Myelodysplastic syndrome (MDS) is a heterogeneous group of hematologic neoplasms classically described as a clonal disorder of hematopoietic stem cells leading to dysplasia and ineffective hematopoiesis in the bone marrow. Some patients with MDS may have a transformation into acute myeloid leukemia (AML). MDS is usually diagnosed in older patients over the age of 65. Clinical manifestations include a decrease in the number of red blood cells (RBC), platelets, and white blood cells (WBC). The disease course is variable. Not all patients require treatment initially, as there is no survival benefit with the treatment of asymptomatic, low-risk patients. Treatment is reserved for symptomatic patients, such as those requiring frequent blood transfusions. Prognosis and overall survival depend upon multiple factors such as the severity of cytopenias, the percentage of blasts in the peripheral blood and bone marrow, and karyotype.
MDS is a clonal disorder of myeloid stem cells which may occur de novo or secondary to various insults to the bone marrow. Various environmental and iatrogenic etiologies have been implicated in MDS, including exposure to chemotherapy (alkylating agents in particular), radiation or environmental toxins such as benzene. Familial MDS has been reported but is a rare entity. The actual preceding factor(s) for de novo MDS is not entirely understood but assumed to occur from an oncogenic process resulting in one or more somatic mutations. Over recent years, we have gained much insight into mutations that are commonly altered in MDS due to advances and rapid availability of gene sequencing. With these developments, researchers can identify one or more driver mutations in up to 80% to 90% of patients with some of the most common ones including SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2. RUNX1, for example, is a mutation noted to disrupt normal hematopoiesis. More than 100 genes have been found to be recurrently mutated in MDS, and these encode spliceosome components, chromatin remodeling factors, epigenetic pattern modulators, and transcription factors among others. These driver mutations have been found to correlate with different clinical features, including the severity of cytopenias, blast percentage, cytogenetics, and overall survival. Of note, genetic mutations are not included in prognostic scoring systems for MDS but they have been found to influence overall survival in some cases. TP53 for example, is a tumor suppressor gene that has a poor prognosis compared to other mutations.
MDS may be de novo or related to prior use of chemotherapeutic agents, also known as treatment-related MDS (t-MDS). This entity is associated with a poor prognosis compared to de novo MDS and typically occurs five to seven years after use of chemotherapeutic agents. Alkylating agents such as cyclophosphamide have been associated with this type of MDS. t-MDS is commonly associated with monosomies in chromosome 5 or 7 and complex cytogenetics. This type of MDS also commonly transforms into acute myeloid leukemia (AML.) In a retrospective review of 112 patients with t-MDS, 55% transformed into acute myeloid leukemia, while de novo MDS transforms into AML only around 30% of the time. The median overall survival for secondary, or treatment-related MDS, is only around 30 weeks.
The incidence of de novo MDS in the United States varies but Surveillance Epidemiology and End Results (SEER)-Medicare database from 2007 through 2011 estimate incidences around 4.9 per 100,000 persons and around 20,541 new cases annually. The incidence of MDS increases with age with most cases occurring after age 65 and most frequently seen in patients over 80 years old, with a rate of 58 per 100,000. It is usually seen more in males and Caucasians.
Development of MDS may occur due through various mechanisms such as environmental exposures to chemicals like benzene, radiation, prior exposure to chemotherapeutic agents, or may be idiopathic, which is typically seen in the elderly population. Bone marrow failure syndromes like acquired aplastic anemia and Fanconi anemia have a risk of developing MDS and sometimes mimic this syndrome. MDS can be de novo or secondary to other causes, also known as treatment-related MDS. Chemotherapeutic agents such as alkylators or topoisomerase II inhibitors have been implicated as known causes of MDS, usually occurring 2 to 7 years after exposure. 
The mechanism for the development of MDS has been implicated by various genetic and chromosomal abnormalities, which may occur de novo or secondary to one of the above etiologies. Cytogenetic abnormalities are seen in more than 80% of patients and include translocations or more commonly, aneuploidy (loss or gain of a chromosome). Changes in cytogenetics play a large role in the International prognostic scoring system (IPSS). Deletion of the long arm of chromosome 5 (5q) is the most common abnormal karyotype and may be subdivided into 2 categories: treatment-related MDS with 5q deletion, usually with exposure to alkylating agents, versus de novo isolated 5q deletion. Patients with 5q deletion related to prior chemotherapeutic agents usually also have other cytogenetic abnormalities and/or TP53 mutations and usually portends a poor prognosis. Isolated 5q deletion without other cytogenetic abnormalities has a significantly better prognosis. Other cytogenetic abnormalities commonly studied include normal karyotype, deletion 7q (-7), trisomy 8 and -Y.
Over 100 somatic point mutations have been implicated in MDS, and there is some overlap with AML. The most common somatic alterations include mutations in TET2, SF3B1, ASXL1, DNMT3A, SRSF2, RUNX1, TP53, U2AF1, EZH2, ZRSR2, STAG2, CBL, NRAS, JAK2, SETBP1, IDH1, IDH2, and ETV6. These mutations have been shown to correlate with various features. TP53 mutations are associated with complex cytogenetics and poor overall survival. RUNX1 and TP53 tend to correlate with worse thrombocytopenia. TET2 mutations have a better response to hypomethylating agents.
The World Health Organization (WHO) 2016 Classification of Myeloid Neoplasms describes several subcategories of myelodysplastic neoplasms, in addition to overlap syndromes which have both myeloproliferative and myelodysplastic features. This classification is based on differences in morphology, dysplasia and karyotype, particularly 5q deletion.
The classification of MDS by WHO (2016) is as follows:
Additionally, there are overlap syndromes included in the WHO 2016 classification, including:
There are also a number of other overlap syndromes with myeloproliferative and myelodysplastic features such as chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML) and juvenile myelomonocytic leukemia (JMML.)
Evaluation of the complete blood count (CBC) usually reveals anemia or pancytopenia. A bone marrow biopsy and aspirate are usually performed after exclusion of other causes of their cytopenias. There is no one histopathologic feature that defines MDS but rather a constellation of findings from the peripheral blood and bone marrow which meet the accepted criteria for diagnosis. Additional diagnostic workup includes flow cytometry immunophenotyping, cytogenetics with karyotype and fluorescent in situ hybridization (FISH), along with genetic profiling to assess for relevant somatic mutations.
During evaluation of a bone marrow biopsy, a pathologist will determine marrow cellularity, the number of blasts, dysplasia of the megakaryocyte lineage, the presence of ring sideroblasts by iron stains, fibrosis, as well as exclusion of metastases from outside the bone marrow. Bone marrow evaluation is performed using Giemsa and iron stains. The bone marrow is typically normocellular or hypercellular, though it can be hypocellular. Dysplasia in more than 10% of a single cell lineage is part of the diagnostic criteria for MDS and can be seen in red cell precursors, granulocytes and/or megakaryocytes.  Morphologically, in the erythroid lineage, there may be dyserythropoietic changes and ring sideroblasts evident by iron stain. Iron staining with Prussian blue reaction is performed to evaluate for ring sideroblasts, which are described as a ring of iron-laden mitochondria around the nucleus of erythroid progenitors. Granulocytic precursors may have hyposegmentation and hypogranulation. Quantification of myeloblasts must number less than 20% on bone marrow evaluation, as greater than 20% indicates acute myeloid leukemia. Myeloblasts, or immature myeloid cells, are noted to have a high nucleus to cytoplasm ratio (N:C ratio), fine nuclear chromatin, visible and prominent nucleoli, with or without granules. Auer rods, which are pink/red rod-like structures in the cytoplasm of blasts, are an uncommon finding in MDS but can be seen in MDS with excess blasts-2 (MDS-EB-2).
Relevant immunostains are performed such as myeloperoxidase (MPO), CD34, CD117, CD61 or CD42b for megakaryocytes, CD68 for monocytes, CD20 for B-cell lineage and CD3 for T-cell lineage.  CD34, is an antigen expressed on progenitor and early precursor cells, which is a marker for blasts. 
Patients with MDS may be clinically asymptomatic for years and may have incidental findings of cytopenias on routine labs. Others may present with signs and symptoms related to bone marrow failure such as fatigue, bleeding, or infections. These symptoms may be gradual and progress with time. Anemia is the most common clinical manifestation, and patients may complain of fatigue, shortness of breath, chest pain or dizziness due to this. Bleeding or petechiae from thrombocytopenia, as well as infections from neutropenia, are less commonly noted.
On physical exam, patients may only be noted to have signs consistent with anemia such as pallor or petechiae. Organomegaly can be seen in overlap syndromes but is otherwise infrequently seen in MDS.
MDS may be suspected if one or more cytopenias are apparent. Per the International Working Group guidelines for MDS, there are 2 prerequisite criteria for diagnosis: (1) stable cytopenia for 6 months or longer, or 2 months if a certain karyotype or bilineage dysplasia is apparent, and (2) exclusion of other causes of dysplasia and/or cytopenia(s). Anemia is the most common manifestation in MDS, and this may be normocytic or macrocytic. Evaluation of other potential causes of anemia should be performed with additional laboratory testing including iron and ferritin levels, B12 and folate levels, hemolysis work-up with lactate dehydrogenase (LDH), haptoglobin and Coombs testing, and serum protein electrophoresis (SPEP) and immunofixation (IFE) as part of multiple myeloma work-up, if clinically applicable. Zinc and copper deficiencies are rare nutritional causes of anemia which can mimic MDS. Macrocytosis is commonly seen in MDS; however, it is usually not responsive to B12 or folate replacement. Neutropenia and/or thrombocytopenia may also be apparent with anemia or occur later in the disease course. Initial evaluation includes a complete blood count (CBC) with differential, a peripheral blood smear along with any other laboratory investigation that would be clinically relevant. A diagnostic evaluation should also include a bone marrow biopsy and aspirate, flow cytometry immunophenotyping, evaluation of cytogenetics by karyotype and FISH, along with genetic profiling (performed with genomic profiling) to assess for relevant somatic mutations such as SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2.
On the peripheral blood smear, there are decreased numbers of one or more cell lines (red cells, platelets or neutrophils). Neutrophils may be hypogranular and have hyposegmented neutrophils (pseudo-Pelger-Huet anomaly), and platelets may be larger in size and lack granules. Myeloblasts, or blasts, are immature myeloid progenitors which are rarely seen in the peripheral blood and if seen, should also raise suspicion for acute myeloid leukemia. A bone marrow biopsy, which is required for diagnosis, is typically cellular or hypercellular, with dysplasia in one or more cell lines. A small number of patients may have hypoplastic bone marrow with MDS, but this is less common.
Diagnosis of MDS requires a histopathologic evaluation of the peripheral blood and bone marrow with a bone marrow aspirate and biopsy. The following criteria are required for diagnosis:
A pathologist will examine both the peripheral blood and marrow smears using Giemsa and iron staining. When evaluating the bone marrow, greater than 10% dysplasia of granulocytic cells is required as part of the diagnosis for MDS. Additionally, quantifying the number of blasts in the peripheral blood and bone marrow is also important. Myeloblasts, or blasts of myeloid lineage, can be described as cells with a high nuclear to cytoplasm ratio (N:C ratio), fine nuclear chromatin, visible nucleoli, with or without granules. Auer rods are pink rod-like structures in the cytoplasm which are pathognomonic for myeloblasts. Myeloblasts should only account for less than 20% of nucleated cells in the bone marrow. If the percentage is above 20%, this would be considered acute myeloid leukemia. Iron staining with Prussian blue reaction is performed to evaluate for ring sideroblasts, which are described as a ring of iron-laden mitochondria around the nucleus of erythroid progenitors.
Cytogenetic analysis by FISH is also typically done to identify chromosomal abnormalities as this can influence both prognosis and treatment. It also helps determine clonality. While a normal karyotype does not rule out MDS, around half of patients will have some type of cytogenetic abnormality. MDS is typically associated with aneuploidy, while translocations are less common. The most frequently observed alterations include del(5q), monosomy 7 or del(7q), trisomy 8, and del(20q). Deletion of the long arm of 5, or del(5q), is associated with a better prognosis compared to others and responsiveness to lenalidomide, one of the treatments for MDS. The WHO MDS classifications lists MDS with isolated 5q as one of the categories. This category is defined as isolated del(5q) and can include one other cytogenetic abnormality except for monosomy 7 or del(7q). Some cytogenetic abnormalities are associated with prior exposure to chemotherapeutic agents. Deletion of all or part of chromosomes 5 and 7 have been associated with prior use of alkylating chemotherapeutic agents such as cyclophosphamide. Translocation of 11q23 is usually seen in patients with prior exposure to topoisomerase II inhibitors such as doxorubicin and is commonly associated with p53 mutations.
Somatic mutations have recently proven to be vital in understanding the underlying pathophysiology of MDS. They also have been shown to correlate with survival in some cases. There have been hundreds of mutations implicated in MDS, and a mutation can be found in 80% to 90% of patients. There is overlap of mutations shared with AML. The most common mutations include TET2, SF3B1, ASXL1, DNMT3A, SRSF2, RUNX1, TP53, U2AF1, EZH2, ZRSR2, STAG2, CBL, NRAS, JAK2, SETBP1, IDH1, IDH2, and ETV6. These mutations are also associated with various clinical features. TP53 for example, carries a poor prognosis and is associated with higher blast percentage in the bone marrow and worse thrombocytopenia. It is also associated with complex cytogenetics.
The mainstay of treatment for MDS involves assessment of symptoms and potential morbidity attributed to the disease. Patients do not always require treatment as long as they are asymptomatic and most can be treated with supportive measures such as intermittent blood or platelet transfusions. MDS often portends an indolent or gradual course, though some patients have risk factors that put them at risk for transformation into AML. Oncologists will use the IPSS or R-IPSS scoring system to help guide the course of treatment. Treatment options include supportive measures, low intensity treatment with systemic agents, or high intensity treatment such as allogeneic stem cell transplant. The only curative modality remains an allogeneic stem cell transplant, but this is often difficult as MDS occurs more commonly in the elderly population. Candidates for allogeneic stem cell transplant must be carefully selected, as the transplant process itself can be morbid for patients with potentially significant treatment-related mortality, especially in the elderly population. However, high-risk patients who are able to undergo transplant have around 50% survival at 3 years. Treatment decisions are often individualized to each patient and based upon potential morbidity and mortality from treatment. Patients in intermediate or high-risk categories are generally considered for treatment.
MDS has proven to be refractory to cytotoxic chemotherapy, but there has been some success with the use of hypomethylating agents and lenalidomide. High-risk and some intermediate-risk patients are often considered for allogeneic stem cell transplant or systemic treatment. Low-risk patients may be managed with supportive measures such as transfusions or hematopoietic growth factors, though they may be offered treatment with systemic agents.
Hematopoietic growth factors may be used in low-risk patients with mild pancytopenia and low requirements for transfusion. In these patients, erythropoietin (EPO) levels should be measured. If the level is less than 500 mU/mL, erythropoiesis-stimulating agents (ESAs) such as agents such as recombinant human erythropoietin or darbepoetin may be given with or without granulocyte colony stimulating factors (G-CSF). G-CSF does not appear to affect survival but may have a synergistic effect with EPO agents to effectively improve anemia with improvement in anemia in 40% to 60% of patients. If serum EPO level is greater than 500 mU/mL, patients may be considered for treatment with either immunosuppressive agents such as anti-thymocyte globulin +/- cyclosporine or one of the hypomethylating agents as ESAs are unlikely to improve anemia in this subset of patients.
Lenalidomide, a thalidomide derivative, is an agent used in patients with symptomatic anemia and deletion 5q (+/- one other cytogenetic abnormality except monosomy 7) in a low or intermediate risk category. This is an oral agent given daily, with responses typically noted after 3 months of treatment and often allows patients to become independent of blood transfusions.
Azacitidine and decitabine are pyrimidine analogues which are classified as hypomethylating agents or epigenetic modifiers. Low doses of these medications have shown to aid in allowing the differentiation of blasts into mature cells. These agents are given monthly and generally require several months before assessing response. Treatment is usually continued for a prolonged period of time though patients will often eventually have progression of their disease and experience worsening of cytopenias.
Data to support the usage of these drugs has been gained from prospective randomized trials and retrospective data. Azacitidine has been shown to improve both cytopenias and survival, especially those with high-risk MDS. A large randomized phase 3 trial, which randomized patients to azacitidine (75 mg/m subcutaneous or intravenously daily for 7 days every 28 days) versus supportive measures or conventional care (low dose cytarabine or intensive chemotherapy) showed 50.8% survival at 2 years in the azacitidine group compared to the conventional care group. It also showed the potential to delay time to progression to AML, compared to supportive care. Another crossover trial assigned patients to either supportive care or azacitidine with complete and partial remission rates of 60% versus 5% in the supportive care group. Patients receiving azacitidine also required fewer transfusions. Of note, azacitidine may achieve a duration of response of around 15 months.
Decitabine is a closely related hypomethylating agent that can be given intravenously (IV) daily over 3 to 10 days every 28 days. It offers response rates of 30% to 50% and is thought to be more potent than azacitidine. One randomized trial compared decitabine to supportive care, which showed improvement in progression-free survival but no difference in overall survival. There have been no cross-comparisons of these 2 hypomethylating agents at the current time.
The differential diagnoses for other etiologies with similar clinical features include nutritional deficiencies such as B12 and folate, infections such as parvovirus and human immunodeficiency virus (HIV), medications such as methotrexate, and alcohol use. Other primary bone marrow disorders should be considered, such as myeloproliferative disorders or overlap syndromes with both myelodysplastic and myeloproliferative features such as CMML.
The prognosis of patients with MDS varies widely depending upon several characteristics including cytogenetics and severity of cytopenias. Patients with 5q- generally have a much better prognosis compared to MDS with monosomy 7, for example. The International Prognostic Scoring System (IPSS) and revised IPSS (R-IPSS) are risk stratification system used by clinicians to guide treatment and the potential clinical course. These systems can be used in addition to a clinical assessment of the patient including age and co-morbidities to determine the best therapeutic options. The IPSS includes the percentage of blasts in the bone marrow, karyotype, and the number of cell lineages with cytopenias. Karyotype with a good prognosis includes normal karyotype, -Y, deletion 5q, deletion 20q. Poor risk karyotypes include complex cytogenetics (greater than three abnormalities), or chromosome 7 abnormalities. All other karyotypes are categorized as intermediate risk. Based on these findings, a score is calculated to determine a risk score of either low, intermediate-1 or intermediate-2, or high risk.
There is a Revised International Prognostic Scoring System (R-IPSS) which risk stratifies patients based on cytogenetics, blast percentage, and has separate scores for absolute neutrophil count, hemoglobin value, and platelet value and has been shown to better predict outcome than the older IPSS. For example, patients in a very high-risk category for R-IPSS have a median overall survival of 0.8 years, compared to very low-risk patients with median overall survival of 8.8 years.
Those patients who are classified as high-risk or have an unfavorable prognosis will probably require treatment and may be considered for allogeneic stem cell transplant to maintain their remission. However, even favorable risk patients with MDS may still have considerable morbidity and mortality from their disease. About a third of patients will also have transformation into AML, and these patients often have a very poor prognosis.
Patients with isolated 5q deletion might experience longer survival than other types of MDS, with one study noting 5-year survival of 40% if they did not receive treatment and 54% if they received treatment.
Myelodysplastic syndrome (MDS) is a heterogeneous group of hematologic neoplasms classically described as a clonal disorder of hematopoietic stem cells leading to dysplasia and ineffective hematopoiesis in the bone marrow. Because of the diverse presentation and complex management, this syndrome is best managed by an interprofessional team of healthcare professionals that includes a hematologist, oncologist, internist, infectious disease specialist and a geneticist. The prognosis for patients with MDS is variable; depending on the severity and type of cytogenetic defect. Karyotype with a good prognosis includes normal karyotype, -Y, deletion 5q, deletion 20q. Poor risk karyotypes include complex cytogenetics (greater than three abnormalities), or chromosome 7 abnormalities. All other karyotypes are categorized as intermediate risk. Based on these findings, a score is calculated to determine a risk score of either low, intermediate-1 or intermediate-2, or high risk.
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