When to Treat Myelodysplastic Syndromes

May 15, 2011

Myelodysplastic syndromes, also referred to collectively as MDS, have significant biological and clinical heterogeneity, a highly variable natural history, and a complex pathobiology that is not clearly understood.

The myelodysplastic syndromes represent a heterogeneous series of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and a variable risk of progression to acute myeloid leukemia. These syndromes have a complex pathobiology, and ineffective hematopoiesis is a well-recognized feature of all of them. Normal blood cell maturation, differentiation, function, and survival are impaired, and these abnormalities contribute to the development of peripheral blood pancytopenia. The majority of patients succumb to complications of either bone marrow failure or leukemic progression. The fact that the majority of patients are elderly and have other comorbidities complicates therapeutic decision making and necessitates the development of individualized treatment strategies.


Myelodysplastic syndromes, also referred to collectively as MDS, have significant biological and clinical heterogeneity, a highly variable natural history, and a complex pathobiology that is not clearly understood. It is becoming increasingly clear that MDS is a relatively common hematological disease. MDS is primarily a disorder of older adults (median age, 69 years), and the average annual age-adjusted incidence rate for MDS from 2001 through 2003 was 3.3 per 100,000. Overall, MDS affects approximately 1 in 500 persons over 60 years of age, making it the most common hematologic malignancy in this age group.[1-3] The number of diagnoses has risen dramatically in recent years as a result of increased recognition of the disease; the increase in diagnoses may also reflect the aging of the population and the development of effective therapies for these disorders. MDS is a potentially fatal disease; the common causes of death in a cohort of 216 MDS patients included bone marrow failure (infection/hemorrhage) and transformation to acute myeloid leukemia (AML).[4] Treatment of MDS can be challenging in these generally older patients. This review describes current treatment options for lower- and higher-risk patients.

Diagnosis and Prognosis

The diagnosis of MDS requires a detailed history, physical examination, and morphological examination of blood and bone marrow cells. Examination of the bone marrow (via aspirate, biopsy, flow cytometry, and cytogenetics) is necessary to make a confident diagnosis and to distinguish MDS from other conditions that can cause cytopenia and dysplastic hematopoiesis (eg, megaloblastic anemia, HIV infection, alcohol abuse, and severe intercurrent illness), as well as from other clonal hematologic malignancies. MDS is a common cause of mild to moderate chronic anemia in elderly patients, and it is often mistaken for anemia of chronic disease or anemia of renal insufficiency. However, MDS is sometimes overdiagnosed, since morphologic dysplasia is not specific for MDS (there are reactive causes of dysplasia). Clinicians and pathologists need to collaborate closely in order to reach the final diagnosis and label a patient with MDS, since receiving this diagnosis is a life-changing event with implications for both prognosis and therapy.

Bone marrow assessment in MDS provides important descriptive and prognostic information. There are two classification systems: in the French-American-British (FAB) system, the presence of ≥ 30% blasts in peripheral blood or bone marrow is required for the diagnosis of AML,[5] and in the World Health Organization (WHO) classification system, the presence of ≥ 20% blasts is sufficient for an AML diagnosis (also, the WHO classification system is based on a combination of morphology, karyotype, and clinical features).[6]

MDS is different from other cancers in that it does not have a staging system. The two prognostic scoring systems that are most commonly used to predict overall survival and risk of transformation to AML are the International Prognostic Scoring System (IPSS)[7] and the WHO classification–based Prognostic Scoring System (WPSS).[8] The IPSS is the most widely used prognostic system; however, it has certain limitations, such as the inclusion of largely untreated patients, and the exclusion of patients with secondary and therapy-related MDS. In the IPSS, the presence of > 20% blasts in bone marrow warrants a higher score than poor risk cytogenetics; however, there is evidence that those two groups have a similar median survival.[8,10] The WPSS takes into account red blood cell (RBC) transfusion requirements, which have prognostic value. There are other adverse prognostic markers, such as the abnormal localization of immature precursor cells or the clustering of immature myeloid cells in the bone marrow biopsy specimen,[11] the presence of marrow fibrosis,[12] and mutation and/or loss of heterozygosity of the tumor suppressor gene p53[13]; none of these are included in either the IPSS or the WPSS.

Treatment Options: General Principles

Therapeutic decisions in MDS patients should be based on three clinical features: age, performance status, and the IPSS-defined risk category (the IPSS score must be calculated when the patient is in stable clinical condition rather than during an acute illness). The treatment goals are to prevent or delay transformation to AML, and to extend the patient’s life and improve his or her quality of life. MDS is not curable without the performance of allogeneic hematopoietic stem cell transplantation (HSCT). However, the majority of patients are not eligible for such intensive therapy due to a combination of advanced age, the presence of comorbidities, and limited donor availability. Practice guidelines for MDS have been published by the National Comprehensive Cancer Network (NCCN),[14] the UK MDS Guidelines Group,[1] and the Italian Society of Hematology.[15] An International Working Group (IWG) of investigators has proposed standardized response criteria for evaluating the outcome of therapy in MDS; hopefully these will facilitate more consistent interpretation of new therapies.[16,17]


Overall Survival and Risk of Transformation to AML Based on the IPSS[7]

Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic HSCT is the only curative therapeutic modality available to MDS patients, and 35% to 40% of patients undergoing transplant achieve longterm disease-free remissions.[18] Better outcomes of allogeneic HSCT are associated with several factors, including lower IPSS score, younger recipient age, lower percentage of blasts in bone marrow, and good risk cytogenetics.[ 19-24] Thus, for patients with IPSS intermediate-1 (INT-1), intermediate- 2 (INT-2), and high-risk category MDS, my clinical approach is to ask this question up front: Is this patient a candidate for allogeneic HSCT? If the answer is yes, then HLA typing and a formal donor search should be undertaken early in the course of the disease. There is evidence that both myeloablative and nonmyeloablative transplant approaches may be curative.[25- 30] There is not agreement on exact timing and optimal selection of patients for allogeneic HSCT. There is one study, which used a Markov decision analytic technique to compare HSCT outcomes in MDS patients; this study showed that IPSS INT-2 and high-risk patients who were age 60 years or younger got the most benefit from an allogeneic HSCT if it was performed soon after diagnosis. However, IPSS low-risk or INT-1 patients did better delaying the transplant until the time of leukemic progression.[ 31] It should be kept in mind, though, that this study did not include patients older than 60 years or patients on non-myeloablative conditioning regimens. There have also been advances in allogeneic HSCT techniques and newer therapeutic modalities (such as hypomethylating agents and lenalidomide [Revlimid]) that should be taken into consideration. There are two other reports suggesting that lower-risk patients could benefit from an earlier transplant soon after diagnosis. The first one is from an Italian group that analyzed the impact of the WPSS score on outcomes in MDS patients who underwent an allogeneic HSCT. They showed that patients with WPSS lower-risk disease had a 5-year overall survival of 80%. [32] The Chronic Leukemia Working Party (CLWP) MDS subcommittee of the European Group for Blood and Marrow (EBM) analyzed outcomes of allogeneic HSCT for patients with refractory anemia and showed that earlier transplantation was associated with an absolute increase in the overall survival rate of 10% at 4 years.[33] Nonetheless, it is important to make recommendations on an individual basis, particularly in older patients.

Treatment of Lower-Risk MDS (IPSS Low or INT-1)

These groups of MDS patients usually have cytopenias and they need supportive care, including RBC transfusion, which is the main element in their management. Therapeutic interventions consist of erythropoiesis-stimulating agents (ESAs), granulocyte colony-stimulating factor (G-CSF), thrombopoietic growth factors, and iron chelation therapy.

Treatment of Anemia

Anemia is the most common finding in MDS patients, and the majority of patients present with hemoglobin (Hb) levels of less than 10 g/dL.[4,34] If a patient has symptomatic anemia or if the Hb level is less than 10 g/dL, the finding should be addressed methodically and appropriately, since anemia is associated with morbidity, worsening performance status, and decline in quality of life. Transfusion dependency is associated with decreased overall survival[35] and increased risk of progression to leukemia.[36,37] One practical approach is to see whether the patient’s symptoms are due to anemia and determine the cellularity of the bone marrow. Younger patients with lower-risk MDS who have symptomatic anemia-and particularly those who have hypocellular bone marrow, are HLA-DR15-positive, or have a paroxysmal nocturnal hemoglobinuria (PNH) clone-may benefit from immunosuppressive therapy with antithymocyte globulin (ATG). In a phase II trial with a small cohort of 25 patients, 11 (44%) responded to ATG.[38] In a subsequent update, 21 of 61 patients responded to ATG and became transfusion independent.[39] In another phase II study, 10 of 20 (50%) responded to treatment and achieved transfusion independence.[40] In a large phase II study performed by the National Institutes of Health, 39 of 129 patients (30%) showed either complete or partial response to immunosuppressive therapy, 18 of 74 patients (24%) demonstrated response to ATG, 20 of 42 patients (48%) responded to a combination of ATG and cyclosporine (CSA), and 1 of 13 patients (8%) responded to CSA alone.[41] In a British retrospective study, 96 MDS patients were treated with ATG, and 40 patients (42%) responded, of whom 30 patients (75%) showed a durable hematological response. In this study, low IPSS score and hypocellular marrow were associated with a response to ATG.[42] Hypocellular marrow has also been shown to be associated with response to ATG in other studies[39,40]; however, there are studies in which hypocellular marrow did not predict response to ATG.[43-46] A recent phase III trial showed that the combination of ATG and CSA produced a hematological response in 29% of patients; however, the immunosuppressive therapy did not improve two-year transformation-free survival or overall survival.[47]

Lenalidomide is effective for patients with lower-risk MDS who have del(5q) chromosomal abnormalities and symptomatic anemia. The recommended starting dose is 10 mg per day or 10 mg on days 1 through 21 of a 28-day cycle. Grade 3 or 4 cytopenias are common, and it is recommended that therapy be withheld until toxicities have resolved and then restarted at 5 mg daily or on alternating days. In a phase II study (MDS-003), 67% of 148 MDS patients (low- and INT-1–risk) who were transfusion dependent and had del(5q) achieved transfusion independence, and 45% of these patients had a complete cytogenetic response. The response took an average of 9 to 12 weeks to develop.[48] A phase III study (MDS-004) showed that lenalidomide, 10 mg daily, resulted in better response rates in terms of achieving transfusion independence and cytogenetic remission than did a 5-mg daily dose, with a similar adverse effects profile.[49] There are phase II data on using lenalidomide in MDS patients (low- or INT-1–risk) who are transfusion dependent without del(5q); these data show a 26% response rate and achievement of transfusion independence after a median of 4.8 weeks of therapy, with a median duration of response of 41 weeks.[50]


Overall Survival Based on WPPS Score[8]

It is important to determine a serum erythropoietin level before starting RBC transfusions. ESAs should be considered for patients with lower-risk MDS and symptomatic anemia (Hb < 10 g/dL). Patients with erythropoietin levels of ≤ 500 IU/L and low transfusion requirements (< 2 units/month) show a better response to ESAs with or without G-CSF. Recombinant human erythropoietin has been used extensively to treat anemia in MDS patients.[51-53] The efficacy of erythropoietin alone is relatively low, and overall erythroid response rates from 7.5% to 36% have been reported.[54,55] A combination of ESAs and G-CSF for 6 to 12 weeks can be considered for patients with refractory anemia with ring sideroblasts (RARS).[56] A recently published phase III prospective randomized clinical trial of 73 MDS patients treated with erythropoietin with or without G-CSF plus supportive care vs supportive care alone demonstrated an erythroid response of 31% in 12 of 39 patients who received the G-CSF and erythropoietin combination. This study did not reveal any difference in overall survival between the erythropoietin and supportive care arms after a median follow-up of 5.8 years; it also did not show an increased incidence of transformation to AML. However, a survival benefit was observed in the erythroid responders compared with non-responders.[57]

Hypomethylating agents (5-azacytidine [or azacitidine; Vidaza] and 5-aza-2-deoxycytidine [or decitabine; Dacogen]) can be considered for low- and INT-1–risk MDS patients who have serum erythropoietin levels > 500 IU/L and who require > 2 RBC transfusions per month, but who are not candidates for immunosuppressive therapy.[58] There is evidence that lower-risk MDS patients with higher ferritin and β2-microglobulin levels could benefit from early therapeutic interventions.[59]

There is not a single hemoglobin threshold for using RBC transfusions in MDS patients, and the frequency of transfusion therapy should be based on the patient’s symptoms and comorbidities. Iron chelation therapy is only recommended in patients for whom long-term RBC transfusion is anticipated and who have received more than 20 to 30 units of packed RBCs. Iron chelation treatment is also recommended for MDS patients who are candidates for an allogeneic HSCT.[60] Desferrioxamine, 20 to 40 mg/kg by 12 hour subcutaneous infusion 5 to 7 days a week, can be used. Deferasirox (Exjade) 20 mg/kg by mouth is another iron chelation modality that can be considered.

Treatment of Thrombocytopenia and Neutropenia

Thrombocytopenia and neutropenia are common problems in MDS patients that can be associated with serious complications. Platelet functions are often abnormal, contributing to the increased risk of bleeding. Androgens can improve thrombocytopenia in MDS patients.[61,62] ATG can improve platelet counts in about one third of low-risk MDS patients.[42,43,45] The role of thrombopoietin receptor agonists in MDS patients is being studied in clinical trials.[63] Prophylactic antibiotics are not recommended in MDS patients with neutropenia. However, prophylactic low-dose G-CSF can be used in the management of patients with severe neutropenia to keep their neutrophil count above 1 × 109/L.[64] Hypomethylating agents (5-azacytidine or azacitidine, and 5-aza-2-deoxycytidine or decitabine) can be considered for low- and INT-1–risk MDS patients with thrombocytopenia and neutropenia.[58]

Treatment of Higher-Risk MDS (IPSS INT-2 or High)


Therapeutic Agents
Mentioned in This Article

Antithymocyte globulin (ATG)
Azacitidine (Vidaza)
Decitabine (Dacogen)
Deferasirox (Exjade)
Granulocyte colony-stimulating factor
Lenalidomide (Revlimid)
Topotecan (Hycamtin)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

The available treatment options for IPSS INT-2 or high-risk MDS patients who are not candidates for allogeneic HSCT include hypomethylating agents (azacitidine and decitabine), cytotoxic chemotherapy, and experimental therapeutic agents in clinical trials. Hypomethylating agents are able to alter the natural history of MDS. The results of a multicenter phase III trial (Cancer and Leukemia Group B [CALGB] 9221) comparing azacitidine (75 mg/m2 subcutaneously for 7 days every 28 days) to supportive care showed statistically significant improvements in response rate, survival, delay in leukemic transformation, and quality of life for azacitidine-treated patients. The median time to death or transformation to AML was 21 months in azacitidine-treated patients vs 12 months in the supportive care arm (P = .007). Azacitidine improved survival in all FAB subtypes of MDS. [65] This was followed by a phase III trial (AZA-001) comparing azacitidine (75 mg/m2 per day for 7 days every 28 days) to conventional care (best supportive care, low-dose cytarabine, and intensive chemotherapy) in high-risk MDS patients; this trial showed a statistically significant overall survival difference, with a median survival of 24.5 months for the azacitidine-treated patients and 15 months for the conventional care arm (P = .0001).[66] The data from a phase III trial comparing decitabine (15 mg/m2 every 8 hours for 9 doses intravenously given in an inpatient setting) to supportive care in higher-risk MDS patients showed a response rate of 30% vs 12% in the supportive care arm; in addition, decitabine- treated patients had a trend toward a longer median time to leukemic progression or death compared with patients who received supportive care. [67] The results of a European phase III trial of decitabine were presented at the 2008 annual meeting of the American Society of Hematology.[68] This was a randomized study that compared lowdose decitabine (15 mg/m2 intravenously over 4 hours every 8 hours for the first 3 three consecutive days, in an every-6-week cycle, for a maximum of 8 cycles) to supportive care. This study showed a lack of survival benefit with decitabine compared with best supportive care; however, the majority of patients received a median of four cycles of decitabine, as opposed to the median number of nine cycles administered to patients in the clinical trial with azacitidine (AZA-001). This highlights the need for repeated cycles of hypomethylating agents over a longer period of time, in order to achieve the full therapeutic benefits.

Intensive cytotoxic chemotherapy can be considered for higher-risk MDS patients, particularly those with refractory anemia with excess of blasts in transformation (RAEB-t) who are not candidates for allogeneic HSCT; patients with RAEB showed significantly shorter event-free survival than both those with RAEB-t and those with AML. Adverse risk karyotype, length of MDS phase, age, and performance status predicted an inferior outcome to intensive chemotherapy.[69] It is important to determine whether MDS patients have abnormal cytogenetics, particularly complex cytogenetics or chromosome 7 abnormalities, since patients with these abnormalities would not benefit from intensive cytotoxic chemotherapy.[69-71] The results from a phase II trial of topotecan (Hycamtin) (2 mg/m2 given as a continuous 24-hour intravenous infusion for 5 days) in a cohort of 47 high-risk MDS patients showed a complete remission rate of 28%; however, a high treatment-related mortality of 19% was also reported.[72] The combination of topotecan and cytarabine was associated with a higher response rate of 56%, but it did not show any overall benefit.[73] No specific intensive cytotoxic chemotherapy is recommended; standard induction chemotherapy is an option.[58]


The treatment of MDS is complex, and therapeutic decision making can be challenging. It is necessary to develop meaningful treatment strategies for each patient based on age, prognostic factors, performance status, and comorbidities. A minority of patients will be candidates for allogeneic HSCT, which carries many potential risks but offers the possibility of cure. The optimal timing of allogeneic transplantation remains a point of debate. For other patients, hypomethylating agents, lenalidomide, hematopoietic growth factors, and supportive care are the mainstays of therapy. Further clinical trials will identify additional effective agents, and answer critical questions regarding the optimal timing and duration of existing therapies.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Acknowledgement:The author is very thankful to Dr. Amelia A. Langston, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, for critical discussion and review of the manuscript.



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