Adv Ther (2011) 28(Suppl.2):1-9. DOI 10.1007/s12325-011-0001-9
REVIEW
Treatment of Myelodysplastic Syndromes in Elderly Patients Jesus Feliu Sanchez
Received: December 14, 2010 / Published online: March 9, 2011 © Springer Healthcare 2011
ABSTRACT Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal neoplasms with the median age at diagnosis being in the seventh decade. If left untreated, the disease progresses to acute myeloblastic leukemia (AML). There are many options for the management of MDS, but the only potentially curative treatment is allogenic hematopoietic stem cell transplantation (allo-HSCT), which is often not an option because of advanced age or comorbidities at diagnosis or lack of a human leukocyte antigen-identical donor. MDS in the elderly should be managed similar to that in young patients, but the fact that many advanced age patients cannot undergo allo-HSCT precludes any chance of cure. Despite the main objective of prolonging overall survival and the time to progression to AML, the key is to improve quality of life for the longest possible time. To achieve
Jesus Feliu Sanchez () Hematology and Hemotherapy Service, Hospital San Pedro, Logroño, Spain. Email:
[email protected]
these objectives, supportive care is essential. Likewise, immunomodulatory drugs, such as lenalidomide, can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients with MDS with chromosome 5q deletion. Elderly patients with high-risk MDS can benefit from 5-azacitidine (5-AZA), with efficacy and safety profiles comparable with those found in patients under 75 years of age. In any patient, predictive drug response scores are required in order to ensure more rational use of these medications. Keywords: acute myeloblastic leukemia; 5-azacitidine; elderly; myelodysplastic syndromes
INTRODUCTION Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal neoplasms characterized by the presence of morphological and functional changes in the three hematopoietic series, a normocellular or hypercellular bone marrow, and peripheral blood cytopenias. The estimated annual incidence of MDS is approximately 3.3-4.5 cases per 100,000.
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However, the incidence increases with age, with the median age at diagnosis in the seventh decade.1,2 If left untreated, the disease progresses to acute myeloblastic leukemia (AML) within a variable period of time, depending on the type of MDS according to the French-American-British (FAB) and the World Health Organization (WHO)3,4 classifications and on the prognostic index of the disease – the International Prognostic Scoring System5 (IPSS) being the most widely used because of its simplicity and feasibility of application. Patients with low and intermediate-1 IPSS scores are considered low-risk patients, as the time required to evolve to AML is 9.4 and 3.3 years, respectively, in 25% of these patients, with a median survival of 5.7 and 3.5 years, respectively. Conversely, intermediate-2 and high IPSS groups are considered high-risk patients, as 25% of these patients evolve to AML within 1.1 and 0.2 years, respectively, with a median survival of 1.2 and 0.4 years, respectively.5 There are many options for the management of MDS, ranging from only supportive care to intensive disease-directed chemotherapy treatments. Although allogenic stem cell transplantation (allo-HSCT) carries significant risks of morbidity and mortality, it is currently considered the only potentially curative therapy for MDS.6,7 The main problem lies in that bone marrow transplantation may only be performed in a minority of patients based, on one hand, on age restrictions (only 25% of patients are under 60 and may be considered for transplantation)7 or comorbidities and, on the other hand, because a human leukocyte antigen (HLA)-identical sibling donor cannot be found in many cases. Patients who are not candidates for allo-HSCT may benefit from other treatments including immunomodulatory and hypomethylating drugs, such as lenalidomide, 8 -10 5-azacitidine
Adv Ther (2011) 28(Suppl.2):1-9.
(5-AZA),11-14 and decitabine.15,16 Although still investigational, chemotherapy followed by maintenance with 5-AZA may be an option in a subset of patients (ie, good cytogenetic risk), whereas 5-AZA may be more appropriate when the cytogenetic study is unfavorable. Immunosuppressive therapy, low-dose cytarabine, and erythropoiesis-stimulating agents are other possible alternatives.
ONCOLOGICAL TREATMENT IN ELDERLY PATIENTS Tumor management in elderly patients is a controversial issue and requires an overall assessment of each case, which should include both the characteristics of the patients (comorbid conditions, life expectation, and potential tolerability of aggressive treatments) and the disease (tumor aggressiveness and sensitivity to radiotherapy and chemotherapy). These variables should be taken into account for defining the treatment goal, which may range from curative to palliative. Age itself should not be an exclusion criterion for administration of chemotherapy or radiotherapy, because chronological age of patients does not always agree with biological age. Some of the geriatric assessment models available consider the overall patient characteristics and correlate them to their life expectancy.17 Such prognostic scores may be of great value for defining the most suitable therapeutic approach for the management of malignant diseases in elderly patients. In addition, while the objective of tumor treatment should be to prolong survival, adequate management of symptoms produced by both the disease itself and the treatment are essential to achieve an improvement in the quality of life of these patients, which gives sense to their fight against disease.
Adv Ther (2011) 28(Suppl.2):1-9.
TREATMENT OF MDS The choice of treatment for a MDS is not an easy task for physicians. To define the treatment the subtype of the disease must be established (according to the FAB and WHO classifications) and then an integrated prognostic system is applied, usually the IPSS. The therapeutic strategy differs depending on the prognostic group. In low-risk MDS (low and intermediate-1 IPSS), the treatment objective is to reduce cytopenias, transfusion dependence, and improve the quality of life. This is achieved by supportive treatment consisting of bloodproduct transfusion, hematopoietic growth factors, immunosuppressive drugs, ironchelation therapy, treatment of infectious or hemorrhagic complications, and psychological support to patients and relatives.18 Although erythropoietin (EPO) is not licensed for MDS in any country, most treatment guidelines19-23 consider erythroid-stimulating agents as the first-line treatment for anemia in low-risk MDS patients, in cases where the serum EPO is lower than 500 units/L and the patient has low transfusion requirements. Out of these conditions the response rate is only 15% to 20%. Some studies have concluded that EPO plus granulocyte colony-stimulating factors (G-CSF) is better than EPO alone to treat anemia in lowrisk MDS, although other studies suggest G-CSF may increase the risk of AML evolution.24 When there is no response to these drugs blood-product transfusion is necessary in order to reduce the risk of cardiovascular events. The use of G-CSF in MDS can increase the absolute neutrophil count in neutropenic MDS patients, but there are no data supporting the continuous long-term use of G-CSF. Intermittent administration of G-CSF may be considered in patients with severe neutropenia and recurrent infections.25
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Immunosuppressive drugs, such as antithymocyte globulin, with or without cyclosporine, can achieve reversal of cytopenias in 30% to 40% of low-risk patients.26 Responses to antithymocyte globulin are seen mainly in hypoplastic MDS in young patients with a recent-onset requirement for red blood cell (RBC) transfusion, absence of excess blasts, a normal karyotype, and HLA-DR15 positivity.26,27 However, the conjunction of such features is infrequent in the MDS population. A few retrospective studies suggest ironchelating agents have a beneficial impact on survival in multitransfused MDS patients. Although there is an absence of prospective studies, consensus expert guidelines recommend starting iron chelation in MDS low-risk patients who have received at least 20 to 40 RBC concentrates and/or have a serum ferritin level greater than 1000 ng/mL.28 Likewise, patients with MDS with chromosome 5q deletion may benefit from the administration of lenalidomide.8,9 A study conducted specifically in this MDS subtype9 showed that lenalidomide reduced the need for transfusions in 76% of cases and transfusion independence in up to 67% of patients. The median time to response was 4.6 weeks, with sustained responses of more than 1 year in almost two-thirds of the patients. In addition, lenalidomide achieved a complete cytogenetic response in 45% of the patients evaluated and complete remission of the cytological bone marrow abnormalities in more than one-third of the cases. Moderate-to-severe neutropenia (55%) and thrombocytopenia (44%) were the most common reasons for interrupting (in 20% of patients) or adjusting (in 84% of patients) the dose. Hypomethylating drugs, such as 5-AZA and decitabine, can yield an erythroid response in 30%-40% of patients with low-risk MDS resistant to an erythroid-stimulating agent.
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These drugs may be used in low-risk MDS in clinical trials when the disease is refractory to other treatments and transfusion-dependency is high,29 reserving allo-HSCT for young patients with a high probability of progression to highrisk MDS (refractory anemia with excess blasts, unfavorable cytogenetics, or severe neutropenia/ thrombocytopenia). Although the optimal time for bone marrow transplantation in MDS is unknown, a study evaluating patients with MDS treated with allo-HSCT 7 demonstrated that delaying transplantation in low and intermediate-1 IPSS groups maximized the overall survival, whereas immediate transplantation for intermediate-2 and high IPSS patients was associated with maximal life expectancy. These results were attributed to the considerable mortality associated with the transplantation procedure. A new scoring system30 has been developed to determine the subgroup of low-risk patients (low and intermediate-1 IPSS) who have a poor prognosis. This score detects those low-risk patients who may benefit from transplantation at diagnosis. In contrast, in high-risk MDS (intermediate-2 and high IPSS), the therapeutic goal is to modify the natural history of the disease by eliminating the malignant clone due to the early progression to AML and short median overall survival observed in these patients. Allo-HSCT should be performed as soon as possible in these patients as it is the only potentially curative treatment.6,7 However, despite advances in transplantation technology, there is still considerable morbidity and mortality associated with this approach. Moreover, regardless of transplant complications this procedure may only be carried out in a minority of cases, due to advanced age, comorbidities, and lack of a HLA-identical donor. Patients with high-risk MDS who are not candidates to transplantation may benefit from
Adv Ther (2011) 28(Suppl.2):1-9.
treatment with hypomethylating drugs. 5-AZA is the first drug that has been able to modify the natural history of the disease. A phase 3, randomized, clinical trial showed that 5-AZA improves overall responses, reduces the risk of AML transformation and improves the quality of life in patients with MDS as compared with supportive treatment.11 A subsequent phase 3 clinical trial comparing 5-AZA with conventional treatment (supportive care, low-dose cytarabine, or intensive chemotherapy) in patients with highrisk MDS12 showed an increased overall survival and a prolonged time to progression to AML in the 5-AZA group. At 2 years, 50.8% of patients in the 5-AZA group were alive compared with 26.2% in the conventional care group (P
