Development of palliative medicine in the United Kingdom and Ireland
Eduardo Bruera, Irene Higginson, Charles F von Gunten, Tatsuya Morita in Textbook of Palliative Medicine and Supportive Care, 2015
26 Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M et al. Correction of anemia with epoetin alfa in chronic kidney disease. The New England Journal of Medicine. 2006;355(20):2085-2098. 27 Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. The New England Journal of Medicine. 2009;361(21):2019-2032.28 Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebocontrolled trial. Lancet. 2003;362(9392):1255-1260. - 29 Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. Journal of Clinical Oncology. 2005;23(25):5960-5972.
The science of biotechnology
Ronald P. Evens in Biotechnology, 2020
In the human body, proteins are all glycosylated, possessing carbohydate (CHO) molecules in their structure, which are comprised of a combination of several different CHO species, that is, mannose, or fucose, or galactose, or sialic acid, or n-acetylglycine. The CHOs are combined and configured as shown in the cartoon diagram (Figure 5.5) in a candelabra-like formation. However, many proteins can remain functional without the CHO content. Some proteins must have the glycosylation content the same as created naturally in mammals to be a fully physiologically active molecule, for example, epoetin alfa for red blood cell production in bone marrow. The impact of the CHO on a protein can be extensive, with changes in protein folding; ligand/receptor binding; biological activity, stability, or solubility of the molecule; protection from enzyme proteolysis; half-life of the molecule; and immunogenicity. The glycosylation entails changing or adding CHO species, for example, sialic acid residues, to the amino acid backbone of a protein. A CHO molecule is attached to an oxygen or nitrogen species in the protein structure and only at the amino acid sites in the protein where a series of three adjacent amino acids (asparagine-serine-threonine) exist. The CHO molecular engineering also requires site-directed mutagenesis (genetic engineering to alter the amino acid sequences), along with a specific transferase enzyme in the endoplasmic reticulum and chaperone proteins engaged as well. Figure 5.5 displays increased glycosylation of the epoetin alfa molecule to create darbepoetin alfa, both utilized to correct the anemia in chronic renal disease and some cancers. The molecular changes and the net outcomes are outlined in Figure 5.5.
The Patient with Anemia and Iron Deficiency
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
Erythropoiesis-stimulating agents (ESA) or exogenous erythropoietin are commonly used to treat anemia in chronic kidney disease. Initially, several smaller trials showed that ESA therapy improved HF-related symptoms, exercise capacity, and quality of life.43–45 These promising findings prompted the conduct of the large, randomized controlled morbidity and mortality trial “Reduction of Events by Darbepoetin Alfa in Heart Failure” (RED-HF). This trial enrolled 2,278 patients with chronic symptomatic HFrEF and mild-to-moderate anemia (hemoglobin 9.0–12.0 g/dL), who were randomized to either darbepoetin alfa or placebo in a double-blind fashion. The starting dose of darbepoetin alfa was 0.75 µg/kg every two weeks until the target hemoglobin concentration of 13.0 g/dL was reached. In the maintenance phase, darbepoetin alfa was administered monthly to keep hemoglobin levels between 13.0 and 14.5 g/dL. Oral and intravenous iron supplementation were provided in patients with transferrin saturation <20% during follow-up. The primary endpoint was the composite of all-cause mortality and HF-related hospitalization. One month after randomization, hemoglobin level was significantly higher in the ESA group compared with placebo and remained higher throughout the study. However, darbepoetin alfa did not affect the primary endpoint after a median follow-up of 28 months (HR 1.01; 95% CI 0.90–1.13; P=0.87), with no clear benefit toward quality of life (clinical meaningful improvement in Kansas City Cardiomyopathy Questionnaire: 53% in darbepoetin alfa arm vs 48% in placebo; P=0.06). On the contrary, rates of thromboembolic events and ischemic stroke were increased in patients receiving darbepoetin alfa (13.5% vs 10.0% in the placebo arm, P=0.009; 4.5% vs 2.8%, P=0.03, respectively).46 These findings were similar to a comparable study in patients with anemic chronic kidney disease and diabetes, the “Trial to Reduce Cardiovascular Events With Aranesp Therapy” (TREAT).47 In a subset of ~1,400 patients with HF from this trial, darbepoetin alfa did not show a significant reduction in mortality (HR 1.10, 95% CI 0.93–1.29) or non-fatal HF-related events (HR 1.02; 95% CI 0.87–1.20).48 In a post-hoc analysis of RED-HF, non-responders to darbepoetin alfa had a greater risk of mortality and HF hospitalizations compared with responders.49 Taken together, ESA therapy in HF does not improve outcomes and is associated with an increased risk of thromboembolic events. It is therefore not recommended to use ESAs for the treatment of anemia in HF patients.50,51
Novel therapies in low- and high-risk myelodysplastic syndrome
Published in Expert Review of Hematology, 2019
Ulrich Germing, Thomas Schroeder, Jennifer Kaivers, Andrea Kündgen, Guido Kobbe, Norbert Gattermann
Platzbecker et al [17] published a very similar randomized, placebo-controlled phase III trial on darbepoetin alfa administered subcutaneously every three weeks in lower-risk MDS (IPSS low/intermediate-1). Patients included in the study had a Hb <10 g/dl, low RBC transfusion dependency, and a serum erythropoietin level <500 mU/ml. In patients with a Hb increase <1.5 g/dl, but without RBC transfusions during the last 28 days, dosage was escalated from 500 µg every three weeks to 500 µg every two weeks. Darbepoetin alfa was reported to significantly reduce the need of RBC transfusions and to induce hematologic improvement of the erythroid lineage (HI-E) (14.7% vs. 0%). Regarding transfusion need in the darbepoetin alfa group, patients with serum EPO levels <100 mU/ml needed fewer RBC transfusions than patients with serum EPO levels >100 mU/ml (23% vs. 57%). Drug safety results were similar for grade 3 adverse events in both the darbepoetin alfa and the placebo group, providing no evidence of a higher-risk for thrombovascular events in the darbepoetin alfa group. AML transformation rates were also similar in both groups. These results suggested that darbepoetin alfa is a useful treatment option for lower-risk MDS. However, the drug has not been submitted to EMA and FDA for approval.
Characteristics of Japanese patients with non-dialysis-dependent chronic kidney disease initiating treatment for anemia: a retrospective real-world database study
Published in Current Medical Research and Opinion, 2022
Yoshimasa Kokado, Manabu Ishii, Kiichiro Ueta, Hiroyuki Yamamoto, Hiraku Kumamaru, Masaaki Isshiki, Sven Demiya, Hiroaki Miyata
In the sub-cohort, the mean hemoglobin level increased from 9.2 ± 1.0 g/dL at the index date to 10.3 ± 1.4 g/dL after six months. The percentage of patients with hemoglobin levels of ≥10.0 and ≥11.0 g/dL were 61.9% and 31.1%, respectively, but only 20.6% and 2.3%, respectively, at the index date. The proportion of patients on ESA therapy was 76.4% 6 months after the index date (Table 2). During the follow-up period, the mean doses of darbepoetin alfa and epoetin beta pegol were 11.0 and 11.6 μg/week, respectively, with the average of 5.2 and 4.7 dosing frequency, respectively, over the six-month period (Table 3). In the sub-cohort, 17.6% of patients were on iron supplementation at the index date; after 6 months, the proportion of patients receiving iron therapy was 5.6% (Table 2).
Exercise and anemia in cancer patients: could it make the difference?
Published in Expert Review of Hematology, 2021
Alice Avancini, Lorenzo Belluomini, Daniela Tregnago, Ilaria Trestini, Michele Milella, Massimo Lanza, Sara Pilotto
As previously mentioned, one of the possible treatments for anemia consists of administering erythropoiesis-stimulating agents, such as epoetin alfa and darbepoetin alfa. Given the efficacy in terms of Hb response by the darbepoetin alfa and the possible benefits achieved through an exercise program, theoretically, the two interventions may have a synergic effect. The studies of Roth et al. [38] and Courneya et al. [39] tried to explore and clarify this point. In a nonrandomized trial, Roth and colleagues compared a sample of cancer patients receiving darbepoetin alfa and exercise with subjects participating in the same exercise program. After six weeks of training, including aerobic and resistance activities, an increase in Hb was detected only in patients treated with darbepoetin alfa, while a small decrease was noted in the group that attended only exercise [38]. Instead, in a randomized controlled trial, Courneya has evaluated the effects of darbepoetin alfa alone with those of darbepoetin alfa plus aerobic exercise training. A total of 55 anemic patients with solid tumors participated in the study; the exercise program was composed of three cycle-ergometer sessions per week (at 60–100% of the peak power output) for a total of 12 weeks. Although the overall Hb differences between the two groups were not significant, a trend toward a more rapid Hb response with less drug administration was observed in the exercising group, suggesting a possible synergistic effect between erythropoiesis-stimulating agents and exercise. Moreover, similar to Dolan and colleagues [36], the researchers found that an aerobic program was demonstrated to be effective in improving exercise capacity and cardiorespiratory fitness, typically impaired in anemic subjects [39].