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 cytarabineanthracycline combination, which yields a response rate of 30-40% (high complication rate and
morbidity in elderly patients).
Drugs such as 5-azacytidine (azacitidine [Vidaza]),[15] 5-aza-2-deoxycytidine (decitabine
[Dacogen]), and lenalidomide (Revlimid)[16] are now approved by the US Food and Drug
Administration for MDS (see Medication).[17]
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
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.

This bone marrow film (400 magnification) demonstrates an

almost complete replacement of normal hematopoiesis by blasts in a refractory anemia with an
excess of blasts in transformation. Note the signs of abnormal maturation such as vacuolation,
double nucleus, and macrocytosis. Courtesy of U. Woermann, MD, Division of Instructional
Media, Institute for Medical Education, University of Bern, Switzerland.
Iron chelation
Patients with low-risk or intermediate-1risk 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 g/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/L) 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[18] ) 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 (GCSF; Neupogen).[19] 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
erythropoietinin 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.
Thrombopoietin receptor agonists (TPO-RA) like romiplostim and eltrombopag have been
approved to treat immune thrombocytopenia. Their use in MDS is limited in current practice
owing to the increase in the blast percentage seen with the use of eltrombopag in some studies.

Pharmacologic Therapy
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 cytarabineanthracycline 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), 1year 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 risk1 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 intermediate1 risk categories.

Hypomethylating agents
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 and decitabine are the 2
hypomethylating agents currently used in the treatment of MDS. Azacitidine and decitabine may
reduce hypermethylation and induce re-expression of key tumor suppressor genes in MDS.
Azacitidine and decitabine are approved by the US Food and Drug Administration for treatment
of all 5 MDS subtypes. They are 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).[15]
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.[20]

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

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.[21]
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.

Retinoids
Class Summary
Retinoids are the most active agents in MDS. Vitamin D-3 also has activity but is not of
clinically significant value.
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Isotretinoin or 13 cis-retinoic acid (Accutane Claravis, Amnesteem, Sotret)

This agent is the most active among retinoids. This form of therapy is not generally accepted as
standard therapy.

Hematopoietic Growth Factors

Class Summary
Ineffective blood cell production is due to excess cellular apoptosis (programmed cell death)
caused by activation of the Fas-Fas ligand. Hematopoietic growth factors are capable of
reversing this process to some extent.
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Epoetin alfa (Procrit, Epogen)

Epoetin alfa is a glycoprotein that stimulates red blood cell (RBC) production by stimulating
division and maturation of committed RBC precursor cells. It is effective in 20-26% of MDS
patients when administered alone and in as many as 48% of patients when combined with
granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating
factor (GM-CSF).
View full drug information

Darbepoetin (Aranesp)

Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a primary

growth factor that is produced in the kidney and stimulates development of erythroid progenitor
cells in bone marrow. This agent's mechanism of action is similar to that of endogenous
erythropoietin, which interacts with stem cells to increase red cell production.
Darbepoetin differs from epoetin alfa (recombinant human erythropoietin) in containing 5 Nlinked oligosaccharide chains, whereas epoetin alfa contains 3. Darbepoetin has a longer half-life
than epoetin alfa, and may be administered weekly or biweekly.
View full drug information

Sargramostim (Leukine)

This GM-CSF stimulates division and maturation of earlier myeloid and macrophage precursor
cells. It has been reported to increase granulocytes in 48-91% of patients with MDS.
View full drug information

Filgrastim (Neupogen)

This G-CSF stimulates division and maturation of granulocytes, mostly neutrophils, in 75-100%
of MDS patients and seems to enhance erythroid response when given in combination with
erythropoietin.

Demethylation Agents
Class Summary
Demethylation agents are a ntineoplastics that exert anticancer effects by causing DNA
demethylation or hypomethylation in abnormal hematopoietic bone marrow cells. These agents
may restore normal function to the tumor suppressor genes responsible for regulating cell
differentiation and growth.
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Azacitidine (Vidaza)

Azacitidine is a pyrimidine nucleoside analogue of cytidine. It interferes with nucleic acid

metabolism. It exerts antineoplastic effects by DNA hypomethylation and direct cytotoxicity on
abnormal hematopoietic bone marrow cells. Nonproliferative cells are largely insensitive to
azacitidine. This agent is approved by the US Food and Drug Administration for treatment of all
5 MDS subtypes.
View full drug information

Decitabine (Dacogen)

Decitabine is a hypomethylating agent believed to exert antineoplastic effects by incorporating

into DNA and inhibiting methyltransferase, resulting in hypomethylation. Hypomethylation in
neoplastic cells may restore normal function to genes that are critical for cellular control of
differentiation and proliferation.
Decitabine is indicated for treatment of MDSs, including previously treated and untreated, de
novo, and secondary MDSs of all French-American-British (FAB) subtypes (ie, refractory
anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts,
refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia) and
International Prognostic Scoring System (IPSS) groups intermediate-1 risk, intermediate-2 risk,
and high risk.

Immunomodulators
Class Summary
Immunomodulators elicit immunomodulatory, antiangiogenic properties, and inhibit
proinflammatory cytokines.
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Lenalidomide (Revlimid)

Lenalidomide is indicated for the transfusion-dependent MDS subtype of deletion 5q cytogenetic

abnormality. This agent is structurally similar to thalidomide. It elicits immunomodulatory and
antiangiogenic properties, inhibits proinflammatory cytokine secretion, and increases release of
anti-inflammatory cytokines from peripheral blood mononuclear cells. The dose used in MDS is
much lower than that used for multiple myeloma.