Twist and shout: one decade of meta-analyses of erythropoiesis-stimulating agents in cancer patients

Anemia associated with cancer and cancer therapy is a common and important issue in the treatment of patients with malignant disease. Conventionally, blood transfusions are used to treat severe cancer-related anemia. Short- and long-acting preparations of recombinant human erythropoiesis-stimulating agents (ESAs) offer an alternative treatment option. Multiple studies and subsequent meta-analyses have demonstrated that ESA treatment increases hemoglobin levels and reduces the likelihood of transfusion for a proportion of treated patients. However, studies that attempted to evaluate whether ESAs improve tumor response and survival have generated conflicting evidence. Results of smaller trials reporting improved survival outcomes were contradicted by large randomized controlled trials that reported more deaths in patients receiving ESAs. In addition, there is strong evidence that cancer patients receiving ESAs have an increased risk of thromboembolic and cardiovascular events. We herein review the main meta-analyses published in the field, their strengths and weaknesses, their contribution to patient management and future perspectives for systematic reviews.     

Erythropoiesis-stimulating agents for anemic patients with cancer

Anemia in cancer patients is common and often associated with decreased survival and quality-of-life scores. The introduction of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with solid tumors and nonmyeloid malignancies in the 1990s has proved an important alternative to red blood cell transfusions. ESAs have been consistently shown to increase hemoglobin levels and reduce transfusion requirements in anemic cancer patients whilst also being associated with improvements in quality of life. Several recent studies, however, have raised concerns about the safety of ESAs with regards to an increased number of thrombo-embolic events, decreased on-study survival and possible effects of ESAs on tumor progression. This has led to a reappraisal of the role of ESAs in the treatment of anemic cancer patients. It remains generally accepted that, if used within current guidelines and labeling recommendations, ESAs can still be considered safe in patients receiving chemotherapy once individual risks are balanced against possible benefits.     

Anemia of aging: the role of chronic inflammation and cancer

Aging is associated with increased incidence and prevalence of anemia, leading to a number of adverse health outcomes. These include death, functional dependence, increased risk of therapeutic complications, falls, and dementia. In approximately 30% of cases, anemia in older individuals is due to either relative or absolute erythropoietin (EPO) deficiency. Absolute EPO deficiency may be primary or secondary to declining renal function. Relative EPO deficiency is due to an age-related pro-inflammatory status that reduces the sensitivity of erythropoietic precursors to EPO. Despite this condition of EPO deficiency, the management of anemia of aging with erythropoiesis-stimulating agents (ESAs) is controversial, unless the anemia is due to renal insufficiency. The main concern related to this treatment arises from eight studies of ESAs in cancer, suggesting that ESAs may reduce patient survival in addition to increasing the risk of deep vein thrombosis. The results of these studies contrast with a host of other trials showing the safety of ESAs. The discrepancy may be explained in part by the fact that, in the trials suggesting a detrimental effect of ESAs, the goal was to obtain hemoglobin (Hb) levels higher than 12 g/dL. Because of this concern, correction of anemia in elderly individuals with relative EPO insufficiency should not be attempted outside clinical trials.     

Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-β superfamily inhibitors

Patients with lower-risk myelodysplastic syndromes (MDS) are mainly affected by chronic anemia and fatigue. Treatment strategies aim to improve anemia and quality of life, as well as iron overload due to red blood cell transfusion support. To promote proliferation and differentiation of erythropoiesis, erythropoiesis-stimulating agents (ESAs) such as erythropoietin (EPO) and mimetics are applied as first-line therapy in a large fraction of lower-risk MDS patients. In general, ESAs yield favorable responses in about half of the patients, although responses are often short-lived. In fact, many ESA-refractory patients harbor defects in late-stage erythropoiesis downstream of EPO action. Novel transforming growth factor (TGF)-β superfamily inhibitors sotatercept and luspatercept represent a promising approach to alleviate anemia by stimulating erythroid differentiation.     

Erythropoiesis-stimulating agents and heart failure

Anemia is a common comorbidity in heart failure (HF) patients. Its occurrence and severity are associated with worse prognosis. Although the etiology of anemia is multifactorial, inappropriate erythropoietin (EPO) production and/or bone-marrow resistance to EPO appear crucial in majority of anemic HF patients. Consequently, treatment based on this pathophysiological background may prove to be most effective and beneficial. In a number of smaller clinical studies, administration of erythropoiesis-stimulating agents (ESAs) to anemic HF patients improved a number of surrogate endpoints, including left ventricular function, exercise capacity, renal function, and different quality of life parameters. However, two larger, phase II studies, did not fully confirm these promising results. Furthermore, many concerns have been raised on the safety of ESAs after the recent publication of studies correcting anemia in patients with chronic kidney disease (CKD). On the other hand, chronic HF population varies significantly from CKD patients, with different comorbidities, renal function, and etiology of anemia. Moreover, ESAs have been shown to possess robust nonhematopoietic effects in the heart, namely inhibition of apoptosis and stimulation of neovascularization. Therefore, large-scale trials with ESAs are required to examine the effect and safety of anemia treatment in HF patients.     

Biosimilar epoetin in elderly patients with low-risk myelodysplastic syndromes improves anemia,quality of life,and brain function

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and a risk of progression to acute myeloid leukemia (AML). Anemia affects the course of disease, quality of life (QOL), and cognitive function of MDS patients. Erythroid-stimulating agents (ESAs) are effective; however, not all patients respond to ESAs. To evaluate the effectiveness of a biosimilar epoetin α (Binocrit) for the treatment of anemia in low-/intermediate-1 risk MDS patients and to evaluate the impact of ESAs on QOL and on cognitive function, 24 consecutive patients aged over 65 years were treated with Binocrit at 40,000 IU once a week for 12 weeks and were followed for at least 3 months. Responsive patients continued with 40,000 IU once a week for a further 12 weeks. Changes in QOL were assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An), while cognitive assessment was carried out by mini-mental state examination (MMSE). All patients completed 12 weeks of therapy. Sixteen patients (66.67 %) achieved an erythroid response (ER), 15 patients (62.5 %) became transfusion independent and remained free from transfusion requirement for at least 3 months, while two patients had reduction in transfusion requirement of at least four RBC transfusions/8 weeks compared with the pretreatment transfusion requirement. Seven patients were nonresponders (29.1 %), of whom four patients were low risk and three intermediate-I risk. Seven transfusion-independent patients were low risk, and eight were intermediate-1 risk. Median hemoglobin (Hb) values were significantly higher after treatment in responders (p?<?0.001). ER was maintained after 24 weeks. Statistically significant positive correlations between improvement in Hb and variations in patients’ mini-mental (Spearman’s Rho?=?0.54, p?<?0.01) and FACT-An scores (Spearman’s Rho?=?0.59, p?<?0.003) were demonstrated. This preliminary study shows that Binocrit is promising for the treatment of anemia of MDS patients. ER positively correlates with improvements in patients’ cognitive status and positive changes in QOL.     

Biological functions and therapeutic use of erythropoiesis-stimulating agents: perplexities and perspectives

Randomized clinical studies, carried out in patients with haematological malignancies and with solid tumours, have consistently demonstrated that treatment with recombinant human erythropoietin (Epo) increases haemoglobin levels, reduces blood transfusion requirements, and improves the quality of life. In addition, identification of erythropoietin receptor (EpoR) expression on many types of non-erythroid and cancer cells has spurred an interest in the extra-haematological activities of Epo itself and other erythropoiesis-stimulating agents (ESAs). Epo and its derivatives have emerged as major tissue-protective cytokines in ischaemic and degenerative damage of cardiovascular, neurological and renal diseases, while their angiogenetic and immunomodulatory properties indicate that their therapeutic potential may extend well beyond erythropoiesis alone. Both preclinical and clinical data, however, have suggested that they may contribute to tumour progression and prejudice survival when administered to anaemic cancer patients, though the results are equivocal and the assumed mechanisms by which tumour growth could be promoted are not fully understood. While these findings offer new perspectives, they nonetheless demand caution in the employment of ESAs. Further, well-designed experimental and clinical studies are warranted.     

Modulation of platelet activation in chronic kidney disease patients on erythropoiesis-stimulating agents

Background: Clinical trials demonstrate either no benefit or increased risk of cardiovascular events and mortality in patients with chronic kidney disease (CKD) targeted for higher hemoglobin levels, who are treated with erythropoiesis-stimulating agents (ESAs). The mechanism underlying this observation remains unexplained. Methods and Results: We assessed platelet activation by measuring soluble P-selectin (sPsel), CD40 ligand (CD40L), and circulating microparticles (CMP) in patients with CKD. Higher hemoglobin levels were associated with increased Psel levels in patients on ESAs but not in ESA-na?ve anemic and nonanemic patients. Psel positively correlated with CMP and CD40L in both anemic and nonanemic patients. Multivariate linear regression analysis revealed an association between increased Psel levels and hemoglobin concentration in patients receiving ESAs. Conclusions: Anemic CKD patients on ESAs demonstrate increased levels of markers of platelet activation. These observations suggest a potentially complex interplay between platelet activation, impaired kidney function, and treatment of CKD anemia with ESAs.     

American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer

Purpose: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. Methods: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. Results: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. Recommendations: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.     

慢性肾脏病合并肾性贫血的处理策略

本文概述了慢性肾脏病合并贫血的病因;着重阐述其诊断思路;系统介绍了慢性肾脏病合并贫血的治疗策略,特别是刺激红细胞生成药物和铁剂的合理应用;并提出目前在慢性肾脏病合并贫血诊治上存在的问题。目的在于规范慢性肾脏病合并贫血的临床诊断和治疗,促进该领域的临床研究,提高基层医生慢性肾脏病的治疗水平。     

Two faces for Janus: recombinant human erythropoiesis-stimulating agents and cancer mortality

Untreated anemia in cancer patients has severe consequences for many organ systems. Erythropoiesis-stimulating agents (ESAs) are indicated for the treatment of chemotherapy-induced anemia in cancer patients. Several studies in patients with solid tumors have shown that these agents effectively increase hemoglobin levels, improve the quality of life and reduce the requirement for emergency blood transfusions, regardless of the type of concomitantly administered chemotherapy. The meta-analysis evaluates the impact of ESAs during the active study period on mortality and the overall survival during the longest available follow-up, irrespective of anticancer treatment, with little heterogeneity between trials. A total of 10,441 patients on chemotherapy were enrolled in 38 trials. There was little evidence for a difference between trials of patients administered different anticancer treatments (p for interaction = 0.42). The meta-analysis demonstrated that ESAs increased mortality by 17% during the active study periods and worsened overall survival in patients with cancer. However, 62% of patients evaluated in this analysis started the ESA therapy with basal hemoglobin values over that recommended by ASCO/ASH guidelines. However, the high quality of meta-analysis and the novelty of the information do not represent an obstacle for the continued the use of ESAs within the revised European Organisation for Research and Treatment of Cancer (EORTC) guidelines and the revised labels.     

Erythropoietin and the vascular wall: The controversy continues

Background and aimsErythropoietin (EPO) stimulates erythropoiesis through its specific receptor (EPO-R). Preclinical work has assigned a role for the EPO/EPO-R system in the heart and blood vessels. The potential use of erythropoiesis-stimulating agents (ESAs) for nonhematopoietic indications is a focus of current research. This article considers proven actions of EPO in the cardiovascular system, with emphasis on the human responses.Data synthesisBy use of specific anti-EPO-R antibody no EPO-R protein was detected by Western blotting in normal non-erythroid tissues. Clinical trials failed to demonstrate clear beneficial effects of high-dosed ESAs in patients with coronary syndrome or myocardial infarct. While ESA therapy may lead to an elevation in arterial blood pressure in previously anemic patients, several studies have reported no effects on vessels/blood pressure with ESAs. EPO has been reported to stimulate angiogenesis. EPO-R mRNA is detectable in human vascular endothelium. However, in most vitro studies very high concentrations of EPO were applied and well-designed studies have failed to show direct effects of ESAs on endothelial cells. Whether EPO promotes the mobilization of myeloid progenitor cells into the blood stream still needs to be studied in more detail, as this effect may prove useful for augmenting the neovascularization of ischemic tissues. With respect to the administration of ESAs to tumor patients, a deeper insight into the role of EPO for tumor angiogenesis is desirable.ConclusionsThe enthusiastic reports of the nonhematopoietic cytoprotective potential of EPO and its derivatives in the cardiovascular system have not yet been confirmed in placebo-controlled clinical trials.     

Correcting Anemia in Heart Failure: The Efficacy and Safety of Erythropoiesis-Stimulating Agents

BackgroundRandomized controlled trials (RCTs) evaluating the efficacy and safety of erythropoiesis-stimulating agents (ESAs), including erythropoietin and darbepoetin, among patients with chronic heart failure (CHF) and anemia have yielded heterogeneous results, and important safety questions remain unanswered. We therefore undertook a meta-analysis to examine the effects of ESAs in this population.Methods and ResultsWe systematically searched EMBASE, Medline, the Cochrane Library, ClinicalTrials.gov, and relevant bibliographies to identify all relevant RCTs. Data were aggregated using random-effects models. We identified 9 RCTs (n = 747 patients). Compared with control, ESAs were associated with a significant reduction in CHF-related hospitalizations (odds ratio [OR] = 0.41; 95% confidence interval [CI] = 0.24-0.69). The effect of ESAs on mortality was inconclusive (OR = 0.60; 95% CI = 0.32-1.11). ESAs were associated with improved quality of life and left ventricular ejection fraction, lower brain-natriuretic peptide levels, and improved exercise tolerance test performance. There was no evidence of an increase in the incidence of adverse events among patients randomized to ESAs (OR = 0.86; 95% CI = 0.51-1.42).ConclusionsIn patients with CHF and anemia, ESAs are associated with a decrease in CHF-related hospitalizations and improved quality of life and exercise tolerance. However, RCTs completed to date have involved a small number of patients, and available mortality data are inconclusive.     

Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials

Background  

Iron supplementation could improve the hematopoietic response of erythropoiesis-stimulating agents (ESAs) used for chemotherapy-induced anemia.     

Anemia and cardiovascular risk in the patient with kidney disease

Patients with chronic kidney disease (CKD) often experience anemia, which causes fatigue and diminished quality of life. In addition, anemia in CKD has been associated with increased risk for cardiovascular events and left ventricular hypertrophy. To the extent that anemia plays a causal role in these relationships, treatment with erythropoiesis-stimulating agents (ESAs) could potentially help improve outcomes. To date, however, results from interventional studies have been disappointing in this regard. This article reviews the relationship between anemia in CKD and cardiovascular risk and explores current knowledge on ESA treatment.     

Successful Treatment of Antibody-mediated Pure Red Cell Aplasia Induced by Continuous Erythropoietin Receptor Activator with Prednisolone

Pure red cell aplasia (PRCA) associated with erythropoiesis-stimulating agents (ESAs), which were first reported in 1998, usually occurs with subcutaneous administration of epoetin alfa (Eprex^Ⓡ). Improvements in ESA storage, handling, and administration methods have reduced the PRCA incidence. Continuous erythropoietin receptor activator (CERA) is a third-generation ESA that is rarely reported to induce PRCA. We herein report a case of CERA-induced PRCA presenting with positive anti-erythropoietin (EPO) and anti-CERA antibodies, which was successfully treated with prednisolone. Clinicians should be aware of the possibility of antibody-mediated PRCA induced by an ESA in CKD patients with anemia with reticulocytopenia and low serum EPO levels.     

Eisen- und ESA*-Therapie bei renaler Anämie

Recently, the general framework of treatment with erythropoiesis-stimulating agents (ESA) for renal anemia has changed fundamentally. Results from the CREATE and CHOIR trials for chronic kidney disease (CKD) patients prompted the regulatory authorities to reduce target hemoglobin (Hb) levels to the 11–12 g/dl range for all patients with renal anemia and full correction is explicitly discouraged. The first biosimilar ESAs for the treatment of renal anemia have been approved in Europe, but it remains to be seen whether efficacy and safety will be as good as with the original preparations, and whether the cost of treatment will come down by increasing the number of suppliers. A new area of concern in ESA therapy is the stability of Hb levels, as it is feared that excessive fluctuations in Hb levels might be associated with an unfavorable outcome. According to the Food and Drug Administration (FDA), hyporesponsive patients rather than being treated with excessive ESA doses, should receive ESA doses which are just sufficient to avoid the necessity of transfusions.     

Methods and progress in assessing the quality of life effects of supportive care with erythropoietin therapy

Anemia is a common disorder in patients with cancer and can be caused by the disease itself or by cancer-related therapy. The cardinal symptom of anemia, fatigue, is the most commonly reported symptom in patients with cancer and has profound effects on patient well-being and quality of life. Until recently, blood transfusions were the mainstay of management of cancer-related anemia, despite attendant risks of transfusion-related reactions and transmission of infection. Recombinant human erythropoietin (epoetin-alpha), an effective alternative to blood transfusion, has been shown to improve hematologic parameters, including hemoglobin levels, Hematocrit, and transfusion requirements. Clinical trials have also suggested that this intervention has a positive impact on the quality of life of patients with cancer. The literature published between November 2000 and October 2001 continues to support a positive effect of epoetin-alpha therapy on the quality of life of patients with cancer and includes investigations of dosing schedules more convenient for patients and trials of longer-acting versions of epoetin-alpha, such as the novel erythropoiesis-stimulating protein. Future studies that incorporate measures of patient-reported outcomes and rigorous methodologic designs are needed to strengthen and elucidate this association between these pharmacologic therapies for cancer-related anemia and quality of life.     

A phase 3, open-label,single-arm study of vadadustat for anemia in chronic kidney disease for Japanese patients on hemodialysis not receiving erythropoiesis-stimulating agents

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open-label, single-arm study evaluated the efficacy and safety of vadadustat in 24 Japanese patients with CKD-associated anemia on hemodialysis who were not receiving erythropoiesis-stimulating agents (ESAs). Patients received vadadustat for 24 weeks; the starting dose was 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 10.0–12.0 g/dL. The least squares mean of average Hb at Weeks 20 and 24 (95% confidence interval) was 10.75 g/dL (10.35, 11.14). The most common adverse event was shunt stenosis (25.0%). Adverse drug reactions (diarrhea and vomiting) occurred in two patients (8.3%) and the severity was mild. Vadadustat increased and maintained Hb levels within the target range and was generally well-tolerated in Japanese patients with anemia on hemodialysis not receiving ESAs.     

Transfusion Burden among Patients with Chronic Kidney Disease and Anemia

Background and objectives: Although well-described for patients who require dialysis, information on transfusion burden related to anemia in the nondialysis patient population with chronic kidney disease (CKD) is lacking.Design, settings, participants, & measurements: A retrospective study was conducted of patients with CKD and chronic anemia from 2002 through 2007 in the Veterans Administration Healthcare System. Included patients had stage 3 CKD or higher and anemia (one or more hemoglobin [Hb] levels <11 g/dl or received anemia therapy [erythropoiesis-stimulating agents [ESAs], iron, or both]). The outcome of interest was transfusion events, which was evaluated in relation to the absolute Hb level and changes in Hb levels overall and according to the type of treatment received (no treatment, iron therapy, ESA therapy, or ESA and iron therapy) concurrent with each Hb measurement.Results: Among 97,636 patients with CKD and anemia, we observed 68,556 transfusion events (61 events per 100 person-years), 86.6% of which occurred in inpatient settings. At all Hb levels, transfusion events were highest during periods of no treatment and increased with declining Hb levels. Between an Hb of 10.0 and 10.9 g/dl, the transfusion rate was 2.0% for those who received an ESA, iron, or both and 22% for those who received no treatment; at an Hb level of 7.0 to 7.9 g/dl, the transfusion rate was 10 to 12% for treated and 58% for untreated patients. Low absolute Hb levels but not Hb changes was most predictive of a transfusion even after adjustment for patient case mix.Conclusions: Transfusions are still used to treat anemia in patients who have CKD and do not require dialysis, although they occur considerably less frequently in patients who receive other available anemia therapies.Persistent anemia is a common complication for patients with chronic kidney disease (CKD) (1–3), primarily stemming from declining endogenous erythropoietin production (4). After the addition of erythropoiesis-stimulating agents (ESAs) to available treatments for chronic anemia, there has been a marked decline in transfusion events in this population (5). Current anemia management guidelines recommend treating hemoglobin (Hb) levels to 10 to 12 g/dl and using the lowest possible ESA dosages to avoid the need for red blood cell transfusions (6).Although transfusions are considerably safer than in the past (7), transfusion-related risks persist. Risks include iron overload; transfusion reactions; transmission of infectious agents; acute lung injury; and the development of alloantibodies, which can affect a patient’s ability to receive organ transplants (8–9). In addition, significant costs are associated with blood transfusions, including storage and acquisition (10).Ibrahim et al. (11) described a pattern of declining transfusion use between 1992 and 2005 subsequent to the introduction and widespread adoption of anemia management with ESAs using data from the US Renal Data System. The authors also showed that the mean outpatient Hb level before transfusion events increased from 9.0 g/dl in 1992 to 10.3 g/dl in 2005. In the nondialysis setting, anemia management patterns, particularly use of transfusions, have not been explored because of the absence of a national surveillance system that captures information on routine Hb measurements and available anemia management therapies, including ESAs and iron.The Veterans Health Administration (VHA) is a national network of inpatient and outpatient care facilities with longitudinal data on diagnoses, procedures, medications, and laboratory values that may be used to characterize the use of transfusions in a single, nationwide health care system. We used national VHA data to estimate transfusion use and predictors of transfusions in patients with CKD and anemia according to their receipt of alternative anemia therapies.