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Overview of the treatment of myelodysplastic syndromes
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Mar 21, 2012.

INTRODUCTION — The myelodysplastic syndromes (MDS) encompass a series of hematologic conditions characterized by chronic cytopenias (anemia, neutropenia, thrombocytopenia) accompanied by abnormal cellular maturation. As a result, patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as progression to acute myeloid leukemia (AML), which is often refractory to treatment. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)

Most patients with MDS, particularly those with lower risk disease, die because of the consequences of bone marrow failure rather than transformation to AML. Thus, use of terms such as "pre-leukemia" or "smoldering leukemia" can be misleading if taken to imply that death or morbidity from MDS results only when AML develops. Indeed, the distinction between MDS and AML is itself arbitrary, as patients with 20 to 30 percent blasts are considered to have MDS by French-American-British (FAB) criteria, but AML by the World Health Organization (WHO) classification.

For many years, transfusion with packed red blood cells and platelets and the use of erythropoiesis stimulating agents were the only therapy available. More recently, chemotherapy agents directed at the underlying disorder have been developed and continue to be studied for patients with MDS (eg, azacitidine, decitabine, and lenalidomide). However, due to the advanced age of most patients, the chronicity of the disease, and its attendant morbidities, supportive care remains a central component of the management of all patients with MDS. Patients should be treated as needed with antibiotics for infection and platelet transfusions for bleeding in the setting of thrombocytopenia. (See "Management of the complications of the myelodysplastic syndromes".)

A general overview of the treatment of MDS will be reviewed here. More detailed discussions of the following issues are presented separately:

INDICATIONS FOR TREATMENT — Not all patients with MDS require immediate treatment. This is principally because:

  • MDS is a heterogeneous disease with certain subsets of patients surviving for a decade or more with supportive care alone.
  • With the exception of allogeneic hematopoietic cell transplantation (HCT), MDS cannot be cured by current treatment options.
  • The main goals of therapy for most patients with MDS are to control symptoms and to improve quality of life, which includes minimizing the toxicity of therapy.
  • There is no evidence that the treatment of asymptomatic patients improves long term survival.

Immediate treatment is indicated for patients with the following disease-related complications:

  • Symptomatic anemia
  • Symptomatic thrombocytopenia
  • Recurrent infections in the setting of neutropenia

Some physicians may choose to intervene in cases of asymptomatic severe anemia (eg, hemoglobin <10 g/dL) or asymptomatic severe thrombocytopenia (eg, platelets <10,000/microL). It is unclear that the treatment of neutropenia without a history of infection is of benefit. Studies of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) in this setting have demonstrated that these agents can increase neutrophil counts, but do not improve clinically significant endpoints such as infection rates and survival. This is discussed in more detail separately. (See "Management of the complications of the myelodysplastic syndromes", section on 'Myeloid growth factors'.)

MANAGEMENT OF ASYMPTOMATIC MDS — Asymptomatic patients may be followed expectantly with serial examinations and laboratory studies in order to evaluate the disease tempo. This also allows for the more detailed evaluation of cytopenias and exclusion of reversible causes of the cytopenias (eg, vitamin B12 deficiency, iron deficiency, copper deficiency). This is also an opportunity to bring vaccinations up to date, especially against respiratory pathogens such as pneumococcus, haemophilus influenza B, pertussis, and influenza. Smoking cessation should also be emphasized. (See "Management of the complications of the myelodysplastic syndromes", section on 'Anemia' and "Management of the complications of the myelodysplastic syndromes", section on 'Vaccination'.)

Most patients present with a history of documented complete blood counts, which can provide insight into the disease tempo. Less commonly, a patient with little information regarding prior blood counts should be initially scheduled for monthly visits. At these visits, we perform a focused history and physical examination, complete blood count with differential, and evaluate the peripheral blood smear. If the patient remains asymptomatic for several months and the blood counts are stable, the length of time between visits is gradually lengthened. Patients are educated regarding the potential complications of MDS and told to call the office immediately if they develop a fever or bleeding. When patients develop a transfusion requirement or recurrent infections, then it is time to consider treatment.

PRETREATMENT EVALUATION — All patients with MDS should have a history and physical examination that includes documentation of their transfusion history. In addition, it is our practice to perform the following pretreatment studies in patients with MDS:

SELECTION OF INITIAL TREATMENT — There is no consensus regarding a standard treatment approach for patients with symptomatic MDS, and patients should be encouraged to enroll on clinical trials whenever available. Our treatment approach is similar to that proposed by the MDS Panel for Practice Guidelines of the National Comprehensive Cancer Network (NCCN). This approach incorporates knowledge of the patient’s performance status, the International Prognostic Scoring System (IPSS) (table 3) (calculator 1) MDS risk category, and other disease characteristics (ie, cytopenias present, serum erythropoietin level) to help guide management decisions. However, despite the increased availability of treatment guidelines, it is important to individualize care for the patient with MDS.

Treatment options for patients with MDS typically fall into one of three categories:

  • Supportive care includes the use of antibiotics for infection and red cell and platelet transfusions in the setting of symptomatic anemia and thrombocytopenia, respectively. Prophylactic antibiotics are generally not helpful and this strategy may select for antibiotic resistance. Supportive care is an important adjunct to the management of all patients with MDS and can be considered as the sole treatment modality for a subset of patients with lower risk MDS. (See "Management of the complications of the myelodysplastic syndromes".)
  • Low intensity therapies include hematopoietic growth factors, DNA hypomethylating agents, immunosuppressive therapy, and lenalidomide. These can be administered in the outpatient setting and have a low risk of treatment-related morbidity and mortality. Low intensity treatments can improve symptoms and quality of life, but are not curative.
  • High intensity therapies include intensive combination chemotherapy and allogeneic hematopoietic cell transplantation (HCT). They require hospitalization and entail significant risk of treatment-related mortality. However, these treatments may improve blood counts more quickly than less intensive therapy, reduce the risk of death from MDS, and may alter the MDS disease course. (See "Hematopoietic cell transplantation in myelodysplastic syndromes".) As in AML, combinations of daunorubicin and cytarabine should be reserved for patients with normal cytogenetics and de novo MDS. Use of combination chemotherapy in other patients, particularly those with unfavorable cytogenetics, as defined by the IPSS, should be restricted to investigational regimens being studied in clinical trials.

High intensity therapies are generally reserved for patients with intermediate-2 or high risk IPSS scores. This allows for the avoidance of treatment-related morbidity and mortality in most patients with a relatively good prognosis, and allows for the aggressive treatment of disease in those with a poor prognosis.

Of note, there are certain patient populations that require special attention and modification of this approach. As an example, patients with therapy-related MDS have a particularly poor prognosis and are treated in a similar fashion to those with therapy-related acute myeloid leukemia (AML) or may be considered for palliative care/hospice, depending upon the diagnosis, IPSS, and comorbidities. In addition, patients with 5q deletion and those with chronic myelomonocytic leukemia demonstrating a platelet-derived growth factor receptor beta (PDGFRB) fusion gene have superior outcomes when treated with lenalidomide and imatinib, respectively.

The management of patients with MDS requires consideration of the often-confounding issues of comorbid conditions in these generally elderly individuals (average age 65 to 70), who present clinically with single or multiple cytopenias or their sequelae, and often do not tolerate or respond to conventional chemotherapy. Although transformation to AML is less frequent than bone marrow failure as a cause of death in MDS, significant numbers of patients with MDS undergo evolution to a form of AML which is often less responsive to standard treatment than is de novo AML. Advanced age makes these patients less likely to tolerate standard combination chemotherapy with or without hematopoietic cell transplantation. The adverse biologic characteristics of the transformed cells are also a major contributor to this poor prognosis. (See "Treatment of acute myeloid leukemia in older adults" and "Hematopoietic cell transplantation in myelodysplastic syndromes".)

The use of specific therapeutic approaches has been reviewed in detail [1-4]. Some of these treatments are still considered to be experimental. Comparative clinical trials using the above patient- and disease-related stratifications are needed in order to determine the relative value of each therapeutic modality.

PATIENT FOLLOW-UP — Patients are followed longitudinally to assess disease response to therapy and to monitor for disease progression. Standardized response criteria have been developed that use bone marrow and peripheral blood analysis to allow better comparisons between published studies and to help guide treatment.

However, outside of a clinical trial, the examinations included in the response assessment depend at least partially upon the goals of therapy and how treatment decisions may change based upon the results. We follow all patients with complete blood counts in order to assess hematologic improvement. A bone marrow aspirate with or without biopsy is performed if cell counts deteriorate more than anticipated to evaluate for possible progression to higher risk MDS or acute myeloid leukemia. Alternatively, some clinicians perform a bone marrow biopsy and aspirate after two to four cycles of chemotherapy to help guide further treatment for patients receiving active therapy.

Response criteria — Responses are categorized according to the International Working Group (IWG) standardized response criteria for evaluating clinically significant responses in MDS first published in 2000 and modified in 2006. [5,6]

Response criteria for hematologic improvement:

  • Erythroid response — Patients with a pretreatment hemoglobin <11 g/dL demonstrate erythroid response if their hemoglobin increases by ≥1.5 g/dL for at least eight weeks, and there is a reduction in the units of red cell transfusions by an absolute number of at least four red cell transfusions per eight weeks compared with the pretreatment transfusion number in the previous eight weeks. Only red cell transfusions given for a hemoglobin ≤9 g/dL pretreatment will count in the red cell transfusion response evaluation.
  • Platelet response — Patients with a pretreatment platelet count <100 x 109/L demonstrate a platelet response if there is an absolute platelet increase of ≥30 x 109/L for patients starting with >20 x 109/L platelets. For those with an increase from 10 x 109/L to >20 x 109/L must have an increase of at least 100 percent.
  • Neutrophil response — Patients with a pretreatment neutrophil count <1 x 109/L demonstrate a neutrophil response if they have an at least 100 percent increase and an absolute increase >0.5 x 109/L.

Although intuitively sensible, it remains unclear whether achievement of hematologic improvement prolongs survival.

Bone marrow response must persist for a minimum duration of four weeks:

  • Complete remission (CR) — Bone marrow with ≤5 percent myeloblasts with normal maturation of all cell lines. Dysplastic changes may be seen, but should be considered within the normal range of dysplastic changes. Peripheral blood demonstrates hemoglobin ≥11 g/dL, platelets ≥100 x 109/L, neutrophils ≥1 x 109/L, and no circulating blasts. Patients who achieve a CR have improved survival. This survival advantage appears to be due to the achievement of a CR rather than an inherently better prognosis.
  • Partial remission — Criteria for complete remission except bone marrow blasts decreased by ≥50 percent over pretreatment, but are still >5 percent. The cellularity and morphology of the bone marrow is not relevant.
  • Marrow complete remission — Marrow complete remission was developed to describe patients who have achieved a complete remission in the bone marrow, but have not recovered peripheral blood counts. The bone marrow demonstrates ≤5 percent myeloblasts and the percent of myeloblasts has decreased by ≥50 percent over pretreatment. If peripheral blood demonstrates a hematologic improvement response, this should be noted in addition to marrow complete remission. As with hematologic improvement, the clinical significance of response marrow complete remission is not well established.
  • Stable disease — Failure to achieve at least partial remission, but no evidence of progression for at least eight weeks. As with hematologic improvement, the clinical significance of stable disease is not well established.
  • Disease progression — Defined by the percent blasts: those with <5 percent blasts have a ≥50 percent increase in blasts to >5 percent blasts; those with 5 to 10 percent blasts have a ≥50 percent increase in blasts to >10 percent; those with 10 to 20 percent blasts have a ≥50 percent increase to >20 percent; those with 10 to 30 percent blasts have a ≥50 percent increase to >30 percent. Disease progression can also be defined by an at least 50 percent decrement from maximum remission/response in granulocytes or platelets, reduction in hemoglobin by ≥2 g/dL, or transfusion dependence.
  • Cytogenetic response — Complete if the previous chromosomal abnormality disappears without the appearance of new ones, partial if there is an at least 50 percent reduction in the chromosomal abnormality. At least 20 analyzable metaphases by conventional cytogenetic studies are required to diagnose or exclude the presence of any cytogenetic abnormality. Patients who achieve a complete remission (CR) but have persistent cytogenetic abnormalities are more likely to relapse than patients whose CR is characterized by disappearance of the initial cytogenetic abnormality.

Disease progression — Most treatment regimens are often continued until disease progression. However, it is not clear that continuous cycles of therapy lead to a better long-term outcome than stopping treatment after several months in CR and then resuming when the disease recurs. Second responses to the same drug do occur. Disease progression is characterized by worsening cytopenias, an increase in the percentage of bone marrow blasts, or progression to a more advanced MDS French-American-British (FAB) subtype. Progression is categorized according to the International Working Group (IWG) standardized response criteria for evaluating clinically significant responses in MDS first published in 2000 and modified in 2006 [5,6]:

  • Relapse after complete or partial remission requires at least one of the following: return to pretreatment bone marrow blast percentage, decrement of ≥50 percent from maximum remission/response levels in granulocytes or platelets; reduction in hemoglobin concentration by ≥1.5 g/dL or transfusion dependence.
  • Hematologic progression or relapse after hematologic improvement is defined by at least one of the following: at least 50 percent decrement from maximum response levels in granulocytes or platelets; reduction in hemoglobin by ≥1.5 g/L; or transfusion dependence. In the absence of another explanation such as acute infection, repeated courses of chemotherapy, gastrointestinal bleeding, hemolysis, or other.

TREATMENT OF RECURRENT OR REFRACTORY DISEASE — There is a general lack of effective treatments for the management of recurrent or refractory MDS and patients should be encouraged to participate in clinical trials, whenever available. The importance of enrolling these patients on a clinical trial was illustrated in a retrospective analysis of 435 patients with relapsed or refractory MDS following initial treatment with azacitidine for high-risk MDS or refractory anemia with excess blasts in transformation [7]. After a median follow-up after azacitidine failure of 15 months, the median overall survival was 5.6 months and the overall survival at two years was 15 percent. Patients who underwent allogeneic hematopoietic cell transplantation or were enrolled on a clinical trial appeared to have better outcomes when compared with those treated with conventional care. (See 'Clinical trials' below.)

Outside of a clinical trial, the management of patients with recurrent or refractory MDS is largely dependent upon the patient’s prior therapy. Patients who have not yet been treated with DNA hypomethylating agents (ie, those initially treated with transplantation or immunosuppressive therapy) may be offered a trial of azacitidine or decitabine. There is a paucity of data regarding the use of a DNA hypomethylating agent after the failure of another DNA hypomethylating agent (eg, the use of decitabine after failure of azacitidine or vice versa). Despite their name, it is also unclear whether clinical response to hypomethylating agents parallels the hypomethylation induced by these drugs.

Lenalidomide is not approved by the US Food and Drug Administration for use in MDS without del(5q), however there is some evidence of activity in this setting, although much lower than that seen with del(5q):

The safety and efficacy of lenalidomide were initially tested in a phase I/II trial in patients with MDS (with or without 5q minus) and red cell transfusion-dependent disease or symptomatic anemia, the majority of whom had failed prior treatment with thalidomide and/or erythropoietin [8]. Initial results included:

  • Twenty-one of the 43 evaluable patients (49 percent) had either a >2 g/dL increase in hemoglobin level or became red cell transfusion independent. Increases in platelet count (10 percent of patients) and neutrophils (17 percent of patients) were less frequently noted.
  • Restoration of a normal karyotype was noted in 10 of 20 informative patients and in 9 of 12 with the 5q minus (5q-) syndrome
  • Erythroid response was highest in patients with Low/Int-1 IPSS scores (60 percent) and in those with the 5q- syndrome (83 percent). In the latter patients, hematologic improvement was associated with resolution of megakaryocytic dysplasia on bone marrow examination. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)
  • Dose-dependent myelosuppression was the most common adverse event and required treatment interruption or dose reduction in 58 percent of patients.

A phase II study evaluated lenalidomide treatment in 214 transfusion-dependent patients with low- or intermediate-1 IPSS MDS without the 5q- deletion [9]. Eligible patients had a platelet count ≥50,000/microL and required ≥2 units of red cells within the previous eight weeks. They received either 10 mg/day of lenalidomide or 10 mg/day on days 1 through 21 of a 28-day cycle. Results included:

  • Twenty-six percent of patients (56 of 214) achieved transfusion independence (TI) after a median of 4.8 weeks of treatment. TI continued for a median duration of 41 weeks. The median rise in hemoglobin was 3.2 g/dL (range 1.0 to 9.8 g/dL) for those achieving TI.
  • A ≥50 percent reduction in transfusion requirement was noted in an additional 37 patients (17 percent), yielding an overall rate of hematologic improvement of 43 percent.
  • The most common grade 3/4 adverse events were neutropenia (30 percent) and thrombocytopenia (25 percent). Fifty-five percent of patients required a dose adjustment at a median treatment time of seven weeks. There were no differences in hematologic toxicity between the two treatment schedules.

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov). For interested patients, relatives, and physicians, the Aplastic Anemia and MDS International Foundation maintains a website (www.aamds.org), which contains additional information as well as a listing of clinical trials in this disorder [10].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

  • Immediate treatment is indicated for patients with symptomatic cytopenia (anemia, thrombocytopenia, neutropenia with recurrent infections). Asymptomatic patients with lower risk MDS may be followed expectantly with serial examinations and laboratory studies. Immunizations should be updated and smoking ceased. (See 'Indications for treatment' above.)
  • With the probable exception of lenalidomide in RBC transfusion-dependent patients with deletion 5q and low or intermediate 1 MDS, there is no agreed upon standard treatment approach for patients with symptomatic myelodysplastic syndrome (MDS) and patients should be encouraged to enroll in clinical trials whenever available. Our treatment approach incorporates knowledge of the patient’s performance status, the International Prognostic Scoring System (IPSS) (table 3) (calculator 1) MDS risk category, and other disease characteristics (ie, cytopenias present, serum erythropoietin level) to help guide management decisions. (See 'Selection of initial treatment' above.)
  • Supportive care is an important adjunct to the management of all patients with MDS and can be considered as the sole treatment modality for a subset of patients with lower risk MDS. (See "Management of the complications of the myelodysplastic syndromes".)
  • Patients with a low (0 points) or intermediate-1 (0.5 to 1.0 points) risk IPSS score are primarily treated with supportive care or low intensity therapies such as DNA hypomethylating agents, immunosuppressive therapy, or hematopoietic growth factors (eg, erythropoietin). (See "Treatment of intermediate-1 or low risk myelodysplastic syndromes", section on 'Choice of therapy'.)
  • Patients with an intermediate-2 (1.5 to 2.0 points) or high (2.5 to 3.5 points) risk IPSS score with a good performance status are primarily treated with combination chemotherapy or allogeneic hematopoietic cell transplantation (HCT) in an attempt to alter the disease course. (See "Treatment of intermediate-2 or high risk myelodysplastic syndromes", section on 'Choice of therapy'.)
  • Patients are followed longitudinally to assess disease response to therapy and to monitor for disease progression. Standardized response criteria have been developed that use bone marrow and peripheral blood analysis to allow better comparisons between published studies and to help guide treatment. (See 'Patient follow-up' above.)
  • There is a general lack of effective treatments for the management of recurrent or refractory MDS, and patients should be encouraged to participate in clinical trials. Outside of a clinical trial, the management of patients with recurrent or refractory MDS is largely dependent upon the patient’s prior therapy. Patients who have not yet been treated with DNA hypomethylating agents may be offered a trial of azacitidine or decitabine. (See 'Clinical trials' above and 'Treatment of recurrent or refractory disease' above.)

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