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Lancet (London, England) Jul 2023Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.
BACKGROUND
Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial.
METHODS
The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting).
FINDINGS
Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment).
INTERPRETATION
In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups.
FUNDING
Celgene and Acceleron Pharma.
Topics: Male; Humans; Female; Aged; Epoetin Alfa; Hematinics; Erythropoiesis; COVID-19; Anemia; Hypertension; Myelodysplastic Syndromes; Hemoglobins; Neutropenia; Dyspnea; Body Weight
PubMed: 37311468
DOI: 10.1016/S0140-6736(23)00874-7 -
Journal of the American Society of... Apr 2022Concerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Concerns regarding cardiovascular safety with current treatments for anemia in patients with dialysis-dependent (DD)-CKD have encouraged the development of alternatives. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis by increasing endogenous erythropoietin and iron availability.
METHODS
In this open-label phase 3 study, patients with DD-CKD and anemia were randomized 1:1 to oral roxadustat three times weekly or parenteral epoetin alfa per local clinic practice. Initial roxadustat dose depended on erythropoiesis-stimulating agent dose at screening for patients already on them and was weight-based for those not on them. The primary efficacy end point was mean hemoglobin change from baseline averaged over weeks 28‒52 for roxadustat versus epoetin alfa, regardless of rescue therapy use, tested for noninferiority (margin, -0.75 g/dl). Adverse events (AEs) were assessed.
RESULTS
Among 2133 patients randomized (=1068 roxadustat, =1065 epoetin alfa), mean age was 54.0 years, and 89.1% and 10.8% were on hemodialysis and peritoneal dialysis, respectively. Mean (95% confidence interval) hemoglobin change from baseline was 0.77 (0.69 to 0.85) g/dl with roxadustat and 0.68 (0.60 to 0.76) g/dl with epoetin alfa, demonstrating noninferiority (least squares mean difference [95% CI], 0.09 [0.01 to 0.18]; <0.001). The proportion of patients experiencing ≥1 AE and ≥1 serious AE was 85.0% and 57.6% with roxadustat and 84.5% and 57.5% with epoetin alfa, respectively.
CONCLUSIONS
Roxadustat effectively increased hemoglobin in patients with DD-CKD, with an AE profile comparable to epoetin alfa.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease, on Dialysis.
CLINICALTRIALS
gov Identifier: NCT02174731.
Topics: Anemia; Epoetin Alfa; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 35361724
DOI: 10.1681/ASN.2020111638 -
Critical Reviews in Oncology/hematology Jan 2023Biosimilars offer the potential to expand patient access and reduce healthcare costs. Therefore, it is of importance that clinicians and patients are reassured about... (Review)
Review
Biosimilars offer the potential to expand patient access and reduce healthcare costs. Therefore, it is of importance that clinicians and patients are reassured about their efficacy and safety in practice. In 2007, Binocrit® (HX575; Sandoz GmbH, Kundl, Austria) was the first epoetin alfa biosimilar approved for use in chemotherapy induced anaemia (CIA), chronic renal failure (CRF), and more recently myelodysplastic (MDS) anaemia. Since its approval, there has been a plethora of data demonstrating the well-tolerated safety profile of HX575. This review will outline the safety results collected from key studies that have added to the extensive HX575 (Binocrit® unless otherwise stated) clinical experience. With a focus on all approved indications, we will review the safety data collected across a range of study types, to further consolidate the reassurance for the use of HX575 in these indications.
Topics: Humans; Epoetin Alfa; Biosimilar Pharmaceuticals; Erythropoietin; Hematinics; Therapeutic Equivalency; Anemia; Recombinant Proteins
PubMed: 36481307
DOI: 10.1016/j.critrevonc.2022.103894 -
Leukemia Research Jun 2019Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, leading to hematopoietic precursor cell apoptosis and peripheral blood cytopenias. Anemia... (Review)
Review
Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, leading to hematopoietic precursor cell apoptosis and peripheral blood cytopenias. Anemia is the most frequently experienced cytopenia and is the main cause of MDS symptoms, with fatigue and dyspnea contributing to reduced quality of life and increased morbidity. As MDS disease course and prognosis is influenced by disease factors, prognostic scoring systems have been developed for MDS to aid clinical and therapeutic decisions following diagnosis. Erythropoiesis- stimulating agents (ESAs) have been used for many years to treat anemia in patients with lower-risk MDS without chromosomal abnormalities. The use of ESAs is recommended by international clinical practice guidelines, due to the large body of evidence demonstrating their effectiveness in lower-risk MDS. In March 2017, the European Medicines Agency approved epoetin alfa for the treatment of anemia in lower-risk MDS patients, based on the results from a Phase 3 clinical trial and three European registry studies. The effectiveness of biosimilar epoetin alfa (Binocrit, Sandoz) to correct anemia in lower-risk MDS patients has also been demonstrated in a retrospective, single-center, observational study. The recent approval of epoetin alfa by the EMA in this setting will provide clinicians with a welcome, approved treatment option for lower-risk MDS.
Topics: Anemia; Clinical Protocols; Epoetin Alfa; Hematinics; Humans; Myelodysplastic Syndromes; Practice Guidelines as Topic
PubMed: 31005849
DOI: 10.1016/j.leukres.2019.03.006 -
Asian Pacific Journal of Allergy and... Sep 2023Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse... (Review)
Review
BACKGROUND
Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse events, the complications have been previously reported.
OBJECTIVE
To report and review the characteristics and management of ESA hypersensitivities.
METHODS
Case reports and related articles associated with ESA use, published between January 1999 and December 2018, were retrieved through Electronic databases (MEDLINE® and PubMed®).
RESULTS
Forty-seven ESA patients with various immediate and delayed hypersensitivity reactions caused by epoetin and pharmaceutical excipients were identified from nineteen studies and one case report in this paper. Fatal hypersensitivity to ESA and ESA-allergic cross-reactivities have been documented. Desensitization or change of EPO molecular structure has been reported as successful methods of re-introducing the drug.
CONCLUSIONS
ESA hypersensitivity in the various allergic reactions and cross-reactivity have been documented. Desensitization and Epoetin structural changes could be successful methods to re-introduce the drug.
Topics: Humans; Epoetin Alfa; Darbepoetin alfa; Hematinics; Anemia; Pruritus; Recombinant Proteins
PubMed: 32563229
DOI: 10.12932/AP-040719-0592 -
Journal of Pain and Symptom Management Nov 2001Anemia is a common cause of cancer-related fatigue. A systematic review of the literature was performed to establish guidelines on the use of epoetin alfa for the... (Review)
Review
Anemia is a common cause of cancer-related fatigue. A systematic review of the literature was performed to establish guidelines on the use of epoetin alfa for the treatment of anemia. The evidence in support of these guidelines was selected, reviewed, and summarized by the members of the Canadian Cancer and Anemia Guidelines Development Group. The effects of epoetin alfa on quality of life (QOL) in patients with cancer were examined in 5 randomized, placebo-controlled trials and 2 large, open-label, nonrandomized, community-based studies. The effects of epoetin alfa on red blood cell transfusion requirements were examined in 19 randomized controlled trials (RCTs) with 21 comparisons. All trials compared epoetin alfa to a suitable control group, examined specified outcome measures that could be analyzed, and studied patients with cancer who were receiving chemotherapy. Trials involving patients with hematologic malignancies originating in the bone marrow were excluded. Outcome measures included 1) quality of life (QOL) (as measured by scales including the Linear Analogue Self-Assessment [LASA] and the Functional Assessment of Cancer Therapy [FACT] subscales), and 2) transfusion requirements (as measured by the proportion of patients requiring transfusion and amount of transfusion). The analysis confirmed that epoetin alfa produced statistically significant and clinically relevant improvements in QOL in patients with cancer. The overall relative risk ratio for transfusion among patients receiving epoetin alfa was calculated to be 0.60 (95% Cl, 0.53-0.69; P < 0.00001), representing a 40% reduction in the proportion of patients requiring transfusion. These results support recommendations for the use of epoetin alfa in patients with cancer-related anemia.
Topics: Anemia; Epoetin Alfa; Erythropoietin; Evidence-Based Medicine; Humans; Neoplasms; Practice Guidelines as Topic; Recombinant Proteins
PubMed: 11728799
DOI: 10.1016/s0885-3924(01)00357-8 -
American Journal of Health-system... May 2023To determine the effectiveness of pharmacy consultation in managing epoetin alfa-epbx dosing for inpatients on hemodialysis.
PURPOSE
To determine the effectiveness of pharmacy consultation in managing epoetin alfa-epbx dosing for inpatients on hemodialysis.
METHODS
This multisite, retrospective cohort study evaluated the implementation of an initial dose consultation for epoetin alfa-epbx by pharmacists. A pre-post cohort study evaluated patients from August 2020 through January 2021 and August 2021 through January 2022, respectively. Hospitalized patients were included if they were at least 18 years of age, received hemodialysis, and were administered an erythropoiesis-stimulating agent (ESA) for anemia due to chronic kidney disease. Patients were excluded for religious objections to receiving blood products or if patients were discharged or died before their first hemodialysis session. The primary outcome was the average epoetin alfa-epbx acquisition cost per patient. Secondary endpoints were the epoetin alfa-epbx overall pharmacy purchasing cost, the average dose, and the number of administered doses. A subgroup analysis was performed for patients in the post group with an outpatient ESA before admission to determine the epoetin alfa-epbx days saved.
RESULTS
A total of 264 patients were included in the pre group, and 272 patients were included in the post group. The average acquisition cost was significantly lower in the post group ($1,681.77 vs $1,041.35, P < 0.0001). The overall pharmacy purchasing cost was also lower in the post group ($148,970.89 vs $127,873.25). The post group had a significantly lower average dose (13,694 vs 10,112 units, P = 0.0004), while the number of administered doses did not differ significantly between the groups (2.09 vs 1.79 doses, P = 0.0668). The subgroup analysis included 83 patients, which yielded 53 epoetin alfa-epbx days saved.
CONCLUSION
Pharmacist-driven ESA dosing was associated with significant decreases in ESA average acquisition cost and average total dose per patient.
Topics: Humans; Epoetin Alfa; Erythropoietin; Pharmacists; Cohort Studies; Retrospective Studies; Hematinics
PubMed: 36680797
DOI: 10.1093/ajhp/zxad004 -
Expert Review of Clinical Pharmacology Jan 2021: Erythropoietin stimulating agents (ESAs) have been established both to correct anemia and provide the clinical benefits of increased exercise capacity, reduced... (Review)
Review
Epoetin alfa-epbx: a new entrant into a crowded market. a historical review of the role of erythropoietin stimulating agents and the development of the first epoetin biosimilar in the United States.
: Erythropoietin stimulating agents (ESAs) have been established both to correct anemia and provide the clinical benefits of increased exercise capacity, reduced transfusion requirements, and improved quality of life. An increase in physician and patient adoption of biosimilars, as well as changes to healthcare reimbursement policies, have driven market competitors to innovate and expand the range of biosimilar products. While erythropoietin biosimilars have been approved by the EMA since 2007, the FDA's approval of epoetin alfa-epbx in 2018 marks the first erythropoietin biosimilar approved in the United States. : In this article, we critically review the biology, clinical use, manufacturing, safety, and efficacy of ESAs and erythropoietin biosimilars. We then review the regulatory framework and potential impact on healthcare costs offered by erythropoietin biosimilars. : Due to the complex nature of manufacturing large-molecule biologics, it is important to recognize the challenges to quality assurance and overall safety posed by the introduction of biosimilars, which undergo much more limited clinical testing than their reference biologic product before coming to market. With many biologic therapies nearing patent expiration, biosimilars will become increasingly common in clinical practice. Ensuring patient safety with these products will require increased post-marketing surveillance and awareness from prescribers.
Topics: Anemia; Biosimilar Pharmaceuticals; Drug Approval; Epoetin Alfa; Hematinics; Humans; Quality of Life; United States
PubMed: 33307871
DOI: 10.1080/17512433.2021.1863786 -
The New England Journal of Medicine Sep 2019Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis.
METHODS
In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values.
RESULTS
A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group.
CONCLUSIONS
Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).
Topics: Adult; Aged; Analysis of Variance; Anemia; Cholesterol; Double-Blind Method; Epoetin Alfa; Female; Glycine; Hematinics; Hemoglobins; Humans; Hyperkalemia; Hypertension; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 31340116
DOI: 10.1056/NEJMoa1901713 -
Seminars in Hematology Jul 1997To avoid the inherent risk of complications associated with perioperative allogeneic transfusion, preoperative autologous blood donation (PAD) is frequently employed by... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
To avoid the inherent risk of complications associated with perioperative allogeneic transfusion, preoperative autologous blood donation (PAD) is frequently employed by patients undergoing major elective surgical procedures. However, many patients are unable to donate a sufficient quantity of blood prior to surgery. Recent studies have shown that epoetin alfa (Procrit; Ortho-Biotech, Raritan, NJ) effectively increases red blood cell (RBC) mass when administered preoperatively and decreases the requirement for allogeneic transfusion. These studies also demonstrated that patients with baseline hemoglobin levels ranging from 10 to 13 g/dL have the highest risk for requiring allogeneic transfusions and appear to achieve the greatest benefit from epoetin alfa treatment. We evaluated several dosing regimens and schedules for perioperative epoetin alfa administration. In our initial study, the comparative efficacy of three different epoetin alfa regimens was assessed by hemoglobin concentration, hematocrit, and absolute reticulocyte counts. In addition, we analyzed the effect of accelerated erythropoiesis on iron indices and individual RBC hemoglobin content. Our study demonstrated that epoetin alfa is safe and effective in increasing RBC mass; however, iron stores considered sufficient for basal erythropoiesis may not optimally support the accelerated RBC production associated with epoetin alfa therapy. In a subsequent randomized multicenter trial, we compared weekly epoetin alfa dosing to daily dosing in patients undergoing elective major orthopedic surgery. The results of this study indicated that administering epoetin alfa on a weekly schedule for several weeks prior to surgery may be at least as effective and more convenient than perioperative daily epoetin alfa dosing.
Topics: Blood Loss, Surgical; Blood Transfusion; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Transfusion Reaction; Transplantation, Autologous; Transplantation, Homologous
PubMed: 9253783
DOI: No ID Found