Myelodysplastic Syndrome Treatment & Management

The standard care for patients with myelodysplastic syndrome (MDS) and decreased blood counts is constantly changing. Supportive therapy, including transfusions of the cells that are deficient (ie, red blood cells [RBCs], platelets), and treatment of infections are the main treatments. Bone marrow transplantation plays a limited role.

Cytotoxic chemotherapy is used in patients with MDS with increasing myeloblasts and those who have progressed to acute leukemia. The usual combination treatment is a cytarabine-anthracycline combination, which yields a response rate of 30-40% (high complication rate and morbidity in elderly patients).

Drugs such as 5-azacytidine (azacitidine [Vidaza]),^[13] 5-aza-2-deoxycytidine (decitabine [Dacogen]), and lenalidomide (Revlimid)^[14] are now approved by the US Food and Drug Administration for MDS (see Medication).

Patients with MDS should be under the care of a hematologist. Because most treatments of MDS are not standard and are considered experimental, referral to a tertiary care center is often necessary. Encourage patients to participate in clinical trials to determine the optimal therapy for MDS.

Supportive care includes transfusion of RBCs or platelets. The goal is to replace cells that are prematurely undergoing apoptosis in the patient's bone marrow. Guidelines for transfusion in patients with MDS and bone marrow failure are as follows.

Decrease transfusion-related complications by using leukocyte-depleted blood products, which have been shown to decrease nonhemolytic febrile reactions, prevent alloimmunization and platelet refractoriness, and prevent cytomegalovirus transmission. Additionally, this practice has been shown to achieve better quality control of blood products compared with bedside filtering and has been shown to be cost effective.

Splenectomy for the cytopenia associated with MDS is dangerous and fraught with complications and is not recommended.

Red blood cell transfusion

Patients with moderate-to-severe anemia require RBC replacement (see the image below). Transfusing packed RBCs for severe or symptomatic anemia benefits the patient temporarily, only for the life span of the transfused RBCs (2-4 wk). Patients with congestive heart failure may not tolerate the same degree of anemia as young patients with normal cardiac function, and slow or small-volume (eg, packed RBCs) transfusions with judicious use of diuretics should be considered.

Iron chelation

Patients with low-risk or intermediate-1–risk MDS typically have long-term survival and may receive multiple RBC transfusions. These patients may develop transfusion-induced iron overload and can incur significant damage of the liver, heart, pancreas, and other tissues. In addition, some evidence suggests that iron overload in the bone marrow adds to the cellular early apoptosis contributed by the microenvironment.

Current guidelines recommend starting iron chelation therapy in those patients who have received 20-25 units of packed RBCs or who have a serum ferritin level of >1000 μg/L.

Deferoxamine (Desferal) is difficult to administer in elderly patients because it has to be given parenterally subcutaneously by pump over 12 hours daily to be effective. It is often given at the same time as the RBC transfusion, which is ineffective.

Deferasirox (Exjade) is an FDA-approved oral, dispersible tablet that is dissolved in 7 oz of water and administered by mouth once daily. It is excreted in stools rather than urine, and it is 100-fold more active as a chelator of iron.

Platelet transfusion

Platelet transfusion is beneficial to stop active bleeding in thrombocytopenic patients, but the life span for transfused platelets is only 3-7 days. Avoid repeated and frequent platelet transfusions on the basis of low platelet counts (< 20,000/µL) in patients who are not experiencing clinical bleeding.

Long-term measures to prevent skin and mucosal bleeding may be achieved by administering oral antithrombolytic agents such as prophylactic oral epsilon-aminocaproic acid (Amicar) to avoid alloimmunization.

Treatment of neutropenia

Treat infections and neutropenia. Some patients may require granulocyte transfusions, but the risk of alloimmunization is high, as is the risk of developing refractoriness to future transfusion therapy. Life-threatening infections, especially of fungal etiologies, require administration of granulocytes and antifungal agents.

Bone marrow stimulation

Hematopoietic growth factors (eg, recombinant human erythropoietin [Epoetin alfa], darbepoetin^[15] ) can stimulate bone marrow cell production, and decrease excess bone marrow cell apoptosis.

Of MDS patients with neutropenia, 75% respond to granulocyte colony-stimulating factor (G-CSF; Neupogen).^[16] Of MDS patients with anemia and neutropenia, 75% respond to a combination of erythropoietin and G-CSF for their neutropenia, with a 50% increase in erythroid response. The addition of low doses of G-CSF synergistically enhances the erythroid response to erythropoietin—in particular, patients who have refractory anemia with ringed sideroblasts (RARS).

A reanalysis that used the World Health Organization classification demonstrated a significantly better response in RARS (75%) than in refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS; 9%). This may reflect G-CSF's ability to strongly inhibit cytochrome c release and hence mitochondria-mediated apoptosis in RARS erythroblasts.

Cytotoxic chemotherapy is used in patients with MDS with increasing myeloblasts and those who have progressed to acute leukemia. The usual combination treatment is a cytarabine-anthracycline combination, which yields a response rate of 30-40% (high complication rate and morbidity in elderly patients).

New drug combinations using hematopoietic growth factors and new drugs, such as topotecan (Hycamtin), are yielding better response rates with lower morbidity. Aggressive chemotherapy may be indicated in small populations of elderly patients with good performance status and no associated serious medical comorbidity.

Isotretinoin or 13 cis-retinoic acid (Accutane) is the most active retinoid. In a randomized placebo-controlled trial in 70 MDS patients treated with low-dose isotretinoin (20 mg/m²/d), 1-year survival among patients with refractory anemia was 77%, compared with 36% in the placebo group. This is statistically significant, although this form of therapy is not generally accepted. The author limits this treatment to patients who are not transfusion dependent.

Lenalidomide

Lenalidomide is a 4-amino-glutarimide thalidomide analogue that is more potent than thalidomide but lacks its neurotoxicity and teratogenic effects. It is active in patients with MDS categorized as low risk or intermediate risk–1 according to the International Prognostic Scoring System (IPSS).

In particular, patients with the karyotype characterized by deletion 5q31 demonstrate a 75% erythroid response and a 70% cytogenetic response (26% complete response), with 36% achieving a normal bone marrow histologically. A 50% response was observed in non5q-MDS in the low or intermediate–1 risk categories.

Azacitidine

Epigenetic modulation of gene function is a very powerful cellular mechanism, showing that DNA methylation leads to silencing of suppressor genes and increasing the risk for transformation to acute myelogenous leukemia (AML). Azacitidine, a powerful DNA hypomethylating pyrimidine analogue, may reduce hypermethylation and induce reexpression of key tumor suppressor genes in MDS.

Azacitidine is approved by the US Food and Drug Administration for treatment of all 5 MDS subtypes. It is considered standard therapy for high-risk MDS.

In a pivotal trial that included patients in all stages of MDS, patients treated with azacitidine showed a 37% response (7% complete response, 16% partial response) versus a 5% response in the control arm, with an improved median time to transformation or death (21 mo for azacitidine vs 13 mo for controls) and transformation to leukemia (15% for azacitidine vs 38% for controls).^[13]

Compared with supportive care, both agents show an overall response (60% with azacytidine vs 5% with decitabine) and a longer time to progression to AML or death, and improvement of quality of life but no overall survival advantage. In a phase III trial involving 358 patients with an IPSS classification of intermediate-2 or high risk, treatment with azacytidine (75 mg/m²/d for 7 d q28d) significantly increased survival. At 2 years, 50.8% of patients in the azacitidine group were alive compared with 26.2% in the patients who received conventional care.^[17]

Experimental agents

Although treatment of symptoms improves quality of life in MDS, these measures are temporary. More long-term measures are necessary to stimulate the patient's bone marrow production of mature blood cells. Practitioners are encouraged to refer patients for participation in clinical trials at academic centers and the MDS Centers of Excellence.

New drugs for MDS are being generated at a brisk pace as new clinical trials continue to make inroads on improving outcomes in quality of life and, ultimately, in overall survival. Synergy is being sought with new combinations of the active drugs and the less active drugs. As more is being learned about the biology of MDS through the molecular mechanisms and the ability to modify these molecular targets, research has opened new doors for the treatment of this once obscure and poor-outcome disease.

Bone marrow transplantation with a matched allogeneic or syngeneic donor is used in patients with poor prognoses or late-stage MDS who are aged 55 years or younger and have an available donor. Among selected patients with less advanced/low-risk MDS (< 5% marrow myeloblasts), a 3-year survival of 65-75% is achievable with HLA-matched related and unrelated donors. Because hematopoietic stem cell transplantation (HSCT) offers the potential for cure, the timing of the procedure may be important in this subgroup of patients.

Compared with patients with de novo acute myeloid leukemia transplanted in first remission, patients with MDS experience higher mortality rates associated with the procedure (21-30% vs 10%), lower disease-free survival rates, and higher relapse rates (70% vs 40%). Among patients with more advanced/high-risk disease (≥5% marrow myeloblasts and high IPSS scores), the probability of posttransplant relapse ranges from 10-40%; as a result, relapse-free survival is inferior in this group.

Because most patients are elderly and only a few young patients MDS will have a matched donor, the use of bone marrow transplantation is limited.

The use of nonmyeloablative (mini) bone marrow transplantation and reduced-intensity conditioning regimens has been used in elderly patients as old as 75 years with some success. This approach is still considered experimental and should be performed only in a clinical trial setting.