IPSS-R, IPSS-M, or (less often in our practice) WPSS (see mds-foundation.org; see mds-register.de). These models account for the proportion of blasts in bone marrow, karyotype, and number of lineages affected by cytopenia, in addition to molecular profiles in newer models.

The mainstays of treatment involve management of cytopenias, particularly if symptomatic, and disease control if associated with high risk. Supportive care and monitoring for infections is required in patients with severe cytopenias.

1. ESAs are used in patients with low to intermediate risk, as identified by the IPSS score. Patients with hemoglobin levels <10 g/dL, endogenous erythropoietin levels <500 mIU/mL, and requiring transfusion of <2 units of packed red blood cells (PRBCs) per month are more likely to benefit from ESA therapy.

Patients may take up to 12 weeks to respond and dose escalation may be required. ESAs should be avoided in individuals with uncontrolled hypertension and severe coronary artery or peripheral vascular disease. In the setting of transfusion-dependent anemia and failure of ESA treatment in lower-risk MDS with ringed sideroblasts, luspatercept is used.

2. Combined immunosuppressive treatment with antithymocyte immunoglobulin, cyclosporine [INN ciclosporin] in patients with hypoplastic MDS.

3. Lenalidomide is used in patients with del(5q) syndrome with improved rates of transfusion independence.

4. Hypomethylating agents (azacitidine, decitabine) are effective in disease control by preventing progression to AML and can result in transfusion independence and improved quality of life.

5. Intensive induction chemotherapy (using the same agents as in AML) and/or allogeneic hematopoietic stem cell transplant (HSCT) are reserved for younger symptomatic patients with excellent physiologic reserve and low comorbidity index scores. Allogeneic HSCT is the only curative option available for treatment of MDSs.

6. Novel agents are being increasingly applied in combination with hypomethylating agents for the management of high-risk MDSs. Venetoclax, an inhibitor for the antiapoptotic protein Bcl-2, has shown increased efficacy in high-grade MDS and AML. Patients on venetoclax may initially be at risk of tumor lysis syndrome, requiring a planned stepwise increase in dosage and frequent laboratory monitoring.

7. Supportive treatment is the mainstay of therapy:

1) PRBC transfusions (using leukocyte-depleted preparations).

2) Management of febrile neutropenia (see Febrile Neutropenia). The use of granulocyte colony-stimulating factor (G-CSF) is controversial, due to concerns about accelerated progression to AML, although the data supporting this are limited.

3) Platelet transfusions are used in case of bleeding due to thrombocytopenia or in a periprocedural context.

4) Iron-chelating agents (deferoxamine or deferasirox) can be considered in selected younger patients with low-risk disease and long-term predicted survival who have biochemical and/or clinical iron overload, or in patients with significant transfusion requirements.

Prognosis

Low and intermediate-1 risk patients with MDS can have relatively long median survival, up to 8.8 years in very low–risk patients prior to the inclusion of molecular parameters. Considering the median age at diagnosis, a number of low-risk patients do not experience significant disease-related complications or disease-related mortality.

Intermediate-2 or high-risk disease based on IPSS or IPSS-R scores are associated with a risk of progression to AML and early mortality within 5 to 12 months. Poor risk or complex cytogenetic abnormalities, in addition to mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1, are associated with poor overall survival.

In patients undergoing allogeneic HSCT, 3-year to 5-year disease-free survival rates are 30% to 50%. Overall prognosis without intensive treatment is determined by the risk score at presentation and frequency and type of complications.