Treatment of Myelodysplastic Syndromes in Elderly Patients

Transcription

1 Adv Ther (2011) 28(Suppl.2):1-9. DOI /s 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. jfeliu@riojasalud.es 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 cases per 100,000.

2 2 Adv Ther (2011) 28(Suppl.2):1-9. 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 System 5 (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, azacitidine (5-AZA), 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.

3 Adv Ther (2011) 28(Suppl.2): 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 guidelines 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 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 subtype 9 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.

4 4 Adv Ther (2011) 28(Suppl.2):1-9. 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 system 30 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 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 MDS 12 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<0.0001). The median time to AML transformation was 17.8 months in the 5-AZA group compared with 11.5 months in the conventional care group (P<0.0001). Forty-five percent of 5-AZA patients who were dependent on RBC transfusion became transfusion independent, compared with 11.4% in the conventional care group (P<0.0001). In addition, 86% of the patients remained on the programmed drug dose, whereas >50% of patients were able to follow the 28 day cycle, with a median number of nine cycles administrated. In both studies myelosuppression was the most common grade 3-4 adverse event for 5-AZA treatment, with neutropenia (81%-91%) and thrombocytopenia (70%-85%) being the most frequent cytopenias. Injection site reaction was the most common non-hematological adverse event. TREATMENT OF MDS IN ELDERLY PATIENTS Treatment options for elderly patients with MDS are limited, mainly due to age-related comorbidities and functional impairment, poor tolerability of cytotoxic therapies, and patient or relative preferences.

5 Adv Ther (2011) 28(Suppl.2): Low-dose cytarabine therapy has not shown an advantage in survival compared with supportive care in MDS, and it has been associated with frequent grade 3-4 hematological toxicity. 31,32 Conversely, in a retrospective analysis of high-risk MDS and AML patients >65 years of age treated with intensive chemotherapy, the induction mortality was 29%. Age 75 years and poor performance (Eastern Cooperative Oncology Group score of 3-4) were identified as consistent independent poor prognostic factors. 33 Considering these data, the majority of advanced-age MDS patients are managed with palliative care measures. 34 Treatment of elderly low-risk MDS patients does not differ from that in younger patients, as in most cases supportive measures, immunosuppressive drugs, or erythropoiesisstimulating agents are applied. The use of lenalidomide in myelodysplastic syndrome with chromosome 5q deletion has shown results similar to those of younger patients, both in terms of safety and efficacy. 9 However, the management of elderly patients with high-risk MDS is more complex. The impossibility to perform an allo-hsct in most cases leads to the question of whether these patients may benefit from hypomethylating drugs or whether they would better benefit from palliative therapy with supportive care. Thus, one of the first questions arising following the publication of the 5-AZA results in MDS was whether this drug would be equally effective and safe in elderly patients, as most candidates for this treatment are of an advanced age and many have multiple concomitant diseases. Therefore, there were reasonable doubts about treatment compliance in the elderly (outside of clinical trials with unselected patients) and regarding the efficacy and safety of the drug. Subanalyses of patients aged 75 years were performed in the multicenter, randomized, phase 3 AZA-001 trial, to explore the toxicity and outcomes of 5-AZA treatment compared with conventional care regimens (CCR; supportive care, low-dose cytarabine, or intensive chemotherapy) in elderly patients with highrisk MDS (FAB defined refractory anemia with excess blasts [RAEB], RAEB in transformation [RAEB-T], or chronic myelomonocytic leukemia [CMML] with more than 10% bone marrow blasts and white blood cell count < /L, and an IPSS risk of intermediate-2 or high). 13 Although 87 patients were randomized to receive 5-AZA or CCR, only two patients were treated with high-dose chemotherapy. With a median age of 78 years (range, years), patients in both groups had comparable baseline characteristics and comorbidities, including myocardial infarction (20%), angina pectoris (32%), ventricular arrhythmia (13%), congestive heart failure (17%), stroke or transient ischemic attack (7%), chronic obstructive pulmonary disease (28%), and diabetes mellitus (28%). IPSS was intermediate-2 or high in almost all patients of both groups; IPSS intermediate and high-risk cytogenetics was observed in 45% of the AZA group patients and 42% in the CCR group; more than 90% of patients of both groups had two or three cytopenias; and bone marrow blasts were 5% or more in all patients. In this study, 5-AZA showed similar results to those observed in younger patients. At 2 years, 55% of patients in the 5-AZA group were alive compared with 15% in the conventional care group (P<0.0001), with an overall survival after a median follow-up of 17.7 months not being achieved in the 5-AZA group and 10.8 months in the CCR arm. Forty-three percent of 5-AZA patients who were dependent on RBC transfusion became transfusion independent, compared with 22% in the CCR group (P=0.14). The median number of 5-AZA cycles received was seven (range, 1-23 cycles), only two of 38

6 6 Adv Ther (2011) 28(Suppl.2):1-9. patients receiving 5-AZA required a reduction in the dose, and 11 of 38 patients receiving 5-AZA discontinued treatment before completion of the study, with only five due to drug-related adverse events. Myelosuppression was the most common grade 3-4 adverse events for 5-AZA treatment, with neutropenia (61%) and thrombocytopenia (50%) being the most frequent cytopenias. The frequency of adverse events decreased after the first two cycles. Early induction deaths occurred in six patients receiving 5-AZA and three were considered possibly related to treatment. No relevant differences in treatment-related adverse events with 5-AZA were observed between patients aged 75 years and those aged <75 years. Likewise, the rate of hospitalization due to adverse events in the 5-AZA group compared with CCR did not show significant differences. In regard to the inclusion (Eastern Cooperative Oncology Group performance status <3 and life expectancy 3 months) and exclusion criteria (therapy-related MDS, prior 5-AZA therapy, and planned allo-hsct), and the study patient characteristics and comorbidities, it is feasible to think that most of these cases could fit with routine clinical practice. Therefore, these results could be considered reproducible, although confirmatory trials are required. The main disadvantage of 5-AZA therapy is the time to drug response, which is a median of three cycles, with 90% of responders after six treatment cycles. 14 This fact, combined with the increasingly strict economic policies in healthcare, makes the need for clinical trials essential to search for factors associated with 5-AZA response that would allow validation models to predict drug responses in order to rationalize its use. In this sense, in a recent study evaluating the prognostic factors associated with treatment response and overall survival in higher-risk MDS patients treated with 5-AZA, 35 a prognostic score was proposed to identify subgroups of patients with different prognosis with 5-AZA treatment. Factors that predicted a poor survival were performance status 2, intermediate or poor-risk cytogenetic group, circulating blasts, and transfusion-dependency 4 RBC transfusions/8 weeks. Three risk groups of patients with different survival rates could be identified once these risk factors were combined within a model: low (score= 0, median survival not reached), intermediate (score=1-3, median survival 15 months), and high (score=4-5, median survival 6.1 months). This prognostic score was validated in an independent cohort of patients in the AZA-001 trial. Despite this score, more studies are needed to define other potential predictors of response to 5-AZA, mainly those directed to monitor patterns of DNA methylation. In summary, both a geriatric assessment model to evaluate the performance status and capabilities/ limitations and a risk score of the underlying disease (ie, IPSS) and its influence in the quality of life should be applied before deciding how an elderly patient with malignant disease should be treated. Such prognostic indices should be taken into account for defining treatment goals, which may range from curative to merely palliative, with the aim of prolonging survival, while prioritizing the appropriate management of symptoms to ensure quality of life. MDS in the elderly should be managed in a similar manner to that in young patients, but the fact that they cannot undergo allo-hsct precludes any chance of cure. Aside from the main objective of prolonging overall survival and time to progression to AML, the key is to improve the quality of life for the longest possible time. To achieve these objectives supportive care is essential.

7 Adv Ther (2011) 28(Suppl.2): Low-risk patients will also benefit from er y thropoiesis-stimulating agents and immunosuppressive drugs. Immunomodulatory therapy with lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients with MDS with chromosome 5q deletion. Thus, management of elderly low-risk MDS patients does not differ from that in younger patients. Similarly, elderly patients with high-risk MDS may benefit from 5-AZA treatment, which has an efficacy and safety similar to that in patients <75 years and can increase the overall survival compared with the CCR used to date. However, for a more rational use of the drug, it would be appropriate to apply predictive scores of response to 5-AZA, pending further clinical trials to confirm which patients are most likely to benefit from treatment. CONCLUSION The management of MDS in advanced age has undergone changes since the advent of immunomodulatory and hypomethylating drugs. These patients, who were formerly considered amenable to merely supportive care, may currently benefit from a treatment able to modify the natural history of their disease. This represents a radical change in MDS management in the elderly and is a first step in the search for therapies that may cure the disease without using aggressive procedures, such as allo-hsct, which cannot be performed in many elderly patients. ACKNOWLEDGMENTS The author thanks Blanca Xicoy and Ricardo García Muñoz for their helpful comments and critical review of this paper. The author declares that there are no competing financial interests. This supplement was supported by Celgene. REFERENCES 1. Nguyen PL. The myelodysplastic syndromes. Hematol Oncol Clin N Am. 2009;23: Aul C, Gatterman N, Schneider W. Age related incidence and other epidemiological aspects of myelodysplastic syndromes. Br J Haematol. 1992;82: Benett JM, Catovsky D, Daniel MT, et al: The French- American-British Cooperative Group. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51: Swerdlow SH, Campo E, Harris NL, et al (eds). WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th Edition. Lyon: IARC Press; Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997; 89: Sierra J, Pérez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;100: Corey S, Cutler CS, Lee SJ, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104: List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352: List A, Dewald G, Bennett J, et al. Myelodysplastic Syndromes-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med : Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111: Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukaemia Group B. J Clin Oncol. 2002;20:

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