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• W1584395367 abstract "Anaemia is a common presenting feature and complication of a wide variety of conditions. Notwithstanding the underlying pathology, anaemia in itself has an important impact on the quality of life and even on the overall survival of patients. The reasons for this impact are manifold. The increasing life expectancy of the modern population leads to a larger proportion of elderly people, in which anaemia is known to be more prevalent. Studies have revealed that about 17% of hospital in-patients have anaemia and that this proportion increases to almost 30% of elderly people in the community and as many as 50% of those living on assisted homes. Not only age itself is responsible for the poor prognosis conferred by anaemia but also the increasing co-morbidity index presented by these patients means that low haemoglobin has a much more severe impact on the function of other organs, mainly the heart. Chronic anaemia leads to left ventricular hypertrophy and, ultimately, congestive cardiac failure. Anaemia also has a significant impact on the physical performance at all ages but more significantly on that of the elderly. It is associated with increased number of falls, declining cognitive function, immobility and increased frailty. This impact may not be significant when the cause of anaemia is easily corrected, as is the case with vitamin deficiencies and chronic bleeding from identifiable foci. However, in the context of diseases in which anaemia is long-lasting, it has repeatedly been identified as a poor prognostic indicator, resulting in significantly reduced lifespan. In addition, the strategy generally used to correct chronic anaemias is the transfusion of red cells, the dependence of which also confers a poor prognosis to patients. It has, therefore, become an important target of modern haematology to correct anaemia to render patients independent of transfusions and prolong their survival. Perhaps, the most important aspect in approaching a patient with anaemia is to effectively identify correctable causes. The more frequent causes, such as vitamin deficiencies, bleeding and renal failure, are rarely missed. However, there are several diseases which may produce anaemia that will normalize once the underlying condition is treated. Such is the case with hypothyroidism, haemolysis and HIV infection. Of those in whom no readily identifiable cause for anaemia is found, about half will have myelodysplasia (MDS) [1]. It has been in the context of this pathology that significant advances have been made in the impact and correction of anaemia, making it a useful paradigm for the management of the important public health problem which anaemia is. MDS is a haematopoietic clonal disorder characterized by inefficient production of the various blood cell lineages. The most common manifestation of this heterogeneous group of disorders is cytopenias. Approximately, 80% of patients have anaemia, with thrombocytopenia and neutropenia presenting in around 30%. The natural history of MDS is progression to acute myeloid leukaemia, which is often the terminal event in these patients. However, the rate of progression to acute leukaemia is not uniform amongst all patients. The International Prognostic Scoring System (IPSS) stratifies patients into risk groups, which are predictive of the rate of progression to acute leukaemia and survival. Those at risk of more rapid progression can be identified by the increased number of blasts in the bone marrow, the presence of two or three cytopenias and poor risk cytogenetic alterations. According to the IPSS, patients can be classified into four risk groups [2, 3]. This stratification has a significant impact on the treatment intentions for these patients. Those in the higher risk groups are a greatest risk of transformation and therapy is, therefore, aimed at preventing or delaying this progression. Those in the lower risk groups suffer mainly as a consequence of the cytopenias, above all anaemia. Consequently, therapy in these patients must be aimed at reducing transfusion requirements. It is also important to note that transfusion dependence in itself is an independent poor prognostic indicator in MDS [4]. This may be explained by a number of factors, such as iron overload, immune-modulation by transfusion and more aggressive underlying disease. Whichever the biological reason for the negative prognostic impact of transfusions, therapies which reduce transfusion requirements improve the outcome of patients of all risk groups in terms of disease progression and overall survival. For this reason, great efforts have been made in the sense of developing therapies, which produce haematological improvement and transfusion independence in MDS. Before outlining the available strategies to reduce transfusion requirement in MDS patients, it is important to note that an adequate transfusion programme alone is responsible for the continued survival of these patients. Transfusions are almost inevitably required at presentation and until the various treatments outlined below start to take effect. In addition to transfusions, there is an increasing evidence that, for selected patients, appropriate and effective iron chelation confers benefit in terms of reduced morbidity and improved survival [5, 6]. Like transfusion dependence, iron overload has been identified as an independent negative prognostic indicator in MDS. For this reason, most centres will administer Desferrioxamine initially, mainly for economic reasons, but the logistical difficulties of achieving adequate chelation with this drug in transfusion dependent patients has led to the switch to the oral chelator Deferasirox in those for whom chelation is indicated [7]. Chelation has been shown to reduce cardiac failure, diabetes and liver dysfunction in chronically transfused patients and there are anecdotal reports that adequate chelation may even reduce transfusion requirements. Treatments aimed at reducing transfusion requirements in MDS differ mainly depending on the risk group of the patients. Approximately, two-thirds of MDS patients have lower risk disease and transfusion dependence is the main clinical problem in this group. Studies carried out by the Nordic MDS Collaborative Group have identified a subgroup of lower risk patients who obtain haematological improvement with erythropoiesis stimulating agents (ESA). A pre-transfusional serum erythropoietin of less than 500 U/l and transfusion requirement of less than 2 U of red cell concentrate per month was identified as predictive factors for response to ESA. Patients with anaemia in whom both factors are present have a 75% chance of achieving a haematological response with transfusion independence. The presence of only one factor predicts a response rate of 25% but this falls to 7%, where none of the two factors are present. Relatively large doses of erythropoietin are needed: 30 000–90 000 U weekly of erythropoietin or up to 300 μg weekly of Darbopoietin. Responses are similar regardless of the formulation used and it is therefore advantageous to start with the cheapest formulation available. There is no universal consensus regarding the dose titration. Some groups advocate starting at the highest possible dose and reducing to the minimum dose which produces response, whereas other groups use the inverse approach, starting at lower doses and escalating every 4 weeks until a response is obtained. Regardless of the approach used, there is no benefit in continuing therapy if no response has been obtained after 12 weeks’ therapy. Some patients benefit from the addition of G-CSF to ESA. The greatest benefit is seen in those with ring sideroblasts, where G-CSF plays an important role in mobilizing iron trapped in erythroblast mitochondria. These patients benefit from receiving ESA and G-CSF from the outset. The dose of G-CSF should be titrated according to the leucocyte count, aiming to keep it under 20x109/l. Normally, doses of 100 μg one to three times per week are sufficient 8]. Responses obtained with ESA in this group of patients normally last 18–24 months, after which the response is lost and the patients become once again transfusion dependent. Nevertheless, this is an important therapeutic weapon in this disease and all patients should be assessed at the outset for their probability of response to ESA. Recent investigations into the pathophysiology of MDS have revealed that immunological mechanisms are partly involved in its aetiology. Hypocellularity of the bone marrow and T-cell restriction documented in MDS patients indicate that there may an overlap between MDS and aplastic anaemia. This notion was reinforced by the responses obtained with anti-thymocyte globulin (ATG) in MDS patients. Needless to say, in the context of this heterogeneous group of disorders, response is best in selected patients. These include those under the age of 60 years, with lower risk disease, expressing HLA-DR15 or with a PNH clone. Some sources have also identified trisomy of chromosome 8, a hypocellular bone marrow and low transfusion dependence as predictive of response to ATG but this has not been confirmed by other series. In selected patients, a response rate of approximately 30% has reported [9]. A higher rate of haematological responses has been achieved with immunomodulatory agents. Initial trials were carried out with Thalidomide in the beginning of the 21st century. In these studies, haematological improvement was achieved in 20–50% of patients, depending on the study. However, treatment interruption due to intolerance was as high as 65% in one series, rendering this treatment impossible to administer. Yet, the responses seen were encouraging and led to the development of Thalidomide analogues with greater clinical efficacy and a more tolerable side effect profile [10]. Lenalidomide was the first of these drugs to be used in clinical practice. In an initial phase II trial published in 2005, 43 patients with transfusion dependent MDS were treated with 25 or 10 mg of Lenalidomide. In this cohort, an unprecedented haematological response rate of 83% was observed in those with deletion of 5q [11]. This led to a phase III trial in which 143 patients with deletion 5q were randomized to receive 10 mg Lenalidomide for 3 or 4 weeks of a 4-weekly cycle. Haematological improvement was observed in 75% of patients, with transfusion independence achieved by 66%. The median time to response was of 4·4 weeks and the responses were still present at 24 weeks in 73% of patients. Importantly, 70% also achieved a cytogenetic response, with total normalization on the karyotype in 44% [12]. Due to safety concerns, a second study of Lenalidomide in patients with deletion 5q was carried out in which Lenalidomide doses of 5 and 10 mg were compared with placebo. This study confirmed the response rates observed in the initial study (IT 61%), confirmed 10 mg for 3 weeks in a 4-weekly cycle as the ideal starting dose and has not corroborated the safety concerns raised by the initial trial. The full results are to be published in the near future. In the initial phase II trial published in 2005, haematological improvement was also observed in 57% of transfusion dependent MDS patients with normal karyotypes [13]. This observation prompted an ongoing trial in which lower risk transfusion dependent MDS patients who do not respond to ESA are randomized to receive placebo or Lenalidomide. This study is currently recruiting and offers hope to this group of patients whose present therapeutic options are limited to transfusion dependence. Patients with higher risk disease also suffer from anaemia and heavy transfusion dependence. In addition, their rate of disease progression to acute leukaemia is rapid, directing the therapeutic efforts towards prevention of this progression. These patients should be considered for allogeneic bone marrow transplantation in first line as this is the only curative treatment option in MDS. However, due to the toxicity of this procedure, the availability of donor and average advanced age of MDS patients, transplantation is an option only for a minority of patients. Following the publication of the important work by Dr Silverman and the CALGB group [14] reporting the efficacy of low dose Azacitidine in higher risk MDS patients, a large multicentre trial was organized to further study the benefits of this drug in this group of patients. The trial design permitted the comparison of Azacitidine with the conventional care regimens the recruiting physicians would normally use: best supportive care, low-dose Cytarabine or intensive chemotherapy. Three hundred and fifty eight patients were included and the trial showed a significant survival advantage in those treated with Azacitidine, with a median survival of 24·5 months in this group compared with 15 months in those receiving conventional care regimens. This advantage was present in all subgroups regardless of age, blast count or karyotype. As expected, the survival advantage was verified in those who achieved a response but, interestingly, it was independent of the quality of response obtained. Those who achieved haematological improvement had as much survival benefit as those with a complete response. Treatment with Azacitidine delayed progression to AML from 12–26 months and achieved transfusion independence in 45% of patients compared with 11% of those treated with conventional care regimens [15]. These impressive results have led to the international recommendations that Azacitidine should be used as first line therapy in higher risk MDS patients who are not transplant candidates [16]. The transfusion independence seen in higher risk patients also prompted studies in which Azacitidine was tested in transfusion dependent MDS patients with lower risk disease. Transfusion independence rates of almost 50% were achieved, making this a possible therapeutic option for these patients [17]. The clinical and pathophysiological heterogeneity of MDS has led to the search discovery of a variety of therapeutic options with the main objective of improving anaemia and reducing transfusion dependence. With this newly expanded therapeutic armamentarium, it is crucial that patients with anaemia are accurately studied and diagnosed so that they may benefit from the best treatment available. The author declares that there are no potential conflicts of interest." @default.
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• W1584395367 date "2011-05-13" @default.
• W1584395367 modified "2023-09-25" @default.
• W1584395367 title "New approaches to managing anaemia" @default.
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