When to Treat Myelodysplastic Syndromes

When to Treat Myelodysplastic Syndromes

ABSTRACT: 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.


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