Treatment of MDS has rapidly evolved during the past two decades 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. e137-1).
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. The primary goal of therapy is hematologic improvement for lower-risk patients (IPSS low-, intermediate-1-risk or IPSS-R low, very low, and intermediate) and alteration in the natural course of the disease for higher-risk patients (IPSS intermediate-2 and high-risk or IPSS-R intermediate, high, and very high).51 Additional therapeutic 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, in selected patients.7,43,51 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.63
Therapy for MDS is determined by symptoms, risk stratification 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.64 Patients with extensive, life-limiting comorbidities or who are asymptomatic at diagnosis may warrant supportive care alone.64,65 Since lower-risk patients have a better prognosis, less toxic therapies are used to manage MDS, including EPO, darbepoetin, lenalidomide, or DNA hypomethylating agents. Patients with higher IPSS risk MDS have a poorer prognosis and may be candidates for allogeneic HSCT; patients who are not HSCT candidates may benefit from a DNA hypomethylating agent.7,51 Utilization of known genetic and laboratory factors, such as deletion 5q and erythropoietin (EPO) level can also assist with selection of appropriate therapy. However, some biomarkers, such as mutations in TET2 or ASXL1 for predicting DNA hypomethylating agent response, are not widely available or are expensive and thus not used in community oncology setting to determine therapy and are typically reserved for clinical trials.45,50 Clinicians should recognize that the clinical course of MDS is not stable. MDS may progress, or comorbidities or symptoms may change, either of which may necessitate an adjustment in treatment strategy. Therapy for MDS is generally palliative, and enrollment in a suitable clinical trial is always a viable approach.51,64
Careful interpretation is necessary when comparing the results of clinical trials in MDS because baseline patient characteristics, prognostic scores, and response criteria vary widely. Described previously, the clinical course and prognosis are affected by patient-specific characteristics.3,65 Examples of different response criteria used include changes in hemoglobin, changes in RBC transfusion requirements, or effects on quality of life.66 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.51 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.51 Hematopoietic 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 lower-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, although there are no controlled prospective data indicating clinical benefit from iron chelation in MDS.43,51
Patients with MDS may be neutropenic or have functional defects in neutrophils, predisposing them to infection.40 In MDS, the most frequently isolated organisms are bacteria, and the most common sites of infection are the lungs, urinary tract, and bloodstream.67 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.68
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.69 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.69 G-CSF or GM-CSF should only be administered temporarily as monotherapy in the rare neutropenic MDS patient who develops recurrent severe infections.1,64
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.51,65,70 Unlike some solid tumors,71 no detrimental effects on overall survival or progression to leukemia have been noted in patients with MDS. Treatment with ESAs alone results 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.72 A subsequent meta-analysis only included studies from 1990 to 2006 that reported results by International Working Group (IWG) criteria66 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 30 studies with 925 patients with MDS and found an overall erythroid response rate of 58% in patients receiving ESAs.73 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 lower-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.51,64,65 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.51 Darbepoetin doses ranging from 100 to 300 mcg subcutaneously weekly or every other week have also been used for MDS management.64,73 Doses should be titrated up or down, as clinically indicated, to achieve a hemoglobin level of 10 to 12 g/dL (100-120 g/L; 6.21-7.45 mmol/L).51 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.51,64 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.64
Several trials report that the addition of G-CSF to ESAs improves hematologic 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.74 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, but the study was not prospectively powered to determine differences in these outcomes. A subsequent phase II study treated 99 patients with darbepoetin alfa 500 mcg every 2 weeks subcutaneously for 12 weeks; nonresponders at 12 weeks continued the same darbepoetin regimen with the addition of filgrastim 300 mcg twice weekly for an additional 12 weeks.75 At 12 weeks, 48% of patients had a response according to IWG 2006 criteria, improving to 56% at 24 weeks after 40 of the nonresponders had filgrastim added to darbepoetin. 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.76 The overall erythroid response was 49%, 50.6%, and 64.5% for patients who received standard EPO (30,000-40,000 units/wk), standard EPO plus G-CSF or GM-CSF, or high-dose EPO (60,000-80,000 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 of 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.74,75 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 lower risk patients who have a serum EPO level less than 500 mU/mL (500 IU/L) and a limited transfusion history to target a hemoglobin of 10 to 12 g/dL (100-120 g/L; 6.21-7.45 mmol/L).51
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. Both agents are FDA-approved for patients with chronic idiopathic thrombocytopenic purpura and eltrombopag is also labeled for used in chronic hepatitis C-associated thrombocytopenia and severe aplastic anemia. 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; 6% of romiplostim patients developed progression to AML compared with 2.4% of placebo patients.77 A warning about the risk for progression from MDS to AML, potential for an increase in blast percentage without progression to AML, and a limitation of use noting romiplostim is not indicated for use in MDS were subsequently included in the romiplostim label. Only 56 of a planned 250 patients completed the 58 week study; longer follow-up shows no difference in the risk for progression to AML or overall survival. The design of the study limits the ability to detect a true risk for progression to AML to romiplostim.77 The primary outcome of the study of clinically significant bleeding events was not different between the arms, but 37.5% of romiplostim patients had a platelet response at 4 weeks, compared with 3.6% of patients.77 Romiplostim has also been studied in combination with azacitidine, decitabine and lenalidomide in three separate randomized phase II studies to determine feasibility to prevent clinically significant thrombocytopenia caused by these agents. Unfortunately, the studies included small numbers of patients and were unable to demonstrate a difference in the primary endpoint of clinically significant thrombocytopenic events.77 Preliminary data with eltrombopag monotherapy or in combination with azacitidine has not indicated an increased risk for progression to AML or worsening overall survival.77 Clinical trials are currently underway to evaluate the use of eltrombopag monotherapy and in combination with decitabine or lenalidomide (registered at www.clinicaltrials.gov NCT00961054, NCT01772420 NCT02010645). The most recent NCCN guidelines did not provide recommendations on the use of thrombopoietin-stimulating agents in patients with MDS.51 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 and the benefit in patients with MDS.
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 (80-100 g/L; 4.97-6.21 mmol/L).51,78,79 Some clinicians use a transfusion threshold of 10 g/dL (100 g/L; 6.21 mmol/L) in patients with significant cardiovascular disease.80 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.79,80
RBC transfusions are associated with shortened leukemia-free and overall survival times in MDS.81,82 It is unclear if this reflects disease severity or is a direct result of iron toxicity.1,83 Retrospective data indicate MDS patients receiving RBC transfusions are at higher risk for infections, cardiac, hepatic, and endocrine dysfunction compared with nontransfused MDS patients or the general population without MDS.12,81,84 It is likely that anemia contributes to development of heart failure and neutropenia to infections, therefore the role of excess iron is unclear.85 Prospective clinical trials in MDS demonstrate that iron chelation is able to decrease markers of iron overload.86,87,88,89,90 Six studies including over 700 patients with MDS receiving deferasirox for iron overload suggest improvement in hematologic parameters related to chelation with an increase in hemoglobin level ranging from 6% to 45%, an increase in platelet count from 13% to 61%, and in neutrophil count from 3% to 76%.91 Eight observational studies have assessed the relationship between iron chelation and overall survival in about 1,500 patients with low-risk and intermediate-1 risk patients with MDS.92 A meta-analysis reported an improvement in overall survival of 61.2 months, with 7 of 8 studies reporting improvement in overall survival.92 It is possible that patients who had a better prognosis were more likely to receive iron chelation, which would explain the association between improved survival time and iron chelation. 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.93 It is hypothesized that iron chelation may lower infection risk, improve the outcome of allogeneic HSCT, and delay leukemic transformation in patients with MDS.83 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.94 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 (less than 50,000 cells/mm3 [less than 50 × 109/L]). Diarrhea may complicate therapy with deferasirox and recommendations for management have been published.23
Initiation of iron chelation in patients with MDS is controversial because prospective, controlled trials of iron chelation with clinical outcomes have not been completed.43 It is unclear if iron chelation will impact the natural history of MDS or reverse end-organ damage associated with iron overload. Iron chelation is expensive and may have adverse effects including renal dysfunction and GI intolerance. Despite a lack of prospective, controlled data, more than 10 clinical practice guidelines have been published regarding iron chelation in MDS.85 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 suggest 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 (1,000-2,500 mcg/L; 2,250-5,620 pmol/L) in patients with lower-risk MDS who have an anticipated survival of at least 1 year or in patients proceeding to allogeneic HSCT.51,78,80,85,95,96 Patients receiving pharmacotherapy for iron chelation should be monitored for gastrointestinal and ocular toxicity, ototoxicity, renal and hepatic dysfunction, and complete blood counts in addition to markers of iron overload.96
The primary goal of pharmacotherapy of MDS is to change the natural history of MDS. Table e137-5 lists the responses reported in selected clinical trials of non-HSCT therapies. DNA hypomethylating agents may prolong overall survival, but 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 e137-5Results from Pivotal Trials of Low-Intensity Treatment for Myelodysplastic Syndromes ||Download (.pdf) TABLE e137-5 Results from Pivotal Trials of Low-Intensity Treatment for Myelodysplastic Syndromes
|Medication ||Patients (n) ||Median Age (years) ||Percent of Patients by IPSS Risk Category ||Response Criteria ||Complete Response (%) ||RBC Transfusion Independence (%) ||Overall Hematologic Improvement (%) |
|Low ||Int-1 ||Int-2 ||High |
|Azacitidine117 ||191 ||69 ||5a ||53 ||23 ||17 ||Other ||7 ||45 ||37 |
|Decitabine116 ||170 ||70 ||— ||31 ||43 ||26 ||IWG ||9 ||NR ||30 |
|Antithymocyte globulin (equine) + cyclosporine103 ||88 ||62 ||18b ||56 ||14 ||1 ||Other ||NR ||34 ||NR |
|Lenalidomide48 (5q deletions) ||148 ||71 ||37 ||44 ||5 ||— ||IWG ||NR ||67 ||76 |
|Lenalidomide112 ||214 ||72 ||43 ||36 ||4c ||— ||IWG ||NR ||26 ||43 |
Immunosuppressive agents that modulate effector T cells, including antithymocyte globulin (ATG), cyclosporine, and corticosteroids have been evaluated in patients with hypoplastic MDS with a disease pathobiology similar to aplastic anemia. The National Institute of Health has developed an algorithm to predict response to immunosuppressive therapy, and criteria 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.97 ATG, with or without cyclosporine, has been investigated primarily in patients with intermediate-1-risk and low-risk MDS. Treatment with ATG may not be beneficial for all patients because of the potential for infectious complications and serum sickness. Most studies have used equine ATG at a dose of 40 mg/kg/day IV for 4 consecutive days with corticosteroids to prevent serum sickness complications.97,98 A retrospective evaluation of patients enrolled on clinical trials at the National Institutes of Health demonstrated that the combination of equine ATG and cyclosporine was associated with response to therapy compared with either agent administered alone.99 Responses generally occur within 4 months, and about one-third of previously transfusion-dependent patients achieve durable transfusion independence.97,98 Rabbit ATG has also been evaluated in daily doses ranging from 2.5 to 3.75 mg/kg/day administered IV for 4 to 5 consecutive days.100,101,102 Response rates appear similar and treatment with either horse or rabbit ATG is reasonable.
A survival benefit from therapy with ATG has not been demonstrated, despite clinical trials of various regimens, including both formulations, with or without hematopoietic growth factor support, and cyclosporine or corticosteroids. A phase III randomized controlled trial compared equine ATG and cyclosporine versus best supportive care in all IPSS risk categories.103 At 6 months, 29% of patients achieved a hematologic response in the immunosuppressive therapy arm 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.103
Alemtuzumab is a monoclonal antibody with immunosuppressive activity that has been evaluated in MDS. Initial data in 32 patients demonstrated hematologic improvement in 77% of intermediate-1 risk patients with HLA DR15 positivity.104 A small cohort of 9 patients validated these results in low risk patients with hypocellular bone marrow and found a 60% response rate.105 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 anti-inflammatory, 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 limited thalidomide’s use 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. Recent evidence has determined that the pleiotropic effects of lenalidomide are due to modulation of the ubiquitination and degradation process. Lenalidomide binds cereblon, a component of the ubiquitin ligase complex and modulates the substrate specificity of the enzyme, and thus the targeted cellular proteins for degradation. Lenalidomide selectively and specifically degrades casein kinase 1A1, a kinase located on chromosome arm 5q. Cells that are haploinsufficient, or deletion 5q, are more susceptible to the degradation process.106 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.107 Careful consideration is necessary before reducing the dose or holding lenalidomide treatment in low-risk MDS patients who develop myelosuppression.
Lenalidomide has been evaluated in several clinical trials. An uncontrolled trial of lenalidomide in 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.108 A subsequent phase II trial of patients with 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.46 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. Nearly 8 years later, long term follow-up of patients enrolled in these phase II patients shows longer survival for those who achieved transfusion independence for at least 8 weeks as compared with non-responders (4.3 years vs 2 years).109
Low- and Intermediate-1-Risk Patients
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 endpoint of transfusion independence for at least 26 consecutive weeks.110 Transfusion independence was significantly improved in both the lenalidomide 10- and 5-mg groups, 56% and 43%, 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 patients treated with lenalidomide 10 mg and 5 mg, 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. Patients with either isolated deletion 5q or a single additional cytogenetic abnormality were less likely to progress to AML at 24% and 21%, respectively, versus patients with two or more additional abnormalities; the rate of progression was 47%. Further subset analyses have revealed patients who achieved transfusion independence for greater than 182 days demonstrated an improvement in overall survival for lenalidomide-treated patients at either dose level.8
Intermediate-2- and High-Risk Patients
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.111 Patients with thrombocytopenia or additional cytogenetic complexity progressed rapidly despite lenalidomide therapy.
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.112
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 a treatment option for patients who do not respond to initial therapy.51
Two trials have reported on the combination of lenalidomide and EPO.113,114 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.114 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 patients without deletion 5q, 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).
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.52 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.43 Long-term follow-up of high-risk MDS patients who responded to azacitidine therapy reported the median time-to-first response was two cycles, and 91% of responding patients achieved their first response within six cycles. The first response was the best response in 52% of patients, but the remaining 48% did not achieve their best response until a median of three additional cycles beyond their first response.115 Experts recommend continuing therapy until evidence of disease progression or unacceptable toxicity even in patients who only achieve stable disease.43,65 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.116,117 Nausea and vomiting may occur, and antiemetic prophylaxis is recommended. Azacitidine-induced erythema at the site of subcutaneous injection may occur, and can be minimized with the use of hot or cold compresses or topical corticosteroids. Rare hepatotoxicity is reported after either azacitidine or decitabine. Hypomethylating agents should be used cautiously in patients with an estimated glomerular filtration rate of less than or equal to 29 mL/min (0.48 mL/s). Pharmacokinetics of a single cycle in this population do not demonstrate significant variability in area-under-the-plasma-time curve or maximum observed plasma concentration, but cumulative dosing may increase the incidence of grade 3 or 4 myelosuppression, necessitating cycle delays and dose reductions.118,119
It remains unclear if the degree of DNA methylation at baseline or the level of demethylation response predicts success and survival after treatment. Shen et al. showed that higher levels of methylation correlated with shorter median overall survival and progression-free survival (PFS) times.120 The degree of methylation at baseline did not predict response to decitabine. Mutations in TET2 likely affect the global methylation level, but changes in methylation status as a result of treatment have not yet been evaluated.121 At this time, methylation levels are not routinely incorporated into clinical decision making for MDS therapy.
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.117 Patients 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 identified a significant advantage for azacitidine therapy compared with supportive care alone, including improvements in physical functioning, fatigue, dyspnea, psychosocial distress, and affect.122
Decitabine was also evaluated in a multicenter, randomized phase III trial of patients diagnosed with MDS by FAB criteria.116 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.
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.7 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.123 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 point), 15 months in intermediate-risk (1-3 points), and 6.1 months in high-risk (4-5 points) patients. This prognostic scoring system was independently validated in the azacitidine cohort of Fenaux and colleagues.7
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.124 Decitabine 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 for high-risk disease. The lack of survival improvement for decitabine remains controversial because it may reflect suboptimal administration due to dosing interval (4 vs 6 weeks), schedule (3 vs 5 days), and number of cycles received.148 Currently, the NCCN guidelines do not favor one agent over the alternative in lower risk but give a more favorable rating to azacitidine in high-risk MDS (intermediate-2 or higher).51
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.125 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 extended hours or 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.126 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.127,128 An ongoing phase III trial of oral azacitidine in lower-risk MDS with significant cytopenias should provide more definitive information on its place in therapy (available at www.clinicaltrials.gov; NCT 01566695). An additional option is oral decitabine combined with deoxyguanosine to protect it from deamination by cytidine deaminase in the liver and GI tract, thereby significantly prolonging the half-life.129 A phase II study reported a complete response rate of 20% and transfusion independence rate of 32%. Additional phase II studies are ongoing (available at www.clinicaltrials.gov; NCT01261312, NCT02131597). Although 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.
Lack of durable survival benefit with existing therapies and inability to utilize HSCT in many patients has led to attempts at combination therapy with hypomethylating agents. Azacitidine has been combined with lenalidomide in a phase II study of 36 patients with higher-risk MDS who were not candidates for HSCT.130 The regimen included azacitidine 75 mg/m2/day for days 1 through 5 and lenalidomide 10 mg daily on days 1 to 21, with cycles repeated every 28 days. The overall response rate was 72% and complete response rate was 44%. The follow-up was short at 11.5 months. A larger data set evaluated azacitidine monotherapy versus azacitidine plus lenalidomide versus azacitidine plus vorinostat, a histone deacetylase inhibitor.131 Although the population was a mixture of MDS and chronic myelomonocytic leukemia patients, the overall response rate of 33% was similar among treatments. Further studies of combination therapy in varying risk groups and cytogenetics groups are ongoing and the role of combination therapy should be limited to the clinical trial setting.
Patients with higher risk disease, including IPSS intermediate-2- or high-risk MDS or IPSS-R intermediate, high, or very high 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 134. Intensive chemotherapy in MDS patients is often less successful than de novo AML, with complete remission rates of 40% to 60%, a median duration of response of only 10 to 12 months, and a longer period of aplasia.132 Treatment-related mortality in younger patients with current supportive care measures, including antibiotic and hematopoietic growth factor support, is less than 10%.7,133 Patients younger than 55 years who have a favorable karyotype and good performance status are most likely to benefit, but this approach cures fewer than 15% of patients.132,133 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.
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. With a median age of 76 years at diagnosis of MDS, fewer than 5% of patients are referred for allogeneic HSCT.134 Two large retrospective studies indicate that recipient age alone should not be considered a contraindication to allogeneic HSCT.135,136 About 30% to 50% of patients with MDS treated with allogeneic HSCT have prolonged disease-free survival.135,137,138 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.135 Complications of allogeneic HSCT are described in greater detail in Chapter 140. 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.138
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.139 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.138 This model was developed in 2003 and included patients younger than 60 years 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.140 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%.141 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,142 remarkably similar to the median survival rate for untreated patients with refractory anemia.3 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 availability, comorbidities, and availability of effective nontransplant therapies.63,142 Prospective studies comparing allogeneic HSCT with hypomethylating agents or best supportive care are ongoing (available at www.clinicaltrials.gov; NCT01404741 and NCT02016781).
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 while others reporting no difference.137,143 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 (BMT CTN 0901) is underway to compare myeloablative and RIC in patients with MDS undergoing allogeneic HSCT (available at www.clinicaltrials.gov; NCT00682396). A clinical advisory was released May 15, 2014 stating the study suspended enrollment for the clinical study BMT CTN 0901 following preliminary data indicating superiority of myeloablative regimens for allogeneic HSCT patients eligible for the study.144 Pending full publication of the study results, comorbidities and age remain factors used to select the intensity of the conditioning regimen; myeloablative conditioning is preferred for patients healthy enough to tolerate it.63
Experts disagree on whether patients should proceed to allogeneic HSCT without receiving any prior therapy, after receiving a hypomethylating agent or after intensive induction chemotherapy.23,49,144 Pretransplant therapy may be useful to reduce the burden of marrow blasts and clonal cells before HSCT, but this therapy may cause additional toxicity making the patient less likely to tolerate HSCT.23 Observational studies have shown no difference in post-transplant outcomes on the basis of pretransplant management and no prospective, randomized, controlled trials have been completed.48,121,149
Treatment Based on 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.51
Lower-Risk Patients (IPSS Low, Intermediate-1; IPSS-R Very Low, Low, and Intermediate)
Patients with lower-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.51 Patients 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 a DNA hypomethylating agent (azacitidine or decitabine) for treatment of lower-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.51 Small numbers of low-risk and intermediate-1-risk (by IPSS) 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 to hypomethylating agents 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 diverse 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). Either DNA hypomethylating agent is appropriate for lower-risk MDS patients who are transfusion dependent or who are symptomatic despite management with best supportive care.43,49,51
The current NCCN treatment guideline for MDS recommends immunosuppressive therapy (ATG with or without cyclosporine) for select patients with lower-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.51 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 lower-risk MDS with a 5q deletion.51 Patients with multiple cytogenetic abnormalities, in addition to a chromosome 5 deletion, may respond to lenalidomide but the response rate is typically lower. Lenalidomide is also effective for some patients with lower-risk MDS without a chromosome 5 deletion and is considered an alternative treatment approach by NCCN.51,112
Higher-Risk Patients (IPSS Intermediate-2 or High; IPSS-R Intermediate, High, and Very High)
Patients with higher-risk disease who are candidates for intensive therapy should receive an allogeneic HSCT, if possible, because it is the only curative option for MDS.49,63 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. Azacitidine should be considered for higher-risk MDS patients who are not eligible for allogeneic HSCT based on the observation that azacitidine prolongs survival in these patients.7,51
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.