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Myelodysplastic syndromes (MDSs) are clonal disorders characterized initially by ineffective hematopoiesis and subsequently by the development of acute leukemias. Peripheral blood cytopenias in combination with a hypercellular bone marrow exhibiting dysplastic changes are the hallmark of MDS
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Work-up
CBC with differential
Serum liver function tests, electrolytes, serum creatinine
Bone marrow biopsy and aspiration with iron stains, flow cytometry, cytogenetics
HLA typing for patients who are candidates for allogeneic stem cell transplantation
RBC folate, serum B12, serum iron/TIBC/ferritin, serum erythropoietin level (prior to RBC transfusion)
HIV testing if clinically indicated
Thyroid function tests to rule out hypothyroidism
HLA-DR15 typing to assist determination of response to immunosuppressive therapy
Evaluate patients with chronic myelomonocytic leukemia (CMML) for 5q31–33 translocations and/or PDGFRβ gene rearrangements
JAK2 mutation in patients with thrombocytosis
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Classification Systems for MDS
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Classification Systems for De Novo MDS
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Differential Diagnosis of Hypo-Productive Cytopenias
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International Working Group Treatment Response Criteria for MDS
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Treatment Options
IPSS: low/intermediate-1
WPSS: very low, low, intermediate
Patients with symptomatic anemia and del(5q) chromosomal abnormalities should receive lenalidomide. Other patients with anemia can be treated based on their levels of serum erythropoietin (sEPO). Those with levels of ≤500 mU/mL (≤500 IU/L) may be treated with recombinant human epoetin alfa or darbepoetin alfa either with or without granulocyte colony-stimulating factor. Patients with IPSS low or intermediate-1 risk, with moderate-to-severe anemia (hemoglobin below 10 g/dL), serum erythropoietin level <500 mU/mL and/or a red cell transfusion requirement <2 RBC unit per month should be considered for therapy with epoetin alfa or beta at an initial dose ranging from 30,000 to 60,000 IU/week. Patients who do not respond to epoetin alone after 8 weeks of treatment should be given granulocyte-colony stimulating factor (G-CSF 300 μg/week in 2–3 divided doses) in combination with epoetin alfa
Nonresponders should be considered for immunosuppressive therapy with equine thymocyte immune globulin (ATG; ATGAM) and cyclosporine (if there is a high likelihood of response: ≤60 years old, HLA-DR15–positive, PNH-positive clone, or hypoplastic MDS), or treatment with decitabine or azacitidine. Anemic patients with sEPO levels >500 mU/mL who have a low probability to respond to immunosuppressive therapy should be considered for treatment with lenalidomide, decitabine, or azacitidine
Patients with other serious cytopenias (thrombocytopenia, neutropenia) should be considered for treatment with decitabine or azacitidine. Nonresponders should be considered for immunosuppressive therapy with ATG and cyclosporine or allogeneic hematopoietic cell transplantation (allo-HCT)
IPSS: intermediate-2, high
WPSS: high, very high
Allogeneic HCT is the only treatment that can induce long-term remission in patients with MDS. Such therapy, however, is not applicable for many patients, because the median age at diagnosis exceeds 65 years and associated comorbidities. Allo-HCT for MDS is associated with a high rate of treatment-related death (approximately 30% at 1 year and 3 years) and suboptimal disease-free survival (approximately 40% at 1 year and 3 years). The decision to offer HCT as therapy for MDS remains an individual "personalized" decision. Age at transplantation is one of the most important prognostic factors: the older the age, the shorter the overall and disease-free survival. In addition, disease risk according to the IPSS and presence of comorbid disease are among the most relevant clinical variables to be considered in order to judge a patient's eligibility for allo-HCT
The optimal timing of myeloablative allo-HCT from HLA identical siblings was studied in patients <60 years of age. Low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. Also, the use of reduced intensity conditioning allo-HCT regimens in de novo MDS was examined in patients aged 60-70 years. For patients with low/intermediate-1 IPSS MDS, reduced-intensity conditioning transplantation life expectancy was 38 months versus 77 months with non-transplantation approaches. For intermediate-2/high IPSS MDS, reduced-intensity conditioning transplantation life expectancy was 36 months versus 28 months for non-transplantation therapies. The study concluded that for low/intermediate-1 IPSS, non-transplantation approaches are preferred. For intermediate-2/high IPSS, reduced intensity conditioning transplantation offers overall and quality-adjusted survival benefit
For patients who are candidates for transplantation, the first choice of a donor is a HLA matched sibling, although results with HLA-matched unrelated donors have improved to levels comparable to those obtained with HLA-matched siblings. Consider intensive chemotherapy for patients who are eligible for intensive therapy but lack a stem cell donor, or those whose marrow blast count requires reduction. Patients who are not candidates for allo-HCT should receive supportive care and therapies similar to low-risk patients
Cutler CS et al. Blood 2004;104:579–585
Koreth J et al. J Clin Oncol 2013;31:2662–2670
Hellström-Lindberg E et al. Br J Haematol 1997;99:344–351
Hellström-Lindberg E et al. Br J Haematol 2003;120:1037–1046
Malcovati L et al. Blood 2013;122:2943–2964
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Supportive Care
Hematopoietic cytokine support should be considered for patients with refractory symptomatic cytopenias
Aminocaproic acid and other antifibrinolytic agents may be used for bleeding episodes refractory to platelet transfusions or for profound thrombocytopenia
For patients with chronic RBC transfusion needs, serum ferritin levels and associated organ dysfunction should be monitored. Iron chelation therapy should also be considered in patients with MDS who have life expectancy of at least several years and have received at least 20 units of RBCs over 1 year or more, serum ferritin level persistently ≥1000 μg/L, clinically relevant iron overload or if allogeneic hematopoietic cell transplantation is planned
Symptomatic anemic patients should receive red blood cell transfusions (using leukocyte-poor products) and for potential allogeneic hematopoietic cell transplantation candidates CMV-negative (for patients who are serologically CMV-negative) and irradiated transfused blood products
Iron depletion needs to be verified before instituting epoetin alfa or darbepoetin alfa therapy. If no response occurs with these agents alone, the addition of a granulocyte colony-stimulating factor (G-CSF) should be considered. G-CSF, and, to a lesser extent, granulocyte-macrophage colony-stimulating factor (GM-CSF) have synergistic erythropoietic activity when used in combination with erythropoiesis stimulating agents and markedly enhance erythroid responses. A predictive model for response to epoetin alfa or beta and G-CSF in MDS patients was developed and validated in prospective studies. Three groups of patients were identified (high probability of response group, intermediate, and poor) based on serum erythropoietin levels (<500 mU/mL or ≥500 mU/mL) and transfusion needs (<2 RBC units/month or ≥2 RBC units/month) with response rates according to study response criteria to treatment of 74%, 23% and 7%
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Erratum in: Blood 1998;91:1100. Comment in: Blood 1997;90:2843–2846, Blood 2001;98:1985
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Hellström-Lindberg E et al. Br J Haematol 1997;99:344–351
Hellström-Lindberg E et al. Br J Haematol 2003;120:1037–1046
Malcovati L et al. Blood 2013;122:2943–2964
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Tefferi A, Vardiman JW. N Engl J Med 2009;361:1872–1885