Darbepoetin Research Articles

Major Adverse Cardiovascular Events (MACE) in Patients Randomly Assigned to Vadadustat vs. Darbepoetin Alfa during the 3 Months after Dialysis Initiation

Major Adverse Cardiovascular Events (MACE) in Patients Randomly Assigned to Vadadustat vs. Darbepoetin Alfa during the 3 Months after Dialysis Initiation

EP.15B.03 Pilot Web-Based Study of Functional Status and Quality of Life Benefits Associated with Darbepoetin Alfa Use in Anemic Patients with Lung Cancer

EP.15B.03 Pilot Web-Based Study of Functional Status and Quality of Life Benefits Associated with Darbepoetin Alfa Use in Anemic Patients with Lung Cancer

Ubiquitous chromatin opening element enhance Darbepoetin alfa expression in CHO DG44 cell line

Despite extensive efforts in biotherapeutics production, there is a pressing need to enhance the biomanufacturing process to meet the growing demand for recombinant products. Ubiquitous Chromatin Opening Element (UCOE), chromatin-modifying elements derived from CpG islands, are crucial in regulating gene expression. Therefore, to explore the UCOE effect on gene expression, we cloned codon-optimized Darbepoetin alfa (DPO) sequence into the pOptiVEC then the Darbepoetin alfa-IRES-DHFR fragment was digested, and cloned into the UCOE vector. Both pOptiVEC-DPO and UCOE-DPO-IRES-DHFR cassettes were linearized and transfected into the two cell pools of CHO DG44 cells. The transfected cells were adapted with CD OptiCHO™ medium after 20 days. Recombinant DPO expression was evaluated by qRT-PCR technique. Qualitative and quantitative protein expression analysis was also carried out by western blotting and ELISA assays. Our findings showed a boosted DPO expression rate at both mRNA and protein levels in the UCOE-DPO-IRES-DHFR pool compared to pOptiVEC-DPO. These data suggest that UCOE and codon optimization result in high and stable gene expression in the CHO DG44 cell line.

Study of the Efficacy and Safety of Darbepoetin Alfa versus Epoetin Alfa in the Treatment of Anemia in Pediatric Patients on Regular Hemodialysis

Abstract Background Anemia is a common comorbidity in patients with chronic kidney disease (CKD). That affects the vast majority and can have a significant impact on patient morbidity and mortality. Erythropoiesis-stimulating agents (ESAs) are the main lines in management of anemia in hemodialysis patients. Replacement therapy with recombinant human erythropoietin (r- HuEPO) has provided an effective treatment for patients with renal “Epoetin alfa” is a recombinant erythropoietin with the same amino acid sequence as human erythropoietin (EPO). In comparison to epoetin alfa, darbepoetin alfa (DPO) contains an increased amount of sialic acid-containing carbohydrate chains. It shows a much longer elimination half-life than epoetin alfa, with prolonged erythropoietic effect. Aim of the Work to evaluate whether darbpoetin and epopoetin alpha can be used interchangeably on the same patient, achieving the same desired effect and to detect any difference in the occurrence of side effects between both ESAs. Patient and Methods This was a crossover study that took place in the Pediatrics Dialysis unit, Children’s Hospital, Ain Shams University. The study was conducted on 40 children with end stage renal disease on regular hemodialysis over a period of 6 months. The patients were randomly put into two groups A and B, each group contained 20 patients. Each group received one type of ESA either ( darbpoetin alpha or epopoetin alpha )for 3 months and then shifted to the other type of ESA for another 3 months. The dosage of epoetin alfa used was (200 IU/kg/week) and a conversion rate of EPO: DPO, 300:1. A period of 6 weeks was agreed as a washout period after the first drug given in both groups in which no results were recorded but ESA was not stopped due to its essentiality. Blood tests (hemoglobin (Hb), serum urea, serum creatinine and iron profile; (S. iron, S. ferritin, TIBC, and transferrin saturation)) were withdrawn at the start and the end of the 3 months’ period of each drug. Results We found no difference on the Hb level with both drugs. The interchange between them did not yield any significant drop in the Hb levels. Hb target in both EPO and DPO was reached in 22.5% of total cases, and was not reached in 62.5%. This proved that both drugs give the same effect with nearly negligible difference. No serious Sside effect as convulsions, hypertension, and thrombosis were noticed in both groups. Conclusion The target Hb was not reached in most patients of both groups of ESRD on regular hemodialysis at the unit and none of both drugs showed superior results or less side effects than the other.

Impact of transferrin saturation on cardiovascular events in non-dialysis-dependent chronic kidney disease patients treated with darbepoetin alfa

Impact of transferrin saturation on cardiovascular events in non-dialysis-dependent chronic kidney disease patients treated with darbepoetin alfa

#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.

#2769 The impact of carbon footprint in advanced chronic kidney disease treatments

Abstract Background and Aims Climate change has been classified as “the greatest global threat to health in the 21st century”. The quantification of the carbon footprint (CF) currently stands as the most accepted model for assessing the ecological impact of various businesses and healthcare systems. Renal treatments have a significant impact on the CF of healthcare systems, especially in terms of supple chains and waste management. The choice of the most environmentally friendly treatment for pathologies arising from advanced chronic kidney disease (ACKD) or peritoneal dialysis (PD) can impact the amount of waste generated and energy consumed. The objective was to analyze the carbon footprint (CF) impact resulting from the use of two different drugs in patients with the same medical condition: advanced chronic kidney disease (ACKD) or peritoneal dialysis (PD). One group received cinacalcet and another group received subcutaneous darbepoetin. Method Transversal observational study including 41 patients (19 receiving cinacalcet and 22 received darbepoetin alfa) that collected medication from the hospital pharmacy from February 1 to March 30, 2023. The CF was calculated using analytical techniques from hybrid life cycle models of the analyzed medications. For this analysis, three groups were considered: patient travel (distance traveled, trips/year, pickup, mode of transportation, and type of fuel), energy (energy consumption for refrigeration), and waste disposal and transportation (self-administration or administration by a family member, disposal location, and recycling information received). Quantification was performed using the formula: activity x emission factor (activity = sum of CF of the variables composing each group, emission factor = constant provided by the “Ministerio de transición ecológica” database: https://www.miteco.gob.es/es/cambio-climatico). Results Forty-one patients were included with a median age of 72 years [IQR 63-80]. Twenty-seven patients (65%) were male and 28 (68%) were on PD. Nineteen patients (46%) were on treatment with cinacalcet and 22 (54%) with darbepoetin alfa. There were no differences in calcium, phosphorus, parathormone or hemoglobin within the groups. Overall impact: The overall impact of the CF derived from the subcutaneous treatment process with darbepoetin alfa was 95,512.93 kg of CO2/year compared to that derived from cinacalcet treatment, which was 12,199.85 kg of CO2/year (p< 0.001) (Fig. 1). Patient travel to hospital and transportation of supplies Group-wise analysis did not detect significant differences in consumption derived from patient's travel to collect darbepoetin alfa or cinacalcet in the hospital (15.97 [IQR 5.25-28.66] vs 10.20 [IQR 2.08-24.5] kg CO2/year, p = 0.45). The CF of transporting supplies of darbepoetin alfa was 41,526.15 kg CO2/year compared with 10,361.54 kg CO2/year in cinacalcet group. Waste generation and transportation The waste derived CF of patients treated with darbepoetin alfa was 132 kg CO2/year [IQR 93.5-143] compared to patients treated with cinacalcet 36.4 kg CO2/year [IQR 36.3-36.5] with p-value < 0,001. Moreover, the transportation of waste for darbepoetin alfa resulted in a carbon footprint of 42,224.55 kg CO2/year, mainly attributable to the disposal of sharp waste. Energy: The refrigeration of darbepoetin alfa was calculated with a total emission of 8,286.96 kg CO2. Cinacalcet treatment did not require any refrigeration. Conclusion The CF derived from the subcutaneous administration of darbepoetin alfa was significantly greater than the CF derived from oral medication like cinacalcet. This may represent a negative environmental impact of the administration of medications via the subcutaneous route compared to oral medications in this group of patients. The use of drugs that do not require subcutaneous administration could be more sustainable, reducing the carbon footprint by 85%, as they do not require refrigeration or waste incineration.

#406 High ferritin is not needed in hemodialysis patients: a retrospective study of total body iron and oral iron replacement therapy

Abstract Background and Aims In vivo iron levels can be adjusted through intestinal iron absorption to be maintained at a suitable level; however, optimal iron levels in hemodialysis (HD) patients are unclear. Although serum ferritin is useful as an indicator of iron stores, it does not necessarily reflect body iron levels in HD patients with unstable hematopoiesis since iron metabolism is a semi-closed system in vivo. In this study, we investigated total body iron (TBI), new index calculated as the sum of red blood cell (RBC) iron and iron stores, during courses of low-dose oral iron replacement therapy, and evaluated in vivo iron sufficiency and its indicators in HD patients. Method We analyzed data on 105 courses of low-dose iron replacement therapy (50–120 mg of iron daily) administered to 83 patients with serum ferritin <60 ng/mL and Hb <12 g/dL undergoing maintenance hemodialysis at our institution. Low-dose oral iron replacement therapy was initiated between August 2016 and June 2023 and continued for at least seven months. All blood samples were collected at the start of hemodialysis at the beginning of the week. Blood examinations were performed twice a month, and patients were given darbepoetin alfa (DA), long-acting ESAs to maintain Hb at the target level of 10–12 g/dL, in accordance with the guidelines of the Japanese Society for Dialysis Therapy. Iron-related parameters were determined based on blood samples collected once a month, with TSAT calculated from serum iron (Fe) and total iron-binding capacity (TIBC), using the following equation. TSAT=Fe/TIBC × 100. We evaluated changes in TBI, RBC iron, and iron stores from the initiation of treatment to month 7, in two groups of patients, namely, iron-therapy responders and non-responders. Furthermore, we investigated factors associated with steady-state TBI. TBI was regarded as achieving a steady state during the course of therapy when the trend shifted from an increase and the difference from the value at one month was less than or equal to zero. TBI was calculated using the formula proposed by Cable et al (Transfusion. 2016, 56, 2005). Results Mean age was 68.1±12.6 years and median time on hemodialysis was 6.6 years. Of the 105 courses of therapy, 75 were delivered to men and 30 to women, and 66.7% of the patients had diabetic nephropathy. The patients had a mean Hb level of 10.4±0.7 g/dL, a mean serum ferritin level of 27.3±12.5 ng/mL, mean transferrin saturation (TSAT) of 18.1%±5.9%, and a median C-reactive protein level of 0.1 mg/dL at the start of each course. TBI showed significant increases until month 4 and plateaued thereafter in iron-therapy responders, and tended to increase and then reached a similar plateau in non-responders (month 7: 1900±447 vs. 1900±408 mg, Fig. 1). As for RBC iron, iron-therapy responders showed significant monthly increases up to month 3, whereas non-responders showed constant values. Regarding iron stores, iron-therapy responders showed significant monthly increases up to month 5, while non-responders showed a significant increase only at month 1. DA per body weight showed a significant decrease at month 3 and 4 in the effective group, but a slight increase in the non-responder group. Steady-state TBI did not correlate with Hb or serum ferritin, but was strongly correlated with body surface area (BSA) using the Du Bois formula [TBI=−791.914 + 1628.606 × BSA (m2); R2=0.88, p<0.001, Fig. 2]. Conclusion This study showed that hemodialysis patients can increase their body iron levels during oral iron replacement therapy and maintain them at the same level after sufficiency has been achieved, suggesting activation of a “mucosal block.” Furthermore, this result also suggests that determining iron sufficiency based on serum ferritin alone is difficult in HD patients with fluctuations in Hb. However, regression equations using steady-state TBI and BSA showed a high degree of fit. Therefore, BSA might potentially be used in estimations of TBI sufficiency, which may be useful for avoiding excessive iron dosage.

Evaluation of the effect of voxelotor and darbepoetin alfa on hemoglobin levels in patients with sickle cell disease

ABSTRACT Background To date, there is limited evidence on patients utilizing both voxelotor and darbepoetin alfa and its impact on hemoglobin levels. The objective is to evaluate the effect of voxelotor and darbepoetin alfa on hemoglobin levels in patients with SCD. Research design and methods This was a retrospective chart review study that assessed the primary independent variable as the utilization of either voxelotor alone, darbepoetin alfa alone, or the concurrent administration of voxelotor and darbepoetin alfa. Descriptive statistics were utilized to obtain the mean standard deviation for numerical variables and proportions for categorical variables. Results A total of 23 participants were included in this study. When comparing baseline to 2 months and 3 months, participants on voxelotor alone experienced a 3% decrease and a 6.6% increase in hemoglobin, darbepoetin alfa alone group a 4.3% decrease and a 0.6% increase in hemoglobin and voxelotor and darbepoetin group a 4.4% decrease and a 0.5% decrease in hemoglobin levels. Fifty percent of the participants in the voxelotor group and 6 (66.7%) participants in the voxelotor plus darbepoetin alfa group experienced adverse drug events. Conclusions Voxelotor resulted in a clinically significant difference in the percent change of hemoglobin from baseline to 3 months.

Short versus long-acting erythropoiesis-stimulating agents for anemia management in Egyptian hemodialysis patients.

Chronic kidney disease (CKD) often results in renal anemia, impacting the well-being of patients and causing various negative consequences. Erythropoiesis-stimulating agents (ESAs) offer promising solutions for managing anemia in CKD. This study aimed to evaluate and compare the effectiveness, safety profile, and cost-effectiveness of short-acting (Eprex®) and long-acting (Aranesp®) ESAs. This comparative prospective cohort cost-effectiveness study was carried out over 6 months among adult Egyptian hemodialysis patients of either gender. Participants were categorized into two groups based on the type of ESA administered: the Eprex group, receiving epoetin alfa, and the Aranesp group, receiving darbepoetin alfa. These two treatment groups' efficacy, safety, and cost were analyzed and compared. Of 127 hemodialysis patients, 60 (47.2%) received Eprex, while 67 (52.8%) were treated with Aranesp. Target hemoglobin (Hb) was achieved by 50.6% of patients in the Eprex group versus 63.4% in the Aranesp group, with a significant difference (P < 0.001). Both treatment groups exhibited a similar safety profile, while Aranesp® was considered the cost-saving protocol. In hemodialysis Egyptian patients, Aranesp with extended dosing intervals proved to be more effective in achieving target Hb with comparable adverse effect profiles, a substantial cost-saving strategy, and offered time-saving advantages for medical staff workload compared to Eprex. The Clinicaltrial.gov registration ID is NCT05699109 (26/01/2023).

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.

Comparative Safety of Long-Acting vs. Short-Acting Erythropoiesis-Stimulating Agents Among Patients Undergoing Hemodialysis.

Both short-acting (epoetin alfa or beta) and long-acting (darbepoetin alfa or PEG-epoetin) erythropoiesis-stimulating agents (ESAs) are commonly prescribed for patients with kidney failure undergoing maintenance hemodialysis. We compared the risks of major adverse cardiovascular events (MACE) and of all-cause mortality associated with receipt of short- vs. long-acting ESAs. This retrospective cohort analysis included Medicare hemodialysis beneficiaries aged ≥ 18 years in the United States Renal Data System from January 2015 to December 2017. We included adults who survived > 90 days after initiating hemodialysis and received either short- or long-acting ESAs. Outcomes were MACE (first occurrence of stroke, acute myocardial infarction, or cardiovascular-related mortality) and all-cause mortality. After stabilized inverse probability of treatment weighting, Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for each outcome. Of 68,607 patients (mean age: 65 years, 45% females), 33,658 (49%) received long-acting ESAs and 34,949 (51%) received short-acting ESAs. There was no difference in the risk of MACE associated with receipt of short- vs. long-acting ESAs (HR: 1.02 (95% CI: 0.98-1.08)). However, long-acting (vs. short-acting) ESA receipt was associated with a lower risk of all-cause mortality (HR: 0.91 (95% CI: 0.87-0.96)). Compared with short-acting ESAs, long-acting ESAs were associated with a lower risk of all-cause mortality, with no difference in the risk of MACE. Future studies with a longer follow-up are needed to confirm these findings.

Zinc Supplementation Enhances the Hematopoietic Activity of Erythropoiesis-Stimulating Agents but Not Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors.

Since zinc is involved in many aspects of the hematopoietic process, zinc supplementation can reduce erythropoiesis-stimulating agents (ESAs) in patients undergoing hemodialysis. However, it remains unclear whether hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have similar reduction effects. HIF-PHI stabilizes HIF, which promotes hematopoiesis, although HIF-1α levels are downregulated by zinc. This study aimed to investigate the effect of zinc supplementation on the hematopoietic effect of HIF-PHI in patients undergoing hemodialysis. Thirty patients undergoing maintenance hemodialysis who underwent periods of treatment with roxadustat or darbepoetin alfa during the past 3 years were retrospectively observed. Participants who underwent periods with and without zinc supplementation were selected, with nine treated with darbepoetin alfa and nine treated with roxadustat. Similarly to the ESA responsiveness index (ERI), the hematopoietic effect of zinc supplementation was determined by the HIF-PHI responsiveness index (HRI), which was calculated by dividing the HIF-PHI dose (mg/week) by the patient's dry weight (kg) and hemoglobin level (g/L). Zinc supplementation significantly increased ERI (p < 0.05), but no significant change was observed (p = 0.931) in HRI. Although zinc supplementation did not significantly affect HRI, adequate zinc supplementation is required to alleviate concerns such as vascular calcification and increased serum copper during the use of HIF-PHI.

Efficacy and cost-effectiveness of darbepoetin alfa once every 4 weeks versus continuous erythropoietin receptor activator once every 4 weeks for anemia correction in patients with chronic kidney disease not on dialysis.

For anemia management in patients with chronic kidney disease not on dialysis, darbepoetin alfa (DA), which has a shorter half-life but is more inexpensive than continuous erythropoietin receptor activator (CERA), is preferred in Korea. This study evaluated the efficacy, safety, and cost-effectiveness of once-in-4-weeks DA compared with once-in-4-weeks CERA in patients with chronic kidney disease not on dialysis. In this randomized, prospective, non-inferiority study, 40 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis were randomized 1:1 to the DA group and CERA group. They received the study drug once in 4 weeks during 10- or 12-week correction period and 24-week efficacy evaluation period. The primary outcomes were the mean difference in the changes in hemoglobin levels between baseline and efficacy evaluation period and hemoglobin response rates during the correction period. The secondary outcomes included differences in adverse events and costs. DA was non-inferior to CERA for anemia correction; the mean difference in the change in hemoglobin levels between the groups was -0.070 g/dL (95% confidence interval, -0.730 to 0.590 g/dL). Hemoglobin response rates were 100% with DA and 94.1% with CERA. Adverse events were comparable. The mean cost of DA was approximately one-third that of CERA (34,100 ± 7,600 Korean won/4 weeks vs. 115,500 ± 23,600 Korean won/4 weeks; p < 0.001). Once-in-4-weeks DA safely corrects anemia in erythropoiesis-stimulating agent-naïve patients with chronic kidney disease not on dialysis and is more cost-effective than once-in-4-weeks CERA.

Efficacy of ferric carboxymaltose or darbepoetin alfa for chemotherapy-induced anemia in patients with esophagogastric or pancreaticobiliary cancer: a retrospective comparative study.

Esophagogastric and pancreaticobiliary cancers are associated with chronic blood loss, poor nutrition, and surgical interventions that interfere with iron absorption. Patients with these cancers often have a higher incidence of chemotherapy-induced anemia (CIA) than patients with other malignancies. To investigate the efficacy of intravenous iron or erythropoietin-stimulating agents (ESA) for CIA treatment in patients with esophagogastric or pancreaticobiliary cancer. Retrospective, comparative chart review of patients with esophagogastric or pancreaticobiliary cancer who received ferric carboxymaltose (FCM), or darbepoetin alfa (DA), and myelosuppressive chemotherapy at Chungbuk National University Hospital between June 2018 and December 2022. To assess the efficacy of FCM or DA over time, data on hemoglobin (Hb) levels were collected from the time of administration of FCM or DA (baseline) until 6 months post-baseline, when available. In total, 214 patients (124 in the FCM and 90 in the DA group) were included in the analysis. The FCM group had a higher maximum Hb level and Hb changes for 3 months (mean ± standard deviation) following FCM or DA administration from baseline than the DA group (11.3 ± 1.5 versus 10.9 ± 1.2 g/dL, p = 0.02 and 2.0 ± 1.4 versus 1.5 ± 1.1 g/dL, p = 0.004, respectively). The FCM group had a higher proportion of Hb responders than the DA group (83.9% versus 68.9%, p = 0.013). Based on multivariable analysis, only the CIA treatment group was a significant factor for Hb response (odds ratio = 2.06, 95% confidence interval = 1.05-4.06, p = 0.036). Both FCM and DA are effective, and FCM showed a higher Hb response than DA for CIA treatment in patients with esophagogastric or pancreaticobiliary cancer. Therefore, further randomized controlled trials should determine the optimal treatment for CIA in patients with these cancers undergoing myelosuppressive chemotherapy.

The effect of darbepoetin alfa on the glomerulus of new-born mice with intrauterine growth restriction

The effect of darbepoetin alfa on the glomerulus of new-born mice with intrauterine growth restriction

Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial

Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn. We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 μg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed. Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study. Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn. Sanquin Blood Supply. For the Dutch translation of the abstract see Supplementary Materials section.

Use of darbepoetin alfa in haemolytic disease of the fetus and newborn

Use of darbepoetin alfa in haemolytic disease of the fetus and newborn

Unraveling the Clinical Spectrum: A Case Study of Classic and Aplasia-Related Paroxysmal Nocturnal Hemoglobinuria

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare nonmalignant clonal disorder of hematopoietic stem cells characterized by a phosphatidylinositol glycan protein A (PIGA) gene mutation. This mutation results in the deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, on the cell surface, rendering red blood cells (RBC) susceptible to complement-mediated destruction. This leads to hemolytic anemia, thromboses, and bone marrow failure. Here we describe two cases of PNH presenting to a tertiary care center. Case 1 A 29-year-old male with a history of polysubstance use presented to the Emergency Department with a 2-day history of progressively worsening left lower quadrant abdominal pain. CT abdomen pelvis showed multiple renal infarcts and findings suggestive of pneumatosis intestinalis. A complete blood count (CBC) revealed pancytopenia with a leukocyte count (WBC) of 3 x 10 9/L, hemoglobin (Hb) of 94 g/L, and platelet count (Plt) of 48 x 10 9/L. Lactate dehydrogenase (LDH) was elevated (900 IU/L), haptoglobin level was low ( &amp;lt;8mg/dL), and direct antiglobulin test (DAT) was negative. Urine was positive for hemosiderin, and flow cytometry showed RBCs (6.7%), granulocytes (97.97%), and monocytes (89.02%) with PNH phenotype. Bone marrow biopsy (BMB) was negative for dysplasia and fibrosis with normal hematopoiesis but showed increased erythroid precursors. Enoxaparin was started for thromboses and levofloxacin for neutropenia. Treatment for PNH was initiated with a loading dose of ravulizumab and meningococcal vaccination. The patient was lost to follow-up after receiving the first maintenance dose. Case 2 An 81-year-old female with a medical history of hypertension and coronary artery disease was hospitalized for gradually worsening shortness of breath and fatigue ongoing for 2 months. She reported easy bruising but denied a history of obvious bleeding from any orifice. Physical exam was significant for petechial rash in her lower extremities. Labs revealed pancytopenia (WBC 1.44 x 10 9/L, Hb 68 g/L, Plt 8 x 10 9/L), low reticulocyte count, LDH of 276 IU/L, and negative DAT. BMB showed marked aplasia, and she became transfusion dependent. Subsequently, flow cytometry revealed PNH phenotype in 1.45% of RBCs, 54% granulocytes, and 54% monocytes. Eculizumab therapy was started for the diagnosis of PNH. However, her transfusion requirements did not decrease. She developed iron overload and showed positive conversion on DAT. Darbepoetin alfa and romiplostim were added. Her Hb stabilized at &amp;gt;70g/L in 3 years, following which she only required romiplostim to maintain Plt &amp;gt;20,000 ( Graph 1). After 5 years, she opted to discontinue all treatment. She is being followed up regularly and has since remained stable. Discussion The two cases above are reflective of how PNH can present in different ways, ranging from the classic triad of symptoms to those with subclinical findings associated with other underlying conditions, such as aplastic anemia or myelodysplastic syndrome. The introduction of complement inhibitors completely changed the natural history of PNH, as patients' median survival shifted from 15-20 years to align with age-matched controls. Indications for treatment include severe anemia, thrombosis, or PNH symptoms like dyspnea, fatigue, and painful paroxysms. Currently, eculizumab and ravulizumab are the only FDA-approved drugs for PNH treatment. Ravulizumab is non-inferior to eculizumab, with the added advantage of less frequent dosing (every 8 weeks versus 2 weeks). Regular monitoring for hemolysis is warranted with treatment. Many patients require long-term therapy, which continues to be a significant challenge, even with the spaced dosing of ravulizumab. Eculizumab protects from terminal complement-mediated damage preventing intravascular hemolysis. However, these cells are still deficient in CD55, making them vulnerable to opsonization by C3 and premature removal in the spleen. As a result, &amp;gt;50% of PNH patients receiving treatment show positive conversion on DAT, as seen in case 2. Heparin is preferred in acute thrombotic states. Most hematologists recommend anticoagulation till a few months after starting complement inhibition.

Real-World Patient Characteristics, Treatment Patterns, and Outcomes in Patients with Lower-Risk Myelodysplastic Syndromes Who Have Been Treated with Luspatercept

Background: Myelodysplastic syndromes (MDS) are a group of rare, clonal bone marrow malignancies characterized by ineffective erythropoiesis. Erythropoiesis-stimulating agents (ESAs) are a treatment option for anemia in patients with lower-risk MDS (LR-MDS); however as only one in three patients respond to ESAs, there is a need for additional treatment options. In April 2020, luspatercept was approved for the treatment of anemia in adult patients with LR-MDS who failed to respond to ESAs. The aim of this study was to investigate real-world treatment patterns and early clinical outcomes in adult patients in the United States with LR-MDS receiving luspatercept. Methods: This was a retrospective observational cohort study of adult patients (aged ≥ 18 years at initial MDS diagnosis) with an International Prognostic Scoring System/Revised IPSS (IPSS-R/IPSS) classification of Very Low-, Low-, or Intermediate-risk MDS on or before the initial MDS diagnosis date +30 days, who were actively treated with a therapy of interest (including ESAs, hypomethylating agents [HMAs], erythroid maturation agents [EMAs], iron chelation therapy [ICT], white blood cells [WBCs], growth factors, chemotherapy, immunomodulating drugs [IMiDs], and platelet growth factors), and who received at least one dose of luspatercept between initial MDS diagnosis and November 1, 2022 in the COTA Vantage database which contains longitudinal, HIPAA-compliant data pertaining to the diagnosis, clinical management, and outcomes of patients with cancer from a mix of academic and community settings. The index date was the date of luspatercept initiation. Patients were required to have at least 2 months of medical data post-index unless they died during this period. All analyses were descriptive. Results: A total of 86 patients who were treated with luspatercept (median age 78.0 years, 79.1% White, 52.3% male, 80.2% ECOG 0-1) were included. Median baseline hemoglobin level was 7.8 g/dL (range: 5.3-11.4 g/dL). Median time from MDS diagnosis to luspatercept initiation was 35.4 months and the median follow-up time was 13.4 months. The majority of patients (89.5%) were previously treated with ESAs for a median duration of 9.0 months. The two most used ESAs were darbepoetin alfa (54.5%) and epoetin alfa (44.2%). In addition, 40.7% of patients had previously received a non-ESA treatment, most commonly azacitidine (62.9%) or lenalidomide (31.4%). The median duration of treatment (DoT) with luspatercept was 9.9 months. Around a quarter of patients who received luspatercept (25.6%, n = 22) received a further treatment, such as an ESA or an HMA for a median of 2.8 months. Overall, 51/76 (67.1%) patients with a baseline hemoglobin test who received luspatercept had an increase in hemoglobin of ≥1 g/dL compared with baseline (i.e. the closest hemoglobin test within 6 months prior to index date). Of these, 56.9% maintained the ≥1 g/dL hemoglobin level for ≥8 weeks and 45.1% maintained it for ≥16 weeks. Further, 44/76 (57.9%) patients with a baseline hemoglobin test who received luspatercept had an increase in hemoglobin ≥1.5 g/dL compared with baseline. Of these, 50.0% maintained the ≥1.5 g/dL hemoglobin level for ≥8 weeks and 25.0% maintained it for ≥16 weeks. Conclusion: This real-world study described treatment patterns and outcomes in patients with LR-MDS receiving luspatercept. An improvement in hemoglobin levels was observed in more than half of patients. In a quarter of patients who had a ≥1.5 g/dL increase compared to baseline, these improvements were maintained for ≥16 weeks. As this was a relatively small and descriptive study, future analyses are required to further elucidate these findings.