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.
SUPPORTIVE CARE
Supportive care includes transfusion of blood products to minimize complications of cytopenias and to improve quality of life, as well as antibiotics to treat active infections.
Transfusions
Almost all patients with MDS need red cell transfusions at some point, while fewer need platelets. The frequency of transfusion depends on the extent of the disease and on comorbidities.
Red blood cells typically are given when the hemoglobin level falls below 8.5 g/dL, and platelets are given when the platelet count is below 100 × 109/L, in the absence of symptoms. Patients with symptomatic anemia should receive transfusion to relieve their symptoms. Some patients need transfusions occasionally, while others are transfusion-dependent.
Iron chelation
Blood product transfusions can lead to iron overload, particularly with a lifetime administration of more than 20 units, or with a year of continuous transfusions, and this is associated with diminished survival.20
However, considering the short survival of patients with MDS, the benefit of iron chelation is debatable. This intervention should be reserved for patients with lower-risk disease who are expected to survive more than 1 year and who have received more than 25 units of packed red blood cells.21
Antibiotics
Neutropenia is defined as an absolute neutrophil count less than 1.5 × 109/L. The risk of infection, particularly bacterial infection, is significantly increased when the neutrophil count is below 0.5 × 109/L. Fever (temperature > 100.4°F or 38.0°C) in neutropenic patients is an emergency, requiring hospitalization and immediate initiation of broad-spectrum antibiotics along with a workup for the cause of the fever.22 Prophylactic antibiotics have no proven role in MDS patients with neutropenia.
TREATMENT OF LOWER-RISK DISEASE
Erythropoiesis-stimulating agents
Once a patient starts to require red blood cell transfusions, an erythropoiesis-stimulating agent (EPA) can be considered.23,24 These include recombinant agents such as erythropoietin (Procrit) and darbepoetin alfa (Aranesp).
Response is measured as an improvement in hemoglobin or as independence from transfusions in those previously dependent on them. Patients most likely to respond are those whose pretransfusion erythropoietin level is below 100 IU/L and who have minimal transfusion needs.25,26 Addition of a colony-stimulating factor can be considered for patients with neutropenia. On average, about 40% of patients ultimately respond to an EPA, but those who respond eventually develop resistance to the agent. Retrospective data indicate that use of EPAs may improve survival in MDS.23,24
The recommended threshold hemoglobin level for starting an EPA is less than 10 g/dL. Patients need to be monitored with a CBC every time they receive treatment. The agent should be stopped once the hemoglobin level reaches 12 g/dL. A number of studies have shown lower survival rates when ESAs are used in nonhematologic malignancies, particularly if the malignancy is advanced and when the ESA is used to achieve a goal hemoglobin above 12 g/dL. There are no data to suggest a higher death rate in patients with hematologic malignancies who take ESAs. The use of ESAs in MDS patients should be judicious, however, and titrated to a goal hemoglobin level no higher than 12 g/dL.27
Other treatments
If ESA treatment is ineffective, other treatments may be considered, usually initiated by a hematologist or medical oncologist.
Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)28 is an option for patients with hypocellular or immune-mediated MDS. This treatment may decrease the need for transfusion and may improve the blood count.
Lenalidomide (Revlimid) for MDS with isolated chromosome 5q deletion29 can decrease the need for blood transfusion in approximately two-thirds of these patients.
Azacitidine (Vidaza) or decitabine (Dacogen), in patients with more advanced subtypes of MDS (eg, those with excess blasts) or with pancytopenia unresponsive to other therapies, can induce hematologic improvement and decrease transfusion dependence, as well as prolong survival.
Stem cell transplantation, for patients with more advanced subtypes of MDS and who have an appropriately matched donor, has the potential of being curative.
Experimental treatments are available in clinical trials.
TREATMENT OF HIGHER-RISK DISEASE
About 25% of patients with newly diagnosed MDS and 15% to 20% of patients with established MDS have higher-risk disease.30 These patients should almost always be followed by a hematologist or medical oncologist, with therapy initiated immediately, regardless of blood counts, given the high likelihood of transformation to AML or death within 1.5 years.
The treatment options for higher-risk disease include:
- Methyltransferase inhibitors such as azacitidine and decitabine31–34
- Cytotoxic chemotherapy (similar to treatment of acute myeloid leukemia)
- Bone marrow-hematopoeitic stem cell transplantation35,36
- Experimental treatments in clinical trials.
As mentioned earlier, outside of transplantation, only azacitidine has been shown to improve overall survival (with a doubling of survival at 2 years, to 50%), and no drug therapy is curative. Managing patient expectations for treatment outcome is thus crucial in higher-risk disease, and ongoing assessments of quality of life, both on or off therapy, should be considered obligatory.
Stem cell transplantation cures MDS
MDS are complex and heterogeneous, so treatment options range from supportive care to chemotherapy and allogeneic stem cell transplantation.6 The choice depends on the severity of disease, ie, lower-risk or higherrisk (Table 3, not available online), as well as on the prognosis, the availability of therapeutic options, and the patient’s expectations.
Hematopoietic stem cell transplantation is the only curative treatment for MDS. However, it is performed in fewer than 5% of patients,30 usually younger patients with few comorbidities, because the rate of transplantrelated death is high. Therefore, most treatments are palliative, aimed at improving the quality of life and prolonging survival.
The balance between risks and benefits of these treatments must be justifiable.30 Further, patients who have no symptoms or who have lower-risk disease need no treatment and may not for years. However, they do need close follow-up, because their symptoms will worsen and will eventually require treatment.
TAKE-HOME POINTS
- Myelodysplastic syndromes are more prevalent than previously realized. Mainly a disease of older adults, they should be suspected in any patient with unexplained cytopenia.
- Life expectancy at the time of diagnosis depends on the types of cells affected.
- Supportive and disease-altering options are available.
- Prompt referral to a hematologist or oncologist is important for confirmation of the diagnosis and initiation of an appropriate treatment plan. Patients with lower-risk disease can continue follow-up with their primary care provider once treatment goals and plans are established.
ACKNOWLEDGMENT
We thank Dr. Karl Theil of the Cleveland Clinic Department of Clinical Pathology for the photomicrographs used on the cover.
