Agentes estimuladores de la eritropoyetina: revisión bibliográfica de los usos e indicaciones en enfermedad avanzada oncológica y no oncológica en el anciano / Erythropoiesis stimulating agents: Literature review of uses and indications in advanced oncological and non-oncological disease in the elderly

El objetivo de este artículo es revisar las posibles indicaciones y controversias sobre los usos más frecuentes de los agentes estimuladores de la eritropoyetina (AEE) en el tratamiento de la anemia de los pacientes ancianos, con enfermedad oncológica y no oncológica avanzada. Para ello, hemos realizado una revisión sistemática en Pubmed, de artículos publicados desde 1985 hasta septiembre del 2016. Hemos realizado también la revisión de las principales guías de consenso españolas, europeas y americanas, en relación con el manejo de la anemia relacionada con las enfermedades reseñadas en el artículo. Hemos encontrado que existen barreras para su uso en pacientes ancianos con enfermedad avanzada, sobre todo por la falta de uniformidad y consenso en las recomendaciones, y por la ausencia de ensayos prospectivos a gran escala para explorar la eficacia de los AEE en esta población. Parece haber consenso en la utilización en los pacientes con enfermedad renal crónica avanzada, en pacientes con tumores no mieloides, en tratamiento con quimiterapia con intención no curativa, y en pacientes con síndrome mielodisplásico, todavía respondedores, para espaciar el soporte transfusional. En el resto, debe individualizarse, ya que el riesgo de mortalidad y morbilidad cardiovascular está claramente aumentado. No debe ser la solución para tratar la anemia, en casos de urgencia o de necesidad transfusional a corto plazo, muchas veces presentes en este paciente

The aim of this article is to review possible indications and controversies about the most frequent uses of ESAs in the treatment of anaemia in elderly patients with oncological and non-oncological diseases. Using PubMed a systematic review was carried out on articles published from 1985 to September 2016, as well as a review of the main Spanish, European, and American consensus guidelines on each of the following diseases in which could pose the treatment of anaemia associated with ESA. A review was also carried out on the main Spanish, European and American consensus guidelines regarding the management of anaemia related to the diseases outlined in this article. It was found that there are limitations of its use in elderly patients with advanced disease, mainly due to the lack of uniformity and consensus in the recommendations, and the absence of large-scale prospective trials to determine the effectiveness of ESA in this population. There seems to be consensus in the use in patients with advanced chronic kidney disease, individualised in patients with non-myeloid cancer on treatment without curative intent, and in patients with myelodysplastic syndrome, still responders to space transfusional support. In the remainder, it should be individualised, since the risk of mortality and cardioembolic morbidity is clearly increased. It should not be the solution to treat anaemia, in cases of urgency or short-term transfusional need, which are often present in these patients

Using dynamic treatment regimes to understand erythropoietin-stimulating agent hyporesponsiveness.

BACKGROUND: Erythropoietin-stimulating agent hyporesponsiveness (ESAH) is associated with increased cardiovascular mortality in patients with end-stage renal disease (ESRD) on hemodialysis. Dynamic treatment regimes (DTR), a clinical decision support (CDS) tool that guides the prescription of specific therapies in response to variations in patient states, have been used to guide treatment for chronic illnesses that require frequent monitoring and therapy changes. Our objective is to explore the role of utilizing a DTR to reduce ESAH in pediatric hemodialysis patients. METHODS: Retrospective analysis of ESRD patients on hemodialysis who received ESAs. Dosing was adjusted using a locally developed protocol designed to target a hemoglobin between 10 and 12 g/dl. Analyzing this protocol as a DTR, we assessed adherence to the protocol over time measuring how the hyporesponse index (ESA dose/hemoglobin value) changed due to varying levels of adherence. RESULTS: Eighteen patients met study criteria. Median hemoglobin was 11.4 g/dl (range 6.1-15.4), and median weekly ESA dose (darbepoetin-equivalent) was 0.4 mcg/kg/dose (range 0-2.1). Full adherence to the DTR was identified in 266 (71%) of the 4-week periods, with a median average adherence score of 0.80 (range 0.63-0.91). As adherence to the DTR improved, ESAH decreased. During the last 12 weeks, 13 out of 18 patients had lower average ESA/hemoglobin ratio than the first 12 weeks. CONCLUSIONS: A DTR appears to be well-suited to the treatment of anemia in ESRD and reduces ESAH. Our work shows the potential of DTRs to drive the development and evaluation of clinical practice guidelines.

Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia.

Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIFα in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.

Past approaches and future directions for targeting tumor hypoxia in squamous cell carcinomas of the head and neck.

Recurrent squamous cell carcinoma of the head and neck (SCCHN) carries a poor prognosis. Tumor hypoxia (TH) has been implicated as one of many factors contributing to SCCHN recurrence. TH leads to radiation resistance by reversing radiation-induced DNA damage. Effective strategies to overcome TH may improve outcomes in patients with SCCHN. We searched the English literature on PubMed and reviewed the reference sections of key articles related to TH (publications spanning from the early 1900s to the present). We summarized the underlying theory of TH in SCCHN, methods for quantifying it, and the numerous therapies developed to modulate it. We included articles that set the foundation of TH as a theory and the most relevant articles published within the last 15 years related to TH quantification and therapeutic targeting. Despite extensive research, targeting TH in SCCHN has not become a part of routine clinical practice in North America, and we analyze the pitfalls in hypoxia research that have led to this failure. We propose that future studies should test a combined approach of targeting the immune system in addition to cellular pathways rendered aberrant in TH and should include development of novel surrogate markers of TH and/or TH imaging.

[Antioxidant properties of cluster rhenium compounds and their effect on erythropoiesis of rats with guerin carcinoma].

Biochemical characteristics of kidneys, pe- ripheral blood and bone marrow of rats in model of tumor growth under introduction of cisplatin and cis-tetrachlorodi-µ-isobutyratodirhenium(III), cis-Re2(i-C3H7COO)2Cl4 (I) have been investigated. It was shown that introduction of I alone and together with cisplatin led to decrease of biochemical markers of oxidation of lipids and proteins in tissue homogenates of the kidneys, change of enzyme activity in the urea and tissue homogenates of the kidneys, by a decrease of filtration function of kidneys. Introduction of nanoliposomal forms of the rhenium cluster compound led to a practically normal morphological picture of bone marrow and increase of the RBC (by 60%) with normalization of hematocrit counts, and decrease of quantities of destructed RBC (3.2 times) in comparison with the tumor-bearing animals. A tentative scheme of influence of cluster rhenium compound on erythropoiesis through regulation of synthesis of erythropoietin in kidneys has been proposed.

Rational design of humanized dual-agonist antibodies.

The ultralong heavy chain complementarity determining region 3 (CDR3H) of bovine antibody BLV1H12 folds into a novel "stalk-knob" structural motif and has been exploited to generate novel agonist antibodies through replacement of the "knob" domain with cytokines and growth factors. By translating this unique "stalk-knob" architecture to the humanized antibody trastuzumab (referred to hereafter by its trade name, Herceptin, Genentech USA), we have developed a versatile approach to the generation of human antibody agonists. Human erythropoietin (hEPO) or granulocyte colony-stimulating factor (hGCSF) was independently fused into CDR3H, CDR2H, or CDR3L of Herceptin using an engineered "stalk" motif. The fusion proteins express in mammalian cells in good yields and have similar in vitro biological activities compared to hEPO and hGCSF. On the basis of these results we then generated a bi-functional Herceptin-CDR fusion protein in which both hEPO and hGCSF were grafted into the heavy- and light-chain CDR3 loops, respectively. This bi-functional antibody fusion exhibited potent EPO and GCSF agonist activities. This work demonstrates the versatility of the CDR-fusion strategy for generating functional human antibody chimeras and provides a novel approach to the development of multi-functional antibody-based therapeutics.

[The treatment of chemotherapy-induced anemia in lung cancer patients]. / A tüdodaganatos betegek kemoterápia okozta anémiájának kezelése.

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Active oncotherapy, combination chemotherapy of lung cancer is accompanied with many side effects which may impair the patient's quality of life and compromise the effectiveness of chemotherapy, the most frequent one of them being chemotherapy-induced anemia. Anemia decreases not only the patient's quality of life, but also worsens the dose-intensity of chemotherapy. One of the potential treatments of chemotherapy-induced anemia is erythropoietin-stimulating agents (ESAs) for the appropriate indications. Several national and international studies have shown that ESA therapy effectively increases hemoglobin level. However, more recently, contradictory results were published on ESA treatment in terms of survival and tumor progression. The reason for this may be that the tumor cells and endothelial cells may as well express erythropoietin receptor, the role of which has not yet been fully elucidated in tumor progression.

Activation of mitochondrial function and Hb expression in non-haematopoietic cells by an EPO inducer ameliorates ischaemic diseases in mice.

BACKGROUND AND PURPOSE: Many organs suffer from ischaemic injuries that reduce their ability to generate sufficient energy, which is required for functional maintenance and repair. Erythropoietin (EPO) ameliorates ischaemic injuries by pleiotropic effects. The aim of this study was to investigate the effect and mechanism of a small molecule EH-201, and found it as a potent EPO inducer and its effect in non-haematopoietic cells for therapeutic potential in ischemic disorders. EXPERIMENTAL APPROACH: Mice kidney slices, primary hepatocytes, primary cardiomyocytes and C2C12 myoblasts were treated with EH-201. The effects of this treatment on EPO, Hb expression and mitochondrial biogenesis were analysed. In vivo, doxorubicin-induced cardiomyopathic mice were treated with EH-201. The mice were subjected to an endurance test, electrocardiography and echocardiography, and a histological examination of the isolated hearts was performed. EH-201 was also administered to cisplatin-induced nephropathic mice. KEY RESULTS: In non-haematopoietic cells, EH-201 was potent at inducing EPO. EH-201 also stimulated mitochondrial biogenesis and enhanced the expression of Hb by a mechanism dependent on EPO-mediated signalling. In mechanistic studies, using EPO and EPO receptor-neutralizing antibodies, we confirmed that EH-201 enhances EPO-EPOR autocrine activity. EH-201 robustly increased the endurance performance activity of healthy and cardiomyopathic mice during hypoxic stress, enhanced myocardial mitochondrial biogenesis and Hb expression, and also improved cardiac function. EH-201 ameliorated anaemia and renal dysfunction in nephropathic mice. CONCLUSIONS AND IMPLICATIONS: The enhancement and recovery of cellular functions through the stimulation of mitochondrial activity and Hb production in non-haematopoietic cells by an inducer of endogenous EPO has potential as a therapeutic strategy for ischaemic diseases.

Anemia management in patients with chronic viral hepatitis C.

OBJECTIVE: To review the literature regarding current strategies for the management of anemia associated with treatment for chronic viral hepatitis C (HCV) in adults. DATA SOURCES: The MEDLINE/PubMed, EMBASE, and Cochrane databases were searched (January 1980-October 2012) for articles in English using the search terms anemia, ribavirin, dose reduction, erythropoietin stimulating agents, hepatitis C, HIV, liver transplant, telaprevir, and boceprevir. STUDY SELECTION AND DATA EXTRACTION: All relevant original studies, meta-analyses, systematic reviews, guidelines, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search. DATA SYNTHESIS: Standard of care for patients infected with HCV genotype 1 now requires a triple therapy regimen including an HCV NS3 protease inhibitor. These regimens lead to significantly higher rates of anemia compared to prior dual therapy regimens. Development of an optimal management strategy should begin with risk stratification. Ribavirin dose reductions have been recommended in the package inserts for the pegylated interferon products and studies have demonstrated the need for maintenance of 80% of the initial ribavirin dose to achieve optimal sustained virologic response (SVR) with dual therapy. The use of erythropoietin-stimulating agents has been shown to be effective for anemia caused by peginterferon and ribavirin without compromising SVR rates. Limited data have been published regarding the management of anemia with triple therapy; however, efficacy studies for boceprevir and telaprevir have used ribavirin dose reduction and erythropoietin-stimulating agents to successfully manage anemia. CONCLUSIONS: Anemia is a common adverse event associated with the use of ribavirin, and, more recently, the new HCV protease inhibitors. Ribavirin dose reduction should continue to be used as an initial anemia management strategy, with the use of erythropoietin alfa 40,000 units once weekly reserved for patients whose hemoglobin does not adequately respond to initial management strategies.

Impacto de darbepoetina alfa en el manejo de la anemia precoz postrasplante renal: estudio retrospectivo exploratorio / The impact of darbepoietin alfa in early post-transplant anaemia management: retrospective exploratory study

Antecedentes y objetivos: Se ha evaluado el uso de darbepoetina alfa en la primera semana postrasplante renal (TR). Métodos: Estudio observacional, retrospectivo, realizado en cuatro hospitales, que incluyó todos los pacientes adultos que fueron sometidos a TR durante un período de 9 meses con los datos de hemoglobina (Hb) durante los primeros 6 meses postrasplante (n = 129). Darbepoetina alfa fue administrada de acuerdo con la práctica clínica. Resultados: Se administró darbepoetina alfa en la primera semana a 60 individuos (46,5 %), los cuales presentaban una Hb media (± desviación estándar) basal de 12,7 ± 1,6 g/dl. La incidencia de anemia (Hb < 11 g/dl) durante el primer mes fue superior en los pacientes que no recibieron darbepoetina alfa (40,6 % vs. 25,0 % en los pacientes tratados, p = 0,045). No se observaron diferencias en la incidencia de la anemia entre los meses +2 a +6. Hubo una tendencia hacia la disminución de transfusiones en los pacientes que recibieron darbepoetina alfa (13,3 % vs. 20,3 %, p = 0,295). El tiempo de recuperación renal fue similar, pero, en el subgrupo que recibió injertos procedentes de donantes en asistolia, hubo una tendencia hacia una recuperación más rápida con darbepoetina alfa (15,1 ± 7,7 vs. 20,1 ± 8,8 días, p = 0,157). El aclaramiento de creatinina a los 3 y 6 meses fue similar. Catorce pacientes (10,9 %) sufrieron un evento cardiovascular, sin relación con darbepoetina alfa (p = 0,772). Conclusiones: La administración de la darbepoetina alfa en la primera semana tras el trasplante renal reduce la incidencia de anemia durante el primer mes, sin aumentar los eventos cardiovasculare (AU)

Background and objectives: The use of darbepoetin alfa in the first week of post-renal transplant (RT). Methods: Retrospective observational study carried out in four hospitals, which included all adult patients that underwent RT for 9 months with haemoglobin data during the first 6 months of post-transplant (n=129). Darbepoetin alfa was administered in accordance with the clinical practice. Results: Darbepoetin alfa was administered in the first week to 60 individuals (46.5%), who had a mean baseline Hb (±standard deviation) of 12.7g/dl±1.6g/dl. Anaemia incidence (Hb<11g/dl) during the first month was higher in patients who did not receive darbepoetin alfa (40.6% vs. 25.0% in patients treated with darbepoetin alfa, P=.045). No anaemia incidence differences were observed during months +2 to +6. There was a tendency towards transfusion decrease in patients who received darbepoetin alfa (13.3% vs. 20.3%, P=.295). Renal recovery time was similar but in the subgroup which received grafts from donors with asystole there was a tendency towards a faster recovery with darbepoetin alfa (15.1±7.7 vs. 20.1±8.8 days, P=.157). The creatinine clearance rate at 3 and 6 months was similar. Fourteen patients (10.9%) suffered from cardiovascular events with no relation to darbepoetin alfa (P=.772). Conclusions: Administering darbepoetin alfa in the first week following renal transplant reduces anaemia incidence during the first month without increase cardiovascular events (AU)

Erythropoiesis stimulating agents and other growth factors in low-risk MDS.

Anemia and transfusion need constitute major problems for patients with myelodysplastic syndromes (MDS) and are associated with reduced quality of life, poorer survival and an increased risk for transformation to AML. Treatment with erythropoiesis-stimulating agents (ESAs) is first-line treatment for the anemia of most patients with MDS. Erythropoietin acts synergistically with G-CSF to inhibit erythroid apoptosis and promote erythrocyte production. The median duration of response is 2-3 years, with patients responding for more than a decade. Onset of a permanent transfusion need is delayed if treatment is introduced early after the onset of symptomatic anemia. A positive effect on long-term outcome has been suggested by several large epidemiological studies, with no difference in the rate of leukemic transformation between treated and untreated patients. Moreover, responding patients show improvement of quality of life and exercise capacity. Response to treatment can be predicted by combining serum erythropoietin, transfusion rate, and flow cytometry profiling.

An economic evaluation of erythropoiesis-stimulating agents in CKD.

BACKGROUND: The objective was to determine the cost-effectiveness of treating anemic patients with chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs) to a low (9-10.9 g/dL), intermediate (11-12 g/dL), or high (> 12 g/dL) hemoglobin level target compared with a strategy of managing anemia without ESAs. STUDY DESIGN: Cost-utility analysis. SETTING & PARTICIPANTS: Publicly funded health care system. Anemic patients with CKD, overall and stratified into dialysis-/non-dialysis-dependent subgroups. MODEL, PERSPECTIVE, & TIMEFRAME: Decision analysis, health care payer, patient's lifetime. MAIN OUTCOME: Cost per quality-adjusted life-year (QALY) gained. RESULTS: For dialysis patients, compared with anemia management without ESAs, using ESAs to target a low hemoglobin level is associated with a cost per QALY of $96,270. Given a lack of direct trials comparing low and intermediate targets, significant uncertainty exists between these strategies. Treatment to a high hemoglobin target was always associated with worse clinical outcomes and higher costs compared with a low hemoglobin target. Results were similar in non-dialysis-dependent patients with CKD, with a cost per QALY for a low target compared with no ESA of $147,980. LIMITATIONS: Given limitations in the available randomized controlled trials, we were able to model only 4 treatment strategies, balancing the need to consider relevant targets with the requirement for accurate estimates of clinical effect. We assumed that the efficacy of the different strategies would continue over a patient's lifetime. CONCLUSIONS: Using ESAs to target a hemoglobin level > 12 g/dL is associated with worse clinical outcomes and significant additional cost compared with using ESAs to target lower hemoglobin levels (9-12 g/dL). Given a lack of studies comparing low (9-10.9 g/dL) and intermediate (11-12 g/dL) hemoglobin targets for clinical outcomes, including quality of life, the most cost-effective hemoglobin level target within the range of 9-12 g/dL is uncertain, although aiming for higher targets within this range will lead to higher costs.

A diversity of antibody epitopes can induce signaling through the erythropoietin receptor.

Stimulation of red cell production through agonism of the erythropoietin receptor (EpoR) has historically been accomplished through administration of erythropoietin (EPO), the native ligand. The short half-life of EPO has led to the development of a variety of other agonists, including antibodies. It is of considerable interest to understand how these agents might activate the EpoR and whether or not it is important to bind in a manner similar to the native ligand. The binding epitopes of a panel of eight agonistic, single-chain antibody (scFv-Fc) constructs were determined through scanning alanine mutagenesis as well as more limited arginine mutagenesis of the receptor. It was found that while some of these constructs bound to receptor epitopes shared by the ligand, others bound in completely unique ways. The use of a panel of agonists and scanning mutagenesis can define the critical binding regions for signaling; in the case of the EpoR, these regions were remarkably broad.

¿Cambiará la prescripción de agentes estimulantes de la eritropoyesis en prediálisis tras los resultados del estudio TREAT? / No disponible

No disponible

El impacto clínico de los efectos fisiológicos de la eritropoyetina y de los agentes estimulantes de la eritropoyetina en la incidencia de malignidad, trombosis e hipertensión: más allá de la anemia / No disponible

La eritropoyetina (EPO) es una hormona glucoproteica, esencial para la progenie eritrocítica como factor de crecimiento y de viabilidad. La señalización bioquímica de la EPO implica un proceso de fosforilación de la tirosina en el receptor homodimérico de la EPO, con la subsiguiente activación intracelular de proteínas quinasas y factores de trascripción. El tratamiento con los agentes estimulantes de la eritropoyetina (ASE) o eritropoyetina humana recombinante (EPOHuR)(se consideraba efectivo y falto de efectos deletéreos, mejorando así el manejo de las anemias asociadas a la enfermedad renal crónica, permitiendo la disminución del requerimiento de transfusiones sanguíneas. Sin embargo, recientes estudios aleatorizados han mostrado un incremento de la mortalidad, lo que ha hecho que se replantee su uso. Esta revisión quiere mostrar lo que se sabe acerca de la fisiología de este factor plasmático, que representa más que un factor de producción de eritrocitos, y de su efecto pleitrópico con su uso clínico en la incidencia de malignidades, trombosis, hipertensión arterial (HTA) y retinopatía diabétic (AU)

The glycoprotein hormone erythropoietin is an essential viability and growth factor for the erythrocytic progenitors. EPO signalling involves tyrosine phosphorylation of the homodimeric EPO receptor and subsequent activation on intracellular proteins, kinases and transcription factors. Treatment with erythropoietic stimulating agents (ESA) or ecombinant human EPO (rHuEPO) is efficient and safe in improving the management of the anaemia associated with chronic kidney disease, and allowing avoidance of transfusions with blood products. However, the unanticipated increase in mortality found in recent randomized studies is prompting a reassessment of this view. The present review will show what is known about the physiology of this plasma factor that, it is now clear, is more than just an erythrocyte production factor, and its pleitropic effects influencing the incidence of malignancy, thrombosis, hypertension and retinopathy (AU)

Luxury accommodations: the expanding role of structural plasticity in protein-protein interactions.

The recognition of multiple ligands at a single molecular surface is essential to many biological processes. Conformational flexibility has emerged as a compelling strategy for association at such convergent binding sites. Studies over the past few years have brought about a greater understanding of the role that protein plasticity might play in protein-protein interactions.