Treatment Of Anemia In Patients Research Articles

#2063 Safety and efficacy of vadadustat vs darbepoetin alfa in patients on maintenance dialysis by prespecified subgroups of baseline ESA dose

Abstract Background and Aims Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Europe, Australia, Japan for the treatment of anemia in patients with dialysis-dependent (DD)-CKD. In the INNO2VATE global phase 3 trials in patients with DD-CKD, including 2 separate trials in patients new to dialysis [NCT02865850] and on maintenance dialysis [NCT02892149], vadadustat was noninferior to the erythropoiesis -stimulating agent (ESA) darbepoetin alfa for cardiovascular safety and hemoglobin efficacy. Among patients with DD-CKD, high ESA dose requirements have been associated with an increased risk of cardiovascular complications. In this secondary analysis, we compared cardiovascular safety and hematological efficacy of vadadustat and darbepoetin alfa across baseline ESA dose categories. Method In the INNO2VATE trials, 3554 patients on maintenance dialysis were randomized 1:1 to vadadustat or darbepoetin alfa, stratified according to geographic region, New York Heart Association heart failure classification, and hemoglobin concentration at trial entry. Data were analyzed for prespecified subgroups of patients categorized by their baseline ESA (epoetin alfa/equivalents) dose: low (<90 U/kg/week), intermediate (90-299 U/kg/week), or high (≥300 U/kg/week). Within these dose subgroups, the key safety endpoint was the first occurrence of an adjudicated major adverse cardiovascular event (MACE: first occurrence of all-cause mortality, nonfatal myocardial infarction [MI], or nonfatal stroke) using a time-to-event analysis. Primary and secondary efficacy endpoints were mean change in hemoglobin concentration from baseline during the primary (weeks 24-36) and secondary (weeks 40-52) evaluation periods, respectively. Results More participants were in the low (vadadustat: n = 916 [53%], darbepoetin alfa: n = 968 [55%]) and intermediate (vadadustat: n = 724 [42%], darbepoetin alfa: n = 693 [39%]) than in the high (vadadustat: n = 102 [6%], darbepoetin alfa: n = 98 [6%]) baseline ESA dose subgroups. Hazard ratios for the occurrence of first MACE between vadadustat and darbepoetin alfa in the 3 baseline ESA dose subgroups were as follows: low dose, 0.99 (95% CI, 0.81 to 1.23); intermediate dose, 0.93 (95% CI, 0.74 to 1.18); and high dose, 0.62 (95% CI, 0.34 to 1.14) (Fig.). Similar results were observed for other key MACE-related endpoints, including all-cause mortality, MACE plus hospitalizations for heart failure or thromboembolic events, cardiovascular MACE (first occurrence of cardiovascular mortality, nonfatal MI, or nonfatal stroke), and cardiovascular death. Mean hemoglobin concentrations increased in both treatment groups throughout the trial period. The least squares mean treatment difference (vadadustat compared to darbepoetin alfa) for change in hemoglobin concentration from baseline to the primary efficacy period was –0.10 g/dL (95% CI, –0.19 to –0.02), –0.20 g/dL (95% CI, –0.30 to –0.09), and –0.39 g/dL (95% CI, –0.67 to –0.11) for the low, intermediate, and high baseline ESA dose subgroups, respectively. Similar results were observed for the secondary efficacy period. Across baseline ESA dose subgroups, the proportion of patients whose average hemoglobin concentration was within target range was similar between the vadadustat and darbepoetin alfa arms during the primary efficacy period (low: odds ratio [OR], 0.89; 95% CI, 0.74, 1.08; intermediate: OR, 0.87; 95% CI, 0.70, 1.09; high: OR, 0.90; 95% CI 0.49, 1.64). Similar results were observed during the secondary efficacy period. Conclusion The cardiovascular safety and efficacy of vadadustat was similar to darbepoetin alfa in patients with DD-CKD irrespective of baseline ESA dose. In patients requiring higher ESA doses at baseline, the risk of MACE was numerically (but not significantly) lower in vadadustat-treated patients. Further investigation is required to confirm or refute this trend.

#2352 Short-term effect of roxadustat combined with ESA treatment for anemia in patients undergoing hemodialysis with ESA hyporesponsiveness

Abstract Background and Aims The efficacy of roxadustat combined with erythropoiesis-stimulating agent (ESA) on renal anemia in maintenance hemodialysis (MHD) patients is rarely reported, especially for those with ESA hyporesponsiveness. Our study aimed to observe the short-term efficacy of roxadustat combined with ESA for those patients when they were first treated with roxadustat converted from ESA. Method Retrospective data pertaining to MHD patients with ESA hyporesponsiveness from September 2019 to June 2022 were collected. All patients had been on ESA for more than 6 months and were first treated with roxadustat. 19 patients treated with roxadustat combined with ESA and 19 patients treated with roxadustat alone were paired for analysis from 108 patients by propensity score matching. Parameters related to anemia, iron metabolism and adverse events were recorded. Results The haemoglobin (Hb) level was significantly improved in patients treated with roxadustat combined with ESA after 1 month (7.8 ± 1.54 g/dL vs 8.96 ± 1.38 g/dL, p = 0.003), which was not found in patients treated with roxadustat alone (8.2 ± 1.28 g/dL vs 8.35 ± 1.54 g/dL, p = 0.652). Patients treated with roxadustat combined with ESA had a higher Hb response rate (47.4%) than those treated with roxadustat alone (15.8%) during the first month (p = 0.036). In addition, the level of serum iron was increased, and serum ferritin (SF) was decreased in both groups. Conclusion Roxadustat combined with ESA treatment might be more beneficial for improving renal anemia in MHD patients with ESA hyporesponsiveness during the first month of roxadustat therapy replacement.

#437 A multicenter, single-arm study of roxadustat in Chinese patients with chronic kidney disease-associated anemia receiving peritoneal dialysis

Abstract Background and Aims Anemia increases morbidity and mortality in patients with chronic kidney disease (CKD). Phase 3 studies have demonstrated the efficacy of roxadustat for anemia treatment in patients with CKD undergoing dialysis; however, data from Chinese patients undergoing peritoneal dialysis (PD) are limited. We evaluated the efficacy and safety of roxadustat in Chinese patients with CKD-anemia undergoing PD. Method In this phase 4, single-arm, multicenter study, we planned to enroll at least 150 Chinese patients with CKD-anemia undergoing PD (either erythropoiesis-stimulating agent [ESA]-treated or ESA-naïve at enrollment), including at least 50 patients with type 2 diabetes mellitus (T2DM) and 50 patients without diabetes mellitus (DM). Study visits occurred every 2 weeks until Week 8 and then every 4 weeks. All patients received oral roxadustat treatment three times per week for 24 weeks according to the approved product package insert. The primary efficacy endpoint was the proportion of patients with a mean hemoglobin (Hb) ≥100 g/L at Weeks 20–24. The secondary efficacy endpoints were subgroup analyses (T2DM vs. non-DM). The exploratory endpoints were the dose required to maintain Hb at ≥100 g/L over Weeks 20–24, the proportion of time when Hb was 100–130 g/L, changes in residual renal function (RRF), urea clearance index (Kt/V), and creatinine clearance (Ccr), amongst others. For the safety analyses, adverse events (AEs) were assessed during treatment and at 4 weeks after completion. Results Overall, 195 patients (116 male [59.5%]) with a mean (standard deviation [SD]) age of 46.3 (12.3) years were enrolled from 22 centers, and 172 (88.2%) completed the study (main reasons for discontinuation: withdrawal, 7 [3.6%]; AE, 5 [2.6%]; switched from PD to hemodialysis, 5 [2.6%]). Overall, 189 patients (96.9%) were ESA-treated and 43 (22.1%) had T2DM. The median (interquartile range) dialysis duration was 16.1 (5.2–43.2) months. The mean (SD) baseline Hb was 98.1 (10.7) g/L, and the ferritin level and transferrin saturation were 320.9 (287.5) μg/L and 35.5% (17.0%), respectively. The mean (SD) treatment duration was 154.3 (35.6) days, and the mean (SD) weekly dose was 244.9 (88.7) mg. The intention-to-treat (ITT) set and safety analysis set (SAF) included all 195 patients. In the ITT set, 85.1% (95% confidence interval [CI] 79.8%–90.5%) of patients had Hb ≥100 g/L over Weeks 20–24. According to the subgroup analysis, 89.2% (95% CI 78.5%–99.9%) of T2DM patients and 84.0% (95% CI 77.8%–90.1%) of non-DM patients had Hb ≥100 g/L over Weeks 20–24 (Fig. 1). The mean (SD) weekly dose required to maintain Hb at ≥100 g/L at Weeks 20–24 was 215.9 (100.0) mg, and the proportion of time that Hb was 100–130 g/L was 76.4% (23.2%). There was a slight decrease in RRF and Ccr. Table 1 shows the RRF, Kt/V, and Ccr results. Of the 195 SAF patients, 158 (81.0%) had ≥1 treatment-emergent AE (TEAE), 20 (10.3%) had drug-related TEAEs, 40 (20.5%) had treatment-emergent serious AEs, and 1 (0.5%) had a TEAE that led to death. The top three TEAEs were upper respiratory tract infection (25 [12.8%]), hypokalemia (17 [8.7%]), and hypoalbuminemia (15 [7.7%]). Conclusion Treatment with roxadustat for 24 weeks effectively corrected anemia in Chinese CKD patients undergoing PD and maintained Hb at ≥100 g/L in the majority of patients, irrespective of baseline T2DM. The AEs were consistent with the characteristics of patients with CKD undergoing PD and with the known safety profile of roxadustat.

Pharmacological action of epoetin beta in the treatment of anemia in patients with kidney diseases

Chronic kidney disease is becoming one of the leading causes of death globally. Anemia, a common complication in chronic kidney disease, not only diminishes patients’ life quality but also increases the risk of heart-related problems. The use of recombinant human erythropoietin has revolutionized the treatment of anemia in chronic kidney disease patients. By reaching the desired levels of hemoglobin with recombinant human erythropoietin, patients experience significant improvements in life quality and a decrease in death rates. Epoetin beta is among the various erythropoiesis stimulating agents available in the market. Research indicates that weekly doses of epoetin beta are as effective as three weekly doses of epoietin alpha for reaching hemoglobin goals in patients undergoing renal replacement therapy. This not only enhances patients’ adherence to the treatment but also cuts down on the time and costs associated with managing renal anemia, thus allowing for a therapy that is more tailored to patient needs. On the one hand, this improves patients’ adherence to the treatment. On the other hand, the time and cost burden in the management of renal anemia is decreased due to reduction in recombinant human erythropoietin prescribing rates, which eventually makes it possible to better tailor therapy to the patients’ needs. The proven efficacy and safety profile of epoetin beta combined with the increased convenience of less frequent dosing, make epoetin beta a safe and effective treatment option that can help more patients with chronic kidney disease to reach their target hemoglobin levels.

Outcomes of Early Versus Delayed Anemia Treatment in Nondialysis-Dependent CKD

IntroductionThe association of hemoglobin level at treatment initiation with renal and cardiovascular outcomes in patients with anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) is unclear. MethodsThis retrospective cohort study utilized two Japanese databases (Medical Data Vision [MDV] and Real World Data [RWD]). Patients initiated long-acting erythropoiesis-stimulating agent treatment were divided into early (hemoglobin levels ≥9.0 g/dL) and delayed (<9.0 g/dL) treatment groups. The primary outcome was a renal composite (renal replacement therapy, ≥50% estimated glomerular filtration rate [eGFR] reduction, eGFR <6.0 mL/min/1.73 m2, and all-cause mortality), and secondary outcomes were a cardiovascular composite (hospitalization by ischemic heart disease including myocardial infarction, hospitalization by stroke and heart failure, and cardiovascular death) and components of the composite outcomes. ResultsAfter propensity score matching, 1472 (MDV) and 1264 (RWD) patients were evaluated. Delayed treatment was not associated with a risk of the renal composite outcome (MDV: hazard ratio [HR] 1.15, 95% confidence intervals [CI] 0.99–1.33; RWD: 1.08, 0.92–1.28). However, delay was associated with higher risks of the cardiovascular composite outcome (MDV: HR 1.47, 95% CI 1.16–1.84; RWD: 1.34, 1.09–1.64), heart failure (MDV: HR 1.50, 95% CI 1.13–2.00; RWD: 1.53, 1.20–1.96) and all-cause mortality (MDV: HR 1.83, 95% CI 1.32–2.54; RWD: 1.64, 1.21–2.22). ConclusionAlthough the risk of renal events was not increased following delayed treatment of anemia in patients with NDD-CKD, the risks of cardiovascular events and all-cause mortality were increased, suggesting the importance of early intervention before hemoglobin fall below 9.0 g/dL.

Compliance With NCCN Guidelines for Evaluation and Treatment of Anemia Among Patients With Solid Tumors.

NCCN Guidelines for Hematopoietic Growth Factors recommend evaluation and treatment of anemia in patients with cancer. However, a paucity of data exists regarding compliance with these recommendations. A retrospective cohort study was performed of patients diagnosed with any solid tumor at Vanderbilt University Medical Center from 2008 to 2017. Tumor registry-confirmed cancer cases were identified by ICD-O codes using the Synthetic Derivative database. Anemia was defined as hemoglobin (Hgb) level ≤11 g/dL and graded according to CTCAE version 5.0. Absolute, functional, and possible functional iron deficiency were defined based on NCCN Guidelines. A total of 25,018 patients met inclusion criteria. Median age was 60 years. The most common malignancies were respiratory tract, prostate, and nonprostate urologic (11% each). Among 8,695 patients with Hgb levels available prior to diagnosis, 1,484 (17%) were noted to be anemic proximal to diagnosis. Of the 25,018 patients, 11,019 (44%) were anemic within 6 months of diagnosis. Of these patients, 4,686 (43%) had grade 2 (moderate) anemia and 9,623 (87%) had normocytic anemia. Patients with retroperitoneal/peritoneal cancers had the highest prevalence of anemia (83/110; 75%). A total of 4,125 (37%) underwent any evaluation of their anemia, of whom 1,742 (16%) had iron studies performed and 1,528 (14%) had vitamin B12 or folate studies performed. Fewer than half of patients with anemia received treatment (n=4,318; 39%), including blood transfusion (n=3,528; 32%), oral iron supplementation (n=1,279; 12%), or intravenous iron supplementation (n=97; 1%). Anemia treatment was significantly more frequent as the grade of anemia increased (any treatment among grade 1/mild: 12%; grade 2/moderate: 31%; grade 3/severe: 77%; χ2 [2, n=11,019]=3,020.6; P<.001). Patients with penile and testicular cancers had the highest prevalence of anemia evaluation (n=57; 79%). Anemia is common in patients with solid tumors; yet, compliance with NCCN Guidelines for evaluation and treatment of anemia remains low. There are opportunities to improve compliance with guidelines across the spectrum of cancer care.

Daprodustat and Heart Failure in CKD.

Patients with chronic kidney disease (CKD) are at higher risk for heart failure. The hypoxia inducible factor prolyl hydroxylase inhibitor daprodustat is an orally acting alternative to conventional injectable erythropoietin-stimulating agents (ESA) for the treatment of anemia in patients with CKD. Whether daprodustat affects the risk of heart failure hospitalization is unknown. The ASCEND-D (n=2,964) and ASCEND-ND (n=3,872) trials compared daprodustat to conventional ESA in patients with anemia of CKD who did or did not require dialysis, respectively. We identified risk factors for heart failure hospitalization and assessed the effect of daprodustat compared to conventional ESA on heart failure hospitalizations. History of heart failure, diabetes, and higher systolic blood pressure were independently associated with heart failure hospitalization in both trials, irrespective of treatment assignment. The number of first heart failure hospitalizations was greater in the daprodustat arm in patients not receiving dialysis (hazard ratio [HR] 1.22 [0.95-1.56], p=0.12] and in patients receiving dialysis (HR 1.10 [0.84-1.45], p=0.47), though these differences were not statistically significant. HRs in patients with and without history of heart failure were 1.37 (0.89-2.11) vs 1.08 (0.79-1.46) (p-interaction=0.36) in ASCEND-ND, and 1.52 (0.97-2.38) vs 0.93 (0.66-1.30) (p-interaction=0.09) in ASCEND-D, respectively. In post hoc analyses, daprodustat increased total (first and recurrent) heart failure hospitalizations in participants not receiving dialysis (rate ratio 1.46 [1.11-1.92], p=0.007) ) but not in participants receiving dialysis (rate ratio 1.01 [0.74-1.39], p=0.93). Daprodustat did not significantly affect the risk of a composite outcome of first heart failure hospitalization or death. A greater number of first heart failure hospitalization events occurred in patients treated with daprodustat compared with conventional ESA, but this difference did not reach statistical significance. Differences in the number of heart failure hospitalization events were most apparent in patients not receiving dialysis and in patients with history of heart failure.

Thrombopoietin treats erythropoietin resistance by correcting EPO-induced progenitorcell depletion

Recombinant human erythropoietin (rHuEPO) is a prevalent treatment for anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness, which may be caused by the depletion of erythroid progenitor cells. Thrombopoietin (TPO) has the potential to promote the growth of early progenitor cells and correct the depletion. In this study, we investigate the efficacy and the underlying mechanism of the combination therapy of TPO and EPO to EPO resistance. First, the in vivo studies suggested that intensive EPO treatment induced progenitor cell depletion in the bone marrow, where the depletion was corrected by TPO. Then, colony assays showed that EPO and TPO synergistically enhanced the burst-forming unit-erythroid (BFU-E) production but antagonistically boosted the colony-forming units of megakaryocytes (CFU-MK) production. Also, we found TPO promoted hematopoietic stem and progenitor cells (HSPCs) production, while EPO drove HSPCs toward the erythroid lineage. Additionally, EPO induced more megakaryocytic-erythroid progenitors (MEPs) toward the erythroid output. Model-based simulations indicate the efficacy of this combination therapy for treating EPO-resistant anemia in rats. In conclusion, our study demonstrated the efficacy of combination therapy in addressing EPO-resistant anemia by correcting EPO-induced erythroid progenitor depletion.

HLA-B*46:01:01:01 and HLA-DRB1*09:01:02:01 are associated with anti-rHuEPO-induced pure red cell aplasia

Treatment of anemia in patients with chronic kidney disease (CKD) with recombinant human erythropoietin (rHuEPO) can be disrupted by a severe complication, anti-rHuEPO-induced pure red cell aplasia (PRCA). Specific HLA genotypes may have played a role in the high incidence of PRCA in Thai patients (1.7/1,000 patient years vs. 0.03/10,000 patient years in Caucasians). We conducted a case–control study in 157 CKD patients with anti-rHuEPO-induced PRCA and 56 controls. The HLA typing was determined by sequencing using a highly accurate multiplex single-molecule, real-time, long-read sequencing platform. Four analytical models were deployed: Model 1 (additive: accounts for the number of alleles), Model 2 (dominant: accounts for only the presence or absence of alleles), Model 3 (adjusted additive with rHuEPO types) and Model 4 (adjusted dominant with rHuEPO types). HLA-B*46:01:01:01 and DRB1*09:01:02:01 were found to be independent risk markers for anti-rHuEPO-induced PRCA in all models [OR (95%CI), p-values for B*46:01:01:01: 4.58 (1.55–13.51), 0.006; 4.63 (1.56–13.75), 0.006; 5.72 (1.67–19.67), 0.006; and 5.81 (1.68–20.09), 0.005; for DRB1*09:01:02:01: 3.99 (1.28–12.49), 0.017, 4.50 (1.32–15.40), 0.016, 3.42 (1.09–10.74), 0.035, and 3.75 (1.08–13.07), 0.038, in Models 1–4, respectively. HLA-B*46:01:01:01 and DRB1*09:01:02:01 are susceptible alleles for anti-rHuEPO-induced PRCA. These findings support the role of HLA genotyping in helping to monitor patients receiving rHuEPO treatment.

FORTITUDE: A Phase 2 Open-Label Study in Progress to Evaluate Etavopivat for the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes

Background: Most patients with lower-risk myelodysplastic syndrome (LR-MDS) develop anemia and a high proportion of patients become dependent on red blood cell (RBC) transfusions. MDS-related anemia is associated with low hemoglobin (Hb) levels, iron overload and poor quality of life. Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population. Etavopivat is an investigational, once-daily, selective erythrocyte pyruvate kinase (PKR) activator in development for the treatment of sickle cell disease (SCD) and anemia in patients with LR-MDS. In a phase 1 study in adult and adolescent patients with SCD by Saraf et al. HemaSphere. (2022), etavopivat 400 mg once daily was considered well tolerated and showed sustained Hb increases up to 12 weeks for most patients. Additional studies in healthy volunteers and patients with SCD support an acceptable safety profile together with improved RBC health and function during continuous treatment with etavopivat. In patients with LR-MDS, ineffective hematopoiesis may be due, in part, to insufficient ATP production, leading to increased erythroid lineage apoptosis. By activating PKR, etavopivat may improve RBC health and function by stimulating energy production (increasing ATP levels), increasing Hb levels (decreasing anemia), and decreasing erythroid lineage apoptosis. Aims:Describe the design of a multicenter, open-label, phase 2 study (FORTITUDE; NCT05568225) evaluating hematologic improvements in patients with very low-, low- and intermediate-risk MDS during treatment with etavopivat. Study design:Key eligibility criteria include age ≥18 years; very low-, low- and intermediate-risk MDS per the Revised International Prognostic Scoring System; and anemia defined by mean Hb &amp;lt;10.0 g/dL and &amp;lt;3 RBC transfusions &amp;lt;16 weeks prior to first dose for non-transfusion-dependent (NTD) patients or ≥3 units of RBCs for anemia &amp;lt;16 weeks prior to first dose for transfusion-dependent (TD) patients. Key exclusion criteria include MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality, history of acute myeloid leukemia, and an absolute neutrophil count &amp;lt;0.5 × 10 9/L. Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients. Patients will receive etavopivat 400 mg once daily for at least 48 weeks. Treatment may be continued beyond 48 weeks in patients demonstrating clinical benefit. The primary objective of the study is to assess hematologic improvements based on an erythroid response over any continuous period ≥8 weeks within 24 weeks on etavopivat treatment in patients with LR-MDS. The primary endpoint will be based on the combined incidence of: ≥1.5 g/dL increase in Hb from baseline maintained for ≥8 consecutive weeks for NTD patients; absence of any transfusion for ≥8 consecutive weeks for low transfusion-burden patients; and reduction by ≥50% of RBC units for ≥8 consecutive weeks for high transfusion-burden patients. Safety, tolerability, pharmacokinetic, and pharmacodynamic properties of etavopivat will be evaluated. FORTITUDE is open for enrollment in Canada, France, Germany, and the USA. Planned enrollment includes approximately 15 patients in each of the three transfusion requirement-based groups (Figure). Statistical analysis: The primary endpoint (pooled incidence) will be tested with a one-sided Fisher's exact test at the significance level of 0.025 where 0.2 is the assumed null proportion. Summary:Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia.

Longitudinal Safety of Luspatercept in the Treatment of Anemia in Patients with Myelofibrosis: Results from the ACE-536-MF-001 Study

Introduction Luspatercept (LUSPA) is approved for the treatment of anemia in some adults with β-thalassemia or myelodysplastic syndrome who require red blood cell transfusion and has a well characterized safety profile for these indications. The primary readout from the phase 2 ACE-536-MF-001 study (NCT03194542) demonstrated manageable safety and promising efficacy of LUSPA for treatment of myelofibrosis (MF)-related anemia with 19.0%-31.6% of patients (pts) achieving transfusion independence (defined as 84 consecutive days transfusion free), and 18.2%-21.4% of non-transfusion-dependent (NTD) pts achieving anemia response (defined as 84 consecutive days ≥ 1.5 g/dL hemoglobin increase from baseline without transfusion) in the entire treatment period (Gerds ASCO 2023 7016). To characterize further the safety profile of LUSPA in MF and provide data on adverse event (AE) management, we present a detailed longitudinal safety analysis of the MF-001 study. Methods Pts were enrolled into 4 cohorts based on transfusion dependence (TD) and stable ruxolitinib (RUX) treatment - cohort 1: NTD, no RUX; cohort 2: TD, no RUX; cohort 3A: NTD, RUX; cohort 3B: TD, RUX. All pts received LUSPA 1.0 mg/kg subcutaneously with titration up to 1.75 mg/kg in 21-day cycles; the starting dose was 1.33 mg/kg in the cohort 3B expansion group. Response was assessed at day 169 (24 weeks), with treatment extended for pts showing clinical benefit. The primary endpoint was anemia response; AEs alongside LUSPA and RUX dosing were also assessed. On dosing days, seated blood pressure was assessed prior to LUSPA administration. In the case of ≥ grade 3 hypertension (systolic ≥ 160 mmHg, diastolic ≥ 100 mmHg), dosing was delayed until hypertension had resolved to ≤ grade 1 or baseline, followed by dose reduction by 1 dose level. If ≥ 2 dose reductions were implemented due to any suspected treatment-related AE (TRAE), LUSPA was discontinued. Results In the safety population (N = 95; cohort 1, n = 22; cohort 2, n = 14; cohort 3A, n = 21; cohort 3B, n = 38), the most frequently used prior medications for anemia treatment were erythropoiesis-stimulating agents (23.2%, most frequently epoetin alfa [14.7%]), followed by danazol (11.6%), lenalidomide (2.1%), and thalidomide (1.1%). Prior history of hypertension was recorded in 50.5% of pts. Median follow-up duration was 546 days. A total of 47.4% of pts had ≥ 1 TRAE; the most common were hypertension (17.9%), bone pain (7.4%), and diarrhea (6.3%). Incidence of treatment-related grade ≥ 3 diarrhea was low (2.1%). Overall, 13.7% of pts received concomitant antidiarrheals. LUSPA was discontinued in 9 pts due to AEs; 1 event of cerebral toxoplasmosis was considered treatment related by the investigator. Among pts receiving RUX (cohorts 3A/3B), hypertension was the most frequently occurring grade ≥ 3 TRAE ( Table 1) and 5 pts had LUSPA dose modifications related to hypertension events; considered related to LUSPA in 4 pts ( Table 2). In contrast, among pts not receiving RUX (cohorts 1/2), no pts experienced grade ≥ 3 hypertension events. Hypertension was manageable with clinical intervention; during the study the most frequent concomitant medications for hypertension were angiotensin-converting enzyme inhibitors (26.3%), beta-blocking agents (selective, 23.2%; non-selective, 3.2%), and angiotensin II receptor blockers (alone, 20.0%; plus diuretics, 5.3%). Among NTD pts (cohort 3A), there were no changes in RUX dose. Among TD pts (cohort 3B), 25 (65.8%) pts maintained their RUX dose and 6 (15.8%) pts had ≥ 1 dose increase. Overall, 9 deaths occurred during treatment; none were considered treatment related. Causes of death were pneumonia, septic shock, intracranial hemorrhage, ischemic stroke, organ dysfunction, post-procedural hemorrhage, myelofibrosis, renal failure, and pneumonitis (n = 1 each). Conclusions The safety profile of LUSPA in the ACE-536-MF-001 study was consistent with previous studies in other indications, and AEs were mostly low grade. In addition to benefits in anemia, the safety profile of LUSPA allowed most pts receiving RUX to maintain or increase their RUX dose, supporting maintenance of Janus kinase inhibitor therapy for adequate disease control of MF. Study support: Bristol Myers Squibb.

Efficacy and Safety of Roxadustat for Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndrome (LR-MDS) with Low Red Blood Cell (RBC) Transfusion Burden: Results of Phase III Matterhorn Study

Presented on behalf of all MATTERHORN (FGCL-4592-082) study investigators Introduction: For patients (pts) with LR-MDS, anemia poses a major clinical challenge, with limited response to first-line erythropoietin (EPO)-stimulating agents (ESAs) and a median duration of response ≤2 years. Further, pts with RBC transfusion dependence (≥2 packed RBC [pRBC] units every 8 weeks [Q8W]) are less likely to respond to ESAs. Anemia treatments with novel mechanisms of action enabling transfusion independence (TI) are needed to reduce frequent RBC transfusion burden. Roxadustat is a first-in-class, hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia with chronic kidney disease. In the MATTERHORN (NCT03263091) dose-selection stage, roxadustat was well-tolerated, and 37.5% of pts (9/24) with LR-MDS and low RBC transfusion burden ([LTB] 1 pRBC unit Q8W for two consecutive 8-week periods or 2-4 pRBC units Q8W) achieved TI. In the MATTERHORN double-blind stage, TI response rate and safety of roxadustat were further assessed. Methods: MATTERHORN is an ongoing, double-blind, Phase III, randomized, placebo (PBO)-controlled trial. Eligible adult pts (≥18 years of age) had very low-, low-, or intermediate-risk primary MDS per Revised International Prognostic Scoring System (IPSS-R) classification (&amp;lt;5% bone marrow blasts); hemoglobin (Hb) ≤10.0 g/dL at baseline (BL); and LTB. Prior ESA use (&amp;gt;8 weeks before randomization) was permitted. Pts were randomized 3:2 to roxadustat or PBO, then stratified by serum EPO concentration (≤200 or 200-400 mIU/mL), IPSS-R risk, and transfusion burden. Pts received oral roxadustat (starting dosage: 2.5 mg/kg three times weekly based on the dose-selection stage) or PBO with best supportive care (BSC; per institutional criteria, including RBC transfusion) for a 52-week treatment period, followed by a 4-week follow-up period. Primary efficacy endpoint was percentage of pts with TI (the absence of RBC transfusion) for ≥56 consecutive days during the first 28 treatment weeks (TI responder). The percentage of pts with TI and mean Hb increase of ≥1.0 and ≥1.5 g/dL (averaged over 8 weeks) compared with BL pretransfusion Hb was also assessed (to be reported separately). Safety (including treatment-emergent adverse events [TEAEs] and serious TEAEs) was evaluated throughout the study. Results: As of the final 28-week interim analysis of the double-blind stage (data cutoff: April 24, 2023), 140 pts (82 roxadustat, 58 PBO) were randomized and treated. Across arms, median age was 71.5 years (range, 26-96), 59.3% (83/140) were male, and 80.0% (112/140) were white. Most pts (72.1% [101/140]) had IPSS-R low-risk disease and a transfusion burden of 2-4 pRBC units Q8W (92.1% [129/140]). Median (range) BL transfusion burden was 2.5 (1-10) pRBC units. Seventy pts (50.0%) received prior ESAs (98.6% [69/70] were ESA-refractory). Eighty-four pts (41/82 [50.0%] roxadustat, 43/58 [74.1%] PBO) completed 28 weeks of treatment, and 15 pts (6/82 [7.3%] roxadustat, 9/58 [15.5%] PBO) were continuing treatment. Median (range) treatment duration was 24.1 (1.1-28.0) weeks for the roxadustat arm and 28.0 (0.1-28.0) weeks for the PBO arm. A greater percentage of pts in the roxadustat arm compared with the PBO arm were TI responders (47.5% vs. 33.3%). However, this difference did not reach statistical significance ( p=0.22; figure). Percentages of pts with TEAEs of any grade, serious TEAEs, and TEAEs leading to treatment discontinuation were similar across arms (table). Six deaths occurred on study (roxadustat: pneumonia [n=2], acute myocardial infarction and ischemic stroke [n=1], multiorgan failure [n=1]; PBO: urosepsis [n=1], disease progression [n=1]). Three pts (all in roxadustat arm) progressed to acute myeloid leukemia. The study was terminated by the sponsor and is currently being completed. Conclusions: Despite not meeting the primary endpoint, roxadustat plus BSC was well-tolerated, and a high percentage of pts with LR-MDS and LTB were TI responders. The high TI response rate in the PBO arm, historically poor outcomes in pts with ESA-refractory disease, and the inclusion of pts who were not transfusion-dependent (1 pRBC unit Q8W) may have contributed to the lack of a statistically significant difference in TI response rates between arms. MATTERHORN outcomes highlight the continued unmet need for effective and safe therapies that reduce RBC transfusion burden in LR-MDS.

The ELEMENT-MDS Trial: A Phase 3 Randomized Study Evaluating Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Non-Transfusion-Dependent, Lower-Risk Myelodysplastic Syndromes

Background and Significance: Anemia is a common and debilitating symptom in patients with myelodysplastic syndromes (MDS), frequently leading to dependence on red blood cell (RBC) transfusions. Transfusion-dependent (TD) patients have worse overall survival and quality of life, and repeat transfusions are associated with complications, including iron overload. Erythropoiesis-stimulating agents (ESAs) are the standard treatment for anemia in patients with lower-risk (LR)-MDS, but many patients are ineligible for or refractory to ESAs, and responses are limited. Luspatercept, a late-stage erythroid maturation agent, is approved to treat TD patients with LR-MDS after ESA failure. In the phase 3 COMMANDS study, in ESA-naive patients with LR-MDS requiring transfusions, a significantly higher proportion of patients receiving luspatercept than epoetin alfa achieved RBC transfusion independence for ≥ 12 weeks with concurrent hemoglobin (Hb) increase ≥ 1.5 g/dL (weeks 1-24) (Platzbecker U, et al. Lancet 2023. doi: 10.1016/S0140-6736(23)00874-7). The potential of luspatercept to improve moderately severe chronic anemia and reduce RBC transfusion dependence has not yet been investigated in the majority non-transfusion-dependent (NTD) LR-MDS patient population. Preventing transfusion dependence is crucial for improving LR-MDS patient outcomes. The aim of this actively enrolling, phase 3, randomized, multicenter study is to compare the safety and efficacy of luspatercept versus epoetin alfa in reducing progression to RBC transfusion dependence in ESA-naive, NTD adult patients with anemia due to LR-MDS. Study design and methods: The ELEMENT-MDS study includes a 5-week screening period, a 96-week treatment period, an extension phase, and a post-treatment follow-up period (Figure). Target enrollment is 360 patients with anemia due to Revised International Prognostic Scoring System (IPSS-R) Very low-, Low-, or Intermediate-risk MDS. Eligible patients are ≥ 18 years of age with a confirmed MDS diagnosis, baseline serum erythropoietin (sEPO) levels ≤ 500 U/L, and symptomatic anemia defined as a score of moderate or worse on ≥ 1 Patient Global Impression of Severity (PGI-S) item (fatigue, shortness of breath, weakness, or dizziness). Participants must be RBC transfusion-independent per International Working Group 2018 criteria (no RBC transfusions within 16 weeks prior to randomization) and have baseline Hb ≤ 9.5 g/dL. Patients will be excluded if they have a del(5q) cytogenetic abnormality, unclassifiable MDS or myelodysplastic/myeloproliferative neoplasms, anemia due to reasons other than MDS, bleeding disorders, low absolute neutrophil or platelet counts, uncontrolled hypertension, previous acute myeloid leukemia diagnosis, or history of recent malignancies, among other reasons. Participants will be randomized 1:1 to receive luspatercept or epoetin alfa. Stratification factors include baseline sEPO levels, ring sideroblast status, and IPSS-R risk category. Patients will receive luspatercept once every 3 weeks at a starting dose of 1.0 mg/kg (escalation up to 1.75 mg/kg allowed) or epoetin alfa once a week at a starting dose of 450 IU/kg (escalation up to 1050 IU/kg allowed). The primary endpoint will compare the proportion of patients becoming TD (defined as requiring ≥ 3 RBC units/16 weeks) during any continuous 16-week interval in weeks 1-96. The key secondary endpoint is a Hb increase ≥ 1.5 g/dL sustained for ≥ 16 weeks during weeks 1-48. Additional secondary endpoints include time to RBC transfusion dependence, transfusion-free survival, time to achieve modified hematologic improvement-erythroid response, transfusion independence ≥ 24 weeks, and quality of life assessment. Safety endpoints include type and severity of adverse events and relationship to treatment, overall survival, and progression to high-risk MDS and acute myeloid leukemia. Summary: The results of this phase 3 study will determine the efficacy and safety of luspatercept as a therapy for ESA-naive NTD patients with LR-MDS, who have limited treatment options for anemia. The study is registered at ClinicalTrials.gov (NCT05949684) and EudraCT (2022-500430-29-00).

Recombinant Human Erythropoietin Combined with All-Trans Retinoic Acid and Testosterone Undecanoate in the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndromes: Updated Results of a Multicenter, Single-Arm, Prospective Trial

[Background] More than 90% of low-risk MDS face refractory anemia and blood transfusion dependence for a long time. At present, recombinant human erythropoietin (EPO) is the main treatment, but the effective rate of single agent is 30%-40%, which seriously affects the quality of life of patients. Previous studies had shown that testosterone undecanoate could promote erythroid hematopoiesis and all-trans retinoic acid (ATRA) had the function of promoting blood cell differentiation in vitro. We previously reported that EPO combined with ATRA and testosterone undecanoate in the treatment of patients with low-risk MDS and demonstrated promising efficacy and safety in a prospective trial (Chen et al, ASH 2022). Here we present an updated analysis of efficacy and safety results in the ongoing study. [Methods] In this multicenter, single-arm trial, patients with newly diagnosed lower-risk MDS based on the 2016 WHO classification and the Revised International Prognostic Scoring System (IPSS-R) from 3 different tertiary medical centers in China were included. Patients were received EPO (10000IU/day) plus ATRA (25mg/m 2/day) and testosterone undecanoate (80mg twice daily) for 3 months. The primary endpoint was overall hemoglobin response rate, defined as an increase in hemoglobin levels of ≥ 1.5g/dL from baseline in 2 or more consecutive assessments (2 weeks apart) and no red blood cell transfusions during this period. Response was assessed after completion of 3months. The data cut-off date was July 25, 2023. [Results] As of July 2023, a total of 43 patients were enrolled, with a median age of 65 years, 24 males and 19 females, with median hemoglobin of 63 g/L, EPO concentration &amp;gt; 500 IU/L in 18 patients, and the overall hemoglobin response rate of 65.1% (28/43). The hemoglobin response rates were 61.1% (11/18) in patients with EPO concentrations greater than &amp;gt; 500 IU/L and 68.0% (17/25) in patients with EPO concentrations ≤ 500, which were not statistically different. Among them, 112 known or putative mutational gene targets in hematologic malignancy were examined for mutations in 32 patients using a custom targeted next-generation sequencing (NGS) gene panel. The most frequent mutations were SF3B1 (15/32, 46.8%) and ASXL1 (8/32, 25.0%). The hemoglobin response rate was 80.0% (12/15) in patients with SF3B1 mutation and 37.5% (3/8) in patients with ASXL1 mutation, respectively. Among 43 patients evaluable for safety analysis, the most common non-hematological adverse events were dry skin (17/43, 39.5%) and fatigue (12/43, 27.9%). No patients had disease progression during the treatment period. [Conclusion]: This study showed that EPO combined with tretinoin and testosterone undecanoate regimen can effectively improve the anemia of lower risk MDS in approximately 65.1% of patients and is not affected by EPO concentration. It has the better efficacy in patients with SF3B1 mutation, but has worse efficacy in patients with ASXL1 mutation. It is worthy of further randomized controlled studies to verify the efficacy.

Association of anaemia on heart failure and left ventricular function: A bidirectional Mendelian randomization study.

Observational studies have suggested that anaemia is associated with an increased risk of heart failure (HF). But the potential causal association is not clear. We aimed to investigate the association between anaemia and HF risk. A Mendelian randomization (MR) analysis was performed to confirm the causal association of anaemia with the risk of HF and left ventricular structure and function. Furthermore, a reverse-direction MR analyses was conducted to assess the causal effect of HF on anaemia. The MR analysis indicated that genetically predicted anaemia is associated with the increased risk of HF (meta: odd ratio (OR)=1.12; 95% confidence interval (CI) [1.04, 1.20]; P=0.002), and left ventricular mass index (β=1.051; 95% CI [0.384, 1.718]; P=0.002), left ventricular mass (β=2.063; 95% CI [0.578, 3.547]; P=0.006), left atrial minimum volume (β=0.076; 95% CI [0.008, 0.143]; P=0.028), and left atrial maximum volume (β=0.090; 95% CI [0.023, 0.157]; P=0.009). In the reverse-direction MR analyses, we found that genetic susceptibility to HF was significantly associated with the increased risk of anaemia (meta: OR=1.40; 95% CI [1.24, 1.59]; P=1.79×10-7 ). This MR study supports the genetic evidence that there is bidirectional causality between anaemia and the risk of HF as well as anaemia may cause left ventricular hypertrophy and enlargement of the left atrium. Considering the adverse causal effects between the two diseases, more attention should be paid to the prevention and treatment of anaemia in patients with HF.

Efficacy and Safety of Desidustat for the Treatment of Anaemia in Patients with CKD: A Retrospective, Open-Label, Single-Centre Study

Efficacy and Safety of Desidustat for the Treatment of Anaemia in Patients with CKD: A Retrospective, Open-Label, Single-Centre Study

A National, Multi-Center, Prospective Study Evaluating the Long-Term Safety and Effectiveness of Roxadustat for Anemia Treatment in Patients with CKD (ROXSTAR Registry)

A National, Multi-Center, Prospective Study Evaluating the Long-Term Safety and Effectiveness of Roxadustat for Anemia Treatment in Patients with CKD (ROXSTAR Registry)

Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial

Pegmolesatide for the treatment of anemia in patients undergoing dialysis: a randomized clinical trial

Effectiveness of Lactoferrin in the Treatment of Anemia in Chronic Kidney Disease: A Single-Center Pilot Study

Abstract Background: Anemia occurs in majority of patients with chronic kidney disease despite adequate dialysis and iron replete status. This study was done to evaluate the effects of lactoferrin with or without iron supplementation for the treatment of anemia in patients with chronic kidney disease (CKD). Methods: In this prospective, observational, single-center, single-arm pilot study, adult patients aged &gt;18 years, having stage 5 CKD (estimated glomerular filtration rate [eGFR] &lt;15 ml/min/1.73 m2), and who had anemia (hemoglobin [Hb] &lt;10 g/dl; transferrin saturation [Tsat] &gt;20%) were included. Patients were treated with 100 mg of oral lactoferrin twice a day for one month with or without iron supplementation. Patients had been on stable erythropoietin doses for ≥1 month prior to inclusion in the study. We report on the improvement in Hb levels and effect on inflammatory markers from baseline at four weeks. Results: A total of 46 CKD patients having anemia were included. Patients had a mean age of 39.3 years, and a majority were men (69.6%). Improvement in the mean (SD) Hb level (g/dl) was observed from baseline (8.18 [1.19]) to Week 2 (8.54 [1.57]), which attained significance at Week 4 (8.96 [1.93]; P &lt; 0.001; mean difference: −0.76; 95% confidence interval [CI]: −1.291 to − 0.2383). The improvement in Hb was higher in women than in men (P = 0.48) and in patients receiving lactoferrin with iron supplementation than in those receiving lactoferrin alone (P = 0.14). There was a non-significant decrease in the erythrocyte sedimentation rate (P = 0.14) and a non-significant increase in C-reactive protein (P = 0.54) level. Conclusions: Oral lactoferrin therapy was effective in improving hemoglobin levels in patients with advanced CKD and anemia. The effects of lactoferrin therapy on inflammatory markers remain uncertain.

POSTER: MPN-404 Safety and Efficacy of Luspatercept for the Treatment of Anemia in Patients With Myelofibrosis: Results From the ACE-536-MF-001 Study

POSTER: MPN-404 Safety and Efficacy of Luspatercept for the Treatment of Anemia in Patients With Myelofibrosis: Results From the ACE-536-MF-001 Study