Erythropoiesis-stimulating Agents Treatment Research Articles

Lower-Risk Myelodysplastic Syndromes: Erythropoiesis-Stimulating Agent Treatment Approaches and Outcomes in the United States

Lower-Risk Myelodysplastic Syndromes: Erythropoiesis-Stimulating Agent Treatment Approaches and Outcomes in the United States

Overview of Systematic Reviews (SRs) of Erythropoiesis-Stimulating Agents (ESAs) As Standards of Care for Non-Myeloid Cancer Patients with Chemotherapy-Induced-Anemia (CIA)

OBJECTIVES: While chemotherapy is fundamental to the treatment of many cancers, it is associated with adverse events (AEs), including anemia. CIA is linked to many symptoms, including fatigue and cognitive impairment. Most cancer patients receiving chemotherapy experience CIA. ESAs are indicated for treatment of CIA in non-myeloid cancers. Given the extensive data available, we reviewed SRs of the existing evidence on ESAs for treatment of CIA, to assess their relative efficacy and safety.METHODS: A search for published SRs of ESAs for the treatment of CIA in adults with non-myeloid cancers was conducted across seven databases and three online resources, from inception to July 2020. Data were extracted on hemoglobin-related (Hb)-outcomes; mortality; health-related quality of life (HRQoL), iron use, red blood cell (RBC) transfusions, cancer-related outcomes, and serious AEs (SAEs) including thromboembolic events. Risk of bias was assessed by two reviewers using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool.RESULTS: Of 1027 records assessed, 33 records met eligibility criteria; from these, 14 SRs (from 19 publications) were considered core and were extracted. The majority of SRs (n=13) were meta-analyses of randomized, controlled trials. Mortality was evaluated in 9 SRs: 5 reported no difference between ESA vs. control (best supportive care (BSC) and/or placebo and/or no treatment) and 2 reported higher mortality with ESA vs. control (standard care (no iron or oral iron) and/or placebo and/or no treatment). Cancer-related overall survival was not significantly different for ESA vs. control (BSC or placebo) in 2 SRs, or vs. no ESA treatment in 1 SR. Relapse-free, recurrence-free and progression-free survival did not differ between ESA vs. BSC, no treatment, or placebo, according to 1 SR.Two SRs reported a significantly improved change in Hb from baseline for ESA vs. placebo or BSC. Four SRs reported significantly improved hematological response (definitions varied by study) for ESA vs. control (BSC and/or placebo and/or no treatment) (Table). RBC transfusion requirements were reported for 5 treatment comparisons in 12 SRs. For 3 comparisons (ESA vs. control (BSC and/or placebo and/or no treatment); IV iron + ESA vs. standard care; and IV iron + ESA vs. no iron + ESA), there was a consistent statistically significant reduction in transfusion rates with ESA-based treatment. For 2 other comparisons, 1 SR reported no significant difference in transfusion rates with oral iron + ESA vs. no iron + ESA, and 2 SRs found no difference between darbepoetin vs. epoetin. ESA was associated with a requirement for significantly fewer RBC units per patient vs. control (BSC or placebo) in 1 SR.Functional Assessment of Cancer Therapy-Anemia (FACT-An, 6 SRs) and FACT-Fatigue (FACT-F, 7 SRs) were the only HRQoL measures reported. Two SRs reported clinically important improvements in FACT-An with ESA vs. control (BSC and/or placebo); the remaining SRs reported difficulty in interpreting results due to study heterogeneity. Five SRs reported significant improvements in FACT-F with ESA vs. control (BSC and/or placebo and/or no treatment). One SR did not present a meta-analysis, stating that FACT-F results did not differ for ESA vs. placebo groups, and 1 SR reported a significant improvement in FACT-F for IV iron + ESA vs. standard care (no iron or oral iron).Of 2 SRs reporting SAEs, 1 found no difference in incidence for IV iron + ESA vs. standard care (no iron or oral iron) and 1 found significantly greater incidence for ESA vs. no treatment. Of 6 SRs that compared ESA vs. control, 3 reported an increased risk of thromboembolic events with ESAs in the treatment of CIA and 2 reported no significant difference between treatment groups. The remaining SR reported numerically higher incidences of thromboembolic events with ESA vs. control (no statistical comparison).Several outcomes of interest were not reported, including time to first rescue therapy and supplementary iron use. Most SRs did not report on study quality.CONCLUSIONS: In all SRs reporting efficacy, there were improvements in Hb change from baseline, Hb response, and reduction in RBC transfusions for patients with CIA treated with ESAs vs. control. Results were less consistent across SRs for mortality, thromboembolic events, and HRQoL for ESA vs. control. Lack of study quality reporting may affect the strength of these findings. [Display omitted] DisclosuresMorga: Astellas Pharma Europe Ltd.: Current Employment. Atzinger: Astellas Pharma Inc.: Current Employment. Arber: York Health Economics Consortium Ltd: Current Employment. King: York Health Economics Consortium Ltd: Current Employment. Phalguni: York Health Economics Consortium Ltd: Current Employment. Sanderson: York Health Economics Consortium Ltd: Current Employment. Alexandre: Astellas Pharma Europe B.V.: Current Employment.

Vitamin B5 and Succinyl-CoA Improve Ineffective Erythropoiesis in SF3B1 Mutated Myelodysplasia

Myelodysplastic syndrome (MDS) is a hematological clonal stem cell disease. Recurrent splicing factors mutations are reported in 50% of MDS. Interestingly, mutations in the splicing factor gene SF3B1 are over-represented in MDS with ring sideroblasts (MDS-RS), co-occurring in up to 90% of patients. In MDS-RS, anemia is the major clinical manifestation. Erythropoiesis stimulating agents (ESAs) are used to treat anemia; however, the overall response rates are 20% to 40% with a duration of response of 18-24 months. New therapeutic options are needed to improve response to ESAs treatment and delay red blood cell transfusion, which are associated with acute myeloid leukemia progression and increase in morbidity.Mutations in SF3B1 modify the recognition pattern of the 3' splice site and lead to subsequent mis-splicing of its targets. To identify critical mis-splicing events involved in the erythroid differentiation blockage, we performed splicing analysis on RNA sequencing generated from hematopoietic stem/progenitor cells undergoing differentiation. Three MDS primary samples harboring SF3B1 mutations and three age-matched healthy donors cultured under normoxia and hypoxia conditions were initially used for the analysis. High depth RNA sequencing and differential splicing analyses using rMATS identified 2,845 mis-spliced events including 200 shared between hypoxia and normoxia conditions. Here, using a cohort of 42 MDS samples, we report the mis-splicing of the coenzyme A synthase (COASY) transcript. Heme synthesis relies on succinyl-CoA synthesis, and its production itself depends on the availability of cellular CoA. We thus hypothesised that COASY mis-splicing is a key driver of ineffective erythropoiesis in MDS-RS patients.In primary hematopoietic cells, COASY is upregulated during erythroid differentiation and its silencing in CD34 + cells severely impedes the generation of mature erythroid cells CD71 - CD235a + and causes disruption in heme production. Functional characterisations of the CRISPR-CAS9 edited K562 SF3B1K700E and the SF3B1-mutated HNT-34 cell lines confirmed that COASY mis-splicing impairs COASY protein synthesis that ultimately results in 60% loss of the protein. Metabolomic analysis showed that COASY mis-splicing depletes cells in CoA and succinyl-CoA metabolites, however this phenotype can be rescued by supplementation with vitamin B5, a CoA precursor. Consequently, we showed in vitro that saturating the 40% of remaining COASY enzyme with vitamin B5 or supplementing medium with its downstream by-product, succinyl-CoA, improved erythropoietic differentiation in MDS SF3B1mut patients.In summary, our results for the first time show that SF3B1 mutations induce coenzyme A synthase (COASY) transcript mis-splicing, that consequently leads to measurable defects in metabolites essential for heme biosynthesis. Our report reveals a novel critical role of COASY in regulating normal bone marrow erythropoiesis through control of succinyl-coA during human erythroid differentiation. Remarkably, partial loss of the coenzyme A synthase in MDS-RS patients leads to disruption in the erythroid lineage as well as heme deficiency, that can be rescued by exogenous treatment with vitamin B5 or succinyl-CoA. Therefore, vitamin B5 could represent a very attractive agent to combine with existing treatments in order to increase erythroid maturation and delay red blood cell transfusion dependency in MDS-RS patients.Graphical representation: SF3B1 mutant causes mis-splicing in COASY that results in loss of protein. Deficiency in COASY triggers a downregulation of succinyl-CoA that is involved in the rate limiting step of heme synthesis. Heme deficiency subsequently impairs erythroid differentiation. Treatment of MDS SF3B1 mutant cells with vitamin B5 (precursor of CoA), or succinyl-CoA, rescues erythroid differentiation. [Display omitted] DisclosuresPlatzbecker: Geron: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; AbbVie: Honoraria. Wiseman: Bristol Myers Squibb: Consultancy; Novartis: Consultancy; StemLine: Consultancy; Takeda: Consultancy; Astex: Research Funding. Gribben: Abbvie: Honoraria; AZ: Honoraria, Research Funding; BMS: Honoraria; Gilead/Kite: Honoraria; Janssen: Honoraria, Research Funding; Morphosys: Honoraria; Novartis: Honoraria; Takeda: Honoraria; TG Therapeutis: Honoraria.

Efficacy and Safety of Molidustat for Anemia in ESA-Naive Nondialysis Patients: A Randomized, Phase 3 Trial

Introduction: Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the “Molidustat Once Daily Improves Renal Anemia by Inducing EPO” (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment. Methods: This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3–5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 μg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and <13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30–36). The safety outcomes included evaluation of all adverse events. Results: In total, 162 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was −0.38 (−0.67, −0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group. Discussion/Conclusion: In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.

Prognosis of Lower Risk Patients with Myelodysplastic Syndromes without Isolated Del(5q) after Failure of Erythropoiesis-Stimulating Agents. a Multicenter Study By the Hellenic MDS Study Group

INTRODUCTIONMost anemic non-del(5q) lower risk myelodyplastic syndromes (MDS) patients are treated with erythropoiesis stimulating agents (ESAs). Second-line treatments, including hypomethylating agents (HMA), lenalidomide (LEN) and other drugs, may be used after ESA failure in some countries, but their effect on disease progression, transformation to acute myeloid leukemia (AML), and overall survival (OS) is unknown. We analyzed MDS patients' outcome after primary or secondary failure of treatment with ESAs as a first-line treatment option. METHODSThis retrospective study included 1065 non-del(5q) lower risk (low or intermediate-1 IPSS risk) MDS patients, registered in the Hellenic National MDS Registry, treated with ESAs. Extensive biostatistical analysis performed in this study included Kaplan-Meier survival analysis. The level of statistical significance was set at a probability value of less than 0.050 (P <0.050). RESULTSBaseline patient characteristics are presented in Table 1. 848 (79.6%) of 1065 MDS patients included in this study were first treated with ESAs. Erythroid response (HI-E) to ESAs was 26.3%, and the median response duration was 21 months. Stable disease (SD) was achieved by 139 (19.4%) MDS patients, while 204 (28.4%) patients receiving ESA had progression of disease (PD) or primary treatment failure. Moreover, 353 (41.6%) MDS patients relapsed after an initial response. Primary failure to ESA was associated with a higher risk of transformation to AML, as well as poorer prognostic outcome regarding OS. The 5-year cumulative incidence of AML transformation in patients with primary and secondary failure was 32.2% and 16.1% respectively (P <0.001). In a median follow-up time period of 28 months, the mean survival from ESA failure was 40 and 80 months for primary refractory patients and relapsing patients, respectively (P <0.001). The estimated mean time to transformation to AML patients with primary failure to ESA treatment was 71.2 months (95% confidence interval [CI] = 63.0-79.3) vs. 104.6 months (95% CI = 99.6-109.6) for those having a secondary failure (P <0.001) (Figure 1a). The estimated mean OS for patients with primary failure to ESA treatment was 40.1 months (95% CI = 34.5 - 45.6) vs. 79.9 months (95% CI = 73.9-85.9) for those having a secondary failure (P <0.001) (Figure 1b). Out of 412 patients who received a second-line treatment, 48 received HMAs, 22 were treated with LEN and 176 had other treatments. CONCLUSIONSThe data of this large, multicenter, retrospective cohort of non-del(5q) lower-risk MDS patients, treated with ESAs, show that patients not responding to ESAs, as first-line treatment, are at a higher risk of transformation to AML and have poorer OS, compared to those who initially respond to ESAs but lose response thereafter. This information combined with other parameters, predictive a worse outcome (eg IPSS-R, duration of ESAs response) can be used in future clinical studies, distinguishing candidate patients for a more intensive treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pleiotropic effect of erythropoiesis-stimulating agents on circulating endothelial progenitor cells in dialysis patients

Recent studies have suggested that erythropoiesis-stimulating agents (ESAs) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis. We conducted a 12-week prospective study in 51 dialysis patients; 13 were treated with recombinant human erythropoietin (EPO, 5290.4 ± 586.9IU/week), 16 with darbepoetin (DA, 42.9 ± 4.3µg/week), 12 with epoetin β pegol (CERA, 40.5 ± 4.1µg/week) and 10 with no ESAs. Vascular mediators comprising endothelial progenitor cells (EPCs), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and high-sensitivity C-reactive protein (hs-CRP) were measured at 0 and 12weeks. EPCs were measured by flow cytometry as CD45lowCD34+CD133+ cells. The EPC count increased significantly to a greater extent in the EPO group than in the other three group, and increased significantly from 0 to 12weeks in a EPO dose-dependent manner. In both the DA and CERA groups, the EPC count did not change at 12weeks. Serum levels of VEGF, MMP-2 and hs-CRP were not affected by ESA treatment in all groups. In the CERA group, serum ferritin decreased significantly compared to the no-ESA group and correlated with CERA dose, although use of iron was permitted if required during the prospective study period of 12weeks. When patients on dialysis were treated with clinical doses of various ESAs, only EPO induced a significant increase of circulating EPCs from bone marrow, whereas, DA and CERA had no effect.

Oxidative Stress Parameters Can Predict the Response to Erythropoiesis-Stimulating Agents in Myelodysplastic Syndrome Patients.

Oxidative stress has been implicated in the development of several types of cancer, including myelodysplastic syndromes (MDS), as well as in the resistance to treatment. In this work, we assessed the potential of oxidative stress parameters to predict the response to erythropoiesis-stimulating agents (ESAs) in lower-risk MDS patients. To this end, we analyzed the systemic levels of reactive species (peroxides and NO), antioxidant defenses (uric acid, vitamin E, vitamin A, GSH, GSSG, TAS, as well as GPX and GR activities], and oxidative damage (8-OH-dG and MDA) in 66 MDS patients, from those 44 have been treated with ESA. We also calculated the peroxides/TAS and NO/TAS ratios and analyzed the gene expression of levels of the redox regulators, NFE2L2 and KEAP1. We found that patients that respond to ESA treatment showed lower levels of plasma peroxides (p < 0.001), cellular GSH (p < 0.001), and cellular GR activity (p = 0.001) when compared to patients who did not respond to ESA treatment. ESA responders also showed lower levels of peroxides/TAS ratio (p < 0.001) and higher levels of the expression of the NFE2L2 gene (p = 0.001) than those that did not respond to ESA treatment. The levels of plasmatic peroxides shown to be the most accurate biomarker of ESA response, with good sensitivity (80%) and specificity (100%) and is an independent biomarker associated with therapy response. Overall, the present study demonstrated a correlation between oxidative stress levels and the response to ESA treatment in lower-risk MDS patients, with the plasmatic peroxides levels a good predictive biomarker of drug (ESA) response.

MO539HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH KIDNEY FAILURE ON DIALYSIS

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase being developed for treatment of anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two of the four phase 3, randomized, open-label, sponsor-blind trials (the INNO2VATE trials) in adult patients with dialysis-dependent (DD) CKD and anemia, where vadadustat met prespecified noninferiority criteria compared with darbepoetin alfa with respect to cardiovascular safety and correction/maintenance of hemoglobin (Hb) target concentrations. Method The mean screening Hb range for the incident DD-CKD trial (NCT02865850) was 8.0-11.0 g/dL; for the prevalent DD-CKD trial (NCT02892149), it was 8.0-11.0 g/dL in the United States (US) and 9.0-12.0 g/dL for non-US. Patients in the incident and prevalent DD-CKD trials had initiated dialysis within &amp;lt;16 weeks with limited or no prior ESA exposure and &amp;gt;12 weeks with established ESA treatment prior to screening, respectively. Vadadustat starting dose was 300 mg/day for all patients, whereas initial darbepoetin alfa dose depended on each patient’s prior dose or product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) during the primary evaluation period (PEP; weeks 24-36) and the secondary evaluation period (SEP; weeks 40-52). Herein, we present topline results from PEP and SEP endpoints, as well as other, more detailed hematologic erythrocyte parameters. Results A total of 3923 patients (369 with incident DD-CKD and 3554 with prevalent DD-CKD) were randomized 1:1 to vadadustat or darbepoetin alfa. Vadadustat was noninferior to darbepoetin alfa in achieving target-range Hb concentrations (primary efficacy endpoint) among patients who were new to, or established on, dialysis. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 43.6% versus 56.9% and 39.8% versus 41.0% in the incident trial and 49.2% versus 53.2% and 44.3% versus 50.9% in the prevalent dialysis trial. The proportion of patients who achieved an Hb increase &amp;gt;1.0 g/dL from baseline to week 52 was assessed only for the incident trial and was 84.0% (95% CI: 77.8%, 89.0%) for vadadustat versus 89.9% (95% CI: 84.7%, 93.8%) for darbepoetin alfa. Hematologic erythrocyte parameters at time points within the PEP and SEP are presented in Table 1. In the incident trial, reticulocyte count was slightly increased from baseline at 28 and 52 weeks for vadadustat, whereas for darbepoetin alfa, reticulocyte count was slightly decreased or unchanged in both trials. Erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb showed increases by week 52 for both groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of anemia associated with CKD in adults in both incident dialysis and prevalent dialysis settings.

IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment.

TPS7056 Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients (pts) with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001) is a Phase 2/3 global study of imetelstat for TD pts with non-del(5q) LR MDS post ESA therapy. The results from Phase 2 part indicated that imetelstat achieved durable RBC transfusion independence (RBC-TI) and the most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. Among 38 pts with median follow-up of 24 months, 8-week, 24-week and 1-year TI rates were 42%, 32% and 29%, respectively; these responses were seen across different LR MDS subtypes. Median TI duration was 20 months and the longest TI was 2.7 years. A high and durable hematologic improvement-erythroid (HI-E) rate of 68% for a median duration of 21 months were also achieved. Reduction of variant allele frequency of mutations by imetelstat treatment was observed in some pts and correlated with clinical benefits (Platzbecker et al EHA 2020; Steensma et al JCO 2020). These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 3 part of the study is open for enrollment to adult pts with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs placebo that will enroll approximately 170 pts and will be conducted at approximately 120 centers in North America, Europe, Asia and Middle East. Imetelstat is administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics, and quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. The study is currently recruiting pts. Clinical trial information: NCT02598661.

POS-287 TREATMENT BURDEN AND HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH NON–DIALYSIS-DEPENDENT ANAEMIA OF CHRONIC KIDNEY DISEASE RECEIVING ERYTHROPOIESIS-STIMULATING AGENTS: A SYSTEMATIC LITERATURE REVIEW

Anaemia of chronic kidney disease (CKD) is associated with morbidity, poor health-related quality of life (HRQoL) and increased mortality. Standard of care includes erythropoiesis-stimulating agents (ESAs), but they are not widely used in non–dialysis-dependent (NDD) patients, due to safety concerns. A broader assessment of patient-centric outcomes is needed. We performed a systematic literature review of treatments for anaemia of CKD in NDD patients. We report the treatment burden, including safety, and HRQoL in patients with NDD anaemia of CKD from ESA trials. We searched electronic databases and other sources to identify randomised controlled trials (phase 2+) for ESAs in the treatment of anaemia of CKD in adults. The search was not limited to outcomes or countries. Other criteria were English publications between database inception and 23 January 2020 (search date). We conducted risk of bias and descriptive assessments of study and patient characteristics, treatment burden and HRQoL. Overall, 4,024 abstracts were screened, and 325 publications were reviewed; 38 ESA NDD-CKD trials of 12,594 randomised patients with anaemia were included. Although 27 trials (71%) had a risk of bias based on quality appraisal, these were included in the descriptive analysis. Overall, 6/38 (16%) trials were phase 3, 24 (63%) were open-label, and 9 (24%) were double-blind. ESAs, such as darbepoetin alfa (DPO) and epoetin alfa, were investigated and often compared with an active comparator, such as other ESAs or iron. Four trials compared high/low haemoglobin (Hb) targets in both ESA treatment arms. Rescue therapy included iron use (45%; 17 trials) and RBC transfusion (3%; 1 trial). Across trials, the mean age was 46.0–84.4 years; baseline Hb range was 8.2–12.2 g/dL. Treatment burden (e.g. discontinuations and adverse events) was evaluated in the safety populations (n=13,082); the burden of treatment administration was not observed. Hypertension was reported frequently as an adverse event across treatment arms (up to 37% of patients) in 18 trials. Treatment discontinuation was reported in 27 trials; common reasons included adverse events, dialysis, treatment failure or other illnesses. The most commonly used HRQoL instruments were Short Form-36 (SF-36; 9 trials), EQ-5D (2 trials), Linear Analogue Self-Assessment (2 trials) and the KDQoL Questionnaire (2 trials). SF-36 scores were statistically significant for ESA vs. placebo as early as 8 weeks (1 trial) and through 1 year (1 trial), though domain-specific results were inconsistent across trials. HRQoL outcomes, such as changes in physical functioning and fatigue scores, were reported in 14 trials; 2 trials evaluated exercise capacity. HRQoL was generally maintained or showed clinically relevant improvements across instruments, particularly for patients receiving ESAs vs. other comparators. Hypertension, as an adverse event was common across treatment arms. Patient-reported treatment burden and HRQoL outcomes were not measured consistently. Questionnaire use was low; SF-36 was mostly frequently used, which is not specific to kidney disease/anemia of CKD. More consideration and consistency of patient-centric outcomes, including complementary evidence from observational studies, may help better understand the holistic impact of ESA treatment on clinical management.

POS-288 THE BURDEN OF HEART FAILURE IN PATIENTS WITH NON–DIALYSIS-DEPENDENT ANAEMIA OF CHRONIC KIDNEY DISEASE RECEIVING ERYTHROPOIESIS-STIMULATING AGENTS: A SYSTEMATIC LITERATURE REVIEW

Anaemia of chronic kidney disease (CKD) is associated with significant morbidity and increased mortality, particularly cardiovascular complications such as heart failure (HF). We performed a systematic literature review of the treatment options for anaemia of CKD in non-dialysis-dependent (NDD) patients. This abstract reports HF-related outcomes from clinical trials in patients with NDD anaemia of CKD. We identified randomised controlled trials (RCTs; phase 2+) for erythropoiesis-stimulating agents (ESAs) for the treatment of anaemia of CKD in adults, from electronic databases (Embase®, MEDLINE®, Cochrane library), grey literature and other sources. Outcomes were not used in the search to avoid excluding eligible trials. Other criteria were, English publications between database inception and 23 January 2020 (search date). Risk of bias was assessed using a quality appraisal checklist. Descriptive statistics assessed study and patient characteristics and HF-related outcomes in ESA trials. A total of 4,024 abstracts were screened and 325 full-text publications reviewed; 38 ESA RCTs that randomised 12,594 patients with NDD-CKD and anaemia met the inclusion criteria. Mean age range was 46.0–84.4 years; median study duration was 50.5 weeks. Most trials (24; 63%) were open-label; 9 (24%) were double-blind. Twenty-seven trials were determined to have a risk of bias but remained in the descriptive assessment. Comparative trials most often investigated darbepoetin alfa or its biosimilar (DPO; 12 trials), epoetin alfa (EPO A) or its biosimilar and recombinant human erythropoietin (16 trials) and continuous erythropoietin receptor activator (3 trials). HF-related outcomes were reported in 19 trials, including as the primary endpoint in 7 trials. HF occurrence as an adverse event (AE; 15 trials), change in left ventricular mass index (LVMI; 7 trials), and hospitalisation related to HF (1 trial) were reported. Heterogeneity in outcome definitions and reporting was observed. One trial comparing a low haemoglobin (Hb) target (9.0–11.0 g/dL) with low dose ESA vs. a high Hb target (11.0–13.0 g/dL) with DPO reported significant LVMI reduction from baseline in the high Hb group (−7.8 g/m2; 95% CI: −12.1 to −3.6 g/m2; P<0.001). Another study reported a significantly reduced LVMI (P=0.02) with EPO A (−5.7±14.2 g/m2) and DPO (−5.6±15.8 g/m2) vs. controls (no ESA); however, no difference in LVMI decrease was observed between treatment arms. One study included hospitalisation for congestive HF without renal replacement therapy as a component of the composite primary endpoint. Of the 222 composite events, 101 (45.5%) hospitalisations for congestive HF were reported in the high and low Hb EPO A treatment arms combined. The proportions of patients from the safety populations (n=13,082) with a congestive HF AE ranged from 0% to 9.0% across trials and treatment arms. Findings of this review suggested a potentially high occurrence of HF-related outcomes, such as LVMI reduction and hospitalisations. We observed substantial heterogeneity in the reporting and results of HF-related outcomes in ESA RCTs. Information from observational studies may also be needed to fully characterise the burden of HF in patients with NDD-CKD and anaemia on ESA treatment.

NIMO-CKD-UK: a real-world, observational study of iron isomaltoside in patients with iron deficiency anaemia and chronic kidney disease

BackgroundIntravenous iron is often used to treat iron deficiency anaemia in non-dialysis chronic kidney disease (ND-CKD), but the optimal dosing regimen remains unclear. We evaluated the impact of high- versus low-dose intravenous iron isomaltoside on the probability of retreatment with intravenous iron in iron-deficient ND-CKD patients.MethodsThis real-world, prospective, observational study collected data from 256 ND-CKD patients treated for anaemia in the UK. Following an initial course of iron isomaltoside, patients were followed for ≥12 months. Iron dose and the need for retreatment were determined at the investigators’ discretion. The primary study outcome was the need for retreatment at 52 weeks compared between patients who received >1000 mg of iron during Course 1 and those who received ≤1000 mg. Safety was evaluated through adverse drug reactions.ResultsThe probability of retreatment at Week 52 was significantly lower in the >1000 mg iron group (n = 58) versus the ≤1000 mg group (n = 198); hazard ratio (95% confidence interval [CI]): 0.46 (0.20, 0.91); p = 0.012. Mean (95% CI) haemoglobin increased by 6.58 (4.94, 8.21) g/L in the ≤1000 mg group and by 10.59 (7.52, 13.66) g/L in the >1000 mg group (p = 0.024). Changes in other blood and iron parameters were not significantly different between the two groups. Administering >1000 mg of iron isomaltoside saved 8.6 appointments per 100 patients compared to ≤1000 mg. No serious adverse drug reactions were reported. Of the patients who received ≤1000 mg of iron in this study, 82.3% were eligible for a dose >1000 mg.ConclusionsThe >1000 mg iron isomaltoside regimen reduced the probability of retreatment, achieved a greater haemoglobin response irrespective of erythropoiesis-stimulating agent treatment, and reduced the total number of appointments required, compared to the ≤1000 mg regimen. Many of the patients who received ≤1000 mg of iron were eligible for >1000 mg, indicating that there was considerable underdosing in this study.Trial registrationClinicalTrials.gov NCT02546154, 10 September 2015.

Direct healthcare costs of chronic kidney disease management in Italy: What cost-savings can be achieved with higher biosimilar uptake and more appropriate use of erythropoiesis-stimulating agents?

Erythropoiesis-stimulating agents (ESAs), are used for treating chronic kidney disease (CKD)-related anemia, contributing to CKD costs. The study was aimed at investigating direct healthcare costs of CKD patients treated with ESAs and the potential savings achievable by increasing the use of biosimilars and preventing inappropriate ESA use. A multi-center, cohort study was conducted using claims databases of five large Italian geographic areas. Yearly mean direct healthcare costs per patient were estimated, stratifying by CKD stage. The total yearly cost and potential savings related to ESA use were estimated: (a) considering 25/50/75% of originator ESA substitution with biosimilars; (b) eliminating inappropriate ESA dispensing. During the study period, the ESA-related yearly mean cost represented 17% of total yearly costs in stage I-III, decreasing to 13% in stage IV-V and 6% in dialysis. Among originator users, assuming a 25% of biosimilar uptake, the annual cost-savings of ESA treatment would represent 10.5% of total ESA costs in CKD stage I-V and 7.7% in dialysis. Among incident ESA users for which hemoglobin levels were available, 9% started inappropriately ESA treatment, increasing to 62.0% during the first year of maintenance therapy. Hypothesizing prevention of the first inappropriate ESA dispensing, the total yearly cost-savings would amount to €35 772, increasing to €167 641 eliminating the inappropriate dispensing during maintenance therapy. Higher use of lowest cost ESA, prevention of inappropriate ESA use as well as other strategies aimed at slowing down the progressive renal impairment are essential for minimizing clinical and economic burden of CKD.

Niedokrwistość u chorych na nowotwory — zalecenia grupy ekspertów. Aktualizacja 2020 r.

Anemia is a common feature in about 40% of patients at the moment of cancer diagnosis and in more than half of patients on anticancer therapy. Therapeutic alternatives in cancer patients with anemia include substitution of lacking agents, red blood cell transfusions, and erythropoiesis-stimulating agents (ESAs). The advantages of red blood cell transfusions are rapid increase of hemoglobin concentration and effectiveness independent of the cause of anemia. However, several adverse reactions may occur after blood component transfusion. ESAs act through stimulation of erythropoietin receptors. Use of ESAs reduces the need for red blood cell transfusions, decreases the risk of post-transfusion adverse reactions, and improves the quality of life of cancer patients with chemotherapy-induced anemia. In accordance with registered indications, ESA may be administered in non-myeloid cancer patients with chemotherapy-induced anemia. Thromboembolic events and arterial hypertension are known risks of ESA treatment. If ESAs are used in accordance with currently approved indications and are not administered when hemoglobin (Hb) concentration is 12 g/dL or above, there is no observed unfavorable effect on survival or thromboembolic risk. The administration of RBC transfusions without delay is justified in patients with Hb under 7–8 g/dL and/or severe anemia-related symptoms (even at higher Hb levels) and the need for immediate Hb and symptom improvement. The goal of ESA treatment is maintenance of the lowest hemoglobin concentration needed to avoid red blood cell transfusion. ESAs may be used in patients with symptomatic chemotherapy-induced anemia and Hb concentration at 10 g/dL or below. There is no indication for ESAs in patients who are not receiving chemotherapy or who are receiving radiotherapy.

No effect of 10 weeks erythropoietin treatment on lipid oxidation in healthy men.

Studies indicate that erythropoietin (EPO) has effect on lipid and energy metabolism; however, the impact of EPO on lipid oxidation in vivo has not been well documented. Here, we evaluate whether long-term erythropoiesis-stimulating agent (ESA) treatment affects the oxidation of plasma very low-density lipoprotein triglycerides (VLDL-TG) fatty acids (FA), plasma free fatty acids (FFA) and non-plasma (residual) FA in healthy, young, sedentary men. Infusion of [1-14C]VLDL-TG and [9,10-3H]palmitate was used in combination with indirect calorimetry to assess resting lipid fuel utilization and kinetics, and resting energy expenditure (REE) before and after 10 weeks of ESA exposure compared with placebo. REE increased significantly during ESA compared with placebo (P = 0.023, RM-ANOVA). Oxidation rates of VLDL-TG FA, FFA, and residual FA remained unchanged during ESA compared with placebo. The relative contribution of the lipid stores was greatest for FFA (47.1%) and the total lipid oxidation rate and was not significantly different between ESA and placebo-treated subjects. We conclude that long-term ESA treatment of healthy young men increases REE but does not alter the oxidation rates of plasma and non-plasma FA sources.

Content validity of patient-reported outcomes for use in lower-risk myelodysplastic syndromes

BackgroundThe lower-risk (low and intermediate-1 risk based on IPSS) myelodysplastic syndrome (MDS) has a negative impact on patients’ health-related quality of life (HRQoL). Patient Reported Outcomes (PROs) instruments, which are used to collect patients’ HRQoL data, should have established content validity in the target population to ensure that the instrument is comprehensive and comprehensible. The present study was conducted to evaluate the content validity of the Quality of Life in Myelodysplasia Scale (QUALMS) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An) PRO instruments in patients with lower-risk MDS.MethodsIn this cross-sectional, qualitative study, 16 patients aged ≥18 years with lower-risk MDS, who were RBC transfusion dependent, literate and fluent in US-English were interviewed. Interviews were semi-structured comprising of two parts: concept elicitation (CE) explored symptoms and impacts important to patients, and cognitive debriefing (CD) assessed understanding and relevance of the QUALMS and FACT-An. A conceptual model was developed, which was used to map the concepts that emerged during CE onto the QUALMS and FACT-An to assess concept coverage and suitability of the instruments.ResultsThe median age of participants was 67.5 years (range: 51–91), with half being female (n = 8). Nine (56.2%) participants had intermediate-1-risk MDS and 10 (62.5%) were relapsed or refractory to erythropoiesis-stimulating agent treatment. Fatigue/tiredness (100.0%), shortness of breath (87.5%), weakness (81.2%), and low energy (75.0%) were reported most commonly and were the most bothersome symptoms as well. Of seven high-level HRQoL domains identified, activities of daily living (n = 16, 100.0%), physical functioning (n = 15, 93.8%), emotional wellbeing (n = 13, 81.3%), social functioning (n = 12, 75.0%), sleep disturbance (n = 9, 56.3%), and impact on work (n = 9, 56.3%) were the most commonly reported. For CD, the QUALMS and FACT-An were found to be mostly relevant and very well understood; response options were easy to use, and recall period was appropriate.ConclusionBoth QUALMS and FACT-An demonstrated a strong face and content validity in patients with lower-risk MDS, suggesting that these instruments are appropriate for assessing HRQoL in this population.

P0847HEPATIC ERYTHROPOIETIN SYNTHESIS IS ENHANCED IN HEMODIALYSIS PATIENTS WHO DO NOT REQUIRE ERYTHROPOIESIS-STIMULATING AGENTS

Abstract Background and Aims Erythropoietin is synthesized in the liver during the fetal period and mainly in the kidney after birth. However, some patients with end-stage chronic kidney disease do not require the administration of erythropoiesis-stimulating agents (ESA) despite their damaged renal function. This study aimed to clarify the origin of extrarenal erythropoietin generation in these patients. Method The origin of erythropoietin was investigated by analyzing the erythropoietin glycation patterns based on the percentages of migrated isoforms (PMI). Sera of stable hemodialysis (HD) patients with (ESA group) or without (non-ESA group) ESA treatment and umbilical cord blood of newborns (UCB group), which contained erythropoietin of liver origin, were analyzed. The non-ESA group was determined as HD patients without ESA treatment for &amp;gt; 6 months. Informed consent was obtained from all included HD patients and from the parents or guardians of the newborns. This study was performed with permission from the institutional ethical committee and was registered as a clinical trial (no. R000033462 UMIN000029335). Results The mean duration of no ESA treatment in the non-ESA group was 29.2 months. There were no differences in major clinical parameters, including age and HD duration. The hemoglobin concentration in the ESA group was 107 ± 5 g/L (mean ± standard error), which was significantly lower than that in the non-ESA group (123 ± 4 g/L) (P = 0.025, unpaired Student’s t-test). The PMI values of the ESA, non-ESA, and UCB groups were 12.6 ± 11.4％, 61.2 ± 13.1%, and 65.0 ± 13.5％, respectively, and the PMI value of the ESA group was significantly lower than that of non-ESA or UCB group (one-way analysis of variance with Tukey-Kramer test), suggesting that the glycation pattern of erythropoietin in the non-ESA group was similar to that in the UCB group but different from that in the ESA group. No significant differences were found in the reticulocyte ratio, serum iron concentration, total iron binding capacity, and ferritin and transferrin saturation between the ESA and non-ESA groups. Conclusion These results suggest that patients in the non-ESA group had enhanced extrarenal erythropoietin synthesis and that their erythropoietin originated from the liver. Further analysis of the underlying mechanism may contribute to the development of internal extrarenal erythropoietin-stimulating therapy.

P0865A QUALITATIVE STUDY OF PATIENTS' PREFERENCE FOR THE TREATMENT OF ANAEMIA ASSOCIATED WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Anaemia is a common complication of chronic kidney disease (CKD) that is associated with fatigue, shortness of breath, and lethargy. CKD anaemia is commonly treated with oral or intravenous (IV) iron and IV or subcutaneous (SC) erythropoiesis-stimulating agents (ESAs). The objectives of this study were to understand patients’ experiences with CKD anaemia and their preferences related to treatment. Method Qualitative 60-minute semi-structured interviews were conducted with ESA-treated adult CKD patients with anaemia, either non–dialysis-dependent (ND) or dialysis-dependent (DD), and with practicing nephrologists in France, Germany, Spain, the UK, and Japan. The patients’ interviews, appropriately tailored for ND and DD patients, comprised three sections: 1) patients’ views on the burden of the disease and its treatment; 2) discussion of vignettes describing different treatment options; and 3) non-experimental choice questions between two hypothetical treatments including mode of administration, need for iron supplement, and risk of adverse events (AEs). Results A total of 51 patients were enrolled (ND, n=6 per country except for France [n=7]; DD [haemodialysis or peritoneal dialysis], n=4 per country). Two nephrologists per country were interviewed. The most commonly reported symptoms associated with anaemia were tiredness (ND, 77%; DD, 85%) and shortness of breath (ND, 42%; DD, 30%); these two symptoms were also reported by nephrologists, who considered clinical efficacy the most important aspect of treatment. In Japan, dizziness was the most common (n=5/6, 83%) symptom among ND patients. Anaemia symptoms were reported to negatively affect different aspects of patients’ lives, including the ability to carry out daily activities (ND, 61%; DD, 65%), work (ND, 42%; DD, 50%), and exercise (ND, 26%; DD, 30%). ESA treatments were perceived to be effective in improving patients’ symptoms and quality of life. Many patients had not experienced AEs associated with treatment and were not concerned about them, however patients who had experienced gastrointestinal (GI) AEs due to oral iron were sensitive to the risk of GI effects. Out of 23 ND patients who were asked, 19 (83%) preferred an oral treatment due to the convenience of administration, and to avoid injection pain and drug storage requirements associated with SC administration. Self-administering SC ESAs was a concern among Japanese ND patients, who often had a healthcare professional administer the medication. Haemodialysis patients (n=12), who often receive IV ESAs during their dialysis sessions, were less likely to prefer oral treatments due to lack of perceived convenience. Peritoneal dialysis patients (n=8), who often receive home dialysis and SC ESAs, preferred oral treatment to avoid self-administration and storage requirements, and to make travel easier. Limitations of the study included the small number of participants and amendments to the eligibility criteria implemented during data collection, including more relaxed requirements for blood pressure, blood transfusion, and insulin use. Conclusion Patients considered the available treatment options to effectively treat CKD anaemia. Besides efficacy, patients’ primary concern was the mode of administration of their medication, rather than safety considerations.

Erythropoietin and a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) lowers FGF23 in a model of chronic kidney disease (CKD).

Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor‐23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) FG‐4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 (“iFGF23”). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild‐type mice were fed an adenine‐containing diet to induce CKD, then injected with EPO or FG‐4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG‐4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein‐6 (Bmp‐6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF‐PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.

Adherence to treatment with erythropoiesis stimulating agents

To establish adherence to treatment with erythropoiesis stimulating agents (ESA) in patients with anemia associated to chronic kidney disease (CKD), and analyze its relationship to response to ESA. Retrospective study of a cohort of 198 patients with CKD who started treatment with epoetin-ß or darbepoetin-a, followed for two years. Basal characteristics, effectiveness (% of hemoglobin (Hb) target attainment, percentage increase of Hb) and adherence (medication possession rate) were registered. A non-adherent patient was one whose mean adherence was <90%. Average global adhesion was 89.6%, slightly higher in treatment with darbepoetin-a than with epoetin-ß; 8.6% of patients were non-adherents. Hb target was accomplished in 87% cases. Level of response to ESA treatment was independent of the degree of adherence to treatment. Adherence to ESA treatment was good, without differences related to degree of response.