Myelodysplastic syndromes: A practical approach to diagnosis and treatment
ABSTRACTThe myelodysplastic syndromes (MDS) are clonal bone marrow disorders that lead to underproduction of normal blood cells. The consequent cytopenias result in infections and bleeding complications. MDS transform to acute myeloid leukemia in one-third of patients. The number of diagnoses has exploded in the past decade as a result of increased recognition and understanding of the disease and the aging of the population. New therapies can extend life. MDS are now considered the most common form of leukemia, and in some cases deserve immediate intervention. This review describes common presentations of MDS, optimal diagnostic approaches, and therapies for lower-and higher-risk disease.
KEY POINTS
- Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the reason for referral to a hematologist-oncologist.
- Factors that make MDS more difficult to manage and that worsen the prognosis are older age at diagnosis and comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease.
- Patients with lower-risk disease can continue followup with their primary care provider once the treatment goals and plans are established.
LABORATORY TESTS NEEDED
Complete blood cell count
Once the common causes of patient’s symptoms are evaluated, a CBC is needed to look for a hematologic cause. If a patient is ultimately determined to have MDS, anemia is the most common finding on the CBC: about 80% of patients with MDS are anemic at presentation. 6
Anemia associated with MDS can be microcytic, normocytic, or, most commonly, macrocytic. 14 Thrombocytopenia and neutropenia can be solitary or associated with anemia, and they are seen in about 40% of patients at the time of diagnosis.6 As the disease progresses, the degree of cytopenia worsens and, in most cases, preserved cell lineages are eventually affected.
Once cytopenia is discovered, a workup for the cause is needed. We emphasize a workup first for anemia, as it is the most common form of cytopenia in MDS. A workup for isolated thrombocytopenia or neutropenia usually requires a bone marrow examination earlier in the course, and we will discuss it only briefly here. Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the basis for referral to a hematologist or oncologist.
Evaluation of anemia
If anemia is detected, it is reasonable to look for nonhematologic causes such as gastrointestinal bleeding, a cardiac cause, or a nutritional deficiency.
Anemia has a variety of possible hematologic causes, as shown in a study in the United States.15 When blood samples were collected from more than 2,000 people age 65 and older, 10.6% were found to have anemia, categorized as follows:
- Nutrient-deficiency anemia, related to low levels of vitamin B12, folate, or more commonly iron
- Anemia of chronic inflammation (formerly anemia of chronic disease, associated with a major medical disorder)
- Unexplained anemia (of those with unexplained anemia, 17.4% had blood findings compatible with MDS).15
- Tests for nutrient deficiencies such as iron, vitamin B12, and folate levels. Subsequent tests can include assessment for copper deficiencies. Vitamin B12 and copper deficiency can mimic MDS.
- Fecal occult blood testing, and, if positive, further evaluation for a source of gastrointestinal bleeding.
- Liver function tests, renal function tests, and tests for endocrine disorders, such as thyroid function tests.
- Review of drugs that can cause megaloblastoid erythropoiesis, such as methotrexate (Trexall), valproic acid (Depakote), phenytoin (Dilantin), phenobarbital (Luminal), sulfasalazine (Sulfazine), and zidovudine (Retrovir).
- Assesment of the responsiveness of the bone marrow to anemia, via a reticulocyte count or an erythropoietin level, or both, prior to any blood transfusion.
- Screening for relevant infections, including human immunodeficiency virus (HIV), hepatitis, or, in rare cases, parvovirus.
- Screening for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake.
Evaluation of other cytopenias
In cases of isolated thrombocytopenia or combined bicytopenia (eg, anemia and thrombocytopenia), abdominal ultrasonography should be done to evaluate for splenomegaly.
Blood tests to evaluate for immune-mediated cytopenias, including idiopathic thrombocytopenic purpura and hemolytic anemia, include the direct and indirect Coombs antiglobulin tests, the lactate dehydrogenase level, the reticulocyte count, and the haptoglobin level. Other immune-mediated causes of cytopenia include connective tissue disorders and vasculitides, and an antinuclear antibody titer and rheumatoid factor level can also be considered.
Referral if tests are negative
If all these tests are negative, the next step is referral to a hematologist-oncologist for further workup, which may include a review of the peripheral blood smear; bone marrow aspiration and biopsy for evaluation of iron stores and bone marrow cellularity; and specialized tests such as assessment of antiplatelet antibodies, protein electrophoresis, or fluorescence in situ hybridization to evaluate for specific clonal disorders. The purpose of bone marrow aspiration and biopsy in MDS is to evaluate the morphology of the bone marrow and the patient’s cytogenetic profile. Each has its prognostic and therapeutic implications.
SCORING SYSTEMS FOR MDS, RATHER THAN STAGING SYSTEMS
The purpose of classification systems for any medical condition is to uniformly evaluate and group patients with a disease subtype to compare patient populations similarly throughout the world, to predict prognosis, and to dictate therapeutic directions.
MDS have two main classification systems, the FAB (French-American-British) and the WHO (World Health Organization). Revised in 2008,16 the WHO classification (Table 2, not available online)17 is widely accepted because it incorporates morphologic and cytogenetic factors and correlates with prognosis.18 The categories are distinguished by specific characteristics of peripheral blood and bone marrow.
Unlike many other cancers, MDS are not “staged.” Rather, prognostic systems have been devised to predict the risk of transformation to AML and to predict overall survival. These systems are based on:
- The number of myeloblasts in the bone marrow (the higher the count, the worse the prognosis)
- The number or degree of cytopenias
- Cytogenetic abnormalities (acquired genetic abnormalities in the neoplastic clone), found in about half of patients with MDS.19
The most widely used prognostic systems are the International Prognostic Scoring System (Table 3, not available online)2 and the WPSS (WHO Classification-based Prognostic Scoring System1). The latter system encorporates transfusion burden.
