Definition, Etiology, Pathogenesis Top
Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by peripheral blood cytopenia, dysplasia of one or more hematopoietic lineages, ineffective erythropoiesis, and frequent transformation to acute leukemia. The etiology is generally unknown. Risk factors include exposure to chemicals (eg, benzene, toluene), heavy metals, tobacco smoke, ionizing radiation, cytotoxic agents, and radiotherapy. MDS may develop in the course of aplastic anemia. The median age of onset is between 60 and 75 years of age, with an incidence ~2/100,000 people per year.
Clinical Features And Natural HistoryTop
Signs and symptoms are uncharacteristic and associated with anemia, neutropenia (resistant bacterial and fungal infections), and thrombocytopenia (cutaneous and mucosal purpura, bleeding). Rare manifestations include hepatomegaly, splenomegaly, or both. Early disease may be asymptomatic, whereas advanced disease is associated with more severe clinical manifestations as well as more frequent and more rapid transformation to acute leukemia. Acute leukemia evolving from MDS carries a grave prognosis. Frequent packed red blood cell (PRBC) transfusions lead to iron overload. Severe infection or bleeding may be the cause of death.
1. Complete blood count: Pancytopenia is found in approximately half of the patients, anemia (rarely microcytic) in almost all patients, and leukopenia with neutropenia in the majority of patients. The proportion of blasts in peripheral blood is 0% to 19%. Dysmorphic neutrophils, thrombocytopenia, and low reticulocyte counts are observed.
2. Bone marrow examination reveals features of abnormal hematopoiesis (most prominently dyserythropoiesis) affecting from one to all lineages; in certain subtypes, the proportion of blasts is increased. Findings may include hypolobular megakaryocytes and agranular leukocyte precursors. In 90% of patients, the cellularity of bone marrow is normal or increased, while in ~10%, it is decreased (hypoplastic MDS). Results of trephine biopsy reveal an abnormal distribution of precursor cells, with fibrosis present in some patients. In some subtypes, cytochemical studies reveal iron deposits in erythroblasts (pathologic sideroblasts, associated with microcytic anemia).
3. Results of cytogenetic studies, if abnormal, are important for confirming the diagnosis of MDS and for assessing the risk of transformation to acute leukemia. Normal cytogenetics, or common abnormalities such as loss of the Y chromosome, do not exclude the diagnosis of MDS. Fluorescence in situ hybridisation analysis may be used for selected specific mutations, such as 5q-.
4. Molecular studies: Microarray panels are used in many centers due to increased sensitivity compared with routine cytogenetics.
5. Other laboratory studies: Any of elevated serum iron, fetal hemoglobin (HbF), and endogenous erythropoietin levels may be seen (lower erythropoietin levels are predictors of a better response to erythropoietin-stimulating agents [ESAs]).
In 90% to 95% of patients, the diagnosis may be established on the basis of the clinical presentation, exclusion of other causes of anemia, and results of bone marrow examination. The diagnostic criteria include 1-, 2-, or 3-lineage abnormal hematopoiesis (features of dysplasia) affecting ≥10% of cells in ≥1 lineage, and characteristic cytogenetic abnormalities.
Anemia (in particular megaloblastic and aplastic anemias), leukopenia with neutropenia, primary immune thrombocytopenia, acute leukemia, idiopathic myelofibrosis, metastatic disease involving the marrow, toxin exposure, chemotherapy or other cytotoxic agents, anemia of chronic kidney disease, mixed anemias (eg, iron deficiency in the setting of megaloblastic anemia).
In patients with cytopenia and no documented features of MDS or with dysplasia not accompanied by cytopenia, the diagnosis of idiopathic cytopenia of undetermined significance (ICUS) or idiopathic dysplasia of uncertain significance (IDUS) is made. These conditions may progress to MDS, acute myelogenous leukemia, myeloproliferative neoplasm (MPN), or MDS/MPN.
Treatment depends on the performance status and age of the patient, as well as on the risk category according to the International Prognostic Scoring System (IPSS) (this takes into consideration the proportion of blasts in bone marrow, karyotype, and the number of lineages affected by cytopenia) or newer prognostic systems (World Health Organization-adapted Prognostic Scoring System [WPSS]: www.mds-register.de/ipss; or revised IPSS [IPSS-R]: www.mds-foundation.org/ipss-r-calculator).
1. Treatment of early disease: In low- to intermediate-risk patients (according to the IPSS score), treatment may include administration of ESAs (+/– granulocyte colony-stimulating factor [G-CSF]), combined immunosuppressive treatment (antithymocyte immunoglobulin, cyclosporine [INN ciclosporin]), or lenalidomide in patients with del(5q). Many patients with asymptomatic anemia are simply monitored without treatment.
2. Intensive treatment: Intensive induction chemotherapy (using the same agents as in acute myeloid leukemia) and hypomethylating agents (azacitidine, decitabine), allogeneic hematopoietic stem cell transplantation (HSCT) (the only curative treatment), or both. This is reserved for younger symptomatic patients with excellent physiological reserve.
3. Supportive treatment is the mainstay of therapy:
1) Anemia: PRBC transfusions (using leukocyte-depleted preparations), ESAs (in IPSS low- to intermediate-1 risk patients with hemoglobin <10 g/dL, endogenous erythropoietin <500 mU/mL, and/or requiring transfusion of <2 U of PRBCs per month; dosage: see Anemia).
2) Neutropenia: G-CSF; see management of febrile neutropenia. Persistence of neutropenia complicates the therapy as some patients have recurrent infections mandating long-term G-CSF therapy.
3) Symptomatic thrombocytopenia: Asymptomatic patients should be monitored. Although platelet concentrate transfusions can ameliorate thrombocytopenia, there is a high risk of developing platelet refractoriness, which reduces the future utility of platelets.
4) Iron-chelating agents (deferoxamine or deferasirox) may be considered in selected younger patients with low-risk disease and predicted long-term survival. The utility of iron chelation in elderly patients with MDS remains the subject of controversy.
Complete hematologic remissions are achieved in ~50% of patients treated with intensive chemotherapy, but are short-lasting (median, 10-12 months). Mortality rates during remission induction therapy are ~15%. In patients undergoing allogeneic HSCT, 3- 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 the frequency and type of complications.