The number of effective drug treatments available to treat MDS has expanded in recent years, providing a range of management alternatives. Some treatments improve hematopoietic function and alleviate symptoms related to blood cytopenia; other therapies alter the natural history of the disease and improve survival. Both approaches may be appropriate in different clinical contexts, and many patients receive different combinations of treatments throughout their disease course.
The goals of therapy in MDS vary in different patient populations. A management plan should consider the patient's age, comorbidities, and disease risk. Patients with low-risk MDS most commonly experience problems related to chronic anemia, and the disease may remain stable for prolonged periods. If these patients are elderly, they may best be managed with relatively nontoxic therapies that aim to maintain quality of life. Treatment options include transfusions of blood products, growth factor therapies (erythropoietin with or without colony-stimulating factors), and non–growth factor therapies with immune modulators (lenalidomide) and epigenetic drug treatment (azacitidine and decitabine). High-risk MDS has a poor prognosis and forms a continuum with acute myeloid leukemia. Aggressive therapies may be warranted in these high-risk patients to eradicate the malignant clone and improve survival. Intensive therapies may include high-dose chemotherapy and consideration of alloSCT in younger patients. Intensive treatment protocols are not suitable for all patients because they expose the patient to significant risks of treatment-related morbidity and mortality. An algorithm for treatment approaches at MD Anderson Cancer Center is shown in Fig. 5-7.
Assessing response to treatment in MDS can be complex as treatment goals in low- and high-risk disease may be different. Clinical response criteria in low-risk disease usually measure improvements in peripheral blood cell counts and quality-of-life factors. Response in high-risk disease is typically more stringent, with measures of resolution of bone marrow changes by morphological and cytogenetic criteria. Standardized criteria are available to assess response to treatment in MDS and are particularly useful to allow comparisons between drug trials (64).
Chronic blood cytopenia is a principal characteristic of MDS. Therapies aimed at alleviating problems related to anemia, neutropenia, and thrombocytopenia are an essential component of management. Bacterial infections require aggressive treatment with antibiotics. Platelet transfusions are administered for episodes of bleeding or for prophylaxis in patients with severe thrombocytopenia. Transfusion thresholds at MD Anderson include a hemoglobin level of 8 g/dL (unless the patient is otherwise symptomatic) and a platelet count of less than 10 K/UL (unless there is evidence of bleeding). Additional hemostatic support with the use of antifibrinolytic agents may be considered for problematic mucosal bleeding or for surgical procedures. The role of prophylactic antibiotics is less established in neutropenic patients. It is our practice at MD Anderson to use triple therapy (antibacterial with a quinolone, antiviral, and antifungal) in all patients with severe neutropenia who are receiving therapy.
Symptomatic anemia is often the major clinical problem in patients with low-risk MDS. In this group, red cell transfusion is effective symptomatic therapy, but a prolonged transfusion program may cause problems with transfusion-related hemosiderosis, alloantibody formation, and volume overload in patients with impaired cardiac function. Deposition of iron in body tissues is treated with iron chelation. The efficacy of iron chelation therapy is best demonstrated in thalassemia major, where regular deferoxamine therapy reduces iron deposition in organs and improves survival (65). In MDS, it is hypothesized to have similar advantages (66), but this needs to be confirmed in ongoing randomized clinical trials. The parenteral administration of deferoxamine is inconvenient. The development of effective oral iron-chelating drugs, such as deferasirox, has allowed iron chelation to be performed more easily (67). Iron chelation should start with parenteral deferoxamine or oral deferasirox after 20 to 40 units of red cells have been administered, particularly if there is an expectation of prolonged survival and continued transfusion therapy. Serum ferritin may be used as a guide to chelation therapy, with a ferritin concentration greater than 1,000 μg/L typically attained after transfusion of 20 red cell units (58). Iron chelation therapy should also be considered in a younger patient who may be a candidate for allogeneic transplantation. An elevated pretransplant ferritin has been associated with a lower overall survival after allogeneic transplantation and an increase in the hepatic transplant complication of veno-occlusive disease (68).
Hematopoietic Growth Factors
Hematopoietic growth factors are the primary regulators of blood progenitor cell proliferation and are used therapeutically to promote effective hematopoiesis. Erythropoietin therapy has been explored as an alternative to red cell transfusion in patients with low-risk MDS. Recombinant erythropoietin (rEPO) in various forms, including epoetin α, epoetin β, and the long-acting darbepoetin, has been studied in different cohorts of patients. Overall, erythroid responses in unselected patients were modest, in the range of 10% to 20% (69). The best responses were identified in patients with low-risk MDS, a low serum EPO level (<200 IU/L), and no red cell transfusion requirement (70). In this favorable subgroup of patients with MDS, an erythroid response to rEPO therapy was observed in 40% to 60% of patients (70). The median duration of response was 2 years, and therapy was associated with improved quality of life (71). Data suggest that patients who respond to growth factor therapy have better survival than historical control cohorts who received supportive care alone (70).
Erythropoietin in combination with G-CSF is also effective, with response rates of 40% to 50% in selected cohorts (71,72). The combination of these two hematopoietic cytokines appears to offer a synergistic clinical benefit and allows improvements in hemoglobin levels in some patients who fail to respond to EPO monotherapy. The benefit of this combination may be most marked in RARS and RCMD, but this has not been confirmed (70). Disease transformation is a theoretical risk in patients receiving chronic hematopoietic growth factors, but long-term observations of these patients suggested that these cytokines do not promote leukemic transformation (70,72). Hematopoietic growth factor therapy should be considered to treat anemia in patients with low-risk MDS associated with a low serum EPO. Erythropoietin can be initiated as monotherapy with the addition of G-CSF if there is no objective response in 2 to 3 months.
Thrombopoietin has been used to promote platelet production and minimize the bleeding complications related to severe thrombocytopenia. Initial trials with recombinant thrombopoietin were disappointing. New second-generation thrombomimetic agents are now being tested (73). These drugs should not be used outside the context of clinical trials due to potential concerns of increased blasts and fibrosis.
Lenalidomide is a chemical analogue of thalidomide with diverse biological actions that encompass immune modulation and antiangiogenic effects. Selective activity of lenalidomide against MDS associated with an interstitial deletion on the long arm of chromosome 5 was first suggested in a study examining the effects of this drug on anemia in patients with low-risk MDS (74). Erythroid responses were noted in 56% of the cohort, with the most significant response found in the subgroup with a del(5q) abnormality. This observation was confirmed in a larger multicenter phase II study of lenalidomide (6). This second trial demonstrated an overall erythroid response in 76% of patients with the del(5q) abnormality. Responses were prolonged and occurred rapidly, with a median time to a hematologic response of 4 to 5 weeks. A cytogenetic response was documented in 73% of patients, with 44% developing complete cytogenetic remission. Cytogenetic responses were observed in patients with the del(5q) abnormality alone and in patients with the del(5q) abnormality associated with additional cytogenetic defects. This clearly demonstrated that the activity of lenalidomide was not limited to patients with the 5q- syndrome but was also observed in patients with low-risk MDS, with a variety of WHO classifications associated with a del(5q) abnormality on cytogenetic studies. A randomized trial comparing different doses of lenalidomide versus observation further confirmed the activity of the drug at a dose of 10 mg daily (75). Although none of these studies was powered to document improvement in survival, a recent analysis indicated that achieving a cytogenetic response with lenalidomide was associated with prolonged survival (76).
Lenalidomide therapy in MDS is usually started at 10 mg daily. A favorable response is typically characterized by normalization of anemia and cytogenetic response (6). The most important side effect of therapy with lenalidomide is myelosuppression, which may necessitate dose reduction in patients with persistent thrombocytopenia and neutropenia. Interestingly, the degree of myelosuppression has been associated with response. Thrombocytopenia at diagnosis (platelet count <100 × 109/L) has been associated with a worse response to lenalidomide treatment. This may reflect repeated or prolonged treatment interruptions secondary to myelosuppression.
Lenalidomide and thalidomide also demonstrated activity in low-risk MDS without the del(5q) abnormality. Lenalidomide has been studied in 214 patients with low-risk MDS (IPSS low and intermediate-1) and predominantly a normal karyotype (7). In this cohort, 26% of patients achieved transfusion independence, and 17% developed a reduction in transfusion requirement. The median duration of transfusion independence was 41 weeks, and cytogenetic responses were documented in 19% of patients with karyotypic abnormalities. These results were confirmed in a randomized trial (77).
5-Azacitidine and 5-aza-2′-deoxycytidine (decitabine) are chemically related drugs with a spectrum of activity that includes both low- and high-risk MDS. The mechanism of action of these drugs is uncertain, although both agents reverse abnormal promoter DNA methylation that surrounds the promoter of some tumor-suppressor genes in cancer cells. Aberrant promoter methylation is associated with transcriptional repression, or silencing, and may contribute to the loss of tumor-suppressor gene function in MDS. Decitabine and 5-azacitidine are both cytidine analogues that incorporate into DNA and form covalent bonds with DNA methyltransferase enzymes. Depletion of methyltransferase activity within the cell then causes newly synthesized DNA to be hypomethylated compared to the parent strand. After at least two cycles of cell division, DNA becomes globally hypomethylated with alteration in gene expression within the leukemic cell. Both agents display cytotoxicity at high doses, while hypomethylating activity remains prominent at lower doses. These biochemical changes are an attractive target for drug therapy as normal tissues have little gene promoter methylation, so hypomethylating therapy may have some degree of specificity for the malignant clone.
5-Azacitidine first demonstrated broad-spectrum activity in MDS. Comparison of azacitidine (75 mg/m2 subcutaneously for 7 days every 28 days) to best supportive care in a randomized control trial demonstrated an overall response rate of 48% with azacitidine compared to 5% with supportive care (78,79). Azacitidine therapy was associated with a prolongation in the time to leukemic transformation and better quality of life. The median time to response was three cycles, and response rates were independent of MDS classification. Complete responses were observed in relatively few patients (10%), with most patients experiencing hematologic improvement. A report of a multicenter phase III study of azacitidine in patients with high-risk MDS demonstrated an increase in overall survival of approximately 9 months for patients receiving azacitidine compared to other standard therapies (80). This was the first drug trial that demonstrated a survival advantage in MDS. A subset analysis of the trial data suggested that azacitidine may have significant activity in MDS associated with abnormalities in chromosome 7, a cytogenetic abnormality associated with a poor outcome.
Decitabine has similar clinical activity to azacitidine and has been studied in various dose regimes in predominantly high-risk MDS and AML. Comparison of decitabine (45 mg/m2 in three divided doses administered for 3 consecutive days every 6 weeks) to best supportive care in a randomized trial demonstrated an overall response rate of 17%, with complete remissions in 9% of patients with predominantly high-risk MDS (81). Subgroup analysis revealed that patients who received decitabine had a longer median time to transformation to AML or death if they were treatment naïve or had high-risk MDS. Myelosuppression was the major drug toxicity. Data from this trial may underestimate the efficacy of the drug as a significant proportion of patients on decitabine received a small number of treatment cycles, which may have been insufficient to demonstrate a response. This is supported by previous phase II trial data that suggested decitabine had an overall response rate similar to azacitidine (82). Subsequent clinical trial development with decitabine has focused on improving response rates by lowering the daily dose and lengthening administration schedules. One such schedule of intravenous administration of decitabine for 5 days every 4 weeks demonstrated a complete response rate of 39% in a high-risk MDS cohort (83,84). Improvements in hematopoietic function are often delayed after the initiation of azacitidine or decitabine therapy, and drug treatment should continue for four to six cycles before cessation because of poor response.
Chemical modification of histone proteins by acetylation contributes to the regulation of gene expression and probably interacts with abnormal DNA methylation to cause transcriptional suppression of tumor-suppressor genes. Histone deacetylase inhibitors alter chromatin structure to promote gene transcription, and their combination with hypomethylating agents demonstrates significant in vitro synergy (85). Initial clinical drug trials in MDS and AML at MD Anderson indicated increased clinical activity with this type of combination (86,87) azacitidine. None of the randomized trials (hypomethylating agent with or without HDAC inhibitor) showed a survival improvement (88).
The relatively poor prognosis associated with high-risk MDS has initiated intensive treatment strategies incorporating high-dose chemotherapy in the same protocols used to treat acute myeloid leukemia. In high-risk MDS, AML-type treatments produce a complete response rate of about 40% to 60%, but remissions are brief (89,90). This poor response to high-dose chemotherapy is due, at least in part, to the relatively greater proportion of patients diagnosed with RAEB having poor prognosis cytogenetics involving complex changes of chromosomes 5 and 7. Elderly patients with significant comorbidities tolerate high-dose chemotherapy poorly.
Patients with high-risk MDS have been treated with a variety of intensive chemotherapy regimens at MD Anderson Cancer Center (91,92). Studies have examined using intermediate- to high-dose cytosine arabinoside (ara-C) (A) in various combinations with idarubicin (I), cyclophosphamide (C), fludarabine (F), and topotecan (T), as regimens: IA, FA, FAI, TA, and CAT. The overall complete response rate for these regimens was 55% to 58%. A short antecedent history of hematological disorder, a normal karyotype, performance status, age, and treatment in a laminar airflow environment were all predictive of attaining a complete response. This intensive approach was beneficial in some patients as those who developed a complete response within 6 weeks of chemotherapy obtained a survival advantage. However, these regimens were toxic, with significant treatment-related mortality in the first 6 weeks, ranging from 5% with TA to 21% with FAI. Consolidation chemotherapy was used in most cases where a remission was achieved with a regimen containing the drugs used in induction but at a reduced intensity of 50% to 66% of the initial dose. Survival of patients treated with IA and TA therapies were comparable and superior to those patients treated with FA, FAI, and CAT regimens, but prognosis remained poor. Nevertheless, this approach does benefit some younger individuals (<65 years) with a normal karyotype, achieving an encouraging 5-year survival rate of 27% with intensive treatment. For older patients, the TA combination can be considered as it has a relatively low treatment-related mortality and it does not contain anthracycline drugs (relatively contraindicated in the presence of heart disease).
Immune dysfunction contributes to blood cytopenia in some patients with MDS, producing a clinical overlap with aplastic anemia. Immunosuppressive therapy with antithymocyte globulin (ATG) with or without the addition of cyclosporine has been explored in small numbers of patients with MDS. Response rates of 30% to 50% have been observed in selected cohorts of patients with low-risk MDS administered a course of ATG, with a minority of patients experiencing prolonged remission (93,94,95). Features that may predict a good response to immunosuppressive therapy include younger age, HLA-DR status, shorter duration of red cell transfusion, low-risk IPSS, and bone marrow hypocellularity (95,96,97). Selection of appropriate patients for immunosuppression is important as ATG therapy is poorly tolerated in an older population with low-risk MDS (98). The PD-1 axis is expressed in patients with MDS. This may allow the development of new forms of therapy and combinations using inhibitors of this pathway (99).
Hematopoietic Stem Cell Transplantation
In MDS, alloSCT is potentially, but the therapy carries significant risk associated with treatment toxicity, prolonged cytopenia, infection, and graft-versus-host disease. In young patients with suitable donors, the transplant procedure offers the best chance of cure, with a long-term disease-free survival of 30% to 50% (100,101,102,103,104). Given the risks associated with this procedure, patient suitability and timing of the transplant are important issues.
Allogeneic transplantation with myeloablative conditioning has been examined exclusively in younger patients (median age in the mid-30s) in most studies. Patients with low-risk disease (RA/RARS) have experienced the best survival rate. However, this is also the subgroup of patients predicted to experience prolonged survival without aggressive therapies. This procedure is associated with a significant treatment-related mortality of up to 30% to 50% in some studies (102, 103). Relapse after transplantation occurs in approximately 20%, and the relapsed disease has a relatively poor response to donor lymph ocyte infusion (102,103,105). Increased risk of allogeneic transplantation mortality in MDS is associated with older age, poor risk cytogenetics (particularly abnormalities of chromosome 7 or a complex karyotype), the presence of excess blasts in the bone marrow, and longer duration of disease (106, 107). Patients with treatment-related MDS also have a poor transplant outcome, but this is related to the frequency of high-risk cytogenetic changes (107, 108).
The development of nonmyeloablative allogeneic transplantation with reduced-intensity conditioning has allowed allogeneic transplantation to be considered in older patients with MDS and in patients whose comorbidities or organ dysfunction would exclude them from myeloablative treatment (109). This procedure has reduced the transplant-related mortality, the major problem limiting the availability of this potentially curative therapy to older patients. This therapy aims to minimize organ toxicity related to initial chemo- or radiotherapy and allow stable engraftment of donor cells that provide the curative potential associated with the graft-versus-leukemia effect. Comparison of reduced-intensity conditioning transplantation with standard myeloablative conditioning showed reduced transplant-related mortality but increased relapse rate, resulting in comparable rates of overall survival between the two transplantation strategies (106,110,111).
Statistical modeling based on historical allogeneic transplantation outcomes for matched sibling transplantation suggested that the maximal overall survival is achieved by different transplant strategies in different MDS risk groups (112). Patients with low-risk disease (IPSS low and intermediate-1 groups) maximize overall survival by delaying transplantation after diagnosis until evidence of disease progression but before the development of overt acute leukemia. This delayed transplant approach provided the greatest survival benefit to younger patients (<40 years).
Specific features of disease progression have not been defined, but evidence of new cytogenetic abnormalities, progressive cytopenia, and increasing blast percentage in the bone marrow are suggested as potential triggers for transplantation. Patients with high-risk disease (IPSS intermediate-2 and high) should ideally receive the transplant as soon as possible after diagnosis. The presence of bone marrow fibrosis delays engraftment in allogeneic transplantation and its presence is an additional risk factor in transplant outcome in high-risk MDS. In this group, fibrosis considerably increases transplantation risk.
Early consideration of transplantation is suggested in a younger patient with significant MDS-associated fibrosis (108). The IBMTR studied the outcomes of patients older than 60 years of age with MDS treated with either reduced-intensity transplantation or hypomethylating agents (8). The results of this analysis indicated that transplant should not be considered as first-line therapy in lower risk MDS. Of interest, in higher risk MDS it appears that there is a benefit toward transplant compared to hypomethylating-based therapy, but survival curves cross significantly later than after 24 months of therapy. This indicated that there is probably a specific group of patients, not yet defined, that derive the maximal benefit from transplantation.