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Myelodysplastic syndromes are a group of diseases in which the bone marrow does not make enough healthy blood cells. It is also called preleukemia or smoldering leukemia. Learn about myelodysplastic syndromes and find information on how we support and care for people with myelodysplastic syndromes before, during, and after treatment.
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Myelodysplastic syndromes are diseases of the blood and bone marrow. Normally, the bone marrow makes blood stem cells (immature cells) that develop into mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. The lymphoid stem cell develops into a white blood cell. The myeloid stem cell develops into one of three types of mature blood cells:
In myelodysplastic syndromes, the blood stem cells do not mature into healthy red blood cells, white blood cells, or platelets. The immature blood cells, called blasts, do not function normally and either die in the bone marrow or soon after they enter the blood. This leaves less room for healthy white blood cells, red blood cells, and platelets to develop in the bone marrow. When there are fewer blood cells, infection, anemia, or easy bleeding may occur.
Myelodysplastic syndromes have too few of one or more types of healthy blood cells in the bone marrow or blood. Myelodysplastic syndromes include the following diseases:
See the following PDQ summaries for information about other blood cell diseases:
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get a disease; not having risk factors doesn't mean that you will not get a disease. People who think they may be at risk should discuss this with their doctor. Risk factors for myelodysplastic syndromes include the following:
Myelodysplastic syndromes often do not cause early symptoms and are sometimes found during a routine blood test. Other conditions may cause the same symptoms. A doctor should be consulted if any of the following problems occur:
The following tests and procedures may be used:
The prognosis (chance of recovery) depends on the following:
Treatment options depend on the following:
There is no staging system for myelodysplastic syndromes. Treatment is based on whether the disease developed after the patient was exposed to factors that cause myelodysplastic syndrome or whether the disease was previously treated. Myelodysplastic syndromes are grouped for treatment as follows:
De novo myelodysplastic syndromes
De novomyelodysplastic syndromes develop without any known cause.
Secondary myelodysplastic syndromes
Secondary myelodysplastic syndromes develop after the patient was treated with chemotherapy or radiation therapy for other diseases or after being exposed to radiation or certain chemicals that are linked to the development of myelodysplastic syndromes. Secondary myelodysplastic syndromes may be harder to treat than de novo myelodysplastic syndromes.
Previously treated myelodysplastic syndromes
The myelodysplastic syndrome has been treated but has not gotten better.
Different types of treatments are available for patients with myelodysplastic syndromes. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with a myelodysplastic syndrome. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Treatment options for patients with myelodysplastic syndromes range from supportive care that helps relieve symptoms to aggressive treatment that may slow or preventprogression of the disease.
Problems caused by low blood cell counts, such as fatigue and infections, may be treated with transfusions of blood products or the use of growth factors.
Chemotherapy may be used to delay progression of the disease. Other drug therapy may be used to lessen the need for transfusions. Certain patients may benefit from aggressive treatment with chemotherapy followed by stem cell transplant using stem cells from a donor.
In myelodysplastic syndromes, chemotherapy is a treatment that uses drugs to stop the growth of immature blood cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the disease being treated.
Supportive care is given to lessen the problems caused by the disease or its treatment. Supportive care may include the following:
Transfusion therapy (blood transfusion) is a method of giving red blood cells, white blood cells, or platelets to replace blood cells destroyed by disease or treatment. Patients who receive frequent red blood cell transfusions may have their tissues and organs damaged from the buildup of extra iron. Iron chelation therapy is a treatment that uses drugs that attach to the extra iron. The drug and the iron are removed from the body in the urine.
Platelet transfusions are usually given when the patient is bleeding or is having a procedure that may cause bleeding.
Erythropoietin may be given to increase the number of red blood cells and lessen the effects of anemia. Sometimes granulocyte colony-stimulating factor (G-CSF) is given with erythropoietin to help the treatment work better.
Deferoxamine may be used to treat the build-up of too much iron in the blood of patients receiving blood transfusions. It is sometimes given with vitamin C.
Lenalidomide may be used to lessen the need for transfusions in patients who have myelodysplastic syndrome caused by a specific chromosome change.
Antithymocyte globulin (ATG) may also be used to lessen the need for transfusions in patients with a certain form of myelodysplastic syndrome.
Antibiotics may be given to fight infections.
Stem cell transplant is a method of giving chemotherapy and replacing blood-forming cells destroyed by the treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of a donor and are frozen for storage. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
Information about clinical trials is available from the NCI Web site.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the medical research process. Clinical trials are done to find out if new treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for disease are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way diseases will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose disease has not gotten better. There are also clinical trials that test new ways to stop a disease from recurring (coming back) or reduce the side effects of treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's clinical trials database.
Some of the tests that were done to diagnose the disease may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the disease has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
A link to a list of current clinical trials is included for each treatment section. Check with your doctor for clinical trials that are not listed here but may be right for you.
Treatment of de novo and secondary myelodysplastic syndromes may include the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with de novo myelodysplastic syndromes and secondary myelodysplastic syndromes. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
Treatment of previously treated myelodysplastic syndromes may include the following:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with previously treated myelodysplastic syndromes. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. General information about clinical trials is available from the NCI Web site.
For more information from the National Cancer Institute about myelodysplastic syndromes, see the following:
For general cancer information and other resources from the National Cancer Institute, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on August 14, 2008.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of myelodysplastic syndromes. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
The myelodysplastic syndromes (MDS) are a group of disorders characterized by one or more peripheral blood cytopenias secondary to bone marrow dysfunction. The MDS are diagnosed in slightly more than 10,000 people in the United States yearly for an annual age-adjusted incidence of 3.4/100,000 people.[1] The MDS are more common in men and whites. The syndromes may arise de novo, or secondarily after treatment with chemotherapy and/or radiation therapy for other diseases. Secondary myelodysplasia usually has a poorer prognosis than does de novo myelodysplasia. Prognosis is directly related to the number of bone marrow blast cells and to the amount of peripheral blood cytopenias. The MDS transform to acute myeloid leukemia (AML) in about 30% of patients after various intervals from diagnosis and at variable rates. (Refer to the Cellular Classification section for more information.)
The acute leukemic transformation is much less responsive to chemotherapy than is de novo AML. Prognosis is also related to the type of myelodysplastic syndrome. Supportive care has been the mainstay of treatment. Judicious use of platelet and blood transfusions and iron chelation may prevent or delay alloimmunization and iron overload and favorably affect prognosis.
The MDS are characterized by abnormal bone marrow and blood cell morphology. Megaloblastic erythroid hyperplasia with macrocytic anemia, which is associated with normal vitamin B12 and folate levels, is frequently observed. Circulating granulocytes are frequently severely reduced, often hypogranular or hypergranular, and may display the acquired pseudo-Pelger-Huët abnormality. Early, abnormal myeloid progenitors are identified in the marrow in varying percentages, depending on the type of myelodysplastic syndrome. Abnormally small megakaryocytes (micromegakaryocytes) may be seen in the marrow and hypogranular or giant platelets may appear in the blood.
The MDS occur predominantly in older patients (usually >60 years), though patients as young as 2 years have been reported.[2] Anemia, bleeding, easy bruising, and fatigue are common initial findings. (Refer to the PDQ summary on Fatigue for more information.) Splenomegaly or hepatosplenomegaly may occasionally be present in association with an overlapping myeloproliferative disorder. Approximately 50% of the patients have a detectable cytogenetic abnormality, most commonly a deletion of all or part of chromosome 5 or 7, or trisomy 8.[3] Although the bone marrow is usually hypercellular at diagnosis, 15% to 20% of patients present with a hypoplastic bone marrow.[4] Hypoplastic myelodysplastic patients tend to have profound cytopenias and may respond more frequently to immunosuppressive therapy.
A variety of risk classification systems have been developed to predict the overall survival of patients with MDS and the evolution from MDS to AML. These classification systems include the French-American-British classification,[5] the Bournemouth score,[6] the Sanz score,[7] the Lille score,[8] and the World Health Organization classification.[9] Clinical variables in these systems have included bone marrow and blood myeloblast percentage, specific cytopenias, age, lactate dehydrogenase level, and bone marrow cytogenetic pattern.
An International MDS Risk Analysis Workshop was convened, and the clinical data from 816 patients with primary MDS from seven previously reported studies, which used independent risk-based prognostic systems, were combined and collated.[10] The combined data were analyzed centrally, and a global analysis was performed, which formed the basis of a new prognostic system called the International Prognostic Scoring System for MDS.[10] In multivariate analyses, significant predictors for both survival and AML evolution included bone marrow blast percentage, number of peripheral blood cytopenias, and cytogenetic subgroup. The data are used to assign MDS patients a score, which stratifies patients into one of four risk groups: low risk, intermediate-1, intermediate-2, and high risk. The time for the development of AML in the risk groups was 9.4 years, 3.3 years, 1.1 years, and 0.2 years, respectively. Median survival for the groups was 5.7 years, 3.5 years, 1.2 years, and 0.4 years, respectively. The system has been incorporated into clinical trial design for MDS.
Ma X, Does M, Raza A, et al.: Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109 (8): 1536-42, 2007.
Tuncer MA, Pagliuca A, Hicsonmez G, et al.: Primary myelodysplastic syndrome in children: the clinical experience in 33 cases. Br J Haematol 82 (2): 347-53, 1992.
Gyger M, Infante-Rivard C, D'Angelo G, et al.: Prognostic value of clonal chromosomal abnormalities in patients with primary myelodysplastic syndromes. Am J Hematol 28 (1): 13-20, 1988.
Nand S, Godwin JE: Hypoplastic myelodysplastic syndrome. Cancer 62 (5): 958-64, 1988.
Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982.
Mufti GJ, Stevens JR, Oscier DG, et al.: Myelodysplastic syndromes: a scoring system with prognostic significance. Br J Haematol 59 (3): 425-33, 1985.
Sanz GF, Sanz MA, Vallespí T, et al.: Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 74 (1): 395-408, 1989.
Aul C, Gattermann N, Heyll A, et al.: Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 6 (1): 52-9, 1992.
Brunning RD, Bennett JM, Flandrin G, et al.: Myelodysplastic syndromes. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 61-73.
Greenberg P, Cox C, LeBeau MM, et al.: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89 (6): 2079-88, 1997.
The myelodysplastic syndromes (MDS) are classified according to features of cellular morphology, etiology, and clinical presentation. The morphological classification of the MDS is largely based on the percent of myeloblasts in the bone marrow and blood, the type and degree of myeloid dysplasia, and the presence of ringed sideroblasts.[1] The clinical classification of the MDS depends upon whether there is an identifiable etiology and whether the MDS has been treated previously.
Work on the French-American-British (FAB) classification scheme for the MDS began in the late 1970s under the direction of the French-American-British Cooperative Group (see table below). The version published in 1982 was the first diagnostic classification scheme to clearly and reproducibly distinguish MDS from acute myelogenous leukemia (AML).[1] According to the FAB scheme, the percentage of bone marrow blasts required for the diagnosis of MDS ranges from less than 5% to as much as 29%. The FAB scheme is still frequently used by clinicians to categorize the MDS.
Several weaknesses were identified in the FAB classification of MDS. The inclusion of chronic myelomonocytic leukemia (CMML) was problematic; CMML is a disease that combines features of both MDS and chronic myeloproliferative disorders.[2] In addition, the FAB classification did not take cytogenetic findings into account. For example, the cytogenetically defined MDS subtype del(5q) represents a distinct clinical entity.[3]
In 1997, under the auspices of the World Health Organization (WHO), a working group of pathologists and clinicians from around the world agreed to a new cellular classification scheme for hematopoietic and lymphoid malignancies.[4] Significant changes to the FAB classification of these malignancies were made. For the classification of MDS, the new WHO classification lowered the threshold to 20% for the number of myeloblasts required to make the diagnosis of AML.[5] This arbitrary threshold value for blast percentage eliminated the cellular type, refractory anemia with excess blasts in transformation (RAEB-t), found in the FAB classification scheme. In the WHO cellular classification scheme, RAEB-t is no longer considered a distinct clinicopathologic entity; instead, RAEB-t is included within the broader category, AML with multilineage dysplasia, and identified as AML with multilineage dysplasia following a myelodysplastic syndrome.[6] (Refer to the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)
The elimination of RAEB-t from the WHO cellular classification scheme met some resistance. Some have argued that the biology of RAEB-t is distinct from AML and should be retained as a diagnostic category of MDS.[7][8] Others have emphasized the similar prognoses and responses to treatment for RAEB-t and AML with trilineage dysplasia.[9][10] The diagnosis of AML, which is based upon a threshold of 20% bone marrow or peripheral blood myeloblasts, does not represent a therapeutic mandate. The decision to treat must include other factors, such as patient age, prior history of MDS, clinical findings, disease progression, and most importantly, patient preference, in addition to the blast count. The same factors influence treatment options for patients with 30% or more myeloblasts in the blood or marrow. (Refer to the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)
The addition of refractory cytopenia with multilineage dysplasia (RCMD), myelodysplastic syndrome, unclassifiable (MDS-U), and the myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality completes the WHO cellular classification scheme for MDS. Finally, the WHO classification of MDS removed CMML from MDS and placed it in a new category, myelodysplastic syndromes and myeloproliferative diseases (MDS and MPD).[11] (Refer to the PDQ summary on Myelodysplastic and Myeloproliferative Diseases Treatment for more information.)
Myelodysplastic Syndromes
Refractory anemia
Refractory cytopenia with multilineage dysplasia
Refractory anemia with ringed sideroblasts
Refractory anemia with excess blasts
Myelodysplastic syndrome, unclassifiable
Myelodysplastic syndrome associated with del(5q)
Reclassified from MDS to:
Refractory anemia with excess blasts in transformation
Acute Myeloid Leukemia identified as, AML with multilineage dysplasia following a myelodysplastic syndrome
Chronic myelomonocytic leukemia
Myelodysplastic and Myeloproliferative Diseases
MDS cellular types and subtypes in either cellular classification scheme have different degrees of disordered hematopoiesis, frequencies of transformation to acute leukemia, and prognoses. All WHO cellular types and subtypes and the FAB cellular type, RAEB-t, are described in detail below.
Refractory anemia (RA)
In patients with RA, the myeloid and megakaryocytic series in the bone marrow appear normal, but megaloblastoid erythroid hyperplasia is present. Dysplasia is usually minimal. Marrow blasts are less than 5%, and no peripheral blasts are present. Macrocytic anemia with reticulocytopenia is present in the blood. Transformation to acute leukemia is rare, and median survival varies from 2 years to 5 years in most series. RA accounts for 20% to 30% of all patients with MDS.
Refractory anemia with ringed sideroblasts (RARS)
In patients with RARS, the blood and marrow are identical to those in patients with RA, except that at least 15% of marrow red cell precursors are ringed sideroblasts. Approximately 10% to 12% of patients present with this type, and prognosis is identical to that of RA. Approximately 1% to 2% of RARS evolve to AML.
Refractory anemia with excess blasts (RAEB)
In patients with RAEB, there is significant evidence of disordered myelopoiesis and megakaryocytopoiesis in addition to abnormal erythropoiesis. Because of differences in prognosis related to progression to a frank AML, this cellular classification is comprised of two categories, refractory anemia with excess blasts-1 (RAEB-1) and refractory anemia with excess blasts-2 (RAEB-2). Combined, the two categories account for approximately 40% of all patients with MDS. RAEB-1 is characterized by 5% to 9% blasts in the bone marrow and less than 5% blasts in the blood. Approximately 25% of cases of RAEB-1 progress to AML. Median survival is approximately 18 months. RAEB-2 is characterized by 10% to 19% blasts in the bone marrow. Approximately 33% of cases of RAEB-2 progress to AML. Median survival for RAEB-2 is approximately 10 months.
Refractory anemia with excess blasts in transformation (RAEB-t)
In the FAB classification, RAEB-t represents a panmyelosis in which 20% to 30% of marrow cells are blasts, and more than 5% blasts are seen in the blood. Auer rods may be seen. Sixty percent to 75% of patients develop overt acute leukemia, and median survival is 6 months or less. Approximately 25% of patients present with RAEB-t. In the WHO classification, RAEB-t is not a distinct clinical entity; rather, it is included within the broader category, AML with multilineage dysplasia, and identified as AML with multilineage dysplasia following a myelodysplastic syndrome.[6] (Refer to the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)
Refractory cytopenia with multilineage dysplasia (RCMD)
In patients with RCMD, bicytopenia or pancytopenia is present. In addition, dysplastic changes are present in 10% or more of the cells in two or more myeloid cell lines. There are less than 1% blasts in the blood and less than 5% blasts in the bone marrow. Auer rods are not present. Monocytes in the blood are less than 1 × 109. RCMD accounts for approximately 24% of cases of MDS. The frequency of evolution to acute leukemia is 11%. The overall median survival is 33 months. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) represents another category of RMDS. In RCMD-RS, features of RCMD are present, and more than 15% of erythroid precursors in the bone marrow are ringed sideroblasts. RCMD-RS accounts for approximately 15% of cases of MDS. Survival in RCMD-RS is similar to that in primary RCMD.
Unclassifiable myelodysplastic syndrome (MDS-U)
The cellular subtype, MDS-U, lacks findings appropriate for classification as RA, RARS, RCMD or RAEB. Blasts in the blood and bone marrow are not increased.
Myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality
This MDS cellular subtype, the 5q- syndrome, is associated with an isolated del(5q) cytogenetic abnormality. Blasts in both blood and bone marrow are less than 5%. This subtype is associated with a long survival. Karyotypic evolution is uncommon. Additional cytogenetic abnormalities may be associated with a more aggressive MDS cellular subtype or may evolve to acute myeloid leukemia.
The clinical classification of MDS is used to determine disease prognosis and treatment strategy, and to define entry requirements for many MDS clinical trials.
De novo myelodysplastic syndrome
Most MDS cases occur de novo with no known cause.
Secondary myelodysplastic syndrome
The risk of developing MDS may be increased by exposure to a variety of agents including:[12][13][14]
Patients with documented exposure to such agents are referred to as having secondary MDS or treatment-related MDS and constitute as many as 30% of all patients with MDS. Secondary MDS typically has a poorer prognosis than does de novo MDS.
Previously treated myelodysplastic syndrome
Previously treated MDS are de novo or secondary cases of MDS that have progressed despite previous treatment and, in many cases, are receiving additional treatment.
Vardiman JW, Pierre R, Bain B, et al.: Chronic myelomonocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 49-52.
Mathew P, Tefferi A, Dewald GW, et al.: The 5q- syndrome: a single-institution study of 43 consecutive patients. Blood 81 (4): 1040-5, 1993.
Harris NL, Jaffe ES, Diebold J, et al.: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 17 (12): 3835-49, 1999.
Brunning RD, Matute E, Harris NL, et al.: Acute myeloid leukemia with multilineage dysplasia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 88-9.
Brunning RD, Matutes E, Harrris NL, et al.: Acute myeloid leukemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 77-80.
Huh YO, Jilani I, Estey E, et al.: More cell death in refractory anemia with excess blasts in transformation than in acute myeloid leukemia. Leukemia 16 (11): 2249-52, 2002.
Greenberg P, Anderson J, de Witte T, et al.: Problematic WHO reclassification of myelodysplastic syndromes. Members of the International MDS Study Group. J Clin Oncol 18 (19): 3447-52, 2000.
Estey E, Thall P, Beran M, et al.: Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90 (8): 2969-77, 1997.
Bernstein SH, Brunetto VL, Davey FR, et al.: Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: a Cancer and Leukemia Group B Study. J Clin Oncol 14 (9): 2486-94, 1996.
Vardiman JW: Myelodysplastic/myeloproliferative diseases: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 47-8.
West RR, Stafford DA, Farrow A, et al.: Occupational and environmental exposures and myelodysplasia: a case-control study. Leuk Res 19 (2): 127-39, 1995.
Nisse C, Lorthois C, Dorp V, et al.: Exposure to occupational and environmental factors in myelodysplastic syndromes. Preliminary results of a case-control study. Leukemia 9 (4): 693-9, 1995.
Rigolin GM, Cuneo A, Roberti MG, et al.: Exposure to myelotoxic agents and myelodysplasia: case-control study and correlation with clinicobiological findings. Br J Haematol 103 (1): 189-97, 1998.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
The mainstay of treatment of the myelodysplastic syndromes (MDS) has traditionally been supportive care.[1][2] Prophylactic platelet transfusion should be avoided to forestall alloimmunization, which will make platelet transfusion for bleeding difficult. Anemia should be treated with red cell transfusions regularly, and patients receiving chronic red cell transfusions should be considered for iron chelation therapy with subcutaneously administered desferrioxamine and vitamin C or oral deferasirox.[1][3] (For information on anemia, refer to the Fatigue summary.) Desferrioxamine may improve granulocyte and platelet counts in some patients, and it may reduce red cell transfusion requirements.[4] The use of erythropoietin may improve anemia. The likelihood of response to exogenous erythropoietin administration is clearly dependent on the pretreatment serum erythropoietin level and on baseline transfusion needs. In a meta-analysis summarizing the data on erythropoietin in 205 patients with MDS from 17 studies, responses were most likely in those patients who were anemic but who did not yet require a transfusion, patients who did not have ringed sideroblasts, and patients who had a serum erythropoietin level of less than 200 u/L.[5] Effective treatment requires substantially higher doses of erythropoietin than are used for other indications (150–300 µg/kg/day).
One decision model found that the likelihood of responding to growth factors was higher in patients with a low serum erythropoietin level (defined as a level <500/µL) and low transfusion needs (defined as <2 units of packed red blood cells every month), but ineffective in patients with a high erythropoietin level and high transfusion needs.[6] Some patients with poor response to erythropoietin alone may have improved response with the addition of low doses of granulocyte colony-stimulating factor (GCSF) (0.5–1.0 µg/kg/day).[7][8][9] Rates of response to the combination treatment vary with the French-American-British (FAB) classification, with responses more likely in those with refractory anemia and ringed sideroblasts RARS, and less likely for those with excess blasts.[10] Patients with RARS are unlikely to respond to erythropoietin alone.[5]
A pooled analysis of published MDS trials from 1985 to 2005 examined 1,587 patients from 83 studies of growth factors. The growth factors included recombinant human erythropoietin and GCSF. With the exclusion from analysis of patients with more advanced MDS subtypes and with standardized response criteria, an approximate 40% overall response rate to growth factors was found.[11] The use of high-dose darbepoietin (300 µg/dose weekly) has been reported to produce a major erythroid response rate of almost 50% in patients whose endogenous erythropoietin level was less than 500 u/mL.[12]
Hormones, such as glucocorticoids and androgens, are generally of little benefit to patients with MDS.
Recombinant myeloid growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) have been studied in myelodysplasia.[13] Circulating granulocytes usually increase in a dose-dependent manner during therapy with GM-CSF but usually return to pretreatment levels when the agent is discontinued. Platelet and reticulocyte counts usually do not respond. The effect of GM-CSF treatment on infection rate, morbidity, mortality, and disease progression is not yet known.[14][15][16][17] Some patients respond to GM-CSF with increased circulating blasts.[15] A randomized trial in which granulocytopenic MDS patients were assigned to GM-CSF or observation showed no advantage to the prophylactic use of that cytokine.[18]
The nucleoside 5-azacitidine is an inhibitor of DNA methyltransferase. Following a series of phase II studies suggesting significant activity of 5-azacitidine in patients with MDS, a randomized trial was conducted by the Cancer and Leukemia Group B. In the trial, 191 patients were randomized to receive 5-azacitidine (75 mg/m2/day subcutaneously daily for 7 days every 28 days) or observation. The antineoplastic nucleoside 5-azacitidine was continued for a minimum of four cycles. Patients who did not improve on the observation arm crossed over to receive 5-azacitidine. Hematologic responses occurred in 60% of patients on the 5-azacitidine arm (7% complete response, 16% partial response, and 37% improved response) compared with 5% in the observation arm (responses in the latter group consisted of hematologic improvement associated with an increased white cell count caused by the progression to acute leukemia). The response data of the original Cancer and Leukemia Group B trial have been reanalyzed in the CLB-8421, CLB-8921, and CLB-9221 studies, respectively, using the International Working Group MDS Response Criteria; total hematologic response rate was 47% and included 10% complete responses.[19] Median time to leukemic transformation or death was 21 months for azacitidine versus 13 months for supportive care (P = .007). Median duration of response was 15 months, and fewer than 1% of treated patients died on study. Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to azacitidine.[20][21][22][Level of evidence: 1iiDii]
Results have been reported from a phase III randomized controlled trial (AZA PH GL 2003 CL 001) of 5-azacitidine versus other regimens.[23] The other regimens included low-dose cytarabine, acute myeloid leukemia-type remission induction chemotherapy, or best supportive care, and the trial was limited to patients with higher-risk MDS subtypes. The median and 2-year overall survival (OS) favored the 5-azacitidine arm, at 24 months versus 16 months (P = .0001) and 51% versus 26% (P < .0001), respectively.[23][Level of evidence: 1iiA]
The azacitidine congener decitabine demonstrated similar activity in phase II trials with an overall response rate of 49% and a median response duration of 39 weeks.[24] A randomized trial of decitabine versus supportive care in patients with International Prognostic Scoring System (IPSS) Int-1 or greater led to an overall response rate of 30% in the decitabine arm versus 7% in the observation arm (P < .001).[25] Median time to acute myeloid leukemia (AML) or death was 12.1 months in the treated arm versus 7.8 months in the supportive care arm (P = not significant). Fourteen percent of patients treated with decitabine died on the study. Quality-of-life assessment found advantages to decitabine similar to those of 5-azacitidine. Although considerably fewer than originally planned, the median number of cycles administered was three, the decrease possibly attributable to the toxicity of the dose schedule studied[25][Level of evidence: 1iiDii]
Median number of cycles required to see first hematologic response to 5-azacitidine was 3; 90% of responders showed response by 6 cycles;[19] the median number of cycles of decitabine required to see first response was 2.2.[25]
Preliminary results were reported from a phase III randomized controlled trial of decitabine versus best supportive care in higher-risk MDS patients.[26] The median OS and a combined OS and delay in AML transformation endpoint were similar for patients in both the decitabine and best supportive care arms, at 10.1 months versus 8.5 months, respectively, for OS (P = .38) and 8.8 months versus 6.1 months, respectively, for the combined endpoint (P = .24).[26][Level of evidence: 1iiA]
Phase I and II studies have suggested that decitabine can be given as daily intravenous or subcutaneous infusions at doses that differ from the labeled schedule, which requires a minimum 3-day hospitalization; hematologic response rates are at least as good as in the phase III study.[27][28]
Administration of both nucleosides has been associated with reversal of methylation of cytosines in the promoter regions of silenced genes; however, it is not clear whether the clinical activity of these drugs requires methylation reversal.[29][30][31] While the mechanism of the clinical activity of 5-azacitidine and decitabine are not fully known, these two nucleosides demonstrated the highest single-agent response rates in this group of disorders. Both of these drugs have been approved for refractory anemia, RARS (if accompanied by neutropenia, or thrombocytopenia, or requiring transfusions), RAEB, and refractory anemia with excess blasts in transformation.[32] Trials studying the combinations of both azacytosine nucleosides with histone deacetylase inhibitors have been completed, including the Eastern Cooperative Oncology Group's ECOG-E1905 trial, and are ongoing, including the NCT00326170 study.[31][33][34]
Lenalidomide (CC-5013), a congener of thalidomide, induced erythroid responses in approximately 50% of MDS patients in a phase I and II study, including transfusion independence in 20 out of 32 patients.[35] Patients with MDS that was characterized by interstitial deletions of chromosome 5q31.1 (5q-) appeared particularly sensitive, with responses in 10 out of 12 patients compared with 13 out of 23 patients with a normal karyotype. In a phase II study of 148 low-risk and intermediate-risk I patients with 5q- chromosomal abnormalities (alone, or associated with other abnormalities), lenalidomide-induced transfusion independence in 67%, with a median time to response of 4 to 5 weeks. The median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. Of 62 evaluable patients, 38 patients developed complete cytogenetic remission.[36] Lenalidomide administration is limited by dose-limiting neutropenia and thrombocytopenia.[35][Level of evidence: 3iiiDiv]
Antithymocyte globulin (ATG) has shown activity in MDS patients in several small series. The National Heart Lung and Blood Institute conducted a phase II trial including 25 MDS patients with less than 20% blasts. Of all the patients studied, 11 or 44% responded and became transfusion-independent after ATG (three complete responses, six partial responses, and two minimal responses).[37] Multivariate analysis identified HLA-DR-15 (phenotype) expression, briefer period of red cell transfusion dependence, and younger age as predictors of response to ATG.[38]
Although therapy with cytotoxic agents has occasionally been beneficial, results are usually disappointing, and responses are often brief when achieved.[1][2][39] Low-dose cytarabine has benefitted some patients; however, this treatment was associated with a higher infection rate when compared to observation in a randomized trial. No difference in time to progression or OS was observed for patients treated with low-dose cytarabine or supportive care. In those patients who responded to low-dose cytarabine, response appeared to be caused by a cytotoxic effect of the drug.[40] Low doses of oral melphalan have a similar response rate to low-dose cytarabine in small trials; however, the long-term consequences of ongoing alkylator therapy in this patient population are unknown and potentially harmful.[41] Topotecan, at doses that induce bone marrow aplasia (2.0 mg/m2/day continuous infusion for 5 days), induced complete hematologic remissions in 28% of patients. Toxic effects were significant, and the median duration of remission was 8 months. The extent to which the hematologic improvement induced by this therapy may be offset by adverse changes in quality of life is not clear.[42][Level of evidence: 3iiiDiv] The combination of topotecan and cytarabine has induced complete remission in 56% of patients with MDS; however, median duration of complete response was only 50 weeks, and patients required monthly maintenance therapy.[43][Level of evidence: 3iiDiv] The combination of fludarabine, cytarabine, and granulocyte-colony stimulating factor also appears to have a high response rate (74% complete response); however, this benefit was restricted to patients with good-risk or intermediate-risk cytogenetic abnormalities according to the IPSS.[44][Level of evidence: 3iiDiv]
Autologous bone marrow or peripheral blood progenitor cell transplantation is under clinical evaluation for subsets of patients who achieve remission following cytotoxic remission induction therapy. A retrospective review of 114 patients from the European Group for Blood and Marrow Transplantation reported 25% disease-free survival (dfs) following high-dose therapy and autologous rescue for patients treated in first complete remission. Cytogenetics and the IPSS score were not provided for this patient cohort. Given that the overall remission rate for this group of diseases is not better than approximately 50%, participation in clinical trials is encouraged.[45][Level of evidence: 3iiiA]
Patients with advanced MDS or acute myeloid leukemia (AML), which has progressed from MDS, may be treated with remission induction chemotherapy similar to patients with de novo AML. A retrospective review has suggested that the complete remission rate for patients with RAEB who are treated with dose-intensive cytarabine-based regimens is comparable to the complete response rate for patients with de novo AML; however, event-free survival (EFS) was inferior for RAEB patients. Only 50% of RAEB patients in this series had cytopenias documented for at least 1 month prior to treatment; thus, some of these patients may have had evolving AML with less than 30% bone marrow blasts rather than the more typical MDS.[46][Level of evidence: 3iiDiii] In multivariate analysis, diagnosis of RAEB (as opposed to AML) was not a predictor of EFS. Rather, cytogenetic subset, duration of hematologic abnormalities, and increasing age were all strong predictors of failure to achieve complete remission, and decreased EFS. This suggests that risk assessment for chemotherapy outcome in MDS and AML should not be based solely on FAB classification. Previous studies using conventional seven plus three AML induction regimens have reported inferior remission rates in patients with MDS or AML following MDS.[47]
Allogeneic bone marrow transplantation (BMT) for young patients with MDS offers the potential for long-term dfs.[39] In two large studies, 45% to 60% of patients with de novo MDS were projected to be long-term disease-free survivors.[48][49] Outcome tends to be better in younger patients with fewer bone marrow blasts, but long-term benefit has been noted in all FAB classification types, and in patients with marrow fibrosis, a variety of karyotypic findings, and different preparative regimens.[48][49][50] A retrospective review of outcomes of allogeneic BMT according to pretransplant IPSS score showed that the IPSS score predicted relapse rate and dfs. The 5-year dfs rates were 60% for the low-risk and intermediate-1 risk group, 36% for the intermediate-2 risk group, and 28% for the high-risk group.[51][Level of evidence: 3iiDii] A review of 118 young MDS patients (median age 24, age range 0.3–53 years) who received allogeneic BMT from matched unrelated donors reported an actuarial survival of 28% at 2 years. Transplant-related mortality was influenced by the age of the patient (18 years or younger, 40%; age 18 to 35 years, 61%; 35 years or older, 81%). Relapse rate was influenced by FAB classification. This study included patients who received transplants as early as 1986, which may have influenced the patient survival data.[52][Level of evidence: 3iiiA] Outcomes may not be as good for patients with treatment-related MDS (5-year dfs of 8% to 30%).[53]
Allogeneic stem cell transplantation with nonmyeloablative conditioning is under clinical evaluation for treatment of MDS. A retrospective analysis of 836 allogeneic transplants for MDS using HLA-matched sibling donors was performed and included 215 patients who received nonmyeloablative conditioning regimens. The 3-year probabilities of progression-free survival and OS were similar in both groups (39% after myeloablative condition vs. 33% in reduced intensity conditioning RIC and 45% vs. 41%, respectively; these differences were not significant). Relapses were more common in the reduced intensity group, but nonrelapse mortality was decreased.[54][Level of evidence: 3iiiA]
The farnesyl transferase inhibitor tipifarnib, which is under clinical evaluation, has been examined in 82 patients; 32% of patients responded, and 15% had complete responses. Median response duration was 11 months.[55][Level of evidence: 3iiiDiv]. Arsenic trioxide induced major hematologic improvement in approximately 20% of 185 MDS patients treated in two multicenter phase II trials.[56][57]
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Hellström-Lindberg E, Ahlgren T, Beguin Y, et al.: Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood 92 (1): 68-75, 1998.
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Golshayan AR, Jin T, Maciejewski J, et al.: Efficacy of growth factors compared to other therapies for low-risk myelodysplastic syndromes. Br J Haematol 137 (2): 125-32, 2007.
Mannone L, Gardin C, Quarre MC, et al.: High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol 133 (5): 513-9, 2006.
Greenberg PL: Treatment of myelodysplastic syndromes with hemopoietic growth factors. Semin Oncol 19 (1): 106-14, 1992.
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Hoelzer D, Ganser A, Völkers B, et al.: In vitro and in vivo action of recombinant human GM-CSF (rhGM-CSF) in patients with myelodysplastic syndromes. Blood Cells 14 (2-3): 551-9, 1988.
Estey EH, Kurzrock R, Talpaz M, et al.: Effects of low doses of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with myelodysplastic syndromes. Br J Haematol 77 (3): 291-5, 1991.
Yoshida Y, Hirashima K, Asano S, et al.: A phase II trial of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes. Br J Haematol 78 (3): 378-84, 1991.
Greenberg PL: The role of hemopoietic growth factors in the treatment of myelodysplastic syndromes. International Journal of Pediatric Hematology/Oncology 4 (3): 231-8, 1997.
Silverman LR, McKenzie DR, Peterson BL, et al.: Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 24 (24): 3895-903, 2006.
Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002.
Kantarjian HM: Treatment of myelodysplastic syndrome: questions raised by the azacitidine experience. J Clin Oncol 20 (10): 2415-6, 2002.
Kornblith AB, Herndon JE 2nd, Silverman LR, et al.: Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol 20 (10): 2441-52, 2002.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al.: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10 (3): 223-32, 2009.
Wijermans P, Lübbert M, Verhoef G, et al.: Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 18 (5): 956-62, 2000.
Kantarjian H, Issa JP, Rosenfeld CS, et al.: Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106 (8): 1794-803, 2006.
WijerMans P, Suciu S, Baila L, et al.: Low dose decitabine versus best supportive sare in elderly patients with intermediate or high risk MDS not eligible for intensive chemotherapy: final results of the randomizedpPhase III study (06011) of the EORTC Leukemia and German MDS Study Groups. [Abstract] Blood 112 (11): A-226, 2008.
Issa JP, Garcia-Manero G, Giles FJ, et al.: Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103 (5): 1635-40, 2004.
Kantarjian H, Oki Y, Garcia-Manero G, et al.: Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109 (1): 52-7, 2007.
Daskalakis M, Nguyen TT, Nguyen C, et al.: Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood 100 (8): 2957-64, 2002.
Yang AS, Doshi KD, Choi SW, et al.: DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia. Cancer Res 66 (10): 5495-503, 2006.
Gore SD, Baylin S, Sugar E, et al.: Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66 (12): 6361-9, 2006.
Kaminskas E, Farrell A, Abraham S, et al.: Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11 (10): 3604-8, 2005.
Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al.: Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood 108 (10): 3271-9, 2006.
Soriano AO, Yang H, Faderl S, et al.: Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 110 (7): 2302-8, 2007.
List A, Kurtin S, Roe DJ, et al.: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352 (6): 549-57, 2005.
List A, Dewald G, Bennett J, et al.: Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355 (14): 1456-65, 2006.
Molldrem JJ, Caples M, Mavroudis D, et al.: Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol 99 (3): 699-705, 1997.
Saunthararajah Y, Nakamura R, Nam JM, et al.: HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 100 (5): 1570-4, 2002.
Cheson BD: Chemotherapy and bone marrow transplantation for myelodysplastic syndromes. Semin Oncol 19 (1): 85-94, 1992.
Miller KB, Kim K, Morrison FS, et al.: The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase-III intergroup study. Ann Hematol 65 (4): 162-8, 1992.
Omoto E, Deguchi S, Takaba S, et al.: Low-dose melphalan for treatment of high-risk myelodysplastic syndromes. Leukemia 10 (4): 609-14, 1996.
Beran M, Kantarjian H, O'Brien S, et al.: Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 88 (7): 2473-9, 1996.
Beran M, Estey E, O'Brien S, et al.: Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia. J Clin Oncol 17 (9): 2819-30, 1999.
Ferrara F, Leoni F, Pinto A, et al.: Fludarabine, cytarabine, and granulocyte-colony stimulating factor for the treatment of high risk myelodysplastic syndromes. Cancer 86 (10): 2006-13, 1999.
De Witte T, Van Biezen A, Hermans J, et al.: Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. Blood 90 (10): 3853-7, 1997.
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De Witte T, Zwaan F, Hermans J, et al.: Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndrome: a survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG) Br J Haematol 74 (2): 151-5, 1990.
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Standard treatment options:
Treatment options under clinical evaluation:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with de novo myelodysplastic syndromes and secondary myelodysplastic syndromes. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
With the exception of the use of lenalidomide for low risk patients with abnormalities of chromosome 5, there are no clinical trials informing the appropriate selection of current therapies for patients with specific subtypes of myelodysplastic syndrome. Patients who have ceased to respond or did not respond to one therapy are frequently offered another from the therapies described in the previous sections. There are currently no data evaluating the success of switching from one azacytosine analogue to the other in the case of nonresponse. Patients who have responded, as in the CLB-8421, CLB-8921, and CLB-9221 trials, to an azacytosine nucleoside and relapse off-therapy may respond to the reinstitution of the nucleoside.[1] Relapsed patients should be considered for enrollment in clinical trials. In patients previously treated with growth factors, there are studies that have shown responses to non–growth factor approaches.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with previously treated myelodysplastic syndromes. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
About PDQ
Additional PDQ Summaries
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
This information was last updated on October 8, 2009.
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text:
Hot shooting Eagles burn Spartans
Third-ranked Kirkwood women made 15 3-pointers in routing Southwestern here Saturday, 99-40.
The Eagles improved to 9-0 atop the ICCAC Division II standings, and 20-3 overall. Southwestern, which trailed 51-26 at halftime, fell to 0-7 and 0-20.
"We scouted them against Marshalltown and they went about 1-for-20 on threes," SWCC interim coach Steve Tussey said. "So, they're either on or off. But I've never seen a team shoot like that in person. They were shooting it well, and then when they weren't making it they were crashing the boards for offensive rebounds. They play 11 girls and they can all play."
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I have been looking to purchase a home for about 6 months and one of my criterias is to have direct access to the garage, but I keep on coming across houses that have attached garages, but no direct acess. What are the ways to remodel the house to give it direct access? Most of the houses have a bedroom sharing the wall with the garage, so I would prefer no to have to cut a hole in that wall, but is that the only way? | |||
My homes had garages that opened into a back hallway which led to kitchen. In your case it probably means the garage was added on after house was built instead of during construction. Are the homes you are looking at older- maybe built in the 50s or 60s before it became commonplace to do so. Seems if you put access directly into a bedroom that would negatively affect the resale value of house. Keep looking if you can. | ||||
The other way would be a breezeway type of structure across the back of the house to an appropriate room. Of course, you are talking more money here. Not having direct access is not always terrible. You may want to rethink it. | ||||
Interesting thread, thanks, OP, for posting it and I would have to say from a cost-effective point of view either give up on the direct access idea or keep searching. Myself, I absolutely love the direct access from the garage into the kitchen in our "forever" home although it really never even crossed my mind when we were house hunting! If I had to do it again, that feature would be at the top of my list ~ lucky we got it without even looking for it! BTW, my Dad built our family home in the early 1950's and spent several years designing it. It had 5 bedrooms, 2 bathrooms, an over-sized 2 car attached garage (all almost un-heard of in those days) and the garage had direct access as well ~ for the firewood! The garage shared a common wall with the LR and DR, firewood was stacked along the garage wall and delivered through the wall to the firewood box - Mom loved "no mess" and it was handy for Santa Claus as well! Myself, I would keep looking for an attached garage with kitchen access; wouldn't want to buy a place that needed renovations immediately. | ||||
Years ago when I was looking for a house in Virginia I looked at one that didn't have direct access to the house. I think the garage on that one was beside the bedrooms as well. If it is against the bedrooms and there isn't a hallway unless you want to enter via the bedroom you're kind of stuck. I'd keep looking rather than trying to modify the house to allow direct access. General Disclaimer Any advice given here is general in nature and is not necessarily valid for your given area. If in doubt check with your local codes enforcement department for what is required when doing electrical, plumbing or structural work on your house. Permits may or may not be required in your area and home owners may not be able to DIY some tasks. I have no way of knowing if you have the skills needed to complete the tasks you are asking about, when in doubt seek professional assistance. My advice may be worth exactly what you pay me for it. :-) For the record I did not stay in a Holiday Inn Express last night. | ||||
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by Overlord on Sat May 09, 2009 5:44 am
Could you please create a WMP12 skin for better integration into Windows 7? That would be great!
Morten wrote:Yeah, sorry. Typo from my part. Of course I meant the simplistic light blue skin layout from WMP12.
danasince1979 wrote:hope this is ok but i had the skin saved so i ve reuploaded it here:
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I was able to upgrade the electro-shock plasmid to level 3, and decided I would like to have the telekinesis level 3, so I can throw live splicers around the room. I just thought that sounded like fun.
I guess that if you save all the little sisters, instead of harvesting them, you wouldn't get enough Adam to buy the third level telekinesis, so I played the game through again just to get the telekinesis 3. I harvested all the little sisters after making them gather adam twice, and still I could not get the telekinesis plasmid to come up for sale in the gatherers garden, in the last level, Fontaine Futuristics.
Could someone please tell me how to get the telekinesis 3 plasmid?


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Album review: Cee Lo Green, 'The Lady Killer'
3.5 stars (out of 4)
The vocalist who turned Gnarls Barkley's "Crazy" into one of the 21st Century's first anthems returns with his third solo album, and first in six years. Cee Lo Green, born Thomas Callaway in Atlanta, has built a justified reputation as a roly-poly misfit with a magnificent voice that wouldn't have sounded out of place in '60s Motown or a Baptist church service. His combo of retro-soul classicism and dark-tinged eccentricity jelled on a viral hit "(Expletive) You" last summer, a song that induced gasps, chuckles, frantic dancing and a William Shatner cover version.
Green expands on that notion in "The Lady Killer" (Elektra), an album loosely organized around themes of passion, obsession and revenge. Green is best when he uses his love of classic soul, TV theme songs and new wave as a cover for some of his weirder obsessions. The "Lady Killer Theme" sets the stage by introducing Green's latest character -- part playboy, part assassin -- backed by reverbing spy-movie guitars that could've been hijacked from a John Barry soundtrack. Shotgun blasts introduce "Love Gun," a duel as much as a duet with Lauren Bennett. And "Bodies" is downright disturbing, a murderous nightmare brimming with clipped beats, chilling strings and erotic whispers.
The rest isn't quite as provocative, more of a melodic tribute to Green's era-spanning musical tastes – but who's complaining? A "Billie Jean"-style bass line struts beneath bold strings and blasting synthesizers on "Bright Lights Bigger City." "Satisfied" sounds like a great lost Prince track from the '80s with its layered falsetto voices. "Old Fashioned" updates the orchestrated pop-soul of the Drifters. Even with his quirks dialed down, Green has a voice that can burst any melody wide open.


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- June 2, 2011
- 1:45 p.m.
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jfioravanti writes:
Please note that this event is taking place at Plaza Park in Oxnard (535 S. A Street), not Plaza Park in Ventura. Hope to see you there!
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You're watching...
Creating jewelry to promote a message of peace
Pamela Yeo talks about how her company Saught creates jewelry made from landmines by conflict-afflicted citizens
Dec 3, 2012
Pamela Yeo
You're watching...
Pamela Yeo talks about how her company Saught creates jewelry made from landmines by conflict-afflicted citizens
Dec 3, 2012
Pamela Yeo
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Auto-advanceThis transcript is automatically generated
-- so our very first guest this by the way ladies and gentlemen.
Is a dot com a first -- we have never Skype from southeast Asia before.
But that is where our first guest is joining us from from -- on Penh Cambodia.
We have Pamela you know the co-founder.
And CEO of sought and she's joining us here we can't we we -- we could be more thrilled to have you here.
And especially when they -- I mean this is so exciting I you're here today to talk to us about.
The jury being made it out of land mines -- which is so very interesting and I've seen the photos of some of the jewelry and it's quite beautiful.
-- so we want to get right to you know how this all started.
Why did you find -- found sought and what was your you know kind of -- ha moment to get this whole thing started.
I'm so it can't find it by myself in the future patents -- and an -- I was so I -- have it written that come and he's -- -- -- -- use this material.
And to create jewelry to beauty promote and that's attempt -- And done.
Maybe Flagstaff it and his project Larry were still it's gonna cost you beats you down to don't I don't convert your approached.
The -- again my actions and to just like the -- -- -- mining darkening the -- intent.
And it would be BEB spoke today -- we -- -- I don't ballpark are works yeah.
And aren't the when he told us that he had it basically -- the pilot mental.
Brown I bet you -- -- -- for us not being used for anything that was the more glaring -- you know aha.
Yeah there was something that we can't -- -- -- well -- -- -- -- uses and it's you know the good.
That's amazing we'll -- some kind of briefly about the past conflict and in Cambodia's so our viewers can kind of understand.
What you have had to deal -- there.
Concept but -- known -- when's your Cambodia is very went through periods of and to date that conflicts.
Went the EDS furious the cockpit -- in the -- seventies.
And do it commercially is why didn't he was genocide it's Communist South Asian region.
Though it was Anthony did it.
Even -- -- let us and nick issued Cilic.
And -- compared to push here -- -- -- You're talking about it in the -- -- And am I think a lot of -- on -- about autistic community and keep an don't want -- -- are being Kendall yeah.
I -- -- get a call it.
Okay that the -- NGOs are Cambodia's.
OK very good and as we continue to listen to you we do have a little bit audio issue but -- want to remind everybody you're on -- you look and sound fabulous.
-- we want to ask you about the children made it from land mines and mean what a neat idea how -- -- So I don't begin until provided it is usually need Oprah also caught well.
It is knocked it onto a single sheet when did it on.
The -- -- -- gonna endure as well and and until each this.
OK and you know but -- jewelry obviously you guys want to help people in Cambodia who does it help specifically.
I'm involved I'm gonna go -- being here -- -- I'm probably want to do is you know people you're gonna go -- past -- bucket he.
Saw at bashing by the -- glory he mining.
That aren't that.
And and that you can buy local and international Ngo group and that -- need to debt collection of each team got Yorvit.
The other thing you have he and -- -- an inch ringing of the -- goal and -- that there are issued and -- -- All right in you know that what's the reaction been because again I I went on the web site.
The jury is very cool looking at and of course you've got a great story to tell if you're if you're wearing it you could help raise awareness.
By wearing it how is the response then.
Opening the and -- and that he's very warm -- -- -- I don't know -- Nationally.
And especially in the important that wealthy and very -- and -- There.
And and it could and from -- -- and I think we've -- OK and we know about supply and demand so if you're getting a good response where do you see the organization heading in the next few years.
We still sell extending out what.
Not only we didn't handle it and so but it's young -- extending to other countries such as South Africa Shimon NT SE.
And who it was cities and our product blank as well as -- -- arm -- and art are what you were minus.
Really interesting stuff we're showing.
Web site right now that's where viewers can go for more information that's www.
-- dot com and then dot SG very important part of that.
We can't thank you enough for being with us here today Pamela you know co-founder and CEO.
Sought joining -- -- -- from Cambodia on Skype it is a dot com.
First we want to thank you very much for being here today and congratulations of the best of luck to you in your ventures and thank -- for having me thank -- -- of next.
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Wanted: a universally-popular vice-presidential candidate
Romney's vice-presidential pick is the crucial next decision of White House race.
By Andrew Hammond Published 09 July 2012 15:38With polls indicating this year's race for the White House will be highly competitive, the key decision Mitt Romney has to make before the Republican presidential convention in August is his choice of running mate. Wide-ranging candidates are being touted in the media, including US Senators Marco Rubio and Rob Portman, Governors Mitch Daniels and Tim Pawlenty, and even Hewlett Packard CEO Meg Whitman.
The vice-presidential selection process is an election year custom that attracts high prominence, partly because of several key changes in US politics in recent decades. Firstly, the vice-presidency has become the single best transitional office to the presidency. Secondly, the office of vice-president has assumed more power and resourcing. And thirdly, the electoral stakes have grown of not selecting a deputy who is perceived to be capable of assuming office effectively upon the incumbent's unanticipated death or incapacity.
This latter factor was a major feature of the 2008 presidential election when Republican nominee John McCain, aged 71, made the high-risk decision to select Sarah Palin – whose only major experience of office was less than two years as Governor of Alaska. Rather than boosting McCain's campaign, Palin was – ultimately – widely viewed as too inexperienced to be president. This was also true in 1988 of Dan Quayle, then a two-term US senator, who was selected by George H.W. Bush.
In light of the Palin episode in 2008, Romney will be keen to make a choice that will "do no harm" to his electoral prospects. Hence, part of the reason why Portman and Daniels, with their wide-ranging political experience, have received so much attention from media.
Historically, the process of selecting vice-presidential nominees tended to be fashioned around issues like reconciling important party stakeholders after what can be bruising nomination contests; and the perceived advantage of cultivating so-called 'balanced tickets' in which the vice-presidential and presidential candidates where differentiated by factors such as their 'home' region of the country, or philosophical wings of the party, so as to maximise support across the nation.
One potential balanced ticket candidate for Romney is Rubio, whose life story – he was born in Florida to Cuban immigrants – potentially contrasts favourably with perceptions of Romney's wealth and privilege. Rubio is also a Tea Party favourite, potentially neutralising conservative concerns about Romney's more moderate Republicanism. The selection of Rubio, while containing the potential hazard of his relative national political inexperience (he only entered the US Senate in 2011), would also increase the prospects of Romney winning the key swing state of Florida.
Romney's wife, Anne, also enthusiastically highlighted earlier this month that Romney might choose a woman. As well as Whitman (who stood as the Republican candidate in the 2010 Californian gubernatorial election), potential female candidates touted in the media include three who, like Rubio, are serving only their first term of office in their present post: US Senator Kelly Ayotte (who represents the swing state of New Hampshire); South Carolina Governor Nikki Haley (an American-Indian whose parents emigrated from Amritsar); and New Mexico Governor Susana Martinez (who could potentially appeal to the rapidly growing US Hispanic population).
However, partly because of the changes in the presidential nomination system, and indeed the proliferation of mass media, these traditional considerations (while still of enduring consequence) are less relevant to the modern process. Thus, Al Gore was selected in 1992 by Bill Clinton (a fellow centrist Democrat and southerner) not to balance the ticket, but instead to reinforce a key narrative about Clinton's "New Democrat", change candidacy.
Whether or not these developments have potentially injected greater uncertainty into the vice-presidential selection process, it is unquestionably the case that choices are routinely made that confound the pundits. For instance, few (if any) anticipated the selections in 2008 of Palin and Joe Biden, nor in 2000 of Dick Cheney and Joe Lieberman.
The selections of Washington veterans Cheney and Biden (who looks likely to Obama's running mate again this year) were noteworthy inasmuch as they were chosen, in significant part, to fortify the national and international political inexperience of George W. Bush and Barack Obama. Cheney, in particular, therefore assumed a high profile role as vice-president, and is widely viewed as the most powerful ever holder of the office.
Cheney's influence partly derived from his experience and connections as a former White House chief of staff; congressman and defence secretary, and the innovations he brought to the office of the vice presidency – for instance, he considerably increased his national security staff. However, his influence also reflected the increased status of the vice presidency in recent decades which, as well as being reflected in larger staff budgets, also includes greater proximity to the centre of power through a West Wing office in the White House; weekly one-on-one meetings with the president; and authority to attend all presidential meetings.
The selections of Cheney and Biden were also interesting in another sense: both George W. Bush and Obama made the assumption that neither of their more experienced running mates represented a political threat to them, and would thus be very loyal, because they were too old (and in Cheney's case suffered from too poor health) to run for the presidency themselves in the future. Seen from the prism of the last few decades, this is highly unusual.
Indeed, since 1960, four sitting vice-presidents (Richard Nixon in 1960, Hubert Humphrey in 1968; Walter Mondale in 1984; and Gore in 2000) won their respective party's presidential nomination but then lost the general election, whilst two vice-presidents have been elected president (Nixon in 1968 and George H.W. Bush in 1988). One reason vice-presidents have, in the post-war period, enjoyed particular success in securing their party's presidential nomination relates to the Twenty Second Amendment in 1951.
This constitutional amendment restricted presidents from serving more than two terms. Importantly, for vice-presidents, this allowed for the possibility of organising a presidential campaign in the sitting president's second term of office without charges, from inside or outside his party, of disloyalty.
It is thus in this context of short-term political calculation and historical precedent that Romney will make what could prove his defining decision of the campaign. Miscalculation could prove damaging, especially if the race remains tight. However, if the selection wins strong approval, his candidacy will secure invaluable new momentum.
Andrew Hammond was formerly the North America Editor at Oxford Analytica, and a UK Government Special Adviser.
17 comments
Oops. Crazy Joe forgets again what state he is in...
Can't even visualize a VP debate between Ryan & Crazy Joe... maybe Joe can plagiarize a debate script & some new plugs for a start...
I have my fingers crossed that he picks some nut-job like Paul Ryan or John Boehner. Mitt is keen to show he's a conservative, so a hard right pick isn't totally unrealistic. Oh, forgot Gingrich, that would be instant loss; and Herman Cain would just be hilarious. However, if it was beyond doubt that Romney was to win (which fortunately it isn't) I'd like to see Jon Huntsman.
Reagan's preferred veep was Bonzo the Chimp. Bonzo was not impressed and took a raincheck.
Hence the Bush legacy.
Missed Link
The Presidency & monkey talk is off limits this time around- I'll let you guess why...
Biden could run for president in 2016, he would be about the same age as Dole and McCain when they ran
Biden could run for president in 2016, he would be about the same age as Dole and McCain when they ran
Biden could run for president in 2016, he would be about the same age as Dole and McCain when they ran
Mr N Kinnoch sounds the right quality!
You write that "the vice-presidency has become the single best transitional office to the presidency". While that may be true for presidents who do not live to see the end of their terms, only six other VPs have gone on to become presidents and one of the six, Nixon, waited eight years to achieve his goal.
Pedantry corner: Mondale wasn't the sitting V-P in 1984.
Decent article, though - there's been very little talk about Biden's influence (positive or negative) compared to the speculation about Romney's pick. Obama vs (Romney & Veep) in the electorate's view?
Probably won't happen till the convention in Tampa- anyone's better than gaffey Biden- unemployment & Obamatax will do in the junior Senator from Hawaii/Indonesia/Kenya...
I say draft Richard Nixon for Vice-President. "He's dead," you say. But he's no more brain dead than any other conservative, including Romney and Cameron. Besides, since he passed on, he has not told a lie, insulted an ethnic group or stole a penny. That's more than can be said about Romney or Cameron. He's bound to get the women's vote because in life, they always said there was no end to that Tricky Dick.
Once Mitt spots Obama's basilisk stare he won't need a second. More like a resuscitation team.
Catch-weight Contender
i think you mean Mitt needs a 'volunteer'...


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Maze puzzler makes learning programming an adventure.
Programming puzzler teaches coding logic.
Pricey ebook creator is functional but not stellar.
Mind-mapping tool's visual "pop" will engage teens.
Effective approach to expanding vocab with 40 free words.
Fun programming logic for kids, great resources for parents.
Creative tool lets kids jazz up notes with audio, photos.
Creative app can help kids overcome writer's block.
Easy for beginner animators, but kids can't add narration
Awesome video creator presents some privacy concerns.
Enter and explore the world of art with favorite characters.
Shapes, easy tutorials launch kids into animation creation.
Custom timers, stopwatches, and alarms for many uses.
Fiery explosions and crashes in easy special-effects tool.
Fascinating, hands-on look at Disney's animation studios.
Cool, free interactive textbook teaches design in 3-D.
Uneven mini-games let kids grapple with mechanics concepts.
Dinosaur scenes help kids tell their own giant-size tales.
Great tour guide shows and explains nearby must-sees.
Collaborative whiteboard app can be fun, but watch privacy.
Animated, interactive learning tool about the human body.
Interaction of Color by Josef Albers builds on the quality of the influential book on which it's based by adding interactive content, video commentaries, and other digital extras to appeal to budding color enthusiasts.
Create eye-catching presentations with images and few words.
Simplified interactive whiteboard has privacy issues.
Awesome professional-level tool for digital artists.


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Aktuele Onderwerpen
Informeert u zich hier regelmatig over alle aanbiedingen en nieuwtjes rondom de City Airport Bremen.
Ticket agency at the airport
Open seven days per week and nearly round the clock – the new ticket agency.
All visitors of the Airport Bremen and of course all employees in the Airport City are now able to buy tickets for all kind of events like musicals, theatre and concerts direct in the departure lounge.
This has been made possible as the 140th sales outlet of Nordwest Ticket has been opened there. Not only the place is something special but also the opening hours of the ticket counter: Seven days per week from 5 am to 8 pm. With this quite unusual opening times this ticket agency has the longest ones of all Nordwest Ticket outlets. Even on short notice it is therefore possible to get tickets nearly every time.
With the 140th ticket sales outlet Nordwest Ticket as a regional service company expands its already large network within the region. The network now spreads from Osnabrück up to the North Sea and from the Dutch border in the west to Hamburg in the north-east.
On the photo from left to the right: Florian Kruse, Mr. Brand from Nordwest Ticket, Mrs. Heuermann-Pundt from AHS, Jürgen Bula.