Myelodysplastic Syndromes: Classification, Features, Diagnosis, and Treatment Options

Myelodysplastic syndromes (MDS) are clonal disorders that cause ineffective hematopoiesis, which in turn results in peripheral blood cytopenias, most commonly macrocytic anemia. The World Health Organization (WHO) includes the following conditions in its 2008 classification of MDS^[1,2]: refractory anemia, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, refractory anemia with ring sideroblasts, refractory anemia with excess blasts 1 and 2, unclassifiable myelodysplastic syndrome, and myelodysplastic syndrome associated with del(5q). Dysplasia refers to the failure of cells to differentiate and mature normally. By definition, all patients with MDS have less than 20% of marrow blasts; patients with 20% or more marrow blasts are considered to have acute myeloid leukemia (AML).^[3]

The image shown is an example of a hypercellular (ie, 80% cellular) core bone marrow biopsy from a 70-year-old patient (normocellular for age would be 30%); hypercellular bone marrow is seen in the majority of patients with MDS.

Image courtesy of Stephanie Mathews, MD.

MDS primarily affect the elderly; the median age at diagnosis is 70 years, with a slight male predominance. Although the majority of MDS are thought to develop from an accumulation of somatic mutations over time, the specific etiology is often unknown. However, occupational exposure to organic solvents (eg, benzene) has been associated with the development of MDS. In addition, a rare familial form of MDS that is associated with monosomy 7 has been described, and germline mutations in transcription factors RUNX1 and GATA2^[4] have also been found to predispose some individuals to MDS. The peripheral blood smear shows a hypolobulated neutrophil (pseudo–Pelger-Huët cell), which is often seen in patients with MDS.

Image courtesy of Stephanie Mathews, MD.

A variety of genetic mutations have been reported in patients with MDS at varying frequencies. These findings can play a role in supporting the diagnosis of MDS in cases where morphologic dysplasia is subtle. Such mutations carry prognostic significance and may also play a role in treatment selection. For example, there are reports of higher response rates to azacitidine in patients with TET2 mutation.^[5,6] Other genetic mutations include SF3B1, ASXL1, SRSF2, RUNX1, TP53, U2AF1, EZH2, IDH1 and IDH2, and NRAS. The bone marrow aspirate shown demonstrates dyserythropoiesis in the form of abnormal erythroid precursors (arrows), which is characteristic of MDS.

Image courtesy of Stephanie Mathews, MD.

A small percentage of patients with MDS are also found to have a paroxysmal nocturnal hemoglobinuria (PNH) clone on flow cytometry, but the clone size is usually smaller than that seen in PNH. A prospective study showed that the median size of PNH clones in MDS patients was 17.6%.^[7] The image shows examples of abnormal eosinophils that can be seen in patients with MDS (arrows).

Image courtesy of Stephanie Mathews, MD.

Patients with MDS often present with fatigue or decreased exercise tolerance, but some are asymptomatic at the time of diagnosis, and cytopenias are often found incidentally on bloodwork done for other reasons. The initial diagnostic evaluation of a patient with suspected MDS includes obtaining a thorough medical history and physical examination, followed by a complete blood count (CBC), peripheral blood smear review, bone marrow examination, and basic laboratory testing to evaluate other diseases that can be confused with MDS. Diseases that mimic those of MDS include vitamin B12 deficiency, folate deficiency, and human immunodeficiency virus (HIV) infection.^[8] The image shows excess blasts (arrow) on a bone marrow aspirate from a patient with a subtype of MDS.

Image courtesy of Stephanie Mathews, MD.

Refractory anemia with ring sideroblasts (RARS), a subtype of MDS, shows key features of MDS on bone marrow biopsy, including unilineage erythroid dysplasia; at least 15% of erythroid precursors are ring sideroblasts; and less than 5% are myeloblasts.^[1,2,9-11] Ring sideroblasts are erythroid precursors with iron-laden mitochondria that can be made visible with Prussian blue staining (arrows).

Image courtesy of Stephanie Mathews, MD.

Not all dysplasia seen in the bone marrow is due to MDS. Therefore, it is important to consider the differential diagnosis of dysplasia, particularly because there is a level of subjectivity in morphology assessment. Other etiologies of marrow dysplasia include HIV infection, vitamin B12 deficiency, folate deficiency, chronic liver disease, alcohol abuse, and drugs (eg, azathioprine, methotrexate). The image shows a bone marrow aspirate from a patient with pancytopenia and dysplasia caused by methotrexate therapy.

Image courtesy of Stephanie Mathews, MD.

About 10%-20% of patients with MDS present with hypocellular bone marrow. Therefore, differentiating aplastic anemia from hypoplastic MDS can be a challenge. However, findings most consistent with hypoplastic MDS include hypolobated neutrophils, dysplastic and hypolobated megakaryocytes (arrow), increased numbers of immature precursors that are abnormally located, and an abnormal karyotype.

Image courtesy of Stephanie Mathews, MD.

MDS carry variable risk for transformation to AML. The International Prognostic Scoring System (IPSS) was first developed in 1997 to help stratify patients with MDS by their risk of transformation to AML and by their risk of death. In 2012, a revised version of the IPSS, referred to as the IPSS-R, included a broader range of cytogenetic abnormalities and accounted for the degree of cytopenias in its risk stratification.^[12-14] The prognostic score uses variables such as age, sex, cytogenetic categories, WHO classification, bone marrow blast percentage, hemoglobin level, platelet count, absolute neutrophil count, and treatment. However, the IPSS-R is valid only for patients with de novo MDS, and it divides patients into five different risk categories, which show variations in median survival as well as time to AML progression.

The image shows an increased blast (arrows) count (≥20%) in a background of trilineage dysplasia from a patient with a subtype of MDS and transformed disease.

Image courtesy of Stephanie Mathews, MD.

Cytogenetic studies serve significant roles in the diagnosis, prognosis, and treatment responsiveness of MDS. The IPSS-R risk stratification system for cytogenetics is categorized into the following five groups^[12-14]:

• Very good: -Y, del(11q)
• Good: Normal, del(5q) alone or with one other abnormality, such as del(12p), del(20q)
• Intermediate: del(7q), +8, +19, i(17q), or any other single or double independent clones
• Poor: -7, abnormal 3q, double abnormalities including -7/del(7q), or complex karyotype with 3 abnormalities
• Very poor: Complex karyotype with more than 3 abnormalities

The image shows dysplastic megakaryocytes (arrows), which are often seen in patients with the del(5q) subtype of MDS.

Image courtesy of Stephanie Mathews, MD.

MDS associated with isolated del(5q) are a rare but important subtype of MDS with treatment implications. Less than 5% of patients diagnosed with MDS have this subtype, in which the blood and bone marrow have less than 5% blasts.^[1,2,9] Patients are typically females with erythropoietin-refractory macrocytic anemia, thrombocytosis, and hypolobated megakaryocytes. MDS associated with isolated del(5q) have a favorable prognosis: The risk of transformation to AML is low, and the response rate to lenalidomide is high.^[15] However, major adverse side effects of lenalidomide therapy in this population include neutropenia and thrombocytopenia.

The images show an example of the del(5q) karyotype (left) (red arrow) and a fluorescent in situ hybridization (FISH) (right) that reveals two normal nuclei and two abnormal nuclei (yellow arrows) with del(5q).

Image courtesy of Kathleen W. Rao, PhD, and Susan Bowyer.

Although cytogenetic abnormalities such as deletions and gains are common in MDS, chromosomal translocations are less common. The core-binding-factor–associated recurrent translocations t(8;21) and inv(16) are considered to be AML in the 2008 WHO classification of MDS, regardless of the blast count or marrow dysplasia. Patients with these translocations should receive treatment for AML; they generally have favorable prognoses. The image shows an example of a dysplastic erythroid precursor, (arrow) seen in a patient with a subtype of MDS.

Image courtesy of Stephanie Mathews, MD.

Treatment of patients with MDS depends on multiple factors, including functional status, comorbidities, and clinicopathologic disease variables. Standard treatment options include supportive care, disease-modifying agents, and allogeneic hematopoietic stem cell transplantation (HSCT).^[16] For patients with lower-risk MDS and symptomatic anemia, a trial of 3 months of an erythropoietin-stimulating agent (ESA) would be appropriate if the erythropoietin level is less than 500 U/L.^[16] Note that patients with erythropoietin levels greater than 500 U/L and/or have a significant transfusion history rarely have a response to ESAs. However, although some patients do not reach complete remission, they may achieve hematologic improvement. Complete response rates range between 10% and 40%. The image depicts hypercellularity seen on a core bone marrow biopsy in a patient with a subtype of MDS.

Image courtesy of Stephanie Mathews, MD.

Recognizing therapy-related MDS (t-MDS) is important, as affected patients tend to have poorer outcomes than those with de novo MDS.^[17] Latency periods differ depending on the chemotherapeutic agent: t-MDS arise 1-3 years after treatment with topoisomerase II inhibitors, whereas the latency period is typically 3-7 years after treatment with alkylating agents. Patients almost always show chromosomal abnormalities, and patients who received epipodophyllotoxin-like etoposides often have a specific translocation of 11q23, a gain-of-function mutation involving the mixed lineage leukemia (MLL) gene.^[18]

A 42-year-old male presented with pancytopenia. He had a history of nonseminoma testicular cancer for which he underwent 3 cycles of BEP (bleomycin, etoposide, cisplatin) chemotherapy and achieved complete remission. A bone marrow biopsy performed to investigate cytopenias revealed dyserythropoiesis (shown), which was likely a result of his chemotherapy.

Image courtesy of Stephanie Mathews, MD.

Differentiating treatment effect from transformation to AML is also important in the management of patients with MDS. Bone marrow with hypocellularity (shown) at time of nadir (ie, lowest blood count in a given chemotherapy cycle) is indicative of toxicity from 5-azacitidine. Toxic effects of 5-azacitidine include neutropenia and thrombocytopenia, and they can be exacerbated with a decline in renal function; therefore, monitoring renal function is important. If cytopenias are attributed to azacitidine, consider dose reductions and continuation of therapy.

Image courtesy of Stephanie Mathews, MD.

One of the mainstays of treatment for patients with MDS is transfusion therapy, most commonly with packed red blood cells (PRBCs).^[16] However, patients are at an increased risk for iron overload in the setting of transfusion dependence; consider iron chelation therapy in patients with ferritin levels above 2500 ng/mL. Studies are ongoing to fully evaluate the role of chelation therapy in MDS. The image reveals increased iron storage (stained in blue) on a bone marrow biopsy from a patient with a subtype of MDS.

Image courtesy of Stephanie Mathews, MD.

A 70-year-old female presented with a 1-month history of increased fatigue and dyspnea on exertion. On physical examination, she appeared pale and fatigued, with no lymphadenopathy. Her laboratory results revealed pancytopenia, and a bone marrow biopsy showed findings consistent with high-risk MDS. She received 2 cycles of 5-azacitidine therapy, and she continued to require weekly transfusions of 2 units of PRBCs. A repeat CBC showed persistent pancytopenia, and a peripheral smear revealed no blasts (shown). A repeat bone marrow biopsy continued to demonstrate hypercellularity without an increase in blasts compared to baseline. At this point, it was decided that treatment should continue with 5-azacitidine, as a clinical response can take up to 4-6 cycles, and this agent is currently the only medication shown to improve survival in high-risk MDS.^[5,6] Although decitabine, an alternative hypomethylating agent, has shown activity in MDS, it has not been proven to have a survival benefit.

Image courtesy of Stephanie Mathews, MD.

Allogeneic HSCT is considered the only potentially curative treatment for MDS.^[16] This therapy is generally used in select patients who have higher risk disease, who are typically younger, and who have good performance status, particularly if a matched sibling donor is identified. Allogeneic HSCT is also a consideration for those patients with lower risk disease at the time of disease progression. The image shows increased blasts as detected by CD34 immunohistochemistry (stained brown) from a patient with a subtype of MDS.

Image courtesy of Stephanie Mathews, MD.