Treatment of MDS has rapidly evolved during the last few years 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. 145–1).
The goals of treatment vary with disease-specific factors, including the type of MDS, 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.57 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.55 Additional critical goals for both groups include symptom palliation and quality of life (QOL) improvement. Lower-intensity treatment with a DNA hypomethylating agent or immunosuppressive therapy may improve overall survival and provide symptom palliation and enhanced QOL without significant toxicity.6,55,58 The only curative therapy for MDS is allogeneic HSCT, but most patients lack a suitable donor or are not healthy enough to undergo this intensive therapy.3,11
General Approach to Treatment
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 QOL, and patients' treatment preferences.2 Approximately 30% to 60% of patients with MDS receive supportive care alone.22,59 Patients with low and intermediate-1 IPSS risk scores generally have better prognoses, and lower-intensity therapies are used when treatment is indicated (see Treatment of MDS Based on IPSS Risk Stratification). Patients with intermediate-2 and high IPSS risk MDS have poorer prognoses and may be candidates for allogeneic HSCT; patients who are not transplant candidates may benefit from a DNA hypomethylating agent.6,55 Clinicians should recognize that the clinical course of MDS is not static. MDS may progress and comorbidities or symptoms may change over time, necessitating an adjustment in treatment strategy. Therapy for MDS is generally palliative, and enrollment in a suitable clinical trial is encouraged.2,60
Careful interpretation is necessary when comparing the results of clinical trials in MDS, as patient characteristics and response criteria vary widely. Described previously, the clinical course and prognosis are affected by certain patient characteristics.4,56 Examples of different response criteria used include changes in hemoglobin, changes in RBC transfusion requirements, or effects on QOL.57 Use of RBC transfusion requirement as a primary endpoint 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 QOL is not clear. Some treatments for MDS can cause significant adverse effects resulting in hospitalization or increased clinic visits and may negatively impact QOL, regardless of their positive effects on hematologicalparameters. The impact of treatment on QOL is an important consideration when choosing 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 QOL assessment.55 The NCCN guidelines recommend that patients with symptomatic anemia receive leukoreduced RBC transfusions, and those with bleeding due to thrombocytopenia should receive platelet transfusions.55 Hematopoietic cytokine 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. Iron chelation should be considered in low-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.55
Patients with MDS may be neutropenic or have functional defects in neutrophils, predisposing them to infection.42 In MDS, the most frequently isolated organisms are bacteria, and the most common sites of infection are the lungs, urinary tract, and bloodstream.61 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, intravenous antibiotics.62
Hematopoietic Growth Factors
Filgrastim (G-CSF) and sargramostim (GM-CSF) are colony-stimulating factors that stimulate white blood cell production and may increase circulating neutrophils in 70% to 90% of patients.63 However, 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.41,63 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
Erythropoietin 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 erythropoietin level relative to the degree of anemia present or an elevated erythropoietin level.′The mechanism of action of erythropoietin in MDS is not clear, but exogenous erythropoietin may stimulate a normal clone of cells that is unresponsive to low endogenous levels of erythropoietin, stimulate a dysplastic clone to differentiate that is less responsive to endogenous erythropoietin, or induce apoptosis.64 An immunomodulatory effect of erythropoietin, G-CSF, or GM-CSF has been proposed.
Current guidelines recommend use of erythropoietin or darbepoetin for management of anemia in patients with MDS.55,65 Unlike some solid tumors,66 no detrimental effects on overall survival or progression to leukemia have been noted in patients with MDS. Treatment with erythropoiesis-stimulating agents (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.67 A subsequent meta-analysis only included studies from 1990 to 2006 that used International Working Group (IWG) criteria57 to define erythroid response (an increase in hemoglobin of 2 g/dL [20 g/L; 1.24 mmol/L] or transfusion independence). This report included thirty studies with 925 patients with MDS and found an overall erythroid response rate of 58% in patients receiving erythropoietin or darbepoetin.68 These results suggest that erythropoietin 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 erythropoietin level less than 500 mU/mL (500 U/L) and a history of receiving fewer than 2 units of RBC transfusions per month have the best chance of responding to exogenous erythropoietin.2,69 The doses required to achieve a response in MDS are higher than those used to treat renal causes of anemia, with erythropoietin doses in the range from 40,000 to 60,000 units subcutaneously 2 to 3 times per week.55 Darbepoetin doses ranging from 100 to 300 mcg subcutaneously weekly or every other week have also been used for MDS management.2,68 Doses should be titrated up or down, as clinically indicated, to achieve a hemoglobin level of 10 to 12 g/dL (100 to 120 g/L; 6.21 to 7.45 mmol/L).70 Additionally, patients should receive at least 8 weeks of therapy before doses are adjusted or before patients are considered non-responders because response to ESAs in MDS can be delayed.2,55 The median response duration for ESAs in MDS is 1 to 2 years, and if there is no benefit or the response wanes, the ESA should be discontinued.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 were retrospectively compared with 237 untreated patients who were matched for FAB classification, hemoglobin and transfusion needs.71 A 39% major erythroid response rate by IWG criteria was demonstrated in the erythropoietin plus G-CSF cohort. The median doses required to maintain a stable response were subcutaneous erythropoietin 30,000 units/week and G-CSF 225 mcg/week.72 In a multivariate analysis, the erythropoietin plus G-CSF group was associated with improved overall survival (hazard ratio, 0.61; 95% confidence interval, 0.44–0.83), and decreased risk of non-leukemic death (hazard ratio, 0.66; 95% confidence interval, 0.44–0.99) compared with the untreated group.71 Another retrospective study in 433 patients with MDS treated with erythropoietin or darbepoetin, with or without filgrastim, reported a 50% response rate by IWG 2006 criteria.73 Predictors of response included low and intermediate-1 IPSS risk, RBC transfusion independence, serum erythropoietin level <200 mU/mL (<200 U/L), and shorter interval between diagnosis and treatment. The addition of G-CSF in this report was not significantly associated with response. A large phase III, randomized, controlled trial of ESAs in MDS with long-term follow-up compared erythropoietin with or without G-CSF to best supportive care in 110 patients.74 At 4 months, 34% of patients receiving erythropoietin 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 erythropoietin doses were escalated and/or filgrastim was added. Patients with refractory anemia with ringed sideroblasts (RARS) were most likely to respond to the addition of filgrastim. No difference in overall survival or leukemic evolution was observed between patients receiving erythropoietin compared with best supportive care after a median follow-up 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 erythropoietin as a single agent with those who received erythropoietin plus G-CSF or GM-CSF.75 The overall erythroid response was 49%, 50.6%, and 64.5% for patients who received standard erythropoietin (30,000–40,000 units/week), standard erythropoietin plus G-CSF or GM-CSF, or high-dose erythropoietin (60,000–80,000 units/week), respectively. The authors concluded that higher doses of single agent erythropoietin 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 which could have negatively impacted the outcomes.
Some, but not all, studies have shown that patients who respond to ESAs have improvements in QOL.74 The value of this costly intervention has not been evinced, and long-term safety has not been prospectively measured in randomized controlled trials.76 There is no definitive evidence that erythropoietin, with or without G-CSF, improves overall survival. However, it does not shorten overall survival or time to development of leukemia and may decrease the need for RBC transfusions and improve QOL. Erythropoietin therapy is well tolerated, and the NCCN recommends a trial in low and intermediate-1 IPSS risk patients who have a serum erythropoietin level less than 500 mU/mL (500 U/L) and a limited transfusion history.55
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, and are currently only FDA approved for patients with chronic idiopathic thrombocytopenic purpura. A phase II trial evaluating romiplostim in patients with low and intermediate-1 risk MDS with platelets less than 50,000 cells/mm3 (50 × 109/L) resulted in platelet responses in 46% of patients by IWG 2006 criteria.77 Four of 45 patients developed a transient increase in the proportion of bone marrow blasts and two patients developed AML.77 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.78–80 Preliminary data suggests that romiplostim is safe and effective 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. One advantage of eltrombopag is that it is orally administered, but no data are available to support its use for MDS. An ongoing phase I/II trial of eltrombopag administration for MDS-related thrombocytopenia will determine its efficacy in this patient population.
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 (80 to 100 g/L; 4.97 to 6.21 mmol/L).55,81,82 Some clinicians use a transfusion threshold of 10 g/dL (100 g/L; 6.21 mmol/L) in patients with significant cardiovascular disease.83 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.41,81,83,84
RBC transfusions are associated with shortened leukemia-free and overall survival in MDS.54 It is unclear if this reflects disease severity or is a direct result of iron overload.3,85 Chronic iron overload can result in cardiac, hepatic, and endocrine dysfunction after numerous RBC transfusions, but this has not been proven in patients with MDS.2 Clinical trials in MDS demonstrate that iron chelation is able to decrease markers of iron overload.86–88 Prospective, well-designed trials evaluating the clinical benefits of iron chelation in MDS have not been conducted. In a series of 11 patients given deferoxamine for several years, Jensen et al. demonstrated a reduction in RBC transfusion requirements in 64% of patients, with 46% becoming transfusion independent.89 In a study conducted by Leitch and colleagues, 18 low or intermediate-1 risk patients receiving deferoxamine demonstrated improved overall survival compared with matched controls not receiving iron chelation therapy; the median overall survival was not reached at 226 months in the deferoxamine group compared with a 40-month median overall survival in the matched control group.90 Preliminary data on 165 patients suggest that iron chelation may improve overall survival in patients with MDS.86 Those patients were identified by a survey in 2005, managed by their hematologist and then evaluated for overall survival 2 years later. The treating hematologist elected to give no iron chelation (n = 89) or deferoxamine (n = 60), deferiprone (n = 5), deferoxamine plus deferiprone (n = 5), or deferasirox (n = 6) at the dose, schedule, and duration of the hematologists choice. Concomitant therapy to manage MDS was not reported. Median overall survival from diagnosis was 115 months in patients receiving iron chelation therapy and 51 months in nonchelated patients. 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.91 It is hypothesized that iron chelation may reduce infection risk, improve the outcome of allogeneic HSCT and delay leukemic transformation in patients with MDS.85 Randomized controlled trials are needed to evaluate the clinical benefits of iron chelation in patients with MDS.85,92 The potential toxicity, expense, and benefits of iron chelation should be carefully considered prior to initiating therapy.91
Many clinicians recommend that 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.55,82,83,93–95 Patients receiving deferoxamine and deferasirox should be monitored for ocular toxicity, ototoxicity, and renal dysfunction in addition to markers of iron overload.94
Sidebar: Clinical Controversy
Initiation of iron chelation in patients with MDS is controversial because iron chelation has not been shown to change the natural history of MDS despite the anticipated prevention or reversal of end-organ damage associated with iron overload.92 Despite the fact that no prospective, randomized controlled trials have been conducted, eight different clinical practice guidelines have been published regarding iron chelation in MDS.92 These guidelines differ on whether or not to initate chelation and at what threshold, which agent, dose and duration to employ, and how to monitor for efficacy/toxicity of iron chelation.
Pharmacotherapy of MDS is intended to change the natural history of MDS. Pharmacotherapy often is divided into high-intensity therapy, including HSCT and AML-type induction chemotherapy, and low-intensity therapy, including DNA hypomethylating agents and immunosuppressive therapy. Table 145–4 lists the responses reported in selected clinical trials of lower-intensity therapies. DNA hypomethylating agents may prolong overall survival, however allogeneic HSCT remains the only proven curative option for patients. As most patients with MDS are not candidates for HSCT, less toxic therapeutic modalities are being evaluated in an attempt to improve QOL and disease-free survival for patients with MDS.
Table 145-4 Results from Pivotal Trials of Low-Intensity Treatment for Myelodysplastic Syndromes |Favorite Table|Download (.pdf)
Table 145-4 Results from Pivotal Trials of Low-Intensity Treatment for Myelodysplastic Syndromes
|Percentage of Patients by IPSS Risk Category|
|Medication||Number of Patients||Median Age||Low||Int-1||Int-2||High||Response Criteria||Complete Response (%)||RBC Transfusion Independence (%)||Overall Hematologic Improvement (%)|
|Antithymocyte globulin (equine)119||61||60||18||67||5||10||Other||NR||34||NR|
|Lenalidomide134 (5q deletions)||148||71||37||44||5||–||IWG||NR||67||76|
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, only approximately 8% of patients meet those requirements.11 About 30% to 50% of patients treated with allogeneic HSCT have prolonged disease-free survival.96–104 However, 20% to 50% of patients succumb to treatment-related mortality, and many of the remaining patients relapse. Outcomes vary based on patient age and 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 prior to HSCT, and dose and source of stem cells infused.98,104 Complications of allogeneic HSCT are described in greater detail in Chapter 148. Based on data and expert opinion, 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.96
Because of the high rate of treatment-related mortality in patients with MDS, allogeneic HSCT is not 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 (IMRAW) 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.105 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.96 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 of 80%.106 Another retrospective series by de Witte and colleagues reported a 4-year overall survival of 52% in younger patients with lower risk refractory anemia following allogeneic HSCT,107 remarkably similar to the median survival for untreated patients with refractory anemia.4 The decision to proceed to allogeneic HSCT and optimal timing should be assessed carefully at diagnosis and subsequently at regular intervals for factors that might influence prognosis, such as degree of cytopenias, cytogenetic abnormalities, transfusion requirement, and progression to higher-risk categories.107
Nonmyeloablative conditioning regimens prior to HSCT are being evaluated for treatment of MDS. MDS patients who undergo nonmyeloablative conditioning tend to have lower treatment-related mortality but a higher rate of disease relapse.100 Direct comparison of the results of nonmyeloablative HSCT with myeloablative HSCT is difficult because patients treated with nonmyeloablative conditioning regimens tend to be older or have significant comorbid illnesses preventing them from receiving myeloablative conditioning regimens. A range of pretransplant conditioning regimen dose-intensities are being investigated; until further studies are published the optimal conditioning regimen will likely depend on disease and patient characteristics, such as age and comorbidities.96
Sidebar: Clinical Controversy
As knowledge about how best to improve overall survival and quality of life in MDS increases, the role of allogeneic HSCT continues to be reevaluated. Questions that will require investigation include the following: Which patients should undergo transplantation? What is the optimal time to undergo HSCT? What type of conditioning regimen should be used?
AML-Type Induction Chemotherapy
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.56 AML-type induction therapy is described in detail in Chapter 142. 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.108 Treatment-related mortality in younger patients with current supportive care measures, including antibiotic and cytokine support, is less than 10%.6,108,109 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.108 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.
An open-label, randomized, phase III study compared azacitidine to a conventional care regimen (CCR) in patients with higher risk MDS.6 Prior to randomization, treating physicians selected supportive care alone, low-dose cytarabine, or AML-type induction as the CCR regimen 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 was prolonged by 9 months. This is the only randomized controlled study to demonstrate that therapy improves overall survival in MDS.
Clofarabine is a purine analog FDA approved for pediatric acute lymphoblastic leukemia.70 Preliminary data suggests clofarabine may have activity in patients with higher-risk MDS.110 The optimal dose and schedule to balance activity and toxicity remain to be defined.
DNA Hypomethylating Agents
Azacitidine and decitabine are nucleoside analogs structurally similar to cytosine and capable of being incorporated into DNA in place of cytosine.111 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 re-expression of previously silenced genes.48,111 The activity of both agents is concentration and time dependent, and trials are ongoing to evaluate the optimal route, dose, schedule, and duration of therapy.
Azacitidine was evaluated in a phase III, multicenter, randomized trial of patients diagnosed with any classification of MDS based on FAB criteria.112 Patients in lower-risk categories of MDS, including refractory anemia and refractory anemia with ringed sideroblasts, 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 (CALGB) criteria occurred in 60% of patients in the azacitidine group compared with 5% in the supportive care alone group. Almost one half of the transfusion dependent patients who received azacitidine became transfusion independent. The rate of progression to AML was significantly lower with azacitidine (15%) as compared with supportive care alone (38%), but azacitidine did not significantly improve overall survival. A QOL 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.113
Decitabine was also evaluated in a multicenter, randomized phase III trial of patients diagnosed with MDS using FAB criteria.114 Patients were required to have an IPSS risk of intermediate-1 or greater. A total of 170 patients were randomized to either supportive care alone or supportive care plus treatment with decitabine 15 mg/m2 by intravenous infusion every 8 hours for 3 days, repeated every 6 weeks. Hematopoietic growth factor support was allowed in this trial, unlike the azacitidine trial. 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. There was no significant difference between groups in time-to-progression to AML or overall survival. The patients with known clonal abnormalities at baseline who underwent follow-up cytogenetic evaluation also fared better with decitabine, where the complete cytogenetic response was 35% with decitabine compared with only 10% with supportive care. Decitabine also improved QOL measures, including global health status, fatigue, and dyspnea.
The median time-to-response with DNA hypomethylating agents is 3 to 4 months and patients should continue therapy until evidence of disease progression or unacceptable toxicity.2 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.112,114 Nausea and vomiting may also occur and antiemetic prophylaxis is recommended. Additional side effects include azacitidine-induced erythema at the site of subcutaneous injection that can be minimized with the use of hot or cold compresses or topical steroids, and rare hepatotoxicity following either azacitidine or decitabine.
One important question about DNA hypomethylating agents is whether or not the degree of DNA methylation at baseline predicts response and survival following treatment with these agents. Shen and colleagues evaluated patients who had received decitabine or supportive care only as part of other prospective studies in an effort to answer this question.115 The results of their evaluation demonstrated that higher levels of methylation correlated with shorter median overall survival and progression-free survival. The degree of methylation at baseline did not predict response to decitabine. However, reduced methylation levels over time significantly correlated with the quality of the response; the median decrease in methylation was 41% for those who achieved a complete or partial response and only 10% for those with hematologic improvement, whereas methylation levels increased a median of 27% in patients with progressive disease.115 Notably, methylation levels provided prognostic information regardless of the type of treatment provided and may help serve as a guide to clinicians when determining treatment approaches for individual patients.
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. More convenient alternative regimens have been evaluated and produce response rates and adverse events similar to the current FDA-approved schedules, although these approaches have not been directly compared in a prospective trial.116,117 Further study is needed to determine optimal azacitidine and decitabine treatment schedules.
Immunosuppressive agents that target 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.118
Antithymocyte globulin has been investigated primarily in patients with intermediate-1 and low-risk MDS. Treatment with antithymocyte globulin may not be beneficial for all patients, however, because of the potential for infectious complications, serum sickness, and variations in response.119 Most studies have used equine antithymocyte globulin, and the dose is usually 40 mg/kg/day administered intravenously for 4 consecutive days, plus corticosteroids to prevent serum sickness.120,121 Responses generally occur within 8 months, and approximately one-third of previously transfusion-dependent patients achieve durable transfusion independence.120–122 Rabbit antithymocyte globulin has also been evaluated in daily doses ranging from 3.5 mg/kg to 3.75 mg/kg administered intravenously for 5 days.123,124 This formulation may produce response rates similar to equine antithymocyte globulin, based on the results of a randomized phase II study.
Cyclosporine has also been studied for treatment of low-risk MDS. The dose administered has varied among published trials, and targeted a cyclosporine level between 100 ng/mL and 400 ng/mL (83 nmol/L and 333 nmol/L). Adverse events reported include renal failure, increased liver enzymes, hypomagnesemia, and septicemia.125,126
Patient factors associated with response to immunosuppressive therapy include age less than 60 years, HLA DR15 expression, and shorter duration of transfusion dependence.127 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 also an independent factor associated with response to therapy compared with either agent alone.127
Alemtuzumab is a chemotherapy agent with immunosuppressive properties currently being studied as a single agent or in combination with cyclosporine for treatment of low-risk MDS.128 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 originally marketed in Europe as a sedative and antiemetic. Birth defects developed in some of the children of women who were taking thalidomide, leading to its withdrawal from the market in the 1960s. Thalidomide was later discovered to possess antiinflammatory, antiangiogenic, and antiapoptotic properties, prompting its investigation as a potential treatment of MDS. Responses to thalidomide ranged from 11% to 56%, but there were few complete responses.129,130 Additionally, 15% to 64% of patients discontinued thalidomide treatment in clinical trials because of intolerable adverse effects. 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.131 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, 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 marrow suppression. It is important to note, however, that lenalidomide-induced neutropenia and thrombocytopenia are associated with response in low-risk MDS patients.132 Thus, careful consideration is necessary before reducing the dose or holding lenalidomide treatment in low-risk MDS patients who develop myelosuppression.
An uncontrolled trial of lenalidomide in 43 patients with MDS reported a 56% overall response, and 62% of patients who were transfusion dependent became transfusion independent.133 Additionally, patients with a clonal deletion on chromosome 5q had an 83% complete response rate. These encouraging results led to a subsequent phase II trial of patients with a 5q deletion and transfusion-dependent anemia. In this trial, lenalidomide was administered at a dose of 10 mg orally once daily, and 45% of patients achieved cytogenetic remission, while 67% achieved transfusion independence.134 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's activity in low-risk MDS patients prompted its evaluation in patients with higher-risk MDS with 5q deletion. Results of a phase II trial of lenalidomide were recently reported in patients with higher-risk MDS with a 5q deletion and other cytogenetic abnormalities.135 Responses by IWG 2006 criteria occurred in 13 of 47 patients (27%), but significant myelosuppression was reported and most (64%) required hospitalization. Patients with thrombocytopenia or additional cytogenetic complexity progressed rapidly despite the intervention.
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.136
Lenalidomide produces high rates of sustained transfusion independence in patients with low-risk 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.55
Treatment of MDS Based on IPSS Risk Stratification
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.55,60
Low or Intermediate-1 IPSS Risk
Patients with low-risk or intermediate-1 risk MDS may be managed with supportive care alone; those who are likely to respond to erythropoietic agents should be managed with this strategy because it is well tolerated.55 Patients with endogenous erythropoietin less than 500 mU/mL (500 U/L) and a low transfusion requirement are most likely to respond to erythropoietin. Addition of low-dose G-CSF may benefit some patients who do not respond to erythropoietin alone. Most patients eventually stop responding to erythropoietic agents 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 erythropoietin.55 Few low-risk and intermediate-1 risk MDS patients were enrolled in the clinical trials that evaluated azacitidine or decitabine, and further research is needed to determine their role 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. However, a phase III open-label trial to compare decitabine with azacitidine in patients with MDS is underway in the United States. DNA hypomethylating agents are appropriate for low-risk and intermediate-1 risk MDS patients who are transfusion dependent or who are symptomatic despite management with best supportive care.2,55,60
The current NCCN treatment guideline for MDS recommends immunosuppressive therapy (antithymocyte globulin or cyclosporine) for selected patients with low-risk MDS, such as young patients (≤60 years old), those with hypocellular marrows, disease expressing HLA DR15 or paroxysmal nocturnal hemoglobinuria (PNH), and patients with symptomatic anemia unlikely to respond to erythropoietic agents.55 The potential benefit of transfusion independence must be considered carefully in the context of complications that can arise from immunosuppressive treatments.
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.137,138 Patients with 5q- syndrome typically survive longer and have a low risk for progression to AML. Two thirds of patients become transfusion independent with lenalidomide therapy, and 45% achieve cytogenetic remission.134
Lenalidomide is currently recommended for patients with symptomatic anemia and low-risk MDS with a 5q deletion.55,137,138 Patients with multiple cytogenetic abnormalities, in addition to a chromosome 5 deletion, may respond to lenalidomide, but the response rate is lower.
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.55,136
High or Intermediate-2 IPSS Risk
Patients with high-risk or intermediate-2 risk disease who are candidates for intensive therapy should receive an allogeneic HSCT, if possible, because it is the only curative option for MDS.2,60 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 high-risk and intermediate-2 risk MDS patients.55 DNA hypomethylating agents should be considered for high-risk and intermediate-2 risk MDS patients who are not eligible for allogeneic HSCT based on the observation that azacitidine prolongs survival in these patients.2,6,55
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. Additionally, the optimal management of patients who progress or do not respond to initial therapy is not clear.
Symptom palliation and improved QOL are two critical goals of MDS therapy. Yet the FDA's approval process for new agents continues to focus solely on efficacy and safety, and often overlooks cost-effectiveness and the impact of these agents on QOL. More effective agents are available today for the management of MDS, allowing providers to make a choice not only based on efficacy and safety but also on cost and convenience. Limited analyses have been performed, however, on the comparative cost-effectiveness of the different treatment options. Additionally, most studies have focused on only one treatment or used different methodologies, making it difficult to draw conclusions based on the available data.
The general economic impact of MDS treatment is substantial. The clinical and economic consequences of MDS in the United States were recently compared with a population without MDS using Medicare claims from 2003 to 2005.10 The MDS cohort comprised 705 patients (4.1%) of the 1,713,502 total Medicare patients in the claims file. The mean Medicare payments in 2005 were 3-fold higher for the MDS cohort ($21,533 vs $7,829; P < 0.001). Additionally, patients with MDS who require transfusions often have more complications than those who do not need transfusions.
The NCCN recognizes the financial implications of MDS therapy, and published an analysis of the cost of treatment for low-risk and intermediate-1 risk MDS based on a 2009 version of their treatment guidelines.139 The objective of this report was to assist patients and providers in making treatment decisions, including cost as a factor, when more than one option is available. Drug treatment costs were based on reimbursement from the Centers for Medicare and Medicaid Services, thus using a third-party payer perspective. The model developed to estimate annual treatment costs took into account the expected pathway of likely initial and subsequent therapies used during the first treatment year, while considering such factors as MDS subtype, probability of response, authors' estimate of proportional use of each available treatment option, and direct drug cost. The mean annual cost of treatment for IPSS low-risk or intermediate-1 risk MDS, using NCCN's treatment pathways, was $63,577 (range, $35,921–$86,799). The annual cost increased to an average of $104,989 for patients receiving iron chelation therapy. The economic impact of each individual treatment is also highlighted in the analysis, but a detailed discussion is beyond the scope of this chapter. Additionally, there are other direct and indirect costs of MDS treatment that were not included in the model that further increase the financial burden of this disease.
A prospective, randomized trial compared patients treated with best supportive care with patients who received erythropoietin plus lenograstim for 1 year.140 Investigators evaluated treatment response, but also measured the comparative costs and QOL. Direct costs were measured prospectively and were analyzed using a payer and institutional perspective, and QOL was assessed with the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire. Mean cost per subject was £8,746 for supportive care versus £26,723 for lenograstim plus erythropoietin. The difference was attributed to drug costs because there was no difference in transfusion requirements. The findings from this study demonstrate that combination therapy with erythropoietin and lenograstim is expensive and does not improve QOL over best supportive care, regardless of clinical response. However, another study using a different QOL scale reported improved QOL in patients who responded to therapy with erythropoietin and filgrastim.69 Therefore, the value of this intervention remains inconclusive.
A retrospective cost analysis of the pivotal phase II study of lenalidomide treatment for MDS with deletion 5q was conducted. The results of this analysis demonstrated that the cost of treatment with lenalidomide was offset largely by the decrease in transfusion and exogenous erythropoietin requirements.141 The investigators reported an annual cost of $63,385 for lenalidomide compared with $54,940 for best supportive care, resulting in a cost-effectiveness ratio of $35,050 per quality-adjusted life-year. The results of this analysis were limited, as they were based on assumptions of the QOL impact of transfusion requirements rather than direct measurements of QOL using validated instruments.
Quality of life is one of the primary goals of MDS treatment, as most do not currently impact overall survival. Future clinical trials should incorporate formal QOL measures and cost-effectiveness analyses to aid in MDS treatment decision making when more than one choice is available.