Erythropoiesis-stimulating Agents Therapy Research Articles

#1122 Anaemia in CKD and cardiovascular risk; all cut from the same cloth?

Abstract Background and Aims Anaemia in chronic kidney disease (CKD) has been repeatedly associated with increased cardiovascular morbidity and mortality, but most studies have not investigated its longitudinal association by sex and age. Our aim was to study the association between haemoglobin (Hb) current value and the hazard of major adverse cardiovascular event (MACE) in specific subgroups of CKD patients defined by age and sex. Because erythropoiesis-stimulating agents (ESA) are incriminated to modify the effect of Hb level on the hazard of event for high level of Hb, we have here only focused in non-ESA users CKD patients. Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. We included patients with at least one Hb, estimated glomerular filtration rate (eGFR), transferrin saturation (TSAT) or ferritin measurement. We studied all Hb measurements available until a first MACE defined as the first event among cardio-vascular death, myocardial infarction, stroke or hospitalization for acute heart failure; initiation of kidney replacement therapy; death from other causes; or initiation of ESA therapy, whichever came first. First, we estimated the individual trajectories of Hb, eGFR, TSAT, ferritin using multivariate share random effect joint model. Then, we estimated the association between Hb current value and MACE using a cause specific multivariate Cox model in 4 specific subgroups separately: women ≤ and >70 years, men ≤ and >70 years. All models were adjusted on current value of eGFR, TSAT, Ferritin, and baseline value of albumin-to-creatinine ratio, age, CKD aetiology, heart failure past history, alcohol consumption, iron treatment, antithrombotic and anticoagulant. When appropriate, spline functions were used for continuous variables to account for potential non-linear effects. Reference value of Hb for computing hazard ratio was 12 g/dL in women, and 13 in men according to current definition of anaemia. Results A total of 2742 patients were included in the analysis (median eGFR 33 ml/min/1.73 m2, median age at inclusion 69 years) together with 28423 Hb measurements (median of 13 per patient) collected during a median follow-up of 5.0 years. There were 551 women ≤70 (median Hb 12.4 g/dL, 34 (6.2%) MACE), 349 women > 70 (12.2 g/dL, 61 (17.5%) MACE), 1009 men ≤ 70 (13.4 g/dL, 104 (10.3%) MACE) and 833 men > 70 (13.0 g/dL, 163 (19.6%) MACE). No statistical significant association was found in males whatever their age (Hazard ratio of MACE for each 1 g/dL increase in Hb 1.0 (95% CI 0.9-1.1) in men < 70 and 0.9 (95% CI 0.8-1.1) in men > 70). For women, the hazard of MACE raised as the Hb values decreased, with a more pronounced increase in women > 70 (Fig. 1). For example, the hazard ratio for a Hb value of 10 g/dL compared to the reference was 2.0 (95% CI 0.9-4.7) in women < 70 and 3.3 (95% CI 1.5-7.2) in women > 70. Conclusion In non-ESA users CKD patients, anaemia is associated with the occurrence of MACE in females, especially those older than 70 years. These results raise question about a one-size-fits-all approach in the interpretation of low values of haemoglobin and anaemia management. It also suggests to evaluate the effect of anaemia therapies in men and women separately.

Clinical Outcomes and Healthcare Resource Utilization for Patients With Lower-Risk Myelodysplastic Syndromes Treated With Erythropoiesis-Stimulating Agents

IntroductionReal-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States. Patients and MethodsThis retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019. The primary analysis assessed patient demographic and clinical characteristics, treatment patterns, clinical outcomes (hematologic response, transfusion requirements, disease progression), and HCRU (medical encounters, laboratory tests, and medication use). Subgroup analyses of patients repeatedly treated with ESA therapy evaluated selected clinical outcomes and primary ESA failure by SF3B1 mutational status, per recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines©). ResultsA total of 142 patients were included with a median follow-up time of 17 months (interquartile range [IQR], 7-33). Median age at ESA initiation was 79 years (IQR, 73-85). Patients were predominantly male (54%), overweight or obese (32% and 23%, respectively), of White race (96%) and non-Hispanic ethnicity (89%). Overall, 57% patients were initially treated with darbepoetin alfa and 43% with epoetin alfa. Clinical outcomes were poor, and there was a significant burden on both the health system and individual patients treated with ESA therapies. Hematologic improvement- erythroid was only seen in 26% of 142 patients treated with ESAs, and 65% of 82 retreated patients experienced primary ESA failure. ConclusionOur results indicate that primary ESA failure is largely unrecognized and that many patients should be considered for alternative treatments.

Efficacy of Luspatercept in Low-Risk Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis

BACKGROUND Patients with anemia and lower-risk myelodysplastic syndromes (MDS) in whom erythropoiesis-stimulating agent therapy is not effective, inevitably become RBC-transfusion dependent, unless other lines of therapy are offered. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, has been FDA approved for use in MDS with ring sideroblasts (RS) and/or detection of an SF3B1 mutation. The efficacy of luspatercept in lower risk (LR) MDS (regardless of RS) patients has been evaluated in clinical and real-world (RWD) studies, suggesting conflicting data. OBJECTIVES This study aimed to conduct a systematic review and meta-analysis of clinical trials and RWD evidence to evaluate the efficacy of luspatercept among lower risk MDS patients. METHODS Prospective randomized controlled trials (RCTs) and phase II trials, retrospective cohort studies and case series of patients with MDS treated with single agent luspatercept were retrieved from PubMed, EMBASE and conference proceedings. References were screened until June 30 th 2023. Two reviewers appraised the quality of the studies and extracted data. Primary outcome was the rate of transfusion independence (for at least 8 weeks). Secondary outcomes included erythroid hematologic improvement (HI-e) rate and safety. Subgroup analysis was conducted for MDS-RS and SF3B1 mutation. Studies were critically appraised using Joanna-Briggs Institute checklists. All studies were included in the meta-analysis. RESULTS We screened 244 titles and eventually included 9 studies, conducted between 2013-2022, and including 839 MDS patients who were treated with luspatercept. Of them: 2 RCTs, one single arm phase 2, and 6 retrospective “real-world” (RWD) studies. Six were published in peer reviewed journals and three RWD studies published as abstracts. Median age of patients ranged between 68-75 years and 707/839 patients had MDS-RS. Three studies were of moderate-high quality (N= 389) and 6 were deemed moderate quality (N=450). Rates of transfusion independence for at least 8 weeks were highly variable ranged between 8-87% among all patients and between 42-87% among MDS-RS subgroup. The median duration of longest response ranged between 23.9-42 weeks. Rates of erythroid hematologic improvement (HI-e), ranged between 25-100%. Pooled estimate of achieving independence from red-cell transfusion for >= 8 weeks was 39.5% (95% CI 0.24, 0.55; I²=96.6%, p<0.001) by meta-analysis. Pooled estimate of HI-e was 54.4% (95% CI 0.44,0.65; I²=87.8%, p<0.001). The most common cause for drug discontinuation was lack or loss of response and disease progression. CONCLUSION The response rate to luspatercept is highly heterogenous among different studies. Overall, the response rate and duration in the RWD setting did not compare favorably with clinical trials. Of note, the vast majority of patients had MDS-RS and the role of luspatercept in the management of patients with MDS without RS is still unclear, even when data from several studies are pooled together. This study has many limitations arising from heterogeneity of patient characteristics and outcomes ascertainment. This highlights the need for standardized post-marketing studies of new drugs and the heterogeneity in RWD patient population.

Addressing Chronic Anemia in Sickle Cell Disease: Characterizing Erythropoiesis-Stimulating Agent (ESA) Utilization and Practice Patterns Among Providers

Background: Chronic anemia exerts profound impacts on the morbidity, mortality, and quality of life in individuals with sickle cell disease (SCD), but therapeutic options are limited. Erythropoietin-stimulating agents (ESAs) are the standard of care for managing anemia in chronic kidney disease (CKD). However, their utilization in SCD remains ad hoc, with limited literature and no guidelines supporting the use of ESAs in SCD. To address this knowledge gap, we present preliminary findings from a survey designed to evaluate provider practices and identify factors influencing the use of ESAs in SCD. Methods: We conducted a cross-sectional web-based survey from March-July 2023 among providers taking care of patients with SCD in the United States (US) and internationally. Survey items were developed to assess provider demographic characteristics, practice environments, and provider practices around ESA use in SCD. The data was collected and managed using REDCap electronic data capture tools hosted at the University of Pittsburgh. Descriptive statistics were used to report the data. Results: The survey has been completed by 33 providers as of a cut date of July 23, 2023. Most providers were hematologists who practiced in an academic setting (23/33, 69.7%), with an equal gender distribution (Table 1). The number of patients with SCD seen annually varied, with 101-300 patients being the most common cohort size (13/33, 39.4%). In the 12 months prior to survey completion, 15/33 (45.5%) providers treated at least 1 patient with SCD with ESAs, usually outpatient (Table 2). Commonly reported barriers to outpatient ESA therapy included lack of insurance approval/coverage or cost concerns, lack of provider experience, and patient tolerability/adherence or inability to perform self-injections. Fewer respondents reported no barriers to prescribing ESAs in the outpatient setting, compared to in the acute/inpatient setting (18.2% vs. 48.5%). The most commonly reported indications for starting ESAs in the outpatient setting were chronic anemia from end-stage renal disease or CKD, reduction of blood transfusion requirement, and chronic anemia in patients refractory to approved therapies. Less commonly reported indications include severe or symptomatic anemia alone and chronic anemia in the setting of cardiopulmonary disease. Respondents reported several contraindications to starting ESAs, including a history of venous thromboembolism (VTE), malignancy, stroke, coronary artery disease, hypertension, and frequent vaso-occlusive crises. Respondents also expressed concerns about the cost/insurance coverage, efficacy, safety, patient burden, and appropriate dosing of ESAs in patients with SCD. Only 18/33 (54.5%) respondents reported ever treating outpatients with SCD with ESAs; nearly all of them used 1 st generation ESAs, and a majority used 2 nd generation ESAs. For 1 st generation ESAs, the most common starting dose was 3500-7000 units (U) (50-100 U/kg; 22.2%) or 7001-14000 U (101-200 U/kg; 22.2 %). Once weekly was the most common dosing interval (50%), followed by three times a week (TIW; 27.8%) and twice a week (16.7%). The maximum dose used was 56001-70000 U (801-1000 U/kg) TIW. For 2 nd generation ESAs, the most common starting dose was 141-210 mcg (2.1-3.0 mcg/kg) (22.2%), and administration often occurred once every 2 weeks (44.4%) or weekly (27.8%). The maximum dose used was 211-315 mcg (3.1-4.5 mcg/kg) weekly. Outpatient ESAs were most often initiated for hemoglobin (Hb) < 6 g/dL (8/18, 44.4%), and Hb > 9 g/dL was the most common treatment target (6/18, 33.3%). ESAs were often combined with hydroxyurea, voxelotor, and simple transfusions (Table 2). Conclusion: These preliminary survey results show considerable variability in how ESAs are currently being used in people with SCD. These variations in clinical practice highlight both significant ambiguity about what works in this setting and the need for further research into the optimal use of ESAs for the management of chronic anemia in SCD (ongoing clinical trial: ACHiEvE-SCD, NCT05451940). Future directions include evaluating differences in practice patterns among adult vs. pediatric and US-based vs. non-US-based providers.

Adeno-associated virus-vectored erythropoietin gene therapy for anemia in cats with chronic kidney disease.

A treatment of chronic kidney disease (CKD)-associated anemia in cats is needed. SB-001 is an adeno-associated virus-vectored (AAV)-based gene therapeutic agent that is administered intramuscularly, causing the expression of feline erythropoietin. We hypothesized that SB-001 injection would lead to a sustained increase in PCV in cats with CKD-associated anemia. Twenty-three cats with International Renal Interest Society (IRIS) Stage 2 to 4 CKD-associated anemia were enrolled at 4 veterinary clinics. In a prospective clinical trial, cats were treated with 1 of 3 regimens of SB-001 (Lo 1.2 × 109 genome copies [GCs] on Day 0; Lo ± Hi [supplemental 2nd dose of 3.65 × 109 GC on Day 42]; Hi 3.65 × 109 GC IM on Day 0) and followed for 70 days. A response to SB-001 at any time between Day 28 and Day 70 was seen in 86% (95% confidence interval 65, 97%) of all cats. There was a significant (P < .003) increase in PCV from Day 0 to Day 28 (mean increase 6 ± 6 percentage points [pp]; n = 21), Day 42 (8 ± 9 pp; n = 21), Day 56 (10 ± 11 pp; n = 17), and Day 70 (13 ± 14 pp, n = 14). Twelve cats were hypertensive at baseline, 4 of which developed encephalopathy during the study. An additional 6 cats became hypertensive during the study. Results of this study suggest that SB-001 therapy represents a suitable single injection treatment that can address nonregenerative anemia in cats with CKD. It was generally well tolerated; however, hypertension and encephalopathy developed in some cats as previously described in association with erythropoiesis-stimulating agent therapy.

MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

POSTER: MDS-462 Response to Erythropoiesis-Stimulating Agent Therapy in IPSS-R Lower Risk Myelodysplastic Syndrome Patients Restratified According to IPSS-M

Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), arterovenous fistula (AVF) thrombosis and death. We included 26 RCTs with 24387 patients. Random effect meta-analysis of the unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10g/dL (95% CI 0.02 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21g/dL, 95% CI 0.12 to 0.29 versus -0.01, 95% CI -0.09 to 0.07 in studies using long-acting ESA, P<.001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (-3.1mg/week, 95% CI -5.6 to -0.6, P=.020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs. HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs.

#6131 ANEMIA IN PERITONEAL DIALYSIS

Abstract Background and Aims Anemia is one of the most frequent complications of chronic kidney disease (CKD), affects quality of life and increases morbidity and mortality. Prevalence of anemia in patients on peritoneal dialysis (PD) is 83% according to the RIKAS study. Diagnosis of anemia in CKD is set at a hemoglobin (Hb) below 13 g/dL in men and less than 12 g/dL in women. These values serve to define the diagnosis, but not to indicate treatment. Treatment is based on the use of erythropoiesis stimulating agents (ESA) and iron therapy. Absolute iron deficiency (ferritin less than 100 ng/ml and transferrin saturation index (TSAT) less than 20%) and functional iron deficiency (TSAT less than 20% with normal ferritin), require correction with oral or intravenous iron before the use of ESA. Treatment with ESA is indicated when Hb is below 10g/dL despite adequate iron stores. The goal is to achieve Hb values between 10-12g/dL. The aims are evaluating the situation of patients in our PD program with respect to anemia, its prevalence, treatment and its results. Method This is an observational, descriptive, cross-sectional and single-center study. Inclusion criteria were patients older than 18 years with at least 3 months of permanence in our PD program. We collected: age, sex, cause of CKD, type of PD, time on PD, origin (pre-dialysis, hemodialysis, kidney transplant), residual diuresis, diabetes mellitus (DM), high blood pressure (HBP), ischemic heart disease, bleeding, urea, creatinine, albumin, calcium, phosphorus, Hb, hematocrit, iron, ferritin, TSAT, C-reactive protein (CRP), transfusions and treatments (ESA and/or iron therapy). Descriptive statistical analysis (mean, standard deviations, maximums and minimums) and comparative analysis between variables was performed using Chi-square test and ANOVA for qualitative and quantitative variables, respectively. Results N = 58 patients, 64% men and 36% women. The mean age was 61.3+/- 15.54 years. 31% of patients were CKD secondary to glomerulonephritis (predominant etiology). 5% had no cardiovascular risk factors (CVRF), 48% between one and two and 47% more than three. 74% on continuous ambulatory peritoneal dialysis (CAPD). Mean time on dialysis 28.74 +/- 25.05 months. Mean residual diuresis in 24 hours 1199.22 +/- 703.14 cc. Prevalence of anemia 74%. Mean Hb of 10.97 +/-1.29 g/dL with 78% of patients with values between 10-12 g/dl. Mean ferritin of 356.79 +/-226.84 mg/dL with 79% of patients between 100-500 mg/dl. 83% received treatment with ESA, 33% with intravenous iron. No patient received oral iron. 4 patients needed of blood transfusion and 3 of them due to bleeding (2 gastrointestinal bleeding and 1 urinary bleeding). We observed a statistically significant association between higher residual diuresis volume and adequate anemia control (P = .042) and between lower creatinine values and target Hb values (P = .0005). No statistically significant association was observed between adequate anemia control and type of dialysis (p= 0.106), time on dialysis (P = .28), sex (P = .224) and DM (p= 0.139). Conclusion The high prevalence of anemia continues to be a major problem in PD in our program, but similar to other series. Under treatment (ESA and iron therapy) is achieved an adequate control in most patients, although in approximately 20% of patients do not reach the established target. Higher residual diuresis and lower creatinine values (probably due to increased residual renal function) are associated with better anemia control.

#3258 MECHANISMS OF HEMOGLOBIN CYCLING IN ANEMIC END-STAGE RENAL DISEASE PATIENTS TREATED WITH ERYTHROPOIESIS-STIMULATING AGENTS

Abstract Background and Aims A considerable fraction of renal anemia patients treated with erythropoiesis-stimulating agents (ESAs) experience hemoglobin ‘cycling’ periods during which hemoglobin levels periodically over- and undershoot a specified target range [1]. This is an undesired condition, which also necessitates frequent adjustment of the drug dose. The causes of hemoglobin cycling are not understood on a fundamental level. Through a combination of biomedical simulations and quantitative data analysis, we aimed at identifying mechanisms of hemoglobin cycling and the physiological and treatment-related factors contributing to cycling. Method We developed a biomedical modeling and simulation scheme that captures the essential features of ESA therapy involving a minimal feedback model for the delayed hemoglobin response after ESA administration and a stereotypic ESA dosing algorithm [2]. In this model, hemoglobin cycling emerged as a consequence of the delayed feedback between a patient's physiological response to ESA administrations and the resulting dose adjustments, which mutually maintain themselves in a causal loop. Guided by this model, we developed a set of statistical indicators that can detect this type of self-sustained hemoglobin cycling in clinical time series, including the Pearson cross correlation between hemoglobin levels and given ESA doses and hemoglobin standard deviation. Results A model analysis showed that physiological and treatment-related delays in hemoglobin response and ESA dose adjustment and administration were a major driver of hemoglobin cycling. Such delays are caused, e.g., by the cell cycle and maturation times of erythroid progenitors in response to ESA administration on one hand and restrictions in ESA dose changes and typical administration intervals on the other hand. In clinical time series, this was reflected by a systematic delay between bursts of ESA administrations and hemoglobin cycles. We quantified 1134 such datasets from hemodialysis patients and found that more persistent cycling was associated with negative correlation coefficients between hemoglobin levels and ESA doses. Using model simulations with similar behavior, we found that many patient- and therapy-related factors affect the hemoglobin dynamics in several (sometimes competing) ways, obfuscating their overall effect. For example, a larger RBC lifespan generally both entails higher hemoglobin levels but also prolongs the effect of ESA misdosings. However, model simulations suggested that longer RBC lifespans generally have a favorable effect in requiring less ESA on average and preventing hemoglobin cycling. Moreover, the model showed that for a given patient, ESA-specific properties such as its half-life may have a ‘sweet spot’ range of values within which hemoglobin cycling was suppressed while still showing a desired effect on the hemoglobin dynamics. Furthermore, the choice of the hemoglobin target window had an impact on hemoglobin stability. If the window was chosen too small, more frequent dose adjustments could initiate and maintain a cycling behavior. Conclusion Hemoglobin cycling in renal anemia patients often emerges from a complex interplay of multiple physiological and ESA treatment-related factors, with delays between ESA administration, hemoglobin response and subsequent ESA dose adjustment being a key driver of cycling. Biomedical modeling and simulation can aid in systematically exploring these interplays and find improved dosing strategies.

Clinical outcomes by SF3B1 mutation status in patients (pts) with lower-risk myelodysplastic syndrome (LR-MDS) retreated with erythropoiesis-stimulating agents (ESAs).

7071 Background: Pts with SF3B1-mutated LR-MDS often have a more favorable prognosis versus those with SF3B1 wildtype. A sizeable number of pts with LR-MDS undergo ESA treatment even after experiencing ESA failure in first line. This study evaluated the outcomes of pts with LR-MDS retreated with ESAs in routine clinical practice, stratified by SF3B1 status. Methods: This retrospective cohort study included pts with LR-MDS in the US community setting who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019, and were followed through June 30, 2021. Eligible pts discontinued ESAs (treatment gap ≥ 3 wk for epoetin alfa or ≥ 6 wk for darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Ring sideroblasts (RS) ≥ 15% served as a surrogate for pts with unknown SF3B1 mutation status. Outcomes included ESA switches, dose reductions and escalations, ESA failure, and overall survival (OS). Primary ESA failure was defined as no rise in hemoglobin (Hb) ≥ 1.5 g/dL or no decrease in RBC transfusion requirement by 8 wk of treatment. Transfusion-dependent (TD) status was evaluated for pts who were transfusion independent (TI) at baseline. Results: A total of 82 pts with LR-MDS and repeat ESA treatment were included. Median age at start of ESA treatment was 79 y (interquartile range [IQR], 72–85). Diagnosis of MDS-RS, MDS with isolated del(5q), MDS with multilineage dysplasia, and MDS with single lineage dysplasia was reported in 30 (36%), 7 (9%), 9 (11%), and 9 (11%) pts, respectively; 27 (33%) had unknown classification. Median follow-up was 26 mo (IQR, 13–38) with 65% failing ESA therapy by 8 wk. Table shows pts’ SF3B1 mutation status, median OS, pts who had an ESA switch, dose reduction or escalation, experienced ESA failure, and pts who were TI at baseline and became TD during follow-up. Results were similar when RS was not used as a surrogate, and when analyses were limited to pts who were treated with ESAs only throughout follow-up. Conclusions: In this study of pts with LR-MDS retreated with ESAs, primary ESA failure was high with nearly half of TI pts becoming TD during follow-up. OS was poor regardless of SF3B1 status – 2–4 times lower than the remaining life expectancy for a 79-y-old (108 mo for men; 125 mo for women). Although treatment options were limited during the study period, the high primary failure rate suggests that pts with LR-MDS may benefit from alternatives to ESAs. [Table: see text]

Effect of roxadustat on red blood cell lifespan in patients with long-term haemodialysis: a single-centre, prospective, single-arm study.

Reduced survival of red blood cells (RBCs) in patients with chronic kidney disease (CKD) is thought to contribute to renal anaemia. Although renal anaemia improved greatly because of the wide use of erythropoiesis-stimulating agents (ESAs) and the advancement of dialysis techniques, RBC longevity seems not to be obviously ameliorated. In this single-centre, single-arm trial, patients who had been undergoing haemodialysis and ESA therapy with epoetin alfa for at least 12weeks changed their anti-anaemia drugs from epoetin alfa to oral roxadustat three times per week for 24weeks. The primary endpoint was the change in RBC lifespan from baseline at week 24. The change in the circulating percentage of eryptotic RBCs, RBC deformability and RBC oxygen transport ability were also assessed. A total of 27 patients were enrolled, with 26 completing the full course of intervention. At baseline, the average RBC lifespan was 60.1days [standard deviation (SD) 14.4; n=27]. At the end of the study period, 26 patients had an RBC lifespan measurement (83.9days on average; SD 21.9). The RBC lifespan increased by 22.8days on average [95% confidence interval (CI) 15.5-30.0, P<.001]. This equated to an average RBC lifespan increase of 39.2% (95% CI 27.8-50.6). The percentage of circulating eryptotic RBCs, erythrocyte filtration index and the pressure at which haemoglobin is 50% saturated decreased significantly from baseline to week 24 (1.39±0.44% versus 0.89±0.25%, P<.0001; 0.29±0.12 versus 0.16±0.08, P<.0001 and 32.54±4.83 versus 28.40±2.29, P<.001, respectively). Roxadustat prolonged RBC lifespan in patients with long-term haemodialysis.

Real-Life Anemia Management Among Patients with Non-Dialysis-Dependent Chronic Kidney Disease in Three European Countries.

Anemia is prevalent among patients with chronic kidney disease (CKD), yet current evidence indicates that treatment may not adhere to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. We aimed to document the management of patients with non-dialysis-dependent (NDD)-CKD receiving erythropoiesis-stimulating agent (ESA) therapy in Europe. This retrospective, observational study extracted information from medical records in Germany, Spain, and the UK. Eligible patients were adults with NDD-CKD stages 3b-5 who initiated ESA therapy for anemia between January and December 2015. Anemia was defined as hemoglobin (Hb) <13.0 g/dL (males) or <12.0 g/dL (females). Data regarding ESA treatment, treatment response, concomitant iron therapy and blood transfusions were extracted up to 24 months post-ESA initiation, and data on CKD progression until abstraction date. Eight hundred and forty-eight medical records were abstracted. Approximately 40% received no iron therapy prior to ESA initiation. At ESA initiation, mean ± standard deviation Hb level was 9.8 ± 1.0 g/dL. Most patients received darbepoetin alfa, and switching between ESAs was rare (8.5% of patients). Concomitant intravenous and oral iron therapy was prescribed for 36% and 42% of patients, respectively, during initial ESA therapy. Mean Hb levels reached the target level (10-12g/dL) within 3-6 months of ESA initiation. Hb, transferrin saturation, and ferritin levels were infrequently monitored from 3 months post-ESA initiation. Rates of blood transfusion, dialysis, and diagnosis of end-stage renal disease were 16.4%, 19.3%, and 24.6%, respectively. Rates of kidney transplant and death were 4.8% and 8.8%, respectively. Among ESA-treated patients, ESA initiation was in accordance with KDIGO guidelines, but subsequent monitoring of Hb and iron deficiency were suboptimal.

Soluble transferrin receptor concentration compared with reticulocyte hemoglobin content as a reliable marker of iron deficiency anemia in hemodialysis patients

Abstract Introduction Adequate iron stores are necessary for successful erythropoiesis-stimulating agents (ESAs) therapy in hemodialysis (HD) patients. However, iron status estimation in HD patients remains challenging, as most parameters are affected by inflammation. We aimed to compare the performance of soluble transferrin receptor concentration (sTfR) and reticulocyte hemoglobin content (CHr) as potential markers for iron status assessment. Methods This was a cross-sectional study that included 60 anemic patients with kidney failure on regular HD for a minimum of 3 months. Patients were in the maintenance phase of the ESAs with stable doses for at least 4 weeks and at least 3 weeks free of iron therapy. Patients were classified into two groups; group I: 18 patients with noniron deficiency anemia (NIDA); transferrin saturation (TSAT) greater than 20% and ferritin greater than 200 ng/ml and group II: 42 patients with iron deficiency anemia (IDA); transferrin saturation less than 20% and/or ferritin less than 200 ng/ml. CHr and sTfR were evaluated as reliable markers for diagnosing iron deficiency. Results CHr was significantly lower while sTfR was significantly higher in patients with IDA. Based on the receiver operating characteristic (ROC) curve, the area under the curve (AUC) of sTfR was significantly larger than the area under the curve of CHr; however, this had a borderline significance. Conclusion sTfR has a significantly higher diagnostic power for diagnosis of IDA than CHr.

Individualization of the Dosage Regimen of Erythropoietin is Crucial in End-stage Renal Disease Patients

The objective of this study was to understand the utilization pattern of erythropoietin in end-stage renal disease patients, along with the effect of body weight and sex on the patients' responses. In this retrospective single-center study, 120 patients were included who were on a once weekly (n = 79), twice weekly (n = 37), or thrice weekly (n = 4) regimen. The doses of erythropoiesis-stimulating agents (ESA) were collected, and the erythropoietin resistance index (ERI) was determined. The Kruskal–Wallis test was used to evaluate the dose schedules, and the once-weekly regimen produced a greater response (P = 0.001). The asymptotic significance of Pearson's Chi-square-test equating the mean ERI and body mass index (BMI) was 0.034. No statistically significant correlation was estimated between sex and mean ERI (P = 0.201). Our study demonstrated that the once-weekly regimen dominated over the others in terms of efficacy, and individuals with a higher BMI were found to respond better to the ESA therapy.

Treatment Patterns and Outcomes in Lower-Risk, Non-Del(5q) Myelodysplastic Syndromes: Findings from a Global Real-World Medical Record Review Study

Background: Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell malignancies defined by ineffective hematopoiesis and peripheral blood cytopenias. Patients often present with anemia and frequently require red blood cell transfusions (RBCTs), which may lead them to become transfusion-dependent (TD). This results in poor quality of life and reduced survival. In patients with non-del(5q) lower-risk (LR)-MDS, the standard of care includes erythropoiesis-stimulating agents (ESAs) ± granulocyte colony-stimulating factor as first-line (1L) therapy; however, although clinical trials have demonstrated efficacy, there is little evidence from real-world settings. This study aimed to assess real-world data to investigate treatment patterns and prevailing hematologic outcomes in patients with non-del(5q) LR-MDS. Methods: In this retrospective medical record review, eligible patients ≥ 18 years of age diagnosed with non-del(5q) LR-MDS between July 1, 2013 and September 30, 2018 were identified by participating hematologist-oncologists in the US, Canada (CAN), UK, and EU (France, Germany, Spain). Demographics, clinical characteristics, treatment patterns, and hematologic outcomes data were abstracted (June-November 2021) and reported descriptively. Aggregated analyses were performed using pooled US/CAN and UK/EU data sets for the overall cohort and for patient subgroups treated with clinician-defined 1L and second-line (2L) ESA-containing regimens. Results: Medical record data were abstracted for 119 patients with non-del(5q) LR-MDS in US/CAN (median age, 61.5 years; 71.4% male) and 245 patients in UK/EU (median age, 67.3 years; 71.4% male). Median follow-up duration from MDS diagnosis was 50.5 months (US/CAN) and 67.8 months (UK/EU). At initial diagnosis, 50.4% (US/CAN) and 53.5% (UK/EU) of patients had Low-risk MDS (per Revised International Prognostic Scoring System). Of the 71 patients in US/CAN and 123 patients in UK/EU who were tested successfully for the SF3B1 mutation, 16.9% (US/CAN) and 15.5% (UK/EU) were positive. Most of the patients initiated 1L therapy (US/CAN: 109 [91.6%]; UK/EU: 225 [91.8%]) and more than one-third initiated a 2L therapy (US/CAN: 45 [37.8%]; UK/EU: 89 [36.3%]). In 1L, 2.8% patients in US/CAN and 2.2% in UK/EU received treatment with lenalidomide. Most patients were treated with ESA-containing regimens in 1L, with a median duration of therapy of ≥ 2 years (US/CAN: 97 [89.0%], of which 86.6% was ESA monotherapy; UK/EU: 203 [90.2%], of which 85.7% was ESA monotherapy). Treatment characteristics and hematologic outcomes for patients treated with ESAs are presented in the Table. Among patients who were TD before 1L ESA treatment (36 [37.1%] US/CAN; 104 [51.2%] UK/EU), a small proportion (2.8% US/CAN; 14.4% UK/EU) became transfusion independent (TI) during 1L; RBCT reduction threshold (≥ 50%) was met by 41.7% in US/CAN (median duration, 23 months) and 52.9% in UK/EU (median duration, 13 months). Among patients treated with ESA-containing regimens in 2L (12 [26.7%] US/CAN; 26 [29.2%] UK/EU), most had been treated with ESA in 1L (US/CAN: 10 [83.3%]; UK/EU: 22 [84.6%]). The most frequently reported reasons for reinitiating treatment with ESAs in 2L were overall health status (54.6% US/CAN; 40.9% UK/EU), treatment efficacy (45.5% US/CAN; 63.6% UK/EU), and disease characteristics (36.4% US/CAN; 45.5% UK/EU). In the subgroup of patients who reinitiated ESA in 2L, the most frequently reported reasons for discontinuation of 1L ESA were patient decision (45.5% US/CAN; 22.7% UK/EU), completion of planned course of therapy (45.5% US/CAN; 18.2% UK/EU), and progressive disease (36.4% US/CAN; 68.2% UK/EU). Conclusions: In this real-world study, the most frequently used treatments for the management of anemia in patients with non-del(5q) LR-MDS were ESA-containing regimens. A considerable proportion of patients were TD before initiating 1L ESA therapy. For those who were re-treated with ESAs in 2L, the most common reasons for treatment reinitiation were health status, disease characteristics, and reported treatment efficacy, although only a small fraction of patients who were TD at 1L ESA initiation became TI. These findings highlight an unmet need in anemia management among patients with non-del(5q) LR-MDS, and a requirement for new and more effective treatment options. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adverse events of iron and/or erythropoiesis-stimulating agent therapy in preoperatively anemic elective surgery patients: a systematic review

BackgroundIron supplementation and erythropoiesis-stimulating agent (ESA) administration represent the hallmark therapies in preoperative anemia treatment, as reflected in a set of evidence-based treatment recommendations made during the 2018 International Consensus Conference on Patient Blood Management. However, little is known about the safety of these therapies. This systematic review investigated the occurrence of adverse events (AEs) during or after treatment with iron and/or ESAs.MethodsFive databases (The Cochrane Library, MEDLINE, Embase, Transfusion Evidence Library, Web of Science) and two trial registries (ClinicalTrials.gov, WHO ICTRP) were searched until 23 May 2022. Randomized controlled trials (RCTs), cohort, and case-control studies investigating any AE during or after iron and/or ESA administration in adult elective surgery patients with preoperative anemia were eligible for inclusion and judged using the Cochrane Risk of Bias tools. The GRADE approach was used to assess the overall certainty of evidence.ResultsData from 26 RCTs and 16 cohort studies involving a total of 6062 patients were extracted, on 6 treatment comparisons: (1) intravenous (IV) versus oral iron, (2) IV iron versus usual care/no iron, (3) IV ferric carboxymaltose versus IV iron sucrose, (4) ESA+iron versus control (placebo and/or iron, no treatment), (5) ESA+IV iron versus ESA+oral iron, and (6) ESA+IV iron versus ESA+IV iron (different ESA dosing regimens). Most AE data concerned mortality/survival (n=24 studies), thromboembolic (n=22), infectious (n=20), cardiovascular (n=19) and gastrointestinal (n=14) AEs. Very low certainty evidence was assigned to all but one outcome category. This uncertainty results from both the low quantity and quality of AE data due to the high risk of bias caused by limitations in the study design, data collection, and reporting.ConclusionsIt remains unclear if ESA and/or iron therapy is associated with AEs in preoperatively anemic elective surgery patients. Future trial investigators should pay more attention to the systematic collection, measurement, documentation, and reporting of AE data.

Characteristics of Japanese patients with non-dialysis-dependent chronic kidney disease initiating treatment for anemia: a retrospective real-world database study

Objective Anemia is a common complication of chronic kidney disease (CKD). The aim of this study was to evaluate hemoglobin levels at the initiation of erythropoiesis stimulating agent (ESA) therapy in patients with non-dialysis-dependent CKD (NDD-CKD) and anemia using a large-scale administrative database in Japan. Methods The longitudinal data of adult patients who initiated ESA therapy between April 2008 and December 2018 were extracted from a hospital-based administrative database. The primary outcome was hemoglobin level at the initiation of ESA therapy, whereas the exploratory outcome was hemoglobin level recorded 6 months after the onset of the ESA therapy. Results A total of 4939 patients were included in the primary analysis. The mean hemoglobin level at the initiation of ESA therapy was 9.1 g/dL, which was lower than the level (11 g/dL) recommended for the initiation of treatment by the current Japanese treatment guidelines. Moreover, 42.1% and 15.0% of the patients had hemoglobin levels <9.0 and <8.0 g/dL, respectively, at the initiation of ESA therapy. In 2964 patients for whom hemoglobin levels at 6 months after the initiation of ESA therapy were available, the mean hemoglobin level increased to 10.3 g/dL, and 61.9% and 31.1% of these patients had hemoglobin levels ≥10.0 and ≥11.0 g/dL, respectively. Conclusion This real-world database study revealed that hemoglobin levels at the initiation of ESA therapy in new users of ESA were lower than those recommended by treatment guidelines in Japan.

MDS-502 Supportive Care in Low-Risk Myelodysplastic Syndromes: Role of Erythropoiesis Stimulating Agents (ESAs)

Erythropoiesis stimulating agents (ESAs) are the frontline treatment in low-risk anemic MDS patients, and an employment of this therapy in the earlier stage of the disease can delay the need for RBC transfusion, hypothetically by slowing the disease course. Macrocytosis is one of the cytological hallmarks of dyserithropoiesis in MDS. An analysis of the erythropoietic response to ESAs therapy in a cohort of anemic non transfusion-dependent MDS patients, enrolled in a retrospective register, RECAMDS, subgroup of Italian register, was performed. 183 patients, treated with standard-dose ESAs, have been retrospectively analyzed. Data analysis was performed, according to IWG 2006 criteria, at the baseline, after 3 and 6 months of continuous treatment, with a subanalysis of the patients according to WHO and R-IPSS risk stratification. ESAs were started at mean Hb concentration of 9.31 g/dl, mean serum erythropoietin (EPO) concentration: 51 mU/L, after a mean time from diagnosis of 6 months (r.1-118). ORR was 83.6% (153/183); no difference among WHO and IPSS subgroups was found. 132/183 (72.1%) achieved response after 3 months of treatment, while other 21/183 (11.2%) after 6 months. 19 patients with stable disease (non-responders, according to IWG criteria), in which treatment was continued, achieved response after 9 months. In the macrocytic-responders group, 83.2% exhibited again macrocytosis after 3 months, while 16.8% become normocytic. In the normocytic-responders group, 89.8% exhibited again normocytosis, while 10.2% become macrocytic. In these patients, after 3 months, there was a contemporary worsening in neutropenia and thrombocytopenia, with transfusion-dependence, regarded as first signs of progression of disease. Non-responders were 30/183 (16.3%): in the macrocytic non-responders group 89% exhibited again macrocytosis after 3 months, while 11% become normocytic; in the normocytic group 76% exhibited again macrocytosis, while 24% become normocytic. These preliminary data can suggest that, in the majority of MDS patients responsive to ESAs, the increase of Hb concentration occurs mainly due to stimulating erythroid production in MDS clones; in the minority of patients probably it happens due to recruiting residual polyclonal erythropoiesis. It is interesting to note that stimulating effects of ESAs last even when the expression of dysplasia progresses.

Parathyroidectomy Improves the Consumption of Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Secondary hyperparathyroidism (SHPT) is common in end-stage renal disease (ESRD) patients, and it can suppress erythropoiesis. We aimed to investigate the relationship between the consumption of erythropoiesis-stimulating agents (ESAs) and parathyroidectomy (PTX) in ESRD patients with SHPT and to determine the predictors for anemia improvement. The current standard of chronic kidney disease anemia therapy relies on the prescription of iron supplementation, and ESA. We retrospectively analyzed 81 ESRD patients with PTX at Ditmanson Medical Foundation Chiayi Christian Hospital from July 2004 to Dec 2018. The requirement of ESA therapy markedly declined from a dose of 41.6 (interquartile range [IQR], 0–91.2) to 10.3 (IQR, 0–59.5, p = 0.001) unit/kg/week. In addition, 63.7% of patients required iron replacement therapy preoperatively and the proportion reduced to 52.5% after PTX (p < 0.001). The hemoglobin (Hb) level showed an insignificant change from a median value of 10.7 g/dL (9.5–11.6 g/dL) before PTX to 10.5 g/dL (9.6–11.2 g/dL) at 6 months after PTX. A preoperative Hb level ≤ 10 mg/dL (odds ratio [OR], 20.1; 95% confidence interval [CI], 4.71–125, p < 0.001) and transferrin saturation (TSAT) < 25% (OR, 12.8; 95% CI, 2.51–129, p < 0.001) were predictors for anemia improvement. Our study demonstrated that PTX markedly decreased the requirement of ESA. Patients with a low preoperative Hb level or low TSAT showed an increase in the Hb level after PTX. PTX may be considered not only for SHPT with refractory anemia but also for high ESA-dependent patients.