Julianna A. Merten, Kristen B. McCullough, and Mrinal M. Patnaik
Myelodysplastic syndromes (MDS) primarily affect elderly adults, with median age at diagnosis of 76 years.
MDS are associated with environmental, occupational, and therapeutic exposures to chemicals or radiation.
The clonal population of cells manifested as MDS results from enhanced self-renewal of a hematopoietic stem cell or acquisition of self-renewal in a progenitor cell, increased proliferative capacity in the abnormal clone, impaired cell differentiation, evasion of immune regulation, and antiapoptotic mechanisms in the disease-sustaining cell.
Most patients with MDS present with fatigue and lethargy or symptoms related to anemia-induced tissue hypoxia.
The prognosis of patients with MDS is variable. Overall survival time ranges from a few months to several years and can be estimated with the International Prognostic Scoring System (IPSS) or International Prognostic Scoring System—Revised (IPSS-R).
The primary goal of therapy is hematologic improvement for low-risk patients and alteration in the natural course of the disease for high-risk patients. Palliation of symptoms and improvement in quality of life are goals of therapy for all patients.
Current guidelines recommend erythropoietin (EPO) or darbepoetin for management of anemia in patients with MDS.
Hypomethylating agents are appropriate for patients with low-risk and intermediate-1-risk MDS with clinically significant neutropenia or thrombocytopenia, patients with anemia who are unlikely to respond to or have not responded to a trial of EPO, and patients who qualified for and failed immunosuppressive therapy.
Antithymocyte globulin is appropriate treatment for low or intermediate-1 IPSS risk, human leukocyte antigen DR15 positive expressing MDS in patients with symptomatic anemia that is unlikely to respond to erythropoietic agents.
Lenalidomide is the recommended initial treatment for low-risk 5q- syndrome accompanied by symptomatic anemia.
Allogeneic hematopoietic stem cell transplantation offers potentially curative therapy to patients with MDS who have a donor and are healthy enough for the procedure.
Myelodysplastic syndromes (MDS) are clonal, heterogenous, stem cell disorders characterized by predominantly hypercellular bone marrows, anemia, thrombocytopenia, leukopenia, and an inherent predisposition toward evolution to acute myeloid leukemia (AML).1–3 The diagnostic hallmark for MDS is the presence of bone marrow dysplasia in at least 10% of cells of a single myeloid lineage.3 The clinical course of patients with MDS varies from a slowly progressing indolent disease to more aggressive disease characterized by excess bone marrow blasts and rapid progression to AML.4
Our understanding of MDS and the available treatment options have advanced in recent years. Based on new scientific and clinical information, the World Health Organization (WHO) revised its classification system in 2008 to refine diagnostic criteria and the subcategorization of MDS.1 Genetic aberrations in hematopoietic transcription factors, methylation regulators, spliceosome components, and tumor suppressor genes have redefined the molecular landscape in MDS and have been incorporated into prognostic models predicting survival and leukemic transformation.5–7 Between 2004 and 2006, three medications (azacitidine, decitabine, and lenalidomide) were approved by the FDA for the treatment of MDS. In 2009, the first randomized controlled clinical trial that showed a survival advantage for a therapeutic intervention in MDS was published, and several more randomized trials have been published or are ongoing.8 The change in classification of MDS, improvement in risk stratification, and development of new treatment options represent important steps forward in MDS.
MDS primarily affect elderly adults, with a median age at diagnosis of 76 years and a male predominance, with an estimated male-to-female ratio of about 1.75 to 1.9,10 Overall, an estimated 3 to 12 cases of MDS are diagnosed per 100,000 persons per year. The incidence of MDS increases with age; in patients older than 65 to 70 years, an estimated 27 to 75 new cases occur per 100,000 persons per year.11,12The Surveillance, Epidemiology and End Results (SEER) Program estimates about 19,600 new cases of MDS are diagnosed in the United States each year.10 Recent reports suggest that the incidence of MDS has been grossly underestimated, with an analysis of a Medicare claims database indicating it could be as high as 45,000 per year.12 Many experts predict that the incidence of MDS will increase as the population of the United States ages and clinicians become more aware of MDS.9
The exact cause of MDS is unknown and is probably multifactorial. MDS have been associated with environmental, occupational, and therapeutic exposures to chemicals or radiation.13 Environmental exposure to agricultural chemicals has been associated with an increased risk of developing MDS.13,14 MDS have also been linked in a dose-dependent relationship to ionizing radiation in atomic bomb survivors in Japan and have been reported in workers in the Chernobyl nuclear accident.15 Occupational exposures to hair dyes, cereal dusts, exhaust gases, diesel fuel, and industrial solvents (including benzene and toluene) have been associated with development of MDS.13,14Individuals with a family history of a hematologic malignancy are at increased risk for developing MDS.13,14 Modifiable risk factors for MDS include smoking and obesity.16 Recent data suggest that chronic immune stimulation or therapy to manage infectious and autoimmune diseases increases the risk for development of MDS.17
About 10% to 15% of all cases of MDS are attributed to radiation, chemotherapy, or both and are termed therapy-related MDS (t-MDS).18–20 More aggressive chemotherapy regimens and improved survival after cancer treatment are contributing to an increased incidence of t-MDS.20,21 t-MDS have an increased likelihood of progression to AML and a poorer prognosis than de novo MDS.19,20,22 Chromosomal abnormalities are found in about 90% of t-MDS compared with 50% to 60% of de novo MDS.23–25
The risk for developing t-MDS increases with age, higher doses of chemotherapy or radiation, longer duration of exposure, and exposure to both chemotherapy and radiation.14,22,23 Several chemotherapeutic agents have been associated with t-MDS (Table 114-1). The contribution of a specific agent is difficult to assess because patients are usually exposed to multiple agents, often in combination with radiation.22The most frequently reported classes of chemotherapeutic agents associated with t-MDS are alkylating agents and topoisomerase II inhibitors.18,19,23,24
TABLE 114-1 Therapies Associated with Therapy-Related Myelodysplastic Syndrome
The role of alkylating agents in the development of t-MDS is well established in patients with cancer and those receiving high cumulative doses of alkylating agents for autoimmune disorders such as rheumatoid arthritis.14,18,24The latency period between exposure to alkylating agents and the development of t-MDS is about 4 to 7 years. Characteristic chromosomal abnormalities in t-MDS associated with alkylating agents include deletions on chromosome 5 and chromosome 7.18
Topoisomerase II inhibitors, including the epipodophyllotoxins (etoposide and teniposide), anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin), and the anthracenedione mitoxantrone, are also associated with t-MDS. t-MDS associated with topoisomerase II inhibitors typically occurs a median of 2 to 3 years after exposure, and patients are more likely to present with AML at diagnosis.14Chromosomal abnormalities often found in patients with t-MDS associated with topoisomerase II inhibitors include balanced translocations involving the MLL gene 11q23 and 21q22.18
Radioimmunoconjugates, including ibritumomab tiuxetan and iodine-131 tositumomab, are monoclonal antibodies linked to radioactive isotopes. Radiation is delivered to the antibody-bound targeted cell and to neighboring cells through a “cross-fire” effect. t-MDS or AML is reported to occur in 5% to 10% of patients exposed to iodine-131 tositumomab and in 1% to 5% of patients exposed to ibritumomab tiuxetan.26–30 About 8% of patients receiving myeloablative doses of ibritumomab tiuxetan as conditioning regimen before hematopoietic stem cell transplantation (HSCT) developed t-MDS or AML, similar to the rate in patients receiving myeloablative chemotherapy-based conditioning regimens.31 Both agents are used to treat non-Hodgkin lymphoma, a patient population likely to receive other therapies associated with t-MDS, including alkylating agents, anthracyclines, and radiation. Therefore, it is difficult to determine the additional risk for t-MDS due solely to exposure to one of these agents.26,28,30
Granulocyte colony-stimulating factor (G-CSF) use during treatment of solid tumors and lymphoma in adults has been associated with an increased risk for t-MDS.32 A systematic review of 25 randomized controlled trials comparing patients receiving filgrastim or lenograstim with placebo found an absolute risk increase of 0.41% for development of t-MDS or AML associated with use of a colony-stimulating factor.32 The absolute risk of death was 3.4% lower in the group of patients randomized to a hematopoietic growth factor; the benefit was attributed to lower cancer-related mortality because of a greater chemotherapy dose intensity. This systematic review indicates the administration of hematopoietic growth factors to prevent complications associated with febrile neutropenia outweighs the increased t-MDS risk.21 The risk of development of t-MDS may also be higher in patients with congenital neutropenia and aplastic anemia treated with long-term G-CSF.18,33,34
Patients undergoing autologous HSCT are at increased risk for development of t-MDS. Conditioning regimens given before HSCT usually include high doses of alkylating agents or etoposide, often in combination with total-body irradiation. As many as 8% to 20% of patients with non-Hodgkin lymphoma treated with autologous HSCT will be diagnosed with t-MDS within 10 years of transplantation.35–37Risk factors for development of t-MDS after autologous HSCT include antecedent conventional chemotherapy, prior radiation therapy, low stem cell dose, older age at time of transplant, and use of total-body irradiation in the conditioning regimen.35,36,38
Knowledge of normal hematopoiesis is needed to understand the pathophysiology of MDS (see eChap. 20 for a more detailed description of hematopoiesis). Progressive bone marrow failure is characteristic of patients with MDS and is the result of ineffective hematopoiesis. In addition to peripheral blood cytopenias, the terminally differentiated cells that are produced may have functional defects. Neutrophils may have reduced bactericidal and fungicidal activity despite a normal quantity of neutrophils.39 Platelets may be normal in quantity but have impaired activation, secretion, and aggregation.40The diverse pathophysiology underlying MDS causes the heterogeneity in clinical presentation, pattern of disease progression, and response to therapy and has not been fully elucidated.41 A multistep model for the pathogenesis of MDS has been proposed, and it is likely that the disease can arise via multiple different pathways.3,13,41 The clonal population of cells manifested as MDS results from enhanced self-renewal of a hematopoietic stem cell or acquisition of self-renewal in a progenitor cell, increased proliferative capacity in the abnormal clone, impaired cell differentiation, evasion of immune regulation, and antiapoptotic mechanisms in the disease-sustaining cell.41 The abnormal clone proliferates or evades apoptosis because of genomic instability and abnormalities in cytokines and the bone marrow stroma.3,41These changes create a dysplastic, clonal population of cells in a milieu unable to support normal hematopoiesis.
Bone Marrow Microenvironment
The myelodysplastic clone is associated with cellular dysfunction, including excess secretion of cytokines, defective differentiation, genomic instability, and reduced response to regulatory cytokines.3 In contrast to the peripheral blood cytopenias characteristic of MDS, bone marrow cells often have a paradoxically high rate of cellular division. Apoptosis, or programmed cell death, also is increased, leading to futile cycling of precursor cells and impaired production of mature peripheral blood cells.13 Overproduction of proapoptotic and inflammatory cytokines and vascular endothelial growth factor may contribute to this process.41 Bone marrow stromal cells from MDS patients show decreased ability to support normal hematopoietic cell function.13
Patients with MDS frequently have evidence of immune dysregulation, such as impaired immune surveillance and autoimmune reactions.3 Cytopenias can be related to an autoimmune T-cell–mediated response. A subset of MDS patients characterized by younger age, refractory anemia of short duration, a hypocellular bone marrow, trisomy 8 as the sole cytogenetic abnormality, and expression of human leukocyte antigen (HLA) haplotype DR15 have a high likelihood of response to immunosuppressive therapy.13,41 Immunosuppressive therapy with cyclosporine and antithymocyte globulin may induce durable responses in this subgroup of patients, confirming the role of immune dysregulation.3 Whether B cells and T cells are a part of the MDS clonal population or a secondary reaction after the development of the malignant clone is unclear.13
In the multistep model for development of MDS, one or more transformations occur that confer a growth advantage to the dysplastic cell, leading to the emergence of a clonal population.41 The inciting transformations in genetic material have not been identified. Chromosomal abnormalities, most often genomic losses and gains, are detected by cytogenetic analysis in about 50% of patients with de novo MDS and remain one of the strongest determinants of prognosis.4,20,25,42–44 Multiple cytogenetic abnormalities that correlate with the clinical course of MDS were incorporated in the original International Prognostic Scoring System (IPSS) classification and prognostic assessment, including 5q or 20q deletions and chromosome 7 abnormalities.4 The newly revised IPSS classification (International Prognostic Scoring System–Revised [IPSS-R]) includes several additional cytogenetic abnormalities, including trisomy 8 or 19, 12p or 11q deletions, and double abnormalities, that correlate with the clinical course of MDS.7 Deletions on chromosome 5q occur in up to 12% of patients and are of particular interest because multiple genes involved in hematopoiesis are located there.25 Additionally, MDS with 5q deletions as the sole genetic aberration are recognized as a distinct subtype of MDS with a favorable prognosis and a high likelihood of response to lenalidomide.25,45
High-resolution single nucleotide polymorphism array, a new type of karyotypic analysis that can detect molecular abnormalities that are too minute for traditional metaphase cytogenetics, has shown independent prognostic value for MDS.6,46 One of the most frequently occurring molecular alterations, seen in 22% to 26% of MDS patients, is alteration of TET2 protein thought to be responsible for passive DNA methylation. Mutation in TET2 has been identified as a favorable prognostic factor, although results were not confirmed in larger confirmatory studies.47–49 Transformations in additional tumor suppressor genes, transcription factors, and cell cycle regulators such as ASXL1, RUNX1, EZH2, DNMT3A, and several others are also thought to provide the dysplastic stem cell with a growth advantage and offer additional prognostic insight.50
In addition to changes detected on chromosomal analysis, several transformations have been identified that may contribute to myelodysplasia that do not result from alteration of the nucleic acid sequence in DNA. The term epigenetics refers to mechanisms that regulate the expression of DNA without affecting its sequence. Epigenetic changes have been identified in numerous malignancies and are of particular importance in the context of MDS.51
DNA methylation is the best described and most common epigenetic marker. In the mammalian genome, only cytosine located 5′ to a guanosine (CpG) can be methylated (CpG pair). Clusters of CpG pairs, known as CpG islands, are near the promoter regions for many genes. These regions are unmethylated in normal cells, allowing for standard DNA expression to occur.51 Increased methylation (hypermethylation) of CpG islands occurs via DNA methyltransferase and is associated with aberrant gene silencing, which may lead to further genetic instability and dysfunction of the cell cycle. Decreased methylation (hypomethylation) may lead to reexpression of previously silenced genes.51 Hypermethylation and gene silencing have been identified in patients with MDS, and azacitidine and decitabine reverse this process.51,52
Histone acetylation, a second epigenetic marker, is also gaining significance in MDS.53 Histones coil with DNA to form tightly wound complexes called chromatin. Posttranslational modifications of histones, by acetylation or deacetylation, can alter the structure of chromatin creating opportunities for gene suppression or expression, depending on the structural change of the chromatin.53 Histone hypoacetylation has been documented in malignant cells and several histone deacetylase inhibitors have been studied in patients with MDS as monotherapy or in combination with hypomethylating agents in an attempt to promote histone acetylation and expression of previously suppressed tumor suppressor genes.54,55
CLASSIFICATION AND PROGNOSIS
Several classification systems and models for predicting risk in MDS have been developed. The French-American-British (FAB) and WHO are classification schemes for MDS. The FAB classification established subgroups of MDS based on morphology of bone marrow aspirates and peripheral blood blast percentage.14 In the 2008 WHO classification system, MDS are categorized based on bone marrow and peripheral blood blast percentage, cytogenetics, and whether dysplasia or cytopenias affect a single cell lineage or multiple myeloid cell lines (Table 114-2).56 The most significant changes in the WHO classification compared with the FAB classification include the following: patients with a single cell lineage affected are separated from those with multiple myeloid cell lines affected, patients with greater than 20% blasts in the marrow are now considered to have acute leukemia, patients with deletion on chromosome 5 are now in a distinct category, and chronic myelomonocytic leukemia is classified as a myelodysplastic/myeloproliferative disorder. Two studies showed the ability of the WHO classification to identify patient subgroups with differences in survival and responses to erythropoietin (EPO) and filgrastim. Patients with refractory anemia or refractory anemia with ringed sideroblasts (RARS) had prolonged overall and leukemia-free survival and improved response to therapy compared with those with refractory cytopenia with multilineage dysplasia or refractory anemia with excessive blasts.57 This classification scheme may help predict the prognosis of MDS, but it has not been shown to predict response to a given therapy.
TABLE 114-2 World Health Organization Classification of Myelodysplastic Syndromes
CLINICAL PRESENTATION AND DIAGNOSIS Myelodysplastic Syndromes
• Patients with MDS may develop isolated anemia (hemoglobin <11 g/dL), neutropenia (<1,500 cells/mm3), or thrombocytopenia (<100 × 109/L) or multiple peripheral cytopenias.
• Patients may be asymptomatic, with cytopenia(s) discovered on complete blood count with differential.
• If symptomatic, the patient may report fatigue, lethargy, malaise, palpitations, dyspnea on exertion, or other symptoms associated with hypoxia secondary to anemia.
• Patients may have symptoms of infection, including cough or dysuria.
• Patients may present with complaints of easy bruising or bleeding.
• Pallor, tachycardia, or tachypnea related to anemia
• Fever, chills, rigors caused by infection and immune dysfunction
• Petechiae, bruising, epistaxis, gingival bleeding, excessive vaginal bleeding, bruising, or hematuria caused by thrombocytopenia
• Complete blood count with differential
• Anemia often is macrocytic or normocytic with a low reticulocyte index
• Serum vitamin B12, red blood cell (RBC) folate and copper levels
• Testing for the human immunodeficiency virus (HIV)
• Serum thyroid-stimulating hormone
• Serum EPO level
• Serum ferritin, iron, and total iron-binding capacity
Other Diagnostic Tests
• Bone marrow biopsy and aspirate: send for morphologic examination, cytochemical staining, immunophenotyping, and cytogenetics (chromosome analysis).
• Repeat bone marrow biopsy of patients with MDS often is required because dysplastic features may progress over time or the bone marrow may be unevenly distributed.
Criteria for Diagnosis
• Stable cytopenia for at least 6 months (2 months if accompanied by a specific karyotype associated with MDS or bilineage dysplasia)
• Exclusion of other causes of cytopenia or dysplasia
• One of the following:
1. Dysplasia (>10% in one or more of three major bone marrow lineages)
2. Blast cell count of 5% to 19%
3. Specific MDS-associated karyotype (e.g., del(5q), del(20q), +8, or del(7q))
Data from Tefferi and Vardiman,3 Faderl and Kantarjian,14Valent et al.,161and The NCCN Clinical Practice Guidelines in Oncology™.61
Models to predict overall survival and risk of transformation to AML continue to be developed and refined as new information about the genetic basis of MDS evolves. The IPSS is still used in clinical trials and continues to guide therapy as newer models are developed and validated.3,5 Based on an observational study of mostly untreated MDS patients, the IPSS was developed to identify factors that would predict progression of MDS.4Multivariate analyses identified four prognostic factors: cytogenetic abnormalities, percentage of bone marrow blasts, age, and number of cytopenias. Using these four factors, researchers were able to stratify patients into four risk groups that correlated with overall survival, which ranged from a few months to several years (Table 114-3).
TABLE 114-3 International Prognostic Scoring System for Myelodysplastic Syndromes
The IPSS-R was developed after analysis of more than 7,000 patients whose disease had not been treated with disease-altering therapy (Table 114-4).7 This model differs from the IPSS by identifying five risk categories by incorporating different categories for marrow blast percentage value and depth of cytopenias, expanding the cytogenetic risk groups from three to five groups and including a number of less common cytogenetic abnormalities. Patient age, performance status, and serum ferritin and lactate dehydrogenase levels were additional significant predictors for survival but not for AML transformation. Recent reports have demonstrated that recurrent somatic gene mutations predict prognosis independent of the IPSS score, and their incorporation into a risk classification scheme does enhance the model.6,58About half of patients with MDS have normal cytogenetics; therefore, after the full spectrum of somatic mutations in MDS has been defined, optimal prognostic scoring systems will need to include relevant molecular features. No single method of predicting risk of disease progression, overall survival, or response to therapy has been universally adopted.5 The risk prognostic schemas are derived from patients with primary, untreated MDS and may not be applicable to patients who have t-MDS, those who received disease-modifying therapy, or those who have undergone karyotypic evolution in the course of their disease.
TABLE 114-4 International Prognostic Scoring System—Revised for Myelodysplastic Syndromesa
Several MDS risk scoring systems have been proposed in the past few years. The optimal method to predict overall survival, progression to AML, and likelihood of response to therapy continues to be debated.
Currently, the FAB classification is used for coding and billing purposes, for drug indication languages approved by regulatory agencies, and for some clinical trial inclusion or evaluation criteria.5 The WHO criteria are used by pathologists to describe MDS and in both clinical trial and off-study management of patients with MDS. The IPSS is the most widely used prognostic scoring system for MDS patients enrolling in clinical trials and is used to guide therapy in the United States.3,5 The IPSS-R will likely be adopted by most centers until the role of molecular information in the prognosis of MDS is better defined.59
Treatment of MDS has rapidly evolved during the last decade following discoveries in disease biology, introduction of new methods for predicting the natural history of the disease and response to a given therapy, and development of new treatment strategies (Fig. 114-1).
FIGURE 114-1 Myelodysplastic syndromes treatment algorithm. (HSCT, hematopoietic stem cell transplant; IPSS, International Prognostic Scoring System.)
The goals of treatment vary with disease-specific factors, including the type of MDS; cytogenetics; risk of progression to AML and death; rate of disease progression; and patient factors, including age, organ function, performance status, and presence of symptoms related to myelodysplasia.60 The primary goal of therapy is hematologic improvement for low-risk patients and alteration in the natural course of the disease for high-risk patients.61Additional critical goals for all risk groups include symptom palliation and quality-of-life improvement. Lower-intensity treatment with a DNA hypomethylating agent or immunosuppressive therapy may improve overall survival, provide symptom palliation, and enhance quality of life without significant toxicity.8,60,61 The only curative therapy for MDS is allogeneic HSCT, but most patients lack a suitable donor, are not healthy enough to undergo this intensive therapy, or may not be referred for HSCT because of advanced biologic age despite adequate health and organ function.3,62
Therapy for MDS is determined by symptoms, IPSS risk for progression to AML or death, patient age and comorbidities, likelihood of response to a given therapy and its effects on quality of life, and patients’ treatment preferences.2Patients with extensive, life-limiting comorbidities or who are asymptomatic at diagnosis may warrant supportive care alone.2 About 30% to 60% of patients with MDS receive supportive care alone.25,63 Lower-risk patients are thought to have better prognoses, and thus less toxic therapies are used to manage MDS, including EPO, darbepoetin, lenalidomide, or DNA hypomethylating agents. Patients with intermediate-2 and high IPSS risk MDS have poorer prognoses and may be candidates for allogeneic HSCT; patients who are not HSCT candidates may benefit from a DNA hypomethylating agent.8,61 As outcomes of therapeutic interventions for all risk categories are identified and genetic markers increase the ability of clinicians to stratify patients into even more specific risk categories, the line between therapies for high- and low-risk patients has been blurred.20 Clinicians should recognize that the clinical course of MDS is not static. MDS may progress; comorbidities or symptoms may change over time along with the ability to create more personalized medicine, necessitating an adjustment in treatment strategy. Therapy for MDS is generally palliative, and enrollment in a suitable clinical trial is always a viable approach.2,64
Careful interpretation is necessary when comparing the results of clinical trials in MDS because patient characteristics and response criteria vary widely. Described previously, the clinical course and prognosis are affected by patient-specific characteristics.4,65 Examples of different response criteria used include changes in hemoglobin, changes in RBC transfusion requirements, or effects on quality of life.60 The use of RBC transfusion requirement as a primary end point is especially problematic because decisions concerning RBC transfusion needs are highly individualized and may not be consistent among clinicians. Additionally, the relationship between changes in hemoglobin or decreases in RBC transfusion requirements and improved quality of life is not clear. Some treatments for MDS can cause significant adverse effects, resulting in hospitalization or increased clinic visits, and may negatively impact quality of life regardless of their positive effects on hematologic parameters. The impact of treatment on quality of life is an important consideration when selecting therapy and should be assessed regularly with the use of validated instruments.
All patients with MDS should receive supportive care, including clinical monitoring, psychosocial support, and quality-of-life assessment.61 The National Comprehensive Cancer Network (NCCN) guidelines recommend that patients with symptomatic anemia should receive leukoreduced RBC transfusions, and those with bleeding caused by thrombocytopenia or platelet counts below 10,000 cells/mm3 (10 × 109/L) should receive platelet transfusions.61Hematopoietic growth factor support should be considered in patients with refractory, symptomatic cytopenias. Patients with evidence of infection should have an appropriate diagnostic evaluation based on history and physical examination followed by appropriate antimicrobial therapy. Routine antimicrobial or hematopoietic growth factor prophylaxis is not recommended in the absence of repeated infections. Iron chelation may be considered in low-risk and intermediate-1-risk patients and candidates for allogeneic HSCT who have received more than 20 to 30 RBC transfusions and are expected to continue to require transfusions.61
Patients with MDS may be neutropenic or have functional defects in neutrophils, predisposing them to infection.39 In MDS, the most frequently isolated organisms are bacteria, and the most common sites of infection are the lungs, urinary tract, and bloodstream.66 Patients with evidence of infection should have appropriate diagnostic evaluation based on history and physical examination and then appropriate antimicrobial therapy. Neutropenic patients with evidence of infection or fever of unknown origin should receive empiric broad-spectrum, IV antibiotics.67
Hematopoietic Growth Factors
Filgrastim (G-CSF) and sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) are colony-stimulating factors that stimulate white blood cell production and may increase circulating neutrophils in 70% to 90% of patients, which may decrease risk of infection.68 These agents have not been shown to be beneficial as chronic monotherapy because they do not reliably prevent infection and have no impact on survival.68 G-CSF or GM-CSF should only be administered temporarily as monotherapy in the rare neutropenic MDS patient who develops recurrent severe infections.2,3
EPO is a protein produced by the kidney in response to hypoxia that stimulates proliferation and differentiation of erythroid cells. Anemic patients with MDS may have either a lower than expected endogenous serum EPO level relative to the degree of anemia present or an elevated EPO level. The mechanism of action of recombinant erythropoiesis-stimulating agents (ESAs) in MDS is not clear, but exogenous EPO may stimulate a normal clone of cells that is unresponsive to low endogenous levels of EPO, stimulate a dysplastic clone to differentiate that is less responsive to endogenous EPO, or induce apoptosis. An immunomodulatory effect of EPO, G-CSF, or GM-CSF has been proposed.
Current guidelines recommend use of ESAs for management of anemia in patients with MDS.61,69 Unlike some solid tumors,70 no detrimental effects on overall survival or progression to leukemia have been noted in patients with MDS. Treatment with ESAs alone may result in hematologic improvement and transfusion independence in low- and intermediate-1 IPSS risk patients. Two meta-analyses have evaluated the efficacy of ESAs in MDS. The first analysis, which included 2,106 patients from 59 studies reported between 1990 and 2005, found a hemoglobin response of about 30% based on the definition of hemoglobin response in the original publication.71 A subsequent meta-analysis only included studies from 1990 to 2006 that reported results by International Working Group (IWG) criteria60 to define erythroid response (an increase in hemoglobin of 2 g/dL [1.24 mmol/L] or transfusion independence). This report included 30 studies with 925 patients with MDS and found an overall erythroid response rate of 58% in patients receiving ESAs.72 The latter report also suggests that EPO and darbepoetin can be used interchangeably for the management of MDS based on similar response rates achieved. The higher response rate compared with the previous meta-analysis likely reflects inclusion of a higher proportion of patients most likely to respond to ESAs. Patients with low- and intermediate-1 IPSS risk MDS who have a serum EPO level less than 500 mU/mL (500 IU/L) and a history of receiving fewer than 2 units of RBC transfusions per month have the best chance at responding to ESAs.2,73 The doses required to achieve a response in MDS are higher than those used to treat renal causes of anemia, with EPO doses in the range from 40,000 to 60,000 units subcutaneously two to three times per week.61Darbepoetin doses ranging from 100 to 300 mcg subcutaneously weekly or every other week have also been used for MDS management.2,72 Doses should be titrated up or down, as clinically indicated, to achieve a hemoglobin level of 10 to 12 g/dL (6.2 to 7.44 mmol/L).74 Additionally, patients should receive at least 8 weeks of therapy before doses are adjusted or before patients are considered nonresponders because response to ESAs in MDS can be delayed.2,61 The median response duration for ESAs in MDS is 1 to 2 years, and the ESA should be discontinued if there is no benefit or the response wanes.2
Several trials have evaluated if adding G-CSF to ESAs can enhance the hematologic response, and the conclusions have been inconsistent. Long-term follow-up of 121 patients from three uncontrolled phase II studies was retrospectively compared with that of 237 untreated patients who were matched for FAB classification, hemoglobin, and transfusion needs.75 A 39% major erythroid response rate by IWG criteria was demonstrated in the EPO plus G-CSF cohort. The median doses required to maintain a stable response were subcutaneous EPO 30,000 units/wk and G-CSF 225 mcg/wk.76 In a multivariate analysis, the EPO plus G-CSF group was associated with improved overall survival (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.44 to 0.83), and decreased risk of nonleukemic death (HR, 0.66; 95% CI, 0.44 to 0.99) compared with the untreated group.75 Retrospective data in 433 patients with MDS treated with EPO or darbepoetin, with or without filgrastim, reported a 50% response rate by IWG 2006 criteria.77 Predictors of response included low- and intermediate-1 IPSS risk, RBC transfusion independence, serum EPO level below 200 mU/mL (200 IU/L), and shorter interval between diagnosis and treatment. The addition of G-CSF was not significantly associated with response. A large phase III, randomized controlled trial of ESAs in MDS with long-term follow-up compared EPO with or without G-CSF to best supportive care in 110 patients.78 At 4 months, 34% of patients receiving EPO had an erythroid response by IWG 2006 criteria compared with 5.8% of patients receiving placebo. A total of 47% of patients had a major erythroid response when EPO doses were escalated or filgrastim was added. Patients with RARS were most likely to respond to the addition of filgrastim. No difference in overall survival or leukemic evolution was observed between patients receiving EPO compared with best supportive care after a median follow-up period of 5.8 years; the study was not prospectively powered to determine differences in these outcomes. To further support the results of this study, a meta-analysis of 15 published trials was performed to compare the erythroid response in patients who received EPO as a single agent with those who received EPO plus G-CSF or GM-CSF.79 The overall erythroid response was 49%, 50.6%, and 64.5% for patients who received standard EPO (30,000 to 40,000 units/wk), standard EPO plus G-CSF or GM-CSF, or high-dose EPO (60,000 to 80,000 units/wk), respectively. The authors concluded that higher doses of single agent EPO are more effective than standard doses alone or in combination with G-CSF or GM-CSF. However, a significantly higher proportion of transfusion-dependent patients were enrolled in the trials using combination therapy compared with the other two treatment groups that could have negatively impacted the outcomes.
Some, but not all, studies have shown that patients who respond to ESAs have improvements in quality of life.78 The value of this costly intervention has not been proven, and long-term safety has not been evaluated in randomized controlled trials.80 Although EPO, with or without G-CSF, does not improve overall survival, it does not shorten overall survival or time to development of leukemia and may decrease the need for RBC transfusions and improve quality of life. ESA therapy is well tolerated, and the NCCN recommends a trial in low- and intermediate-1 IPSS risk patients who have a serum EPO level less than 500 mU/mL (500 IU/L) and a limited transfusion history.61
Thrombopoietin is a hormone synthesized in the liver and secreted into the systemic circulation, where it binds to thrombopoietin receptors on stem cells, progenitor cells, and platelets, resulting in increased platelet production. Romiplostim and eltrombopag are novel drugs that stimulate the thrombopoietin receptor similarly to endogenous thrombopoietin, and are currently FDA approved for patients with chronic idiopathic thrombocytopenic purpura. Two small phase II open-label trials evaluating romiplostim in patients with low- and intermediate-1-risk MDS with platelets less than 50,000 cells/mm3 (50 × 109/L) resulted in durable platelet responses in 30% to 46% of patients by IWG 2000 criteria.81,82 Four of 45 patients developed a transient increase in the proportion of bone marrow blasts, and 2 patients developed AML in one of the studies81; in the other study 2 of 28 patients developed progression to AML.82 A randomized, placebo-controlled trial evaluating romiplostim to manage thrombocytopenia in MDS was stopped early in 2011 because of data safety monitoring committee concerns regarding the potential for transient increases in blast cell counts and the risk for progression to AML; 15% of romiplostim patients developed greater than 10% blasts compared with 3.6% of placebo patients.83 Preliminary results of continued follow-up of this cohort of patients indicate a similar risk for progression to AML and similar overall survival between romiplostim and placebo patients.84 Romiplostim is also being combined with a DNA hypomethylating agent or lenalidomide in three separate randomized phase II studies to determine its ability to prevent clinically significant thrombocytopenia caused by these agents.85–87 Preliminary data suggest that romiplostim is safe and possibly beneficial when combined with a DNA hypomethylating agent or lenalidomide, but further evaluation is necessary before any conclusions can be drawn about the use of romiplostim in patients with MDS. Eltrombopag is potentially advantageous over romiplostim because it is orally administered. An ongoing phase II trial of eltrombopag administration for management of MDS-related thrombocytopenia will determine its feasibility for use in this patient population. Preliminary results in 17 patients indicate it is safe, is able to increase platelet counts and reduce platelet transfusions, and may improve quality of life.88 The NCCN guidelines do not address use of thrombopoietin-stimulating agents in patients with MDS. Patients should only receive thrombopoietin-stimulating agents under the auspices of a clinical trial until further knowledge is gained about the risk of accelerating the progression to AML.
Patients generally receive RBC transfusions when they develop signs or symptoms of anemia, including tachycardia, fatigue, or dyspnea, which generally occur when hemoglobin drops below 8 to 10 g/dL (4.96 to 6.2 mmol/L).61,89,90 Some clinicians use a transfusion threshold of 10 g/dL (6.2 mmol/L) in patients with significant cardiovascular disease.91 Platelet transfusion is generally reserved for patients with evidence of bleeding to avoid alloimmunization from repeated platelet transfusions, which leads to refractoriness to donor platelets.89,91
RBC transfusions are associated with shortened leukemia-free and overall survival times in MDS.57,92 It is unclear if this reflects disease severity or is a direct result of iron toxicity.3,93 Recent data indicate MDS patients receiving RBC transfusions more frequently develop infections, cardiac, hepatic, and endocrine dysfunction compared with nontransfused MDS patients or the general population without MDS.12,94 Prospective clinical trials in MDS demonstrate that iron chelation is able to decrease markers of iron overload.95–99 Two studies suggest that patients receiving iron chelation experience hematologic improvement during iron chelation therapy in the absence of other therapy to treat MDS, and three studies suggest iron chelation may improve overall survival.97,98,100–102 In a retrospective study of 18 low- or intermediate-1-risk patients, deferoxamine was associated with improved overall survival compared with matched control participants not receiving iron chelation therapy; the median overall survival time was not reached at 226 months in the deferoxamine group versus 40 months in the control group.100 A prospective cohort of low- or intermediate-1 -risk patients received iron chelation (n = 53) or no iron chelation (n = 44) and was shown to have a median overall survival time of 124 months versus 53 months in nonchelated patients.101 A survival advantage persisted after adjustment for IPSS, age, World Health Organization Classification-based Scoring System (WPSS), level of transfusion requirement, and number of comorbidities. Neukirchen et al. conducted a retrospective, matched-pair analysis of registry data for 94 MDS patients undergoing long-term iron chelation therapy and 94 matched partners in the Düsseldorf MDS Registry; 83% of patients had low- or intermediate-1-risk MDS.102 Patients received supportive care, including growth factors, but no other therapy for MDS other than iron chelation. Median survival time in the iron chelation group was 74 months versus 49 months in the supportive care alone group. It is unclear if the apparent survival benefit with iron chelation is truly a result of reducing iron overload or if confounding factors contributed to these results.103 Preliminary results of a cohort of Medicare beneficiaries with MDS indicate longer duration of deferasirox use correlated with improved overall survival times, but deferasirox was not found to be associated with altered risk of heart failure or endocrine or renal disease.104 It is hypothesized that iron chelation may lower infection risk, improve the outcome of allogeneic HSCT, and delay leukemic transformation in patients with MDS.93 A prospective, randomized trial comparing deferasirox with placebo in low- and intermediate-1-risk MDS patients with transfusional iron overload with a primary outcome of event-free survival is ongoing (registered at www.clinicaltrials.gov; NCT00940602).
The potential toxicity, expense, and benefits of iron chelation should be carefully considered before initiating therapy.103 Deferasirox and deferoxamine are FDA approved for use in patients with chronic iron overload caused by RBC transfusions. Deferiprone is FDA approved for patients with transfusional iron overload secondary to thalassemia when current chelation therapy is inadequate. The prescribing information for deferiprone has a black box warning regarding agranulocytosis, which may lead to serious infection and death. The prescribing information for deferasirox has a black box warning describing renal and hepatic impairment and GI hemorrhage; fatalities were reported. These reactions were more frequently observed in patients with advanced age, high-risk MDS, underlying renal or hepatic impairment, or thrombocytopenia (<50,000 cells/mm3 [50 × 109/L]).
Initiation of iron chelation in patients with MDS is controversial because controlled trials of iron chelation have not been completed. It is unclear if iron chelation will impact the natural history of MDS despite the anticipated prevention or reversal of end-organ damage associated with iron overload.159,160 Even though no prospective, randomized controlled trials have been completed, eight different clinical practice guidelines have been published regarding iron chelation in MDS.159 These guidelines differ on whether or not to initiate chelation and at what threshold; which agent, dose, and duration to use; and how to monitor for the efficacy and toxicity of iron chelation.
Many clinicians recommend iron chelation be initiated after 20 to 30 RBC transfusions are administered or when serum ferritin levels exceed 1,000 to 2,500 ng/mL (1,000 to 2,500 mcg/L) in patients with low- or intermediate-1-risk MDS who have an anticipated survival of at least 1 year or in patients proceeding to allogeneic HSCT.61,90,91,105–107 Patients receiving pharmacotherapy for iron chelation should be monitored for ocular toxicity, ototoxicity due to renal and hepatic dysfunction, and complete blood counts in addition to markers of iron overload.106
Pharmacotherapy of MDS is intended to change the natural history of MDS. Table 114-5 lists the responses reported in selected clinical trials of non-HSCT therapies. DNA hypomethylating agents may prolong overall survival, yet allogeneic HSCT remains the only curative option for patients. Because most patients with MDS are not candidates for HSCT, less toxic therapeutic modalities are being evaluated in an attempt to improve quality of life and disease-free survival.
TABLE 114-5 Results from Pivotal Trials of Low-Intensity Treatment for Myelodysplastic Syndromes
Immunosuppressive agents that modulate T cells, including corticosteroids, antithymocyte globulin, and cyclosporine, have been evaluated in patients with MDS. Clinically significant adverse events and low response rates have limited the widespread use of corticosteroids as a therapeutic option for MDS, but antithymocyte globulin and cyclosporine continue to be studied alone and in combination for the treatment of patients with low-risk MDS.108
Antithymocyte globulin has been investigated primarily in patients with intermediate-1-risk and low-risk MDS. Treatment with antithymocyte globulin may not be beneficial for all patients because of the potential for infectious complications, serum sickness, and variations in response. Most studies have used equine antithymocyte globulin at a dose of 40 mg/kg/day IV for 4 consecutive days with corticosteroids to prevent serum sickness.109,110 Responses generally occur within 8 months, and about one third of previously transfusion-dependent patients achieve durable transfusion independence.109,110Rabbit antithymocyte globulin has also been evaluated in daily doses ranging from 3.5 to 3.75 mg/kg administered IV for 5 days.111,112 Response rates, although modest, appear to be similar and treatment with either horse or rabbit antithymocyte globulin is reasonable. Patient factors associated with response to immunosuppressive therapy include age younger than 60 years, hypocellular marrow, refractory anemia of short duration, trisomy 8 as the sole cytogenetic abnormality, and HLA DR15 positive expression.41,113 A recent retrospective evaluation of patients enrolled on clinical trials at the National Institutes of Health demonstrated that the combination of equine antithymocyte globulin and cyclosporine was an independent factor associated with response to therapy compared with either agent administered alone.113
A survival benefit from therapy with antithymocyte globulin has not been demonstrated despite studying various regimens, including both formulations, with or without hematopoietic growth factor support, and cyclosporine or corticosteroids. A phase III randomized controlled trial compared equine antithymocyte globulin and cyclosporine versus best supportive care in all IPSS risk categories.114 At 6 months, 29% of patients achieved a hematologic response in the immunotherapy cohort compared with 9% of those receiving best supportive care, but no difference was seen in overall, leukemia-free, or 2-year transformation-free survival. Notably, these patients were not evaluated for HLA DR15, and nearly 25% of patients in each group had undetermined risk, intermediate-2-risk, or high-risk IPSS.114
Alemtuzumab is a monoclonal antibody with immunosuppressive properties that is being evaluated in MDS. Preliminary data demonstrated hematologic improvement in 77% of intermediate-1 and 58% of intermediate-2 IPSS risk patients with HLA DR15 positivity.115 Further evaluation will be needed to determine its role in therapy of MDS.
Thalidomide and lenalidomide are immunomodulating drugs, frequently referred to as IMiDs. Thalidomide was discovered to possess antiinflammatory, antiangiogenic, and antiapoptotic properties, prompting its investigation as a potential treatment of MDS. Initial response rates were encouraging, but few complete responses and high rates of discontinuation because of intolerable side effects have made thalidomide rarely used in MDS. Common side effects of thalidomide include fluid retention, peripheral neuropathy, thrombosis, sedation, and constipation.
Lenalidomide is structurally similar to thalidomide but offers a distinct side effect profile and potentially enhanced therapeutic effects. Lenalidomide is more potent in vitro than thalidomide with respect to T-cell modulation and inhibition of tumor necrosis factor-α, a proapoptotic and proinflammatory cytokine. Compared with thalidomide, lenalidomide causes less fluid retention, peripheral neuropathy, thrombosis, and constipation but more frequently induces neutropenia and thrombocytopenia. Pruritus, rash, diarrhea, and hypothyroidism have been reported with lenalidomide use but seldom require treatment discontinuation. Lenalidomide undergoes substantial renal elimination, and dose reduction in patients with renal insufficiency is recommended to decrease the likelihood of significant bone marrow suppression. Treatment-emergent thrombocytopenia and neutropenia during lenalidomide therapy are associated with response in low-risk MDS patients.116 Careful consideration is necessary before reducing the dose or holding lenalidomide treatment in low-risk MDS patients who develop myelosuppression.
Lenalidomide gained recognition after an uncontrolled trial of 43 MDS patients reported a 56% overall response rate and 62% rate of transfusion independence. Patients with a clonal deletion of chromosome 5q demonstrated an 83% complete response rate.117 A subsequent phase II trial of patients with a 5q deletion and transfusion-dependent anemia evaluated lenalidomide 10 mg orally once daily. Cytogenetic remission was seen in 45% of patients with 67% achieving transfusion independence.45 The median time to response was 4 weeks. The results of this pivotal trial led to FDA approval of lenalidomide for treatment of low-risk MDS in patients with a 5q deletion.
Lenalidomide in Low- and Intermediate-1-Risk Myelodysplastic Syndromes A phase III randomized, placebo-controlled study of lenalidomide in low- and intermediate-1-risk MDS patients with a deletion 5q compared the efficacy and safety of lenalidomide 10 mg daily for 21 of 28 days or 5 mg daily with placebo in transfusion dependent patients with a primary end point of transfusion independence for at least 26 consecutive weeks.118 Transfusion independence was significantly improved in both the lenalidomide 10- and 5-mg groups, 56% and 46%, respectively, versus placebo at 6%. The lenalidomide 10-mg group showed significantly better transfusion independence for patients with baseline EPO levels greater than 500 mU/mL (500 IU/L). Cytogenetic remission was achieved in 50% and 25% of the lenalidomide 10- and 5-mg patients, respectively. Overall survival was not significantly different between groups, although this may reflect the crossover of more than 80% of placebo patients beginning at week 16.
Lenalidomide has also been studied in a phase II trial of 214 patients with low- and intermediate-1-risk MDS without 5q deletions. Transfusion independence was achieved in 26% of patients who received lenalidomide after a median of 4.8 weeks, and 43% had hematologic improvement by IWG criteria.119 Two trials have reported on the combination of lenalidomide and epoetin.120,121 Evaluation of lenalidomide in 31 patients without deletion 5q and refractory to ESAs demonstrated transfusion independence in 37% of patients. Response was more robust in patients who remained on ESA therapy at 55% versus those on lenalidomide monotherapy at 36%. Median response duration was 24 months.120 In the second trial, lower-risk MDS patients received lenalidomide 10 or 15 mg daily for 16 weeks; erythroid nonresponders were eligible to receive EPO 40,000 units/wk in addition to lenalidomide. Among 39 patients, 23 patients proceeded to combination therapy, with 6 (26%) achieving erythroid hematologic improvement. In 19 non-del(5q) patients, 4 (21%) showed erythroid hematologic improvement. A randomized, phase III study is currently underway to assess the effects of combination therapy in patients who have failed ESA monotherapy (www.clinicaltrials.gov; NCT00843882).
Lenalidomide in Intermediate-2- and High-Risk Myelodysplastic Syndromes Lenalidomide activity in low-risk MDS patients prompted its evaluation in patients with higher-risk MDS with 5q deletion. A phase II trial of lenalidomide in patients with higher-risk MDS with a 5q deletion and other cytogenetic abnormalities reported responses by IWG 2006 criteria in 13 of 47 patients (27%); significant myelosuppression was reported, and most patients (64%) required hospitalization.122 Patients with thrombocytopenia or additional cytogenetic complexity progressed rapidly despite lenalidomide therapy.
Lenalidomide produces high rates of sustained transfusion independence in patients with low- and intermediate-1-risk MDS with 5q deletions. The response rate to lenalidomide is lower in patients with higher-risk MDS and those without a 5q deletion but may still be considered as a treatment option for patients who do not respond to initial therapy.61
DNA Hypomethylating Agents
Azacitidine and decitabine are nucleoside analogs structurally similar to cytosine and capable of being incorporated into DNA in place of cytosine. When these agents incorporate into DNA, substitution of carbon for nitrogen at the 5′ position prevents methylation by DNA methyltransferase. As a result, DNA methylation is decreased, and genes previously silenced by aberrant hypermethylation are activated. In vitro studies have confirmed that these agents can promote the reexpression of previously silenced genes.51 The activity of both agents is concentration and time dependent, and trials are ongoing to evaluate the optimal dose, route, schedule, and duration of therapy.
The median time to response with DNA hypomethylating agents is 3 to 4 months.2 Minimal evidence exists for appropriate duration of treatment. Long-term follow-up of high-risk MDS patients who responded to azacitidine therapy reported the median time to first response was two cycles, but responses improved in 48% of patients who continued therapy. Best response was achieved in 92% of responders by cycle 12.123 Experts recommend continuing therapy until evidence of disease progression or unacceptable toxicity even in patients who only achieve stable disease.2,124 The primary dose-limiting toxicity of both azacitidine and decitabine is myelosuppression, including leukopenia, granulocytopenia, and thrombocytopenia. Febrile neutropenia and other infectious complications have been reported with azacitidine and decitabine.125,126 Nausea and vomiting may occur, and antiemetic prophylaxis is recommended. Azacitidine-induced erythema at the site of subcutaneous injection may occur; this can be minimized with the use of hot or cold compresses or topical corticosteroids. Rare hepatotoxicity is reported after either azacitidine or decitabine. Caution should be taken when using hypomethylating agents in patients with an estimated glomerular filtration rate of less than or equal to 29 mL/min because of a potential increased incidence of grade 3 or 4 myelosuppression, necessitating cycle delays and dose reductions.127
One important question about DNA hypomethylating agents is whether or not the degree of DNA methylation at baseline predicts response and survival after treatment with these agents. In a quantitative methylation analysis of patients who had received decitabine or supportive care only, Shen et al. showed that higher levels of methylation correlated with shorter median overall survival and progression-free survival (PFS) times.128 The degree of methylation at baseline did not predict response to decitabine. However, changes in methylation levels over time were significantly correlated with the quality of the response; whereas the median decrease in methylation was 40.6% for those who achieved a complete or partial response and only 9.8% for those with hematologic improvement, methylation levels increased a median of 27.2% in patients with progressive disease.128 Notably, methylation levels provided prognostic information regardless of the type of treatment provided and may help serve as a guide for clinicians when determining treatment approaches for individual patients.
DNA Hypomethylating Agents in Low- and Intermediate-1-Risk Patients Azacitidine was evaluated in a phase III, multicenter, randomized trial of patients diagnosed with any classification of MDS based on FAB criteria.125Patients in lower-risk categories of MDS, including refractory anemia and RARS, were required to meet additional criteria for significant bone marrow dysfunction. A total of 191 patients (median age, 68 years) were randomized to treatment with either supportive care alone or supportive care plus azacitidine 75 mg/m2 subcutaneously once daily for 7 days, repeated every 28 days. Hematopoietic growth factor support was not permitted. Responses based on Cancer and Leukemia Group B criteria occurred in 60% of patients in the azacitidine group compared with 5% in the supportive care alone group. Almost half (45%) of the patients previously transfusion dependent who received azacitidine became transfusion independent. The rate of progression to AML was significantly lower with azacitidine (15%) compared with supportive care alone (38%), but azacitidine did not significantly improve overall survival. A quality-of-life analysis was also performed and identified a significant advantage for azacitidine therapy compared with supportive care alone, including improvements in physical functioning, fatigue, dyspnea, psychosocial distress, and affect.129
Decitabine was also evaluated in a multicenter, randomized phase III trial of patients diagnosed with MDS by FAB criteria.126 Patients were required to have an IPSS risk of intermediate-1 or greater; two thirds of patients had intermediate-2- or high-risk MDS. A total of 170 patients were randomized to either supportive care alone or supportive care plus treatment with decitabine 15 mg/m2 by IV infusion every 8 hours for 3 days repeated every 6 weeks. In contrast to the azacitidine trial, hematopoietic growth factor support was allowed. The overall response rate by IWG criteria was 17% in the decitabine group compared with 0% in the supportive care group. Thirteen percent of patients who received decitabine experienced hematologic improvement compared with 7% who received supportive care alone. Time to progression to AML or overall survival was not significantly different between groups. The patients with known clonal abnormalities at baseline who underwent follow-up cytogenetic evaluation were noted to have a complete cytogenetic response of 35% with decitabine compared with 10% with supportive care. Decitabine also improved quality-of-life measures, including global health status, fatigue, and dyspnea.
DNA Hypomethylating Agents in Intermediate-2- and High-Risk Patients An open-label, randomized, phase III study compared azacitidine with a conventional care regimen (CCR) in patients with higher-risk MDS.8 Before randomization, treating physicians selected supportive care alone, low-dose cytarabine, or AML-type induction as the CCR for a given patient if randomized to the conventional care arm. Of the 340 patients receiving treatment, 175 received azacitidine, 102 received best supportive care, 44 received low-dose cytarabine, and 19 received AML-type induction. At 2 years, 51% of azacitidine patients were alive compared with 26% of patients who received a CCR, and median overall survival time was prolonged by 9 months. This is the only prospective, randomized controlled study to demonstrate therapy improves overall survival in MDS.
In attempt to better define which patients are most likely to respond to azacitidine, Itzykson et al. identified four factors that independently predicted overall survival in a cohort of 282 high-or intermediate-2-risk MDS patients who received azacitidine for a median six cycles in a compassionate use study.130 Each factor was given a point-based score: performance status greater than or equal to 2 (1 point), intermediate- and poor-risk cytogenetics (1 and 2 points, respectively), presence of circulating blasts (1 point), and RBC transfusion dependency of at least 4 units within 8 weeks (1 point). Median overall survival was not reached in the low-risk (0 points), 15 months in intermediate-risk (1 to 3 points), and 6.1 months in high-risk (4 to 5 points) patients. This prognostic scoring system was independently validated in the azacitidine cohort of Fenaux and colleagues.8
Decitabine has also been compared with best supportive care in a phase III trial of 233 intermediate- or high-risk MDS patients older than 60 years who were ineligible for intensive chemotherapy.131Decitabine was more active than best supportive care, with a complete and partial response rate of 13% and 6%, respectively, versus 0% for best supportive care. Median PFS was significantly improved with decitabine compared with supportive care at 6.6 months versus 3 months, respectively. Progression to AML at 1 year was significantly reduced with decitabine to 22% versus 33% in the best supportive care arm. However, unlike the trial with azacitidine, no overall survival benefit was observed. Decitabine did demonstrate improvement in quality-of-life measures of fatigue and physical functioning.
Although both azacitidine and decitabine have demonstrated significant improvement in complete response, partial response, and hematologic improvement rates, only azacitidine has demonstrated overall survival benefit. The lack of survival improvement for decitabine remains under intense debate because it may reflect suboptimal administration because of the dosing interval (4 weeks vs. 6 weeks), schedule (3 days vs. 5 days), and number of cycles received.124 Currently, the NCCN guidelines do not favor one agent over the alternative in low- or intermediate-1-risk patients but give a more favorable rating to azacitidine in high-risk MDS (intermediate-2 or higher).61
Despite moderate success with both hypomethylating agents, current data suggest that using decitabine after azacitidine failure is not effective. Bhatnagar and colleagues evaluated 22 MDS or AML patients with disease progression or lack of response to azacitidine who went on to receive decitabine.132 After a median of two courses, all 22 patients demonstrated disease progression or lack of response to decitabine. Higher-risk MDS patients who fail hypomethylating therapy may require therapeutic intervention with an alternative mechanism of action or as part of a clinical trial.
The pivotal trials for azacitidine and decitabine led to the approval of these agents for the treatment of patients with MDS, but their FDA-approved administration schedules are inconvenient and impossible for many cancer centers whose outpatient clinics are not open for extended hours or are closed on weekends, necessitating hospitalization. A more convenient regimen for decitabine (20 mg/m2 by IV infusion daily for 5 consecutive days every 4 weeks) demonstrated similar response rates and adverse events to the traditional regimen.133 In early 2010, the FDA granted approval for this alternative dosing regimen. Preliminary results of an oral azacitidine formulation have been positive, particularly in extended dosing strategies of 14 or 21 days, which also correlated with higher achievement of demethylation.104Although a variety of dosing options have been studied, none of these approaches have been directly compared in prospective trials, and further evaluation is required to determine optimal azacitidine and decitabine treatment regimens.133,134
Patients with intermediate-2- or high-risk MDS may be candidates for intensive chemotherapy with AML-type induction combination chemotherapy regimens, including anthracyclines, cytarabine, fludarabine, and topotecan. AML-type induction therapy is described in detail in Chapter 111. Intensive chemotherapy offers complete remission rates of 40% to 60% but is associated with a median duration of response of only 10 to 12 months.135 Treatment-related mortality in younger patients with current supportive care measures, including antibiotic and hematopoietic growth factor support, is less than 10%.8,135 Patients younger than 55 years of age who have a normal karyotype and good performance status are most likely to benefit, but this approach cures fewer than 15% of patients.135 Intensive chemotherapy can be used as a bridge to allogeneic HSCT to reduce tumor burden and control disease while a suitable donor is found and a referral is made to a transplant center.
Preliminary data suggest oral and IV clofarabine may have activity in patients with higher-risk MDS and those who experienced prior therapy failure with DNA hypomethylating agents.136–139 The optimal dose, route, and schedule to balance activity and toxicity remain to be defined.
Hematopoietic Stem Cell Transplantation
Allogeneic HSCT offers potentially curative therapy to patients with MDS who have a suitable donor and are healthy enough for the procedure. Unfortunately, fewer than 5% of patients are referred for allogeneic HSCT.140 Two large retrospective studies indicate that recipient age alone should not be considered a contraindication to allogeneic HSCT.141,142 About 30% to 50% of patients with MDS treated with allogeneic HSCT have prolonged disease-free survival.141,143–150 However, 20% to 50% of patients succumb to treatment-related mortality, and many of the remaining patients relapse. Outcomes vary based on patient comorbidities, time from diagnosis to transplant, FAB subtype of MDS, percentage of bone marrow blasts at the time of HSCT, IPSS risk category, type of conditioning regimen administered before HSCT, and dose and source of stem cells infused.141,145 Complications of allogeneic HSCT are described in greater detail in Chapter 117. An HLA-matched allogeneic HSCT is recommended if an appropriate donor is available. An autologous HSCT can be considered in the context of a clinical trial if an allogeneic donor is not available, complete remission is achieved with chemotherapy, and adequate stem cells can be collected.143
Because of the high rate of treatment-related mortality in patients with MDS, allogeneic HSCT has not been recommended for lower-risk patients because these patients may have stable disease for several years, and early transplant may shorten overall survival. The International MDS Risk Assessment Workshop conducted a decision analysis based on clinical data from two international registries and a single center to identify the optimal time to recommend allogeneic HSCT for patients who have a donor and meet HSCT eligibility criteria.151 The analysis showed that patients with low- and intermediate-1 IPSS risk scores should be closely observed and transplanted at the time of disease progression. Patients with intermediate-2 and high IPSS risk scores should be transplanted soon after diagnosis to confer the greatest benefit from allogeneic HSCT.143 This model was developed in 2003 and included patients younger than 60 years of age who had undergone HSCT primarily in the 1990s. It did not incorporate treatment with novel agents for MDS, the use of reduced-intensity conditioning (RIC), or all of the known prognostic factors currently available and thus may not be applicable to contemporary patients being evaluated for HSCT.152 The WPSS may enhance selection of patients likely to derive the most benefit from allogeneic HSCT based on recent retrospective data demonstrating patients with low-risk disease have low rates of treatment-related mortality and relapse and a 5-year overall survival rate of 80%.153 Another retrospective series by de Witte et al. reported a 4-year overall survival rate of 52% in younger patients with lower risk refractory anemia after allogeneic HSCT,154 remarkably similar to the median survival rate for untreated patients with refractory anemia.4 The decision to proceed to allogeneic HSCT and optimal timing should be weighed carefully at diagnosis and subsequently at regular intervals for factors that might influence prognosis, such as degree of cytopenias, cytogenetic abnormalities, transfusion requirement, progression to a higher risk category, donor selection, comorbidities, and availability of effective nontransplant therapies.62,154 A prospective study comparing allogeneic HSCT with azacitidine in patients aged 55 to 69 years is ongoing (available at www.clinicaltrials.gov; NCT01404741).
Retrospective comparisons of RIC and myeloablative conditioning regimens before allogeneic HSCT showed inconsistent results with some reporting a lower treatment-related mortality rate but a higher rate of disease relapse with RIC and others reporting no difference.147,155 Comparison of the results from patients receiving RIC with myeloablative conditioning regimens is difficult because patients treated with RIC regimens tend to be older or have significant comorbid illnesses preventing them from receiving myeloablative conditioning regimens. A prospective, randomized controlled trial is underway to compare myeloablative and RIC in patients with MDS undergoing allogeneic HSCT (available at www.clinicaltrials.gov; NCT00682396); in the interim, comorbidities and risk of relapse are the main factors used to select the intensity of the conditioning regimen.62
Treatment Based on International Prognostic Scoring System Risk Group
All patients with MDS should receive appropriate supportive care and be encouraged to participate in clinical trials to determine the role of different approaches in the management of MDS.61,64
Low or Intermediate-1 International Prognostic Scoring System Risk
Patients with low- or intermediate-1-risk MDS may be managed with supportive care alone; those who are likely to respond to ESAs should be managed with this strategy because it is well tolerated.61Patients with endogenous EPO less than 500 mU/mL (500 IU/L) and a low transfusion requirement are most likely to respond to ESAs. Addition of low-dose G-CSF may benefit some patients who do not respond to EPO alone. Most patients eventually stop responding to ESAs and develop an increased need for transfusions; these patients may benefit from more intensive therapy.
The NCCN recommends DNA hypomethylating agents (azacitidine and decitabine) for treatment of low-risk and intermediate-1-risk MDS in patients with clinically significant neutropenia or thrombocytopenia and patients with anemia who are unlikely to respond to or have not responded to a trial of ESAs, and patients who qualified for and failed immunosuppressive therapy.61 Small numbers of low-risk and intermediate-1-risk MDS patients were enrolled in the clinical trial that evaluated azacitidine, and further research is needed to determine its place in therapy for these patients. Responses often require 2 to 4 months of treatment, and the duration of response is generally less than 1 year. Clinical trials of azacitidine and decitabine enrolled different patient populations, used different response criteria, and administered therapy for different durations, making it difficult to determine if one agent is superior. A phase III open-label trial to compare decitabine with azacitidine in low- and intermediate-1-risk patients with MDS is underway in the United States (available at www.clinicaltrials.gov; NCT01720225). DNA hypomethylating agents are appropriate for low- and intermediate-1-risk MDS patients who are transfusion dependent or who are symptomatic despite management with best supportive care.2,61,64
The current NCCN treatment guideline for MDS recommends immunosuppressive therapy (antithymocyte globulin or cyclosporine) for select patients with low-risk MDS; young patients (60 years old or younger) with a hypocellular marrow, normal cytogenetics, expression of HLA DR15, or paroxysmal nocturnal hemoglobinuria are most likely to respond.61 The potential benefit of transfusion independence must be considered carefully in the context of complications that can arise from immunosuppressive treatments.
Lenalidomide is currently recommended for patients with symptomatic anemia and low-risk MDS with a 5q deletion.61,156 Patients with multiple cytogenetic abnormalities, in addition to a chromosome 5 deletion, may respond to lenalidomide but typically to a lower degree. Lenalidomide is also effective for some patients with low-risk and intermediate-1-risk MDS without a chromosome 5 deletion and is considered an alternative treatment approach by NCCN.61,119
Intermediate-2 or High International Prognostic Scoring System Risk
Patients with intermediate-2- or high-risk disease who are candidates for intensive therapy should receive an allogeneic HSCT, if possible, because it is the only curative option for MDS.2,64 Patients may receive intensive chemotherapy with an AML-type induction regimen or a less intensive therapy with a DNA hypomethylating agent to reduce disease during the process of finding a donor and referral to a transplant center. They also may proceed directly to allogeneic HSCT without cytoreduction if they have fewer than 10% bone marrow blasts. The NCCN guidelines suggest that high-intensity chemotherapy without subsequent allogeneic HSCT be conducted as part of a clinical trial for intermediate-2- and high-risk MDS patients.61 Azacitdine should be considered for intermediate-2- and high-risk MDS patients who are not eligible for allogeneic HSCT based on the observation that azacitidine prolongs survival in these patients.2,8,61
Although clinical trials are beginning to determine which therapies are effective in patients with different risk categories, none of the therapeutic options have been directly compared in a clinical trial. The optimal management of patients who progress or do not respond to initial therapy is not clear.
Although many different genetic abnormalities and variances have been discovered in MDS, only two are used to personalize pharmacotherapy: deletion 5q syndrome and HLA DR15 positivity. Patients with an isolated deletion of chromosome 5q and no excess marrow blasts are a distinct WHO category of MDS termed 5q- syndrome. This subtype of MDS is characterized by severe refractory anemia often requiring frequent RBC transfusions.156 Patients with 5q- syndrome typically survive longer and have a lower risk for progression to AML than a similar IPSS risk patient. About 50% to 67% of 5q syndrome patients become transfusion independent with lenalidomide therapy, and 45% to 50% achieve cytogenetic remission.45,118 The NCCN guidelines recommend these patients receive lenalidomide as primary therapy before alternative treatments.61 As discussed earlier (see Immunosuppressive Agents above), patients with HLA DR15 positivity have a superior response to immunosuppressive therapy as first-line management.113 Patients with HLA DR15 are most likely to respond if they are younger than 60 years of age, have IPSS risk of intermediate-1 or lower, and have rapid initiation of immunosuppressive therapy on diagnosis.113 More definitive studies are needed to determine if other recently discovered genetic abnormalities can be linked to treatment success.
EVALUATION OF THERAPEUTIC OUTCOMES
Standardized response criteria in clinical trials of MDS enable clinicians to evaluate study outcomes, compare results from different trials, and tailor therapy according to patient or disease characteristics.60The IWG for MDS guidelines for response criteria in MDS clinical trials categorize patient responses into categories that correlate with quality of life or morbidity.60,157 Based on these criteria, the four treatment goals are altering the natural history of the disease, cytogenetic response, hematologic improvement, and quality of life. Changes in the WHO classification system and new therapies with novel mechanisms of action, time to response, and likelihood of treatment-related cytopenias have created a need for further refinement of these guidelines.107 Patients with MDS should have regular follow-up with a history, physical examination, and complete blood counts. The frequency of follow-up varies with the natural history of each patient from weekly to every 6 months.
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