Erythropoiesis-stimulating Agents Research Articles

A Case Report of a Patient with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan Who Underwent Major Surgery

Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by intravascular hemolysis, thrombosis and bone marrow failure. The appearance of the anti-C5 monoclonal antibody eculizumab revolutionized the treatment of PNH, controlling hemolysis and the incidence of thrombosis. However, some patients persist with anemia, due in part to extravascular C3-mediated hemolysis. More recently, the anti-C3 monoclonal antibody pegcetacoplan, which blocks the most proximal part of the complement cascade, has been marketed in Europe, achieving improvements in anemia in these patients. However, intercurrent infectious episodes or surgical interventions can trigger a hemolytic flare, so dose adjustments are necessary to prevent their occurrence. There is hardly any published information or established consensus on how to treat these patients. We present this case as an example of a successful treatment of a patient diagnosed with PNH under treatment with pegcetacoplan who has undergone major surgery. A 67 year-old man was diagnosed with aplastic anemia in 1997 and treated with immunosuppression (cyclosporine and oxytosone). In 2000, he presented his first intravascular hemolytic crisis with HPN clone detection. He presented several intravascular hemolytic crises for which he was treated with erythropoiesis-stimulating agents, corticosteroids and transfusions. In 2010, due to deterioration of renal function because of acute hemolysis episode, he started treatment with eculizumab. A reduction in the number of hemolytic crises was observed. However, he required an increase in the dose and frequency of administration of eculizumab due to pharmacokinetic breakthrough hemolysis. After one month of treatment, a positive direct coombs test appeared and presented anemia due to extravascular hemolysis, for which he again required treatment with corticosteroids on specific occasions. For this reason, in December 2022, he started treatment with pegcetacoplan at the usual dose of 1080 mg twice a week subcutaneously (sc). Prior to the start of pegcetacoplan, the patient had hemoglobin levels of 10.3 g/dL, hyperbilirubinemia of 3.2 mg/dL (indirect 2.6 mg/dL), consumed haptoglobin, elevated lactate dehydrogenase (LDH) of 281 U/L and reticulocytosis of 5-6%. Subsequently, since the beginning of pegcetacoplan, he presented clinical improvement, stable hemoglobin (12-13 g/dL) and normalization of reticulocytes, LDH and bilirubin levels. The haptoglobin has remained low until the present time. In June 2023, the patient underwent major surgery consisting of radical prostatectomy due to a benign prostatic hypertrophy. Suspecting that it might provoke a hemolytic crisis due to surgical stress, the dose of pegcetacoplan was increased as recommended by clinical experts to a dose of 1080 mg every 72 hours sc from one week prior to surgery until one week after. The procedure was carried out without incident and without an increase in hemolysis parameters. This is the first case report of a patient with PNH treated with pegcetacoplan undergoing major surgery in Spain. In this patient, the perioperative dose increase was successful in preventing the development of a hemolytic crisis.

Red Blood Cell Transfusion Dependence Is Associated with Greater Healthcare Resource Utilization, Higher Medical Cost, and Poorer Prognosis in Patients with Lower-Risk Myelodysplastic Syndromes: A 28-Year Retrospective Observation Study Result

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of myeloid neoplasms characterized by cytopenia due to inefficient hematopoiesis, with a considerable risk of progression to acute myeloid leukemia (AML) or early mortality. In lower-risk MDS (LR-MDS) patients, anemia and its associated complications have been the focus of clinical attention. A significant portion of these patients eventually develop red blood cell transfusion dependence (RBC TD), which has been linked to a poorer prognosis. Given the limited efficacy of available treatments in reducing RBC TD, most patients face increased risks of chronic anemia and various complications. Moreover, RBC TD is known to be associated with reduced overall survival (OS) and leukemia-free survival (LFS). This study aimed to assess the impact of RBC TD on the socioeconomic burden and clinical prognosis of LR-MDS patients, utilizing an electronic medical records (EMR) database spanning nearly 30 years of MDS patient data. This retrospective observational study examined adult MDS patients (≥ 18 years of age) treated at Samsung Medical Center in the Republic of Korea. Eligible patients were diagnosed with MDS between Sep 1, 1994, to Apr 1, 2022 (index period), with the observation period spanning from Sep 1, 1994, to Sep 1, 2022. Baseline assessments included estimation of revised international prognostic scoring system (IPSS-R) scores, categorizing patients with very low, low or intermediate risks as lower-risk MDS (LR-MDS). TD was defined as the occurrence of any 16-week period with RBC transfusion of ≥ 2 units per 8 weeks, without consecutive 56-day period without transfusion. Healthcare resource utilization (HCRU), medical costs, and prognosis indicators including overall survival (OS) and AML-free survival (AFS) were analyzed and compared between patients who experiencing TD and those not (non-TD). Out of 831 MDS patients, 349 (42.0%) were classified as lower-risk at baseline. Among LR-MDS patients, 29.5% (103/349) experienced TD while 23.3% (194/831) experienced TD in the entire study population. The median age at diagnosis of MDS was 63 (ranging from 18 to 89), and 65.3% (543/831) were male. In LR-MDS patients, there were no significant differences in either baseline age (61 vs 63, P=0.16) or gender (71.8% vs 61.0% males, P=0.053) between TD and non-TD groups. However, TD group exhibited significantly higher median erythropoietin (EPO) level than non-TD group (290.5U/L vs. 112U/L, P<0.001) among LR-MDS patients with available baseline serum EPO levels (76 TD and 178 non-TD). Among the 76 TD LR-MDS patients with baseline serum EPO levels, 51 (67.1%) exhibited > 200U/L, which is considered a clinical threshold for erythropoiesis-stimulating agent (ESA) treatment. As shown in Table 1, RBC TD was consistently associated with greater HCRU and higher medical costs, especially in LR-MDS patients. TD LR-MDS patients had higher rates of outpatient department and emergency room visits (15676 vs. 8303 visits and 587 vs. 328 visits per 1000 person-years [PY], respectively), and increased hospitalizations (709 vs. 456 per 1000 PY), with longer hospital stays (13343 vs. 8272 days per 1000 PY). Furthermore, TD LR-MDS patients required over four-times of packed RBC units than non-TD patients (31107 vs. 7073 units per 1000 PY). Consequently, TD LR-MDS patients incurred higher total medical cost than their non-TD counterpart (13.5 million vs. 6.1 million USD per 1000 PY). Median OS (58.4 months vs. 103.1 months) and AFS (52.7 months vs. 102.7 months) were both significantly shorter in the TD group compared to the non-TD group among LR-MDS patients, while the differences in OS and AFS did not reach the level of significance in the entire study population (Table 1 and Figure 1). Notably, median OS after the first documented RBC TD event was 33.8 months (95% confidence interval: 24.7-58.5 months) in LR-MDS patients. The findings of this study indicate that RBC TD can be a strong predictor of increased HCRU and medical costs, as well as decreased OS and AFS over a 20-year period following the initial diagnosis of LR-MDS. Given that a majority of LR-MDS patients experiencing TD may not be eligible for ESA treatment due to elevated EPO levels exceeding 200U/L, and the use of cytotoxic agents is not usually recommended for these patients, these results highlight a substantial unmet need for alternative treatment options to address RBC TD in LR-MDS patients.

Durable Continuous Transfusion Independence (TI) with Imetelstat in IMerge Phase 3 for Patients with Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to or Ineligible for Erythropoiesis-Stimulating Agents (ESAs)

CONCLUSIONS MDS are serious life-threatening hematologic malignancies in which a heterogeneous group of clonal disorders results in ineffective hematopoiesis. An unmet need remains for new therapies for patients (pts) with LR-MDS who are red blood cell transfusion dependent (RBC-TD) and R/R to or ineligible for ESAs. Imetelstat, an oligonucleotide, is a first-in-class telomerase inhibitor that targets cells with high telomerase activity by direct binding to the RNA template of telomerase. In the IMerge phase 3 trial, imetelstat produced higher rates of TI for ≥8 weeks, ≥24 weeks, and ≥1 year (39.8%, 28.0%, and 17.8%) than placebo (15.0%, 3.3%, and 1.7%) in pts with non-del(5q) LR-MDS that was RBC-TD, R/R to/ineligible for ESAs, and naïve to lenalidomide or hypomethylating agents (HMAs; Platzbecker et al. EHA 2023. Abstr S165). We report characteristics and clinical benefit for pts with sustained TI for ≥1 year from this trial. IMerge (MDS3001, NCT02598661) is a global, double-blind, randomized, placebo-controlled, phase 3 trial of imetelstat in RBC-TD, ESA-R/R, non-del 5(q) lenalidomide/HMA-naïve LR-MDS. The primary end point was 8-week TI rate; secondary end points included safety, 24-week TI, duration of response, hematologic improvement, and MDS response. Exploratory end points included assessment of cytogenetic response and mutational status with clinical response. The proportion of pts with>1-year TI and other binary end points, were summarized with percentage and 95% 2-sided exact Clopper-Pearson CI. The Kaplan-Meier method was used to estimate the distribution of TI. Of 118 pts receiving imetelstat, 21 (17.8%; 95% CI, 11.4-25.9) achieved ≥1-year sustained TI, representing 45% of ≥8-week TI (21 of 47 pts) and 64% of ≥24-week TI (21 of 33 pts); of 60 pts receiving placebo plus supportive care, 1 (1.7%; 95% CI, 0-8.9) achieved ≥1-year TI. Of the ≥1-year TI imetelstat responders, 15/21 (71.4%) had ring sideroblasts, as did the 1 placebo pt. The median prior RBC transfusion burden was 6 U over 8 weeks (range, 4-9 U) for the imetelstat group and 5 U for the placebo pt. Additional baseline characteristics are in the table. Pts received imetelstat for a median of 101.1 weeks (range, 75.1-163.9 weeks) and a median of 24 cycles (range, 18-41 cycles). The median duration of TI for imetelstat ≥1-year TI responders was 123 weeks (95% CI, 80.4 to not evaluable); the median increase in hemoglobin during the longest TI interval was 5.18 g/dL (range, 2.67-13.76 g/dL) for the imetelstat group vs 1.67 g/dL for the placebo pt. After a median follow-up of 125 weeks, none of the patients with ≥1 year TI on either arm progressed to acute myeloid leukemia (AML). Of the pts receiving imetelstat, 7 had an abnormal karyotype at baseline, of which 6 had reduction in the cytogenetic abnormal clones (4 with cytogenetic complete response and 2 with cytogenetic partial response by independent review committee). Mutation data were available for 18 pts receiving imetelstat, all with SF3B1 mutations present at baseline, and multiple of these pts concurrently had TET2, DNMT3A, ASXL1, or JAK2 mutations. The maximal reduction ranged from −6% to −100% in SF3B1 variant allele frequency (VAF) in these pts, and 13 of 18 (72.2%) achieved ≥50% VAF reduction, including 7 with complete elimination of the VAF. Reduction in other concurrent mutations was also observed in these pts. Safety was consistent with that previously reported; most frequent adverse events were reversible grade 3 or 4 thrombocytopenia and neutropenia. At the time of data cutoff (May 10, 2023), 13 pts receiving imetelstat and the pt receiving placebo were ongoing (Figure); of the 8 who discontinued treatment, 7 had loss of response, and 1 was due to adverse event. Analyses for progression-free and overall survival were not evaluable as of this cutoff date (insufficient follow-up). Treatment with imetelstat resulted in ≥1-year sustained, continuous TI in 17.8% of pts in the IMerge phase 3 trial. In this ESA-R/R/ineligible population with a high prior transfusion burden, a reduction to 0 RBC transfusions for ≥1 year represents an opportunity to achieve relief from iron overload and other transfusion associated complications, and decreased demand on already limited blood product supply. Furthermore, durable TI and meaningful reductions in mutational burden suggest imetelstat may have disease-modifying activity.

Impact of Mutational Status on Clinical Response to Imetelstat in Patients with Lower-Risk Myelodysplastic Syndromes in the IMerge Phase 3 Study

CONCLUSIONS Imetelstat, a first-in-class telomerase inhibitor, showed higher rates of red blood cell (RBC) transfusion independence (TI) for ≥8 weeks, ≥24 weeks, and ≥1 year (39.8%, 28.0%, and 17.8%) than placebo (15.0%, 3.3%, and 1.7%) in the IMerge (NCT02598661) phase 3 study of patients with RBC transfusion-dependent non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory to erythropoiesis-stimulating agents (Platzbecker et al. EHA 2023. Abstr S165). To evaluate the impact of MDS-associated mutations on clinical efficacy of imetelstat, we performed next-generation sequencing of a panel of 36 genes, recurrently mutated in MDS, using DNA samples from peripheral blood collected at study entry. Further analysis of TI responses to imetelstat was performed across different mutation subgroups, defined based on genes involved in different biological functions, including the splicing process, epigenetic modifiers, transcription regulation, and receptors/kinases. Baseline mutation data were available in 165 of 178 patients (imetelstat, n = 110; placebo, n = 55; 93.2% and 91.7% of total in each group, respectively). Of patients with mutation data, 161 (97.6%) had ≥1 mutation detected, among whom, 75 (70.1%), 33 (30.8%), and 9 (8.4%) patients in the imetelstat group and 38 (70.4%), 15 (27.8%), and 7 (13%) patients in the placebo group had >1, >2, and >3 mutations, respectively. The ≥8-week TI rates in the imetelstat vs placebo groups were 42.7% vs 15.8% ( P = .006) for patients with >1 mutation, 45.5% vs 6.7% ( P = .012) for patients with >2 mutations, and 55.6% vs 14.3% ( P = .089) for patients with >3 mutations, respectively. The ≥24-week TI rates were 26.7% vs 2.6% ( P = .003), 33.3% vs 0% ( P = .014), and 33.3% vs 0% ( P = .117), respectively. In patients with mutations associated with poor prognosis ( TP53, ETV6, RUNX1, ASXL1 or EZH2), 31.8% and 9.1% of patients in the imetelstat group achieved ≥8-week and ≥24-week TI vs 0 of those in the placebo group. TP53 mutations were detected in 2 patients in each group; both patients in the imetelstat group and none in the placebo group had ≥8-week TI. Among patients with ASXL1 mutations, 5 of 18 patients (27.8%) in the imetelstat and 0 of 6 (0) in placebo group had ≥8-week TI. Among patients with ETV6 mutations, 1 of 2 (50%) in the imetelstat group and 0 of 1 patients in the placebo group had ≥8-week TI. Two patients in each group had RUNX1 mutations; none achieved TI. Imetelstat ≥8-week TI rates were 43.8%, 37.7%, 40.0%, and 80.0% for patients harboring mutated genes in the RNA spliceosome, epigenetic modifiers, transcription regulation, and receptors/kinases, respectively; ≥24-week TI was 30.2%, 27.5%, 20.0%, and 80.0%, respectively. The most frequently mutated gene was SF3B1 (125 of 165; 75.8%), the ≥8-week and ≥24-week TI rates were 48.8% vs 16.3% ( P = .001) and 35.4% vs 2.3% ( P < .001) with imetelstat vs placebo. In the imetelstat group, ≥8-week TI was achieved in patients with different spectrum of SF3B1 hot-spot mutations: 2 of 8 patients (25.0%) with E622D, 4 of 7 (57.1%) with R625C/L/G, 7 of 12 (58.3%) with H662Q/N/D/Y, 2 of 2 (100%) with T663P, 2 of 6 (33.3%) with K666R/T/Q/N, 18 of 41 (43.9%) with K700E, 2 of 2 (100%) with A744P, and 1 of 2 patients (50.0%) with E783K. Durable ≥24-week TI was also observed in patients with these hot-spot mutations. Other genes with mutation frequency >10% were TET2 (32.7%), DNMT3A (17.0%), ASXL1 (14.5%), and CUX1 (12.7%). The ≥8-week TI rates in the imetelstat group vs placebo group were 50% vs 21.4% for TET2 mutations; 31.6% vs 22.2% for DNMT3A mutations; 27.8% vs 0 for ASXL1 mutations; 35.7% vs 14.3% for CUX1 mutations (Figure). The ≥24-week TI rates were 40% vs 0, 26.3% vs 11.1%, 11.1% vs 0, and 14.3% vs 0, respectively, for those mutations (Figure). Higher RBC-TI rates were observed in patients with various baseline mutational profiles treated with imetelstat compared with placebo in IMerge. While the sample size for specific mutations was small, consistent with the observation that patients with LR-MDS have a low number of specific mutations, TI responses in patients receiving imetelstat occurred regardless of the presence of mutations associated with poor prognosis or the number of mutations. Imetelstat showed comparable TI rates across different molecularly defined subgroups, suggesting that clinical benefit of imetelstat in patients with LR-MDS is independent of the underlying molecular pattern.

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.

Effect of Luspatercept on Erythropoiesis and Fetal Hemoglobin in β-Transfusion-Dependent Thalassemia Patients: A Real-Life Experience

Background: Luspatercept is the first erythropoiesis-stimulating agent approved for transfusion-dependent β-thalassemia (TDT). In the BELIEVE trial, more than 70% of the patients had a hematological response defined as a reduction of ≥33% of transfusion burden in any 12-week interval. In our experience, some patients have a clinical benefit even if a response as defined by the clinical trial is not reached. Indeed, several aspects remain to be addressed, including its specific effects on erythropoiesis. Fetal hemoglobin (HbF) has been hypothesized as a potential marker in response evaluation. However, no results have been published, excluding an abstract presentation by Cappellini MD et al. at the European Hematology Association meeting in 2019, showing a greater HbF increase in responders vs. non-responders. Aim: This study aims to evaluate the effect of luspatercept on erythropoiesis and the hemoglobin (Hb) fractions in patients with β-TDT treated with luspatercept in a real-life setting at our Center in Milan, Italy. Methods: Inclusion criteria: age ≥18 years, β-TDT eligible for treatment with luspatercept, and signed informed consent. Exclusion criteria: unwilling to participate in the study. We assessed hematological parameters, Hb fractions, and erythropoiesis markers at baseline and over the treatment period of up to 48 weeks (Dose16). We also extracted mRNA from reticulocytes (RET) from peripheral blood at fixed doses and analyzed the expression of a panel of genes involved in erythropoiesis. We evaluated hematological variables dividing the patients into three groups of responses defined: Full responder (FR): reduction of transfusion burden ≥33% and ≥2 units of blood in any 12-week intervalIntermediate responder (IR): patients with a reduction in transfusion burden ≥25% and <33% in any 12-week intervalNon-responder (NR): reduction of the transfusion burden <25%. Statistical analysis at baseline was performed using Kruskal-Wallis test. We fitted linear random intercept regression models to evaluate time trends of hematological variables. Results: Thirty-seven patients have been enrolled in the study. 3/37 have been excluded from the analysis because they developed adverse events leading to drug interruption before completing 12 weeks of treatment. We herein present the data of the 29/34 subjects who reached at least 12 weeks of treatment as of July 20, 2023. The median age was 41 yrs (range 19-63 yrs), 15 were females (52%). 8/29 (28%) had a β0/β0 genotype; 12/29 (41%) patients underwent splenectomy. Twelve patients had a FR, 6 an IR, and 11 were NR. We found that the baseline median absolute value of HbF (g/dL) was different in the three groups (NR: 0.21, range 0.09-0.34; IR: 0.37, range 0.14-1.52; FR: 0.95, range 0.31-1.65, p=0.009) (Figure 1). In all subjects, HbF increased over time. However, the increase was different in the three groups (p-interaction: 0.0001). In the linear regression model (Figure 2), the HbF absolute increase per week was 0.004 g/dL (95% confidence interval (CI): 0.002-0.006) among NR, 0.015 (CI: 0.008-0.022) in the IR group and 0.03 g/dL (CI: 0.02-0.04) in the FR group. EPO baseline value was similar in the three groups, but unexpectedly we observed different increases over time (p-interaction: 0.0001). In the IR and FR groups, the regression slopes were 6.66 U/L (CI: 3.11-10-21) and 9.42 U/L (CI: 5.53-13.31) per week, respectively. In the NR group, there was no EPO increase. Interestingly, the baseline value of erythroblasts (EB) was different between the three groups, with FR having the highest value. EB increased in both IR and FR, with the IR group displaying a steeper increase and finally reaching the FR group. Preliminary results on gene expression in RET showed an upregulation of GATA-1 and its target genes involved in erythroid differentiation and heme biosynthesis, as shown in the murine model (Martinez PA et al. 2019), irrespective of the response group. Conclusions: Our findings identify baseline HbF as a possible predictor of response. Also, the HbF trend could represent a marker of response to luspatercept in β-TDT patients. Furthermore, HbF can be useful in identifying patients in the IR group with the best chance of becoming responders in long-term treatment. Our preliminary results also suggest that luspatercept acts by enhancing erythropoiesis and leads to an increase in EPO levels and EB. Studies on more patients are needed to confirm these findings.

The Heparinoid Sevuparin Improves Anemia and Kidney Status in a Mouse Model of Chronic Kidney Disease

The control of systemic iron availability is essential to sustain the different needs of the body, without causing iron overload disease or deficiency (anemia) meaning that iron is highly regulated and the master regulator is hepcidin. High levels of hepcidin induce ferroportin degradation, inhibiting iron release from enterocytes and macrophages resulting in an internal iron deficiency, which underlies anemia of chronic diseases (ACD). Patients with chronic kidney disease (CKD) often have ACD due to a combination of inflammation, erythropoietin (EPO) insufficiency/unresponsiveness, elevated hepcidin levels, reduced kidney function and decreased iron availability. Treatments involve erythropoiesis-stimulating agents, that in a longer perspective often fail to ameliorate the anemia, highlighting the need for new therapeutic tools. Interestingly, it has been reported that hepcidin suppression improves anemia in rodent models of CKD, suggesting that normalising hepcidin levels may be a means to treat anemia in CKD and in general in ACD. It is known that heparins are potent hepcidin suppressors; sevuparin, a novel, clinical stage, low-molecular weight heparinoid compound with substantially reduced anticoagulant activity is a promising candidate drug to control hepcidin expression in patients with CKD. The authors previously found that sevuparin strongly suppressed basal, BMP6- and IL6-dependent hepcidin expression in vitro with a maximum effect after 6h (90% reduction) persisting for at least 16h. The hepcidin lowering effect of sevuparin was confirmed also in healthy mice. Furthermore, in healthy volunteers, a single dose of subcutaneous sevuparin caused a significant reduction of about 50% (3 mg/kg) and 80% (9 mg/kg) of serum hepcidin after 12 and 24h, respectively, providing a robust translational context to the sevuparin effects on hepcidin levels. The aim of the present work was to investigate the effect of sevuparin on hepcidin, hemoglobin and the kidney status in a CKD mouse model of high hepcidin anemia. Mice fed with “adenine rich diet” (ARD) (0.2% adenine; 0.9% phosphorus; 0.6% calcium; 20% casein) developed moderate or severe signs of kidney damage as manifested by weight loss, increased serum creatinine, high hepcidin levels, low serum iron and anemia (hemoglobin ≤ 12.5 g/dL) after 7-9 weeks. After the onset of CKD, the mice were chronically treated with PBS or sevuparin (10 mg/kg/daily) subcutaneously for 3 or 6 weeks alone or in combination with erythropoietin (EPO) administered intraperitoneally (50 U/mouse twice a week in the first 3 weeks followed by 3 weeks and then 25 U/mouse once a week to simulate EPO hypo-responsiveness). Sevuparin was provided by Modus Therapeutics AB, Sweden, whereas EPO was used in the form of the commercially available darbapoietin alfa (ARANESP ®). Sevuparin treatment alone increased hemoglobin, hematocrit and weight (Hb 11-12 g/dL; Ht 20%; 22 g vs baseline values of Hb 9-10 g/dL; Ht 18%; 14.5 g PBS) with adjoining modest decreases of serum hepcidin and creatinine. The reduction of creatinine was supported by a concomitant improvement of the kidney status visible as a reduction of collagen deposits indicative of reduced fibrosis compared to the mice treated with PBS only. The EPO/sevuparin combination showed a strong reduction from control of serum hepcidin levels (292 ng/mL vs 1382 ng/mL) after 3 weeks of treatment whereas after 6 weeks levels were increased up to 2000 ng/mL suggesting that the chronic treatment with EPO is not optimal, as observed in patients. Interestingly the concomitant benefit on anemia at 3w (about Hb 18 g/dL, Ht 54%) for the combination remained stable at 6w, further supported by the maintained high Ret-He (about 15.62 pg); suggesting a phased dependency on hepcidin in the development of CKD anemia. Furthermore, the improvement of the kidney status (histology and function) was also maintained throughout combination treatment. Our data in this mouse CKD model add new insights to the role of hepcidin in the development of CKD anemia over time. Furthermore, the results are promising and support further mechanistic and clinical studies to elucidate the therapeutic role for sevuparin as a treatment in anemia of inflammatory and/or chronic diseases in monotherapy or in combination with EPO and to explore its role in kidney protection.

Characterization and Management of Cytopenias after Imetelstat Treatment in the IMerge Phase 3 Trial of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS)

CONCLUSIONS Imetelstat, an oligonucleotide and a first-in-class telomerase inhibitor, selectively targets malignant hematopoietic stem and progenitor cells with high telomerase activity by direct binding to the RNA template. In patients with MDS the on-target effects of imetelstat are associated with the development of hematologic treatment-emergent adverse events (TEAEs). In the IMerge phase 3 trial, among patients treated with imetelstat, 68% experienced grade 3-4 neutropenia, and 62% had grade 3-4 thrombocytopenia; however, clinical consequences of grade 3-4 infection or bleeding were similar in patients treated with imetelstat and placebo (Platzbecker et al. EHA 2023. Abstr S165). Here, we report additional data on the occurrence and management of cytopenias after treatment with imetelstat. IMerge phase 3 trial (NCT02598661) is a multicenter study involving 178 patients with a median age of 72 years with red blood cell (RBC) transfusion dependency and LR-MDS relapsed/refractory to or ineligible for erythropoiesis-stimulating agents. Patients were randomized 2:1 to receive either imetelstat or placebo and stratified by prior RBC transfusion burden (4-6 or >6 U) and by International Prognostic Scoring System risk group. The safety population included all patients who received ≥1 dose of study drug and comprised 118 patients treated with imetelstat and 59 with placebo. TEAEs of neutropenia and thrombocytopenia with imetelstat treatment were more prevalent in cycles 1-3 (68.6% and 62.7% respectively), and their frequency decreased over time: 42.7% and 48.5% in cycles 4-6, 36.8% and 44.7% in cycles 7-12, and 31.3% and 37.5% in cycle 13 and beyond. Based on laboratory assessment, neutrophil and platelet counts decreased from baseline levels in patients treated with imetelstat versus those treated with placebo (91.5% and 95.8% vs 47.5% and 33.9%, respectively). Neutropenia decreased to a maximum of grade 4 and 3 in 55 and 29 of imetelstat-treated patients, respectively, and >80% of cytopenia events stabilized to grade ≤2 within 4 weeks (Figure). The median time to grade 4 neutropenia was 5.0 weeks (range,1.1-90.3 weeks) for the imetelstat group vs 23.0 weeks (range, 23.0-23.0 weeks) for the placebo group. Similarly, median time to grade 4 thrombocytopenia was 5.2 weeks (range, 2.0-29.9 weeks) with imetelstat vs 35.5 weeks (range, 28.0-43.0 weeks) with placebo. It is noteworthy that among 47 patients who achieved the primary end point of 8-week RBC transfusion independence with imetelstat, 34 (72.3%) and 28 patients (59.6%) had grade 3-4 neutropenia and grade 3-4 thrombocytopenia, respectively. In the imetelstat group, 3 patients had grade 3-4 neutropenia concurrent with grade 3-4 infections, and no patients experienced grade 3-4 thrombocytopenia associated with grade 3-4 bleeding events. There were no grade 5 cytopenias for either imetelstat or placebo groups. In the imetelstat group, cytopenias were managed with protocol-specified treatment delays and dose adjustments. Dose reductions due to neutropenia and thrombocytopenia occurred in 39 patients (33.1%) and 27 patients (22.9%), respectively. Of imetelstat-treated patients, 6 (5.1%) discontinued treatment due to neutropenia (1 case, grade 4; all others, grade 3), and 4 (3.4%) discontinued due to thrombocytopenia (1 case, grade 2; 3 cases, grade 3). In addition to dose reductions and discontinuation of imetelstat, thrombocytopenia and neutropenia were managed by cycle delays in 46.6% and 50.8% of patients, by platelet transfusions in 17.8% of patients, and by concomitant therapy with growth factor support (mostly during cycles 2-4) in 34.7% of patients. Similar patterns of imetelstat dose modifications were seen in a pooled phase 2 and phase 3 safety analysis of IMerge. In the IMerge phase 3 trial, thrombocytopenia and neutropenia were the most common and most frequently reported grade 3-4 AEs during treatment cycles 1-3. However, these AEs were generally transient, reversible, and manageable through treatment delays and dose adjustments, allowing for patients to remain on treatment and continue to experience clinical benefit. Moreover, occurrence of grade 3-4 cytopenias in responders suggests that these TEAEs do not affect the efficacy of imetelstat.

Anaemia in CKD-treatment standard.

Anaemia is one of the most common complications of chronic kidney disease (CKD), having a significant impact on quality of life, and is also associated with a number of adverse clinical outcomes. Its pathogenesis is multifactorial, caused largely by an inadequate production of erythropoietin from the diseased kidneys, with iron deficiency, inflammation, shortened red cell lifespan and enhanced blood loss also being contributory factors. The management of this condition was transformed in the late 1980s by the advent of recombinant human erythropoietin (epoetin), and treatment paradigms have developed over the last three decades, largely focusing on a combination of epoetin or its analogues (erythropoiesis-stimulating agents; ESAs) along with iron supplementation, often administered intravenously due to increased hepcidin levels limiting iron absorption from the gut. Indeed, in patients with early CKD and iron deficiency, iron per se may be sufficient to improve the anaemia, delaying the need for ESA therapy. Other causes of anaemia should be excluded and corrected (if possible) before resorting to treatment with ESAs and iron. More recently, the hypoxia-inducible factor-prolyl hydroxylase inhibitors have entered the therapeutic arena; these are orally active agents that upregulate endogenous erythropoietin production as well as a number of iron-regulatory genes which may also enhance erythropoiesis. The latter drugs are highly efficacious, and may have advantages in inflammatory conditions causing resistance to conventional ESA therapy, but concerns exist regarding their safety, particularly in the longer term. This article reviews the current standards of treatment, as well as recent novel developments in the management of anaemia in CKD.

An internet-based educational algorithm for the work-up, diagnosis and management of patients with myelodysplastic syndromes from the Canadian Consortium on MDS

Background Myelodysplastic Syndrome (MDS) treatments reduce transfusion dependence, delay progression to acute leukemia, and may improve survival. The Canadian Consortium on MDS (CCMDS) developed the MDS ClearPath, a comprehensive tool for the diagnosis, work-up and management of MDS of any risk category at any point during a patient’s disease course. Methods The draft ClearPath algorithm was revised by 60 Canadian hematologists, finalized by consensus of the Steering Committee and went live in 2013. The update went online in January 2023. Results An approach to the diagnosis and management of MDS is provided. Appropriate investigations are detailed, current scoring systems are included as is a prognostic calculator, and an IPSS-M calculator link is included. Treatments (erythropoiesis-stimulating agents; lenalidomide; hypomethylating agents; immunosuppressive therapy; supportive care [transfusions; antibiotics; bleeding prevention; iron chelation]; investigational agents; links to clinical trial websites) are detailed, including dosing/administration; monitoring; dose adjustments; expected response; side effect management; and provincial reimbursement. Added were details on luspatercept, decitabine and decitabine/cedazuridine; recommendations for mutation analysis; WHO and ICC 2022 classifications; the IPSS-M and Clinical Frailty scores; familial predisposition testing; and response assessment criteria. Recommendations are made where data are lacking. The Treatment Wizard, a series of questions specific to clinical status, leads to treatment recommendations; the self-directed mode is the overall algorithm. References with abstract links are included, and information panels included throughout. The ClearPath in English or French is available at www.MDSClearPath.org; a (free) iPad app is being updated. Discussion The CCMDS presents an internet/app-based algorithm to support MDS management, with recommendations designed to assist in the standardization of MDS care.

Evaluation of bone marrow findings in hemodialysis patients with erythropoietin-resistant anemia.

Treatment with erythropoietin-stimulating agents (ESAs) is widely used in anemia of chronic kidney disease (CKD). Acquired ESA resistance is an important problem. The aim of this study is to examine the bone marrow findings in hemodialysis patients with ESA-resistant anemia. The data of 210 patients with acquired ESA resistance were reviewed retrospectively. The patients were divided into groups according to having diagnosis of dysplasia and hematological disease, and survival analysis was performed. A total of 26 patients were included in the study. While dysplasia was present in 10 (38.5%) patients, five of them were diagnosed hematologically. When survival analysis was performed between those with and without a hematological diagnosis, a difference in survival was observed against the group with the diagnosis (24.4 vs. 72 months, p = 0.045). Unresponsiveness to ESA treatment in CKD patients or a decrease in one of the other cell lines along with hemoglobin, it would be appropriate to perform early bone marrow examination.

Pharmacotherapy for Reducing RBC Transfusion for Patients in the ICU: A Systematic Review and Network Meta-Analysis.

To determine optional therapeutic strategies by comparing monotherapies and combination therapies to reduce RBC transfusion requirement for patients in the ICU. MEDLINE, CENTRAL, and Embase were searched for studies published from database inception until July 2023. We included randomized controlled trials comparing erythropoiesis-stimulating agents (Epo), iron, combination therapy with iron and Epo, hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), vitamin D 3 (VD3), and placebo/no treatment. A frequentist network meta-analysis (NMA) was performed using a random effects model, and the confidence in NMA was rated. Of 117 eligible studies, 75 studies (15,091 patients) were included in the quantitative analysis. Compared with placebo/no treatment, the combination therapy reduces the requirement for RBC transfusion (risk ratio [RR]: 0.60; 95% CI, 0.49-0.74; confidence rating: moderate). The Epo or iron monotherapy may reduce the requirement for RBC transfusion (RR: 0.81; 95% CI, 0.63-1.04; confidence rating: low; RR: 0.83; 95% CI, 0.70-0.98; confidence rating: low, respectively). Combination therapy may not increase the prevalence of both venous thromboembolism (VTE) (RR: 0.73; 95% CI, 0.25-2.08; confidence rating: low) and infection. Epo monotherapy may not increase the prevalence of VTE but may increase that of infections (RR: 1.27; 95% CI, 0.94-1.73; confidence rating: low). Iron monotherapy may not increase the prevalence of both VTE and infection. Evidence for VD3 and HIF-PHI remains uncertain. Combination therapy with iron and Epo likely reduces the requirement for RBC transfusion and may be less harmful than other therapies.

Investigating the relationship between erythropoiesis-stimulating agents and mortality in hemodialysis patients: A systematic review and meta-analysis.

In recent years, various studies have been conducted to investigate the relationship between erythropoiesis-stimulating agents (ESAs) and mortality in hemodialysis patients, who showed contradictory results. Therefore, this study aimed to investigate the relationship between ESAs and mortality in hemodialysis patients. The current study is a systematic review and meta-analysis based on observational and interventional studies published in the Web of Science, Cochrane Library, Science Direct, PubMed, Scopus, and Google Scholar databases between 1980 and the end of 2022. Jadad scale checklist and Newcastle Ottawa scale were used to evaluate the quality of articles. The study data were analyzed using Stata 15 software. In the initial search, 3933 articles were extracted, and by screening and considering the research criteria, 68 studies were finally included in the meta-analysis. According to the meta-analysis results, the risk ratio (RR) of overall mortality in hemodialysis patients receiving ESAs was equal to 1.19 (95% CI: 1.16-1.23, P ≤ 0.001). The RR of mortality in patients aged 60 years and under was equal to 1.33 (1.15-1.55, P ≤ 0.001), in the age group over 60 years was equal to 1.13 (1.10-1.16, P ≤ 0.001), in randomized clinical trial studies was equal to 1.06 (0.80-1.40, P = 0.701), in cohort studies was equal to 1.20 (1.16-1.25, P ≤ 0.001), in American countries was equal to 1.19 (1.10-1.29, P ≤ 0.001), in Asian countries was equal to 1.15 (1.10-1.19, P ≤ 0.001), and in European countries was equal to 1.18 (1.05-1.34, P = 0.007). The results of the study show that receiving ESAs is associated with a 19% increase in the risk of overall mortality in hemodialysis patients.

Effect of finerenone in patients with chronic kidney disease and type 2 diabetes by baseline anaemia status: a FIDELITY analysis

Abstract Introduction Anaemia is a common complication affecting ∼42% patients with chronic kidney disease (CKD) stages 3–5 at 1 year after diagnosis and ∼67% at 5 years, with prevalence increasing as estimated glomerular filtration rate (eGFR) decreases. Despite the fact that anaemia is associated with CKD progression, adverse cardiovascular (CV) events and premature mortality in patients with CKD, management of these patients remains suboptimal. The nonsteroidal mineralocorticoid receptor antagonist finerenone demonstrated significant cardiorenal benefits in patients with CKD and type 2 diabetes (T2D) in FIDELITY (a prespecified pooled analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials). However, the effect of anaemia on CV and kidney outcomes in patients receiving finerenone has not been established. Purpose This post hoc analysis investigated the treatment effects and safety of finerenone vs placebo in patients categorised by baseline anaemia status. Methods Eligible patients with CKD (urine albumin-to-creatinine ratio [UACR] ≥30–<300 mg/g and eGFR ≥25–≤90 ml/min/1.73 m² or UACR ≥300–≤5000 mg/g and eGFR ≥25 ml/min/1.73 m²) and T2D, and on optimised renin–angiotensin system inhibitor were randomised 1:1 to finerenone or placebo. Anaemia was defined using the World Health Organization criteria: serum haemoglobin levels <13 g/dl (male) or <12 g/dl (female) or treatment with an erythropoiesis-stimulating agent at baseline. Key outcomes analysed by baseline anaemia status included a CV composite (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for heart failure [HHF]) and kidney composite (kidney failure, sustained eGFR decrease ≥57%, or kidney-related death), HHF, and all-cause mortality. Safety outcomes were assessed by treatment-emergent adverse events. Results Of 13,007 patients, 4293 (33.0%) had anaemia at baseline. The risk reduction on the CV composite outcome was nominally significant with finerenone vs placebo in patients with anaemia at baseline but not in those without (p-value for interaction=0.04; Figure 1). Finerenone also reduced the risk of the kidney composite outcome vs placebo, with no heterogeneity between the treatment groups and across the anaemia subgroups (Figure 1). In addition, finerenone was associated with a reduced risk of all-cause mortality and HHF outcomes vs placebo, irrespective of baseline anaemia status (Figure 1). Incidence of treatment emergent hyperkalaemia was higher in patients with anaemia at baseline in both treatment arms (21.2% finerenone vs 11.5% placebo) compared to those without anaemia (10.5% finerenone vs 4.6% placebo). Conclusions In patients with CKD and T2D, anaemia was found to be a modifier to the effect of finerenone on the CV composite outcome. There was no heterogeneity of treatment effects with finerenone vs placebo, by anaemia at baseline, on kidney composite outcome, all-cause mortality and HHF.

Iron Surveillance and Management in Gastro-Intestinal Oncology Patients: A National Physician Survey.

Iron deficiency (ID) is a complication of gastrointestinal (GI) cancers that may manifest as iron deficiency anemia (IDA). Serum ferritin monitoring and oral iron supplementation have the limitations of being falsely elevated and poorly absorbed, respectively. This study aims to assess the discordance in surveillance, treatment practices, and awareness of ID/IDA in GI cancer patients by Canadian physicians treating these patients. From February 2020 to September 2021, a 22-question electronic survey was sent to medical oncologists (MOs), surgical oncologists (SOs), and gastroenterologists (GEs). The survey collected information about four domains: physician demographics, surveillance practices, treatment practices, and awareness of ID/IDA in GI cancer patients and ASCO/ASH guidelines. A total of 108 (34 MOs, 19 SOs, and 55 GEs) of the 872 (12.4%) invited physicians completed the survey. Of these, 26.5% of MOs, 36.8% of SOs, and 70.9% of GEs measured baseline iron parameters, with few continuing surveillance throughout treatment. Ferritin was widely measured by MOs (88.9%), SOs (100%), and GEs (91.4%). Iron was supplemented if ID/IDA was identified pre-treatment by 66.7% of MOs, 85.7% of SOs, and 94.2% of GEs. Parenteral iron was prescribed by SOs (100%), while oral iron was prescribed by MOs (83.3%) and GEs (87.9%). Only 18.6% of physicians were aware of the ASCO/ASH guidelines regarding erythropoiesis-stimulating agents with parenteral iron for treating chemotherapy-induced anemia. Results illustrate variations in practice patterns for IDA management across the different physician specialties. Moreover, there appeared to be gaps in the knowledge and care surrounding evidence-based IDA management principles which may contribute to poor clinical outcomes.

The impact of erythropoiesis-stimulating agents administration concomitantly with adjuvant anti-HER2 treatments on the outcomes of patients with early breast cancer: a sub-analysis of the ALTTO study.

To assess whether erythropoiesis-stimulating agents (ESA) administration impacts the outcomes of patients with HER2-positive early breast cancer (EBC). ALTTO (NCT00490139) patients were categorized by ESA use during adjuvant anti-HER2 treatment. Disease-free-survival (DFS), overall survival (OS), and time-to-distant recurrence (TTDR) were analyzed by ESA administration, with subgroup analyses according to prognostic factors. Log-rank tests and Cox modeling were performed. Adverse events (AEs) of ESA-interest were compared. Among 8381 patients recruited in ALTTO, 123 (1.5%) received ESA concomitantly with study treatment. The median age of patients receiving ESA was 54years, 39.0% premenopausal, most had tumor size > 2cm (56.9%), node-positive (58.5%), and positive estrogen receptor expression (61.8%). Median follow-up was shorter in the ESA group [6.1years (IQR 5.3-7.0) vs. 6.9years (6.0-7.1); p < 0.001]. There was no DFS difference by ESA administration (log-rank p = 0.70), with 3- and 7-year DFS of 89.2% (95% CI 81.8-93.8%) and 81.6% (71.4-88.5%) in ESA group vs. 88.3% (87.6-89.0%) and 80.0% (79.1-80.9%) in No-ESA group. In subgroup analyses, the interaction of ESA administration with menopausal status was statistically significant (unadjusted p = 0.024; stratified p = 0.033), favoring premenopausal women receiving ESA. We observed no significant association of ESA administration with OS (log-rank p = 0.57; 7-year OS in ESA 88.6% vs. 90.0% in non-ESA) or TTDR. ESA-interest AEs were experienced by eight (6.5%) patients receiving ESA and 417 (5.1%) in the No-ESA group (p = 0.41). ESA administration to patients receiving adjuvant anti-HER2 treatment for HER2-positive EBC was safe and not associated with a negative impact on survival outcomes.

Effect of roxadustat on iron metabolism in patients with peritoneal dialysis: a real-world 24-week study

BackgroundRoxadustat is an oral hypoxia inducing factor-prolyl hydroxylase inhibitor (HIF-PHI) that regulates iron metabolism in patients with chronic kidney disease (CKD) primarily by reducing hepcidin levels and mobilizing internal iron stores. More data are needed to demonstrate the efficacy of roxadustat in regulating iron metabolism in patients with peritoneal dialysis (PD) compared with erythropoiesis stimulating agents (ESAs).MethodsThis prospective cohort study enrolled PD patients with a mean hemoglobin level of 60–100 g/L. All subjects were randomized into two groups at a ratio of 2:1 the roxadustat group (106 cases), and the ESA group (53 cases). The primary endpoint was the change in the iron biomarker levels and the proportion of patients with absolute iron deficiency and functional iron deficiency.ResultsCompared with ESAs, roxadustat significantly decreased hepcidin level (difference, − 20.09 ng/mL; 95% CI, − 30.26 to − 9.92), attenuated the increase in serum soluble transferrin receptor (sTFR) level (difference, − 7.87 nmol/L; 95% CI, − 12.11 to − 3.64), and reduced the proportion of patients with functional iron deficiency (roxadustat, 11.43%; ESA, 33.33%). There was no significant difference in safety of the two groups over the duration of the study.ConclusionsCompared with ESA group, roxadustat group showed significant differences in all iron biomarker levels except serum ferritin (sFt) and transferrin saturation (TSAT). These results suggest that roxadustat was superior to ESAs as a therapy for iron metabolism in PD patients.Trial registration: This study completed Chinese Clinical Trial Registration on March 4, 2022 (registration number: ChiCTR2200057231).Graphical abstract

Proton Pump Inhibitors and Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Hemodialysis Patients: Results from the Japan Dialysis Outcomes and Practice Patterns Study.

Hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is important problem in dialysis patients. While proton pump inhibitors (PPIs) may inhibit iron absorption, few studies have examined associations between PPIs and ESA-resistant anemia in hemodialysis patients. This study examined the associations between PPIs and ESA-resistant anemia in hemodialysis patients. The present study was a cross-sectional study using repeated 4-month observations, up to eight observations/patient, from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). The primary outcome was erythropoietin resistance index (ERI). ESA dose, hemoglobin, proportion of erythropoietin-resistant anemia, transferrin saturation (TSAT), and ferritin were also examined. Linear or risk-difference regression models were used with generalized estimating equations to account for repeated measurements. Of 1,644 patients, 867 patients had PPI prescriptions (52.7%). Patients prescribed PPI had higher ERI, higher ESA dose, and lower TSAT levels. Multivariable analysis for 12,048 four-month observations showed significantly greater ERI in PPI users (adjusted difference 0.95 IU/week/kg/[g/dL] [95% CI: 0.40-1.50]). Significant differences were also found in ESA dose (336 IU/week [95% CI: 70-602]) and the prevalence of erythropoietin-resistant anemia (3.9% [2.0-5.8%]) even after adjusted for TSAT and ferritin. Among possible mediators between the association of PPIs and anemia, TSAT was significantly different between PPI users and non-users (adjusted difference, -0.82% [95% CI: -1.56 to -0.07]). This study showed the associations between PPI and ERI, ESA dose, and TSAT in hemodialysis patients; physicians should consider anemia's associations with PPIs in hemodialysis patients.

The Risk of Venous Thrombosis for Erythropoiesis Stimulating Agents and Blood Transfusions in Cancer Patients: A Nationwide Population-Based Study in Korea

Introduction: Several previous studies have indicated that both erythropoiesis-stimulating agents (ESAs) and blood transfusions elevate the risk of venous thrombosis in cancer patients. Nevertheless, there has been inconsistency in the evidence regarding whether ESAs or blood transfusions are more closely linked to thrombotic complications. To address this, nationwide population data was analyzed to explore the association between the use of ESAs, blood transfusions, and the risk of venous thrombosis in cancer patients. Methods: This study utilized a case-crossover design and analyzed the National Health Insurance Database of Korea. A total of 710,910 patients diagnosed cancer (ICD-10 code: C00.x-C26.x, C30.x-C34.x, C37.x-C41.x, C45.x-C58.x, C60.x-C76.x, C81.x-C85.x, C88.3, C88.7, C88.9, C90.0, C90.1, C91.x-C93.x, C94.0-C94.3, C94.5, C94.7, C95.x, C96.x) between January 1, 2011, and December 31, 2020 were included. Of these, 57,256 (8.03%) identified with venous thrombosis (ICD-10 code: I80.x). The hazard period, starting from the week of thrombosis and going back 12 weeks, was compared to an earlier 12-week control period separated by a 24-week gap. Secondary analyses were conducted with different durations for the hazard/control periods (8 and 4 weeks) to assess the robustness of the results. Patients served as their own controls, and time-dependent covariates such as granulocyte colony-stimulating factor and chemotherapy were evaluated for their association with thrombotic risk. Patients were categorized based on occurrences of inpatient hospitalization, red blood cell transfusion, platelet transfusion, central venous catheter placement, and major surgery during hazard and control periods, and these variables were compared using χ2 tests. Finally, conditional logistical regression was employed to compare the odds of exposure to ESAs, blood transfusions, and other thrombosis risk factors during the hazard period to the exposure odds during the control period. Results: There were similar rates of ESA use during the hazard period and the control period (0.88% vs. 0.28%; P = 0.477). However, red blood cell transfusions (6.85% vs. 1.79%; P &amp;lt;0.001), platelet transfusions (1.92% vs. 0.48%; P = 0.003), insertion of a central venous catheter (3.34% vs. 0.74%; P &amp;lt;0.001), hospitalizations (11.79% vs. 2.77%; P &amp;lt;0.001), and major surgery (5.70% vs. 2.00%; P &amp;lt;0.001) differed significantly between the two exposure periods. All of these factors were more frequent during the hazard period compared to the control period. In the crude conditional logistical regression model, the odds ratio (OR) for ESA use was significantly increased (OR = 3.14; 95% CI: 2.63, 7.75). However, after controlling for other covariates including red blood cell transfusions, platelet transfusions, central venous catheter insertion, hospitalization, and major surgery in an adjusted model, ESA use was found to be non-significant (OR = 1.12; 95% CI: 0.93, 1.36). In contrast to ESA use, red blood cell transfusion was associated with an increased risk of thrombosis in both the crude model (OR = 3.83; 95% CI: 3.58, 4.11) and the adjusted model (OR = 1.44; 95% CI: 1.32, 1.58). This study also investigated whether varying the lengths of the hazard and control periods (8 and 4 weeks) would affect the association between ESA use, red blood cell transfusions, and thrombotic events. The results showed that the association remained consistent regardless of the duration of the periods. Overall, these findings suggest that while there was an increased risk of thrombosis associated with red blood cell transfusions, the use of ESAs did not show a significant association with thrombotic events after adjusting for other relevant factors. Conclusions: This study revealed a stronger association between red blood cell transfusions and thrombotic complications in cancer patients. These findings suggest that red blood cell transfusions may have a higher thrombotic risk compared to ESAs in this particular patient population. Furthermore, the results indicate that the use of ESAs in cancer patients might not increase the risk of thrombotic complications depending on the exposure duration. Further studies are needed to assess the impact of ESAs and blood transfusions on thrombotic risk in different populations.

Overall Survival and Erythroid Response in Patients with Low-Risk Myelodysplastic Neoplasms after First-Line Treatment in a Low-Middle Income Country

Introduction Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Current standard risk stratification model, the Revised International Prognostic Scoring System (IPSS-R), classifies patients into lower (≤3.5 points) or higher risk MDS. Lower-risk MDS (LR-MDS) treatment is based on the prevailing cytopenia and intends to improve symptomatic burden and minimize transfusion dependency. Anemia is present in 80-90% of patients with MDS. Throughout most of the course of the disease, patients with MDS have a hemoglobin &amp;lt; 10 g/dL, which leads to a decreased quality of life. Also, 50% of patients with MDS will eventually need red blood cell transfusions. Current options for the active treatment of anemia in LR-MDS are limited and vary among countries. Although erythropoiesis stimulating agents (ESAs) are considered standard of care in the absence of del5q, immunosuppressive therapy (IST) and androgens are still used in low income countries. The present study aims to evaluate whether erythroid responses and overall survival differ in patients with LR-MDS, based on their first-line treatment. Methods This is a retrospective study in patients with LR-MDS at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, a tertiary care center in Mexico City. Eligible patients were diagnosed between January 2002 and December 2022 according to World Health Organization (WHO) 2016 criteria. Response was assessed according to International Working Group (IWG) 2018 criteria. We defined erythroid response (HI-E) as the sum of the responses achieved within different transfusion burden categories. First line therapy included ESAs, IST (cyclosporine ± eltrombopag), and androgens (mesterolone, danazol). These were compared through bivariate analysis, Kaplan-Meier curves and log-rank test. Results Until December 2022, 109 LR-MDS patients were considered for inclusion. Among them, 29 patients were lost to follow-up, and 25 patients were solely observed without any further therapy. Also, 7 patients who received other therapies were excluded. Ultimately, 48 patients were included in this analysis, 56.3% (n=27) were female, mean age was 62.8 (±15.9) years. Based on WHO 2016 classification, MDS with uni- and multilineage dysplasia was present in 58.3% (n=28) of the patients, while 29.2% (n=14) had hypoplastic MDS. Anemia was present in 89.6% (n=43) of the patients. When evaluating transfusion burden, 37.5% (n=18) of patients were non-transfusion dependent (NTD), 31.3% (n=15) low-transfusion burden (LTB), and another 31.3% (n=15) high-transfusion burden (HTB). ESAs and IST were the most frequently used frontline therapies, each accounting for 41.7% (n=20) of the patients; the remaining 16% (n= 8) received androgens. When comparing baseline characteristics between treatment arms, we found lower hemoglobin values and a greater proportion of severe anemia in ESA-treated patients (p= 0.039, p= 0.036), however, no differences in transfusion burden was observed (p= 0.212). Erythroid response rates were 25% (n=5), 20% (n=4) and 62.5% (n=5) among those treated with ESAs, IST and androgens, respectively (p= 0.071). When assessing HI-E by transfusion burden, no differences were observed between treatment arms except in HTB patients (p= 0.023). Neither time to response, nor duration of response were significantly different between treatment groups ( Table 1). Importantly, 3 of the 4 responders in the IST group received cyclosporine monotherapy, also 50% were hypoplastic MDS. After a median follow up of 47 months (IQR:22.5-85.5), the median overall survival(OS) for the entire cohort was not reached. The 3-year-OS rates for IST, ESA and androgens were 94%, 54% and 50%, respectively (p= 0.018) ( Figure 1). Conclusions In spite of the bias and limitations in the retrospective nature of this study, IST seems to be a valid option in frontline therapy for LR-MDS, since HI-E rates are similar to those observed with ESAs. Additionally, IST group showed a better OS. Results obtained with androgens merit further study and should be interpreted with caution because of the sample size.