Use Of Erythropoietic Agents Research Articles

Current Status of Use of Erythropoietic Agents in Cancer Patients

Anemia is frequently observed in cancer patients and can cause symptoms and result in red cell transfusions. The erythropoiesis stimulating agents (ESAs) have been shown to increase hemoglobin levels and reduce transfusion requirements in anemic subjects with cancer who are receiving chemotherapy. Initially, these benefits motivated broad use of the ESAs in oncology. Over the past 10 years, recognition of the adverse events that can be associated with ESA use in these patients, particularly venous thrombosis, has resulted in a rethinking of the issue of who are the correct candidates for treatment. Different health care systems have come to different conclusions based upon the available data and additional data are still being generated. This article will review the data concerning the safety of ESAs in cancer patients, including the results of additional trials published in the past 2 years. This will include a discussion of the potential of ESAs to impact tumor progression or survival. Thrombosis remains the most important and best documented adverse event associated with ESA therapy in oncology. The mechanism(s) through which ESAs alter thrombosis risk are still very poorly understood.

Assessing the Risk and Prognosis of Thrombotic Complications in Cancer Patients

Cancer is characterized by the development of a prothrombotic state. Approximately 15% to 20% and 1.5% to 3.1% of cancer patients develop venous and arterial thrombosis, respectively, whereas 18% to 20% of idiopathic venous events are caused by an occult neoplasia. The highest risk is observed in hematologic, gastrointestinal, and lung malignancies, as well as in patients with active disease, especially in the first 3 months after cancer diagnosis. Hospitalization, surgical interventions, and implanted venous devices increase the thrombotic risk. Patients with metastatic disease, febrile neutropenia, infections, and severe comorbidities experience more frequently a thrombotic event. A contemporary prechemotherapy predictive model incorporates both clinical and biologic parameters, such as the primary cancer site, platelet count, white blood cell count, hemoglobin, use of erythropoietic agents, and body mass index. Several studies aim to clarify the prognostic value of tissue factor, P-selectin, thrombin generation, microparticles, and D-dimers. To summarize current views on epidemiology, risk factors, and predictive variables, discussing the future perspectives and existing limitations in clinical practice. Review of published literature, including review papers, epidemiologic studies, and clinical trials, in online medical databases. The thrombogenic properties of tumor cells affect the prognosis and quality of life for the cancer population. Despite the improved awareness and prompt use of thromboprophylaxis, recent studies reported increased rates of thrombotic events, whereas the annual risks for thrombosis recurrence and bleeding are 21% and 12%, respectively. The clinical use of risk factors and prognostic parameters could allow for patient risk stratification and individualization of anticoagulant treatment.

Low risk of symptomatic venous thromboembolic events during growth factor administration for PBSC mobilization

The use of erythropoietic agents has been associated with an increased risk of venous thromboembolic events (VTEs), especially in patients with underlying malignancies. However, it is not known whether there is an increased risk of VTE associated with granulocyte growth factors. We reviewed 621 patients undergoing PBSC mobilization using granulocyte growth factors, alone or in combination with CY. Patients with a diagnosis of AL amyloidosis (AL: 114; 18%), multiple myeloma (MM: 278; 44%) Hodgkin lymphoma (HL: 20; 3%) or non-Hodgkin lymphoma (NHL: 209; 33%) were included. Symptomatic VTE occurred in six (0.97%) patients: two AL, two MM and two NHL. Of the six patients, two had pulmonary embolism, one developed deep vein thrombosis and three developed symptomatic catheter related thrombosis. Two patients with AL had heparin-induced thrombocytopenia and thrombosis. We found a low incidence of VTE among patients undergoing PBSC mobilization.

Therapie der chronischen Entzündungsanämie – Eisen, Bluttransfusionen oder Erythropoetin?

The anaemia of chronic disease is a concomitant phenomenon of various chronic intectious, neoplastic and autoimmune diseases. Whenever possible, the treatment of the underlying disease is the treatment of choice. When this is not feasible at present blood transfusion, iron therapy and the use of erythropoietic agents are further treatment options. Blood transfusions are reserved for the short-term use in the case of life-threatening anaemia (Hb 100 μg/L) without functional iron deficiency should not be treated with iron. The erythropoietic stimulation with the currently available agents epoetin alfa, epoetin beta and darbepoetin can result in a nearly 100% therapeutic response provided the individual iron requirements are considered. Using erythropoietin in combination with iron in patients with RA und ACD, it has been shown that besides the correction of the haemoglobin deficit also disease activity as well as health-related quality of life could be approved. The risk-benefit ratio of the treatment of ACD regarding the underlying disease has, however, not been fully evaluated so far. This is also true for the use of iron and erythropoietin in the treatment of ACD. Further therapeutic options such as the use of iron chelating agents or other agents with an influence on the regulation of the cellular iron metabolism are in preclinical evaluation. It can, however, already be stated with regard to an appropriate management of patients with rheumatic diseases, regardless of the underlying disease, that ACD can be treated effectively.

Biosimilars: Illustration of scientific issues in two examples

Scientific issues and clinical implications associated with the use of biosimilars (biopharmaceuticals that are similar to an innovator product, notwithstanding minor differences) are illustrated in two examples, botulinum neurotoxins and erythropoietic agents. Comparison of Botox and Dysport, products that both contain botulinum toxin type A, revealed distinct differences in physicochemical characteristics, approved indications, dosing, and frequency of adverse events. Differentiating between botulinum toxin products on the basis of immunogenicity in the clinical setting would be of value in product selection, and pharmacists could play a valuable role in collecting antigenicity rate data and reporting them to the Food and Drug Administration (FDA) and the manufacturer. Various ethical and practical considerations are associated with the use of erythropoietic agents. The desire to optimize patient care and outcomes must be weighed against the likelihood of obtaining reimbursement for erythropoietic therapy, and reimbursement policies vary from one state to another. Comparing erythropoietic agents requires the use of a consistent and valid definition of treatment response. The definition of response that FDA will accept in the future when evaluating applications for approval of new biosimilar erythropoietic agents and establishing equivalence remains to be determined. A variety of scientific and practical clinical issues are associated with the use of biosimilars, including product differences in physicochemical characteristics, reimbursement policies, and the need for valid and clinically relevant criteria for comparing the efficacy and safety of biosimilars and innovator products.

Role of Erythropoietin in Cancer-related Anaemia: A Double-edged Sword?

Anaemia often occurs in cancer patients and its origin is multifactorial, resulting from either bone marrow infiltration of cancer cells or cytotoxic effects produced by chemotherapy and radiotherapy. Anaemia impacts significantly on quality of life and appears markedly to limit disease control. Erythropoietin stimulates erythrocyte formation and the human recombinant form is useful in treating anaemia in cancer patients. Over the past decade erythropoietin has been associated with amelioration of anaemia and reduced need for blood transfusions. Nevertheless, several pre-clinical and clinical trials, employing relatively high doses of erythropoietin, have been halted recently following increased mortality and morbidity, primarily due to thrombotic events and possible tumour growth stimulation. It is, therefore, too early to know whether erythropoietin is useful in controlling morbidity and mortality in cancer-related anaemia. The risk-benefit of erythropoietic agents should be studied in carefully controlled trials. This review discusses prevalent issues and addresses key questions concerning the use of erythropoietic agents for the treatment of cancer-related anaemia.

Erythropoietic therapy: Cost efficiency and reimbursement

The practice of blood conservation is aimed at improving patient outcomes by avoiding allogeneic transfusions via a coordinated multidisciplinary, multipronged approach. The numerous blood conservation techniques and transfusion alternatives now available are described. Ongoing concerns exist regarding the availability of the nation's and the world's blood supply. In addition, the number of measures required to ensure blood safety has led to increases in the price of blood and blood products over the past 10-15 years. Moreover, blood transfusion carries inherent risks even under the most favorable circumstances. Investigations have established that injudicious transfusion is associated with development of ventilator-associated pneumonia, nosocomial infection, and organ dysfunction. Because most single blood-conservation techniques reduce blood usage by a mere 1-2 units, a series of integrated conservation approaches are required. These include preoperative autologous donation, use of erythropoietic agents, blood conservation techniques such as acute normovolemic hemodilution, individualized assessment of anemia tolerance, implementation of conservative transfusion thresholds, meticulous surgical techniques, and judicious use of phlebotomy and pharmacologic agents for limiting blood loss. Erythropoietic agents such as epoetin alfa have been used successfully to increase hemoglobin and decrease transfusion requirements, and are appropriate when used in advance of elective surgical procedures. Acquisition costs of erythropoietic stimulating agents versus costs of blood justify economic evaluation by hospitals to make the most cost-effective choice under current economic constraints. Initiating a blood management program requires planning and support from those who are concerned about blood usage reduction and outcomes improvement. Launching a vigorous and ongoing educational program to raise awareness about the risks and hazards associated with blood transfusion is an important step in helping to reshape the medical staffs' attitudes about transfusion and the most cost-effective way to achieve clinical goals.

An Ongoing Study of Anemia Correction in Chronic Kidney Disease

To the Editor: Evidence-based medicine assimilates available data to direct decisions regarding the care of patients. Extrapolations from epidemiologic observations and laboratory or clinical markers of disease severity have supported new treatments that were subsequently found to be without value in randomized, controlled clinical trials.1 In addition, therapies considered to be beneficial and safe owing to their effect on surrogate markers have been found to be ineffective or harmful in such trials.1,2 Even the results of randomized, controlled trials can be misleading, especially when the trials are not adequately powered.3 The use of erythropoietic agents to treat anemia in . . .

The Use of Erythropoietic Agents in Patients with Non-Myeloid Hematological Malignancies.

Practice guidelines for use of an erythropoietic agent (EpA) have been previously developed for patients with all cancers, but these have not specifically addressed non-myeloid hematological malignancies. Given issues of benefit, cost, access to treatment and practice variation for these patients, the Cancer Care Ontario Program in Evidence - Based Care (CCO PEBC) conducted a systematic review and has developed a practice guideline. Entries to MEDLINE, CANCERLIT, EMBASE, the Cochrane Library databases, and abstracts of the American Societies of Clinical Oncology (ASCO) and Hematology (ASH) were searched. A hierarchy of outcomes was developed that included survival, quality of life (QoL), transfusion requirements and improvements in hemoglobin concentration/hematocrit. To validate conclusions and recommendations, the practice guideline was sent to Ontario practitioners in July 2006; responses are now being collated. Eighteen reports (14 articles, 4 abstracts) of randomized trials met eligibility criteria. None of the 3 trials reporting survival outcomes detected a benefit with use of an EpA. Of 7 trials evaluating QoL, 6 reported superior outcomes in patients receiving an EpA. None of those trials sufficiently reported methodologic parameters required by proposed guidelines for analyzing, interpreting and reporting QoL measures. Use of an EpA significantly reduced the proportion of patients transfused in 5 trials evaluating this outcome; reductions ranged from 15% to 40%. The absolute risk reduction ranged from 15% to 24%; the number needed to treat to prevent a transfusion ranged from 4 to 6. Use of an EpA was not associated with a reduction in the mean/median number of units transfused. In 10 studies, either a statistically significant increase in the hemoglobin concentration/hematocrit or in the proportion of patients with an increase in the hemoglobin concentration/hematocrit was seen. For this practice guideline, we interpreted the evidence as providing insufficient data to justify use of an EpA in order to improve survival or QoL. However, there are compelling data showing that use of an EpA reduces the risk of requiring a transfusion. Initiatives such as the Commission of Inquiry on the Blood System in Canada (“the Krever Commission”), state that alternatives to transfusion be offered to patients because of associated known and potentially unknown adverse consequences of blood products. Thus, the use of an EpA is recommended as an alternative to transfusion. However, the decision to use an EpA to reduce transfusion requirements should primarily consider individual patient values and the likelihood that a patient will require a transfusion so that patients are not exposed to unnecessary treatment and the health care system to additional costs.

Targeting Anemia in Patients with Lung Cancer

Anemia is highly prevalent in patients with lung cancer, often occurring at baseline and frequently exacerbated as a result of treatment with platinum-based chemotherapy. Anemia has been shown to have a negative effect on quality of life in patients with lung cancer, and additional data indicate that decreases in hemoglobin in these patients are associated with impaired survival. Multiple clinical studies have demonstrated that treatment of anemia with erythropoietic agents in patients with lung cancer results in a significant increase in hemoglobin, decrease in transfusions, and improvement in quality of life. Ongoing research is evaluating whether erythropoietic therapy can reduce cognitive impairment associated with lung cancer, cytotoxic therapy, and anemia. Despite the known adverse effects of anemia and the established benefits of erythropoietic therapy in anemic patients with lung cancer, more than half of these patients do not receive any anemia treatment. The purpose of this review is to report results of the European Cancer Anaemia Survey that describe the prevalence of anemia in patients with lung cancer, to review the major studies evaluating the clinical outcomes of erythropoietic therapy in patients with lung cancer, to discuss the recent safety concerns regarding the use of erythropoietic agents in patients with cancer treated to high hemoglobin levels, and to describe various novel therapeutic applications of erythropoietic agents in lung cancer.

Cancer- and Treatment-Related Anemia Clinical Practice Guidelines in Oncology

Cancer- and treatment-related anemia has received increasing attention, particularly because relationships between anemia and quality of life (QOL) or treatment outcomes are under investigation. This guideline recognizes the multiple etiologies of cancer- and treatment-related anemia, but specifically addresses the treatment of anemia caused by the myelosuppressive effects of chemotherapy and the anemia associated with chronic disease. It provides guidelines for the use of erythropoietic agents in patients with cancer who are receiving chemotherapy. For the most recent version of the guidelines, please visit NCCN.org

Erythropoietic agents, iron and hemoglobin—What happens beyond the trial setting: Observational data from the ANZDATA Registry

The issues surrounding anemia management in patients receiving dialysis therapy are complex and widely debated. Although numerous trials have been published, clinical practice patterns may differ, particularly in the presence of uncertainty about the optimal management of anemia in this setting. We examined data from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) regarding use of erythropoietic agents (EA), hemoglobin, and ferritin concentrations and transferrin saturation in 8476 prevalent dialysis patients in Australia and New Zealand during the 6 months preceding March 31, 2001. From this cross-sectional survey, we examined the distribution of reported hemoglobin concentration, transferrin saturation, and ferritin concentration. Among hemodialysis patients, other predictors of hemoglobin examined included urea reduction ratio (URR), age, sex, and the presence of comorbidities. In Australia, 87% of dialysis patients received an EA; in contrast, only 42% of New Zealand patients received an EA. Hemoglobin concentrations were significantly higher in Australia, where 16% of reported values were <100 g/L, compared to New Zealand where 37% reported values were <100 g/L. Transferrin saturation and serum ferritin concentrations were significantly correlated, but less strongly among those receiving EA than those not receiving these agents. Both transferrin saturation and serum ferritin were significantly and independently associated with hemoglobin concentration, as were age and sex. The association with ferritin was inverse: higher serum ferritin concentrations were associated with lower hemoglobin concentrations. There was poor agreement (kappa = 0.15) between categories of low transferrin saturation (<20%) and low ferritin concentrations (<200 ng/mL). Among the Australian hemodialysis patients, there was no significant variation in Hb between categories where reported URR was >/=65%, whereas the group with a reported URR <65% had a significantly lower hemoglobin concentration. There was a wide variation in reported hemoglobin concentrations in this population. Potential contributing factors include variable patient responsiveness to EA and iron, differing regulations in Australia and New Zealand regarding government subsidy of EA, and the lack of consensus among physicians regarding hemoglobin target values. Although a cross-sectional study cannot directly address the predictive value of iron indices for iron deficiency, it appears likely that transferrin and ferritin have different relationships with hemoglobin, and measurement of both may have greater clinical utility than either parameter alone.

Anemia impact and management: focus on patient needs and the use of erythropoietic agents

Anemia is a common complication associated with cancer and cancer treatment. As many as 50% to 60% of cancer patients will develop this condition. Fatigue is a major symptom of anemia and is a primary complaint in patients with cancer. Fatigue can be debilitating for patients, reducing their ability to work, decreasing physical and emotional well-being, and interfering with cognitive ability, all of which can lead to anxiety and depression. Despite the high incidence of the disease and the extent of its impact on the cancer patient, anemia remains underdiagnosed and undertreated. Erythropoietic proteins offer a valuable alternative to standard transfusion therapy, and there is increasing evidence that, in addition to raising hemoglobin levels, these therapeutic agents can lead to improvements in quality of life and patient-reported outcomes. The impact of anemia correction on survival is under investigation; a body of evidence suggests a possible benefit, although this has recently been challenged. There is a strong need for increased awareness of cancer-related anemia and the consequences of its lack of treatment.

ESRD in Australia and New Zealand at the end of the millennium: A report from the ANZDATA registry

Background: The incidence and prevalence of treated end-stage renal disease (ESRD) continues to grow throughout the world; however, there is substantial variation between countries in ESRD incidence and outcomes of renal replacement therapy (RRT). The manner of addressing this challenge varies around the world as seen in different patterns of RRT. We present here a summary of the incidence and prevalence of treated ESRD in Australia and New Zealand in 2000. Methods: Data are derived from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), which collects data about all patients receiving RRT from all renal units in Australia and New Zealand on a 6-monthly basis. Results: The crude incidence rates of new RRT patients for 2000 for Australia and New Zealand were 92 and 107 per million population, respectively. Prevalence rates (December 31, 2000) of dialysis-treated patients were 334 per million in Australia and 348 per million in New Zealand, with 273 per million functioning kidney transplants in Australia and 267 per million in New Zealand. The principal area of increase has been in the older patients (≥65 years), where age-specific rates still are increasing. Death rates remained in excess of the general population, with cardiac and infective causes predominant among dialysis patients and cardiac, infective, and malignant causes among transplant recipients. Data about hemodialysis treatments showed a continuing trend toward greater dose of hemodialysis achieved principally through increases in blood flow rate rather than increasing treatment time. Use of erythropoietic agents was common although more restricted in New Zealand by government regulation. Cadaveric transplantation rates were stable, but there has been a steady increase in the proportion of grafts from live donors. Practice in immunosuppression appears to be rapidly changing, with near-universal use of corticosteroids and mycophenolate as part of an initial therapy regimen with a calcineurin inhibitor. Tacrolimus, however, has rapidly increased in its use, presumably reflecting more widespread availability. Conclusion: Relative to other countries, Australia and New Zealand have moderate incidence rates of ESRD. The increased rates in older patients reflect similar trends throughout the world. The traditional reliance of Australia and New Zealand on home- and satellite center-based dialysis therapy and transplantation as modalities of RRT is slowly changing with this growth in older patients. Cross-sectional survey results of iron studies suggest the relationship between iron studies and erythropoietin is modified by confounding. Am J Kidney Dis 40:1122-1131. © 2002 by the National Kidney Foundation, Inc.

Optimizing the use of erythropoietic agents-- pharmacokinetic and pharmacodynamic considerations.

Erythropoietic agents have transformed the management of renal anaemia. Two forms of recombinant human erythropoietin (rHuEPO) have been available since the early 1990s, and more recently, a second-generation erythropoietic agent, darbepoetin alfa, has been granted a licence for treating this condition. The endogenous erythropoietin molecule may contain anything from 4 to 14 sialic acid residues. The various isoforms have different biological potencies in vivo owing to their different metabolic clearance rates. However, there is a continuing debate about those organs potentially involved in the metabolism of the erythropoietin molecule; the kidneys, liver, and bone marrow have all been suggested as possible participants. Darbepoetin alfa contains two extra N-linked glycosylation consensus sequences increasing the potential maximum number of sialic acid residues from 14 up to 22. In vitro, the affinity of darbepoetin alfa for the erythropoietin receptor is less than for the natural ligand, but this is more than compensated for by the increased potency in vivo. One of the most important factors determining the biological activity of erythropoiesis-stimulating agents is the length of time that the serum concentration of the protein remains above the threshold necessary for erythropoiesis. The pharmacokinetic profile of darbepoetin alfa is distinct from that of rHuEPO, the major difference being the much longer elimination half-life and slower clearance in vivo of darbepoetin alfa leading to prolonged erythropoietic activity. Stimulation of erythropoiesis depends both on an ambient circulating level of erythropoietin and on the mechanisms governing the interaction of the hormone with its receptor. Our knowledge regarding the latter is limited and it is difficult to predict the optimum frequency of administration for an erythropoietic agent. In general, rHuEPO is given two or three times weekly. A small number of studies have supported the once-weekly use of rHuEPO. All clinical trials so far conducted on darbepoetin alfa have demonstrated success with once-weekly and once every other week dosing.