Endogenous Erythropoietin Levels Research Articles

Living on High Altitudes Associated with Reduced Requirements of Exogenous Erythropoietin in Patients on Chronic Hemodialysis

Introduction: During the last decades the use of erythropoiesis stimulating agents has significantly diminished the prevalence of anemia in patients receiving chronic hemodialysis. Currently, residing at higher altitudes is associated with higher levels of endogenous erythropoietin. Objective: This study aims to analyze how residing at higher altitudes influences the requirements of exogenous erythropoietin in patients receiving hemodialysis as renal replacement therapy. Methodology: Descriptive observational cross-section, including adult patients from three Ecuadorian centers, receiving chronic hemodialysis, between January and June 2020. Patients were classified into two groups regarding the altitude of residence: those living at low-lying regions (<2000 masl, Santo Domingo de los Tsachilas and Tena) and those living at high altitude (>2000 masl, Quito). Results: We included 580 patients, 45.5% in the high-altitude group and 54.5% at low-lying regions. Median exogenous erythropoietin dose was higher in low-lying regions (22000 international units) versus high altitude (17333.3 international units) (P=0.00003) and the proportion of patients without erythropoietin requirement was higher in high altitude (21.6%), compared to low regions (1.0%) (P<0.01). The multivariate analysis associated residing in low regions (HR 58.9, P<0.01), age (HR 0.98, P=0.03) and Kt/V (HR 38.5, P<0.01) with higher exogenous erythropoietin requirements. Additionally, among patients who required erythropoietin, residing in lower altitudes was linked with a need for exogenous erythropoietin doses exceeding 15000 international units per week (HR 1.92, P=0.001). Conclusion: In Ecuadorian patients receiving hemodialysis, living at high altitude is associated with a reduced requirement of exogenous erythropoietin compared with those patients residing in low-lying regions.

Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis

AbstractUp to 30% of patients with autoimmune hemolytic anemia (AIHA) show inadequate bone marrow (BM) compensatory response with inappropriately low levels of reticulocytes and endogenous erythropoietin. Ineffective BM compensation is associated with more severe anemia, transfusion need, and hospital admission, and treatment with recombinant erythropoietin (rEPO) may be beneficial. Here, we prospectively analyzed the efficacy and safety of rEPO in a single-center cohort of 47 patients with AIHA with inadequate reticulocytosis and endogenous erythropoietin at baseline. Epoetin alpha 40 000 international units per week were administered subcutaneously until hemoglobin (Hb) >11 g/dL and then tapered off. Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months. Consistently, Hb values significantly increased from baseline to each subsequent time point (P<.001) with a median increase of +1.4, +2.4, +3.4, +3.8, and +4.4 g/dL, respectively. Transfusion needs reduced from 30% to <10% at 15 days and thereafter (P < .001). Concomitant medications included prednisone or methylprednisolone (N = 40, stable since >2 weeks from enrollment), mycophenolate mofetil (N = 1, ongoing since >3 months from enrollment), and rituximab (N = 7 patients with cold agglutinin disease from day 8). No association between concomitant medications and response to rEPO was found. Treatment was generally safe without rEPO-related severe adverse events. The comparison with an AIHA population not treated with rEPO showed a significant benefit of rEPO at 15 days and 1 month on response and Hb increase. These data support the use of rEPO as an add on to standard immunosuppression in AIHA with inadequate BM compensation. This trial was registered at www.clinicaltrials.gov as #NCT05931718.

Efficacy and Safety of Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent (ESA)-Naive Patients (Pts) with Transfusion-Dependent (TD) Lower-Risk Myelodysplastic Syndromes (LR-MDS): Full Analysis of the COMMANDS Trial

Introduction: ESAs are an established treatment (tx) for pts with TD LR-MDS and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L; however, eligible pts often do not respond, or the response duration is limited. Luspatercept is approved in the US and EU to treat anemia due to LR-MDS after ESA failure. The preplanned interim analysis of the phase 3 COMMANDS trial (NCT03682536), comparing luspatercept with epoetin alfa in ESA-naive TD pts with anemia due to LR-MDS (with or without ring sideroblasts [RS]) showed for the first time the superiority of another therapy over ESAs in improving red blood cell transfusion independence (RBC-TI) rates (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736[23]00874-7). Here we report the full efficacy and safety analysis of the COMMANDS trial. Methods: Eligible pts were ≥ 18 y of age, had Revised International Prognostic Scoring System-defined LR-MDS with &amp;lt; 5% bone marrow blasts, sEPO &amp;lt; 500 U/L, and were TD (received 2-6 RBC U/8 wk for ≥ 8 wk before randomization). Pts were randomized 1:1 to luspatercept (1.0-1.75 mg/kg) subcutaneously (SC) Q3W, or epoetin alfa (450-1050 IU/kg) SC Q1W for ≥ 24 wk and stratified by baseline RBC transfusion burden (&amp;lt; 4 vs ≥ 4 RBC U/8 wk), RS status (RS+ vs RS−), and sEPO (≤ 200 vs &amp;gt; 200 U/L). The primary endpoint was the achievement of RBC-TI ≥ 12 wk with a concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL (wk 1-24). Key secondary endpoints (wk 1-24) included achievement of RBC-TI ≥ 12 and for 24 wk and hematologic improvement-erythroid (HI-E) ≥ 8 wk. Other endpoints included duration of RBC-TI ≥ 12 wk, progression to acute myeloid leukemia (AML), and safety. Results: As of Mar 31, 2023, 182 pts were randomized to luspatercept and 181 to epoetin alfa, with a median (range) tx duration of 51.3 (3-196) and 37.0 (1-202) wk and median (range) follow-up of 17.2 (1-46) and 16.9 (0-46) months, respectively. The primary endpoint was achieved by110 (60.4%) pts in the luspatercept arm versus 63 (34.8%) in the epoetin alfa arm ( P &amp;lt; 0.0001). Subgroup analysis of the primary endpoint response showed that response rates achieved with luspatercept versus epoetin alfa, respectively, were greater for SF3B1-mutated and non-mutated pts (Table), greater for pts with baseline sEPO ≤ 200 U/L and with baseline sEPO &amp;gt; 200 to &amp;lt; 500 U/L (Table), and greater for RS+ pts (Table). The response rates were comparable between tx arms for RS− pts (Table). RBC-TI ≥ 12 wk was achieved by 124 (68.1%) and 88 (48.6%) pts in the luspatercept and epoetin alfa arms, respectively, RBC-TI for 24 wk by 87 (47.8%) and 56 (30.9%) pts, and HI-E ≥ 8 wk by 135 (74.2%) and 96 (53.0%) pts. The median (95% CI) duration of RBC-TI ≥ 12 wk was longer with luspatercept versus epoetin alfa (128.1 wk [108.3-not estimable (NE)] versus 89.7 wk [5.9-157.3]; HR, 0.534; Figure), and longer for clinically relevant subgroups, including RS+ and RS−. The median duration of tx was longer in the luspatercept arm compared with the epoetin alfa arm (51.3 versus 37.0 wk). Five (2.7%) and 6 (3.3%) pts in the luspatercept and epoetin alfa arms, respectively, progressed to AML. Overall, 178 (97.8%) and 165 (92.2%) pts receiving luspatercept and epoetin alfa reported tx-emergent adverse events (TEAEs) of any grade; 107 (58.8%) and 88 (49.2%) pts reported grade 3/4 TEAEs, respectively. The most common any-grade TEAEs in either arm (≥ 10% of pts) were diarrhea (17.6% luspatercept vs 14.0% epoetin alfa), COVID-19 (14.8% vs 15.6%), asthenia (13.7% vs 16.2%), and anemia (12.1% vs 10.6%). TEAEs of interest were reported by 105 (57.7%) and 81 (45.3%) pts receiving luspatercept and epoetin alfa, respectively, with asthenia including fatigue, malaise, and lethargy (30.8% vs 24.6%), hypertension (15.9% vs 9.5%), malignancies and premalignant disorders (14.3% vs 12.8%), kidney toxicity (8.8% vs 6.7%), and injection site reactions (6.6% vs 2.2%), occurring in &amp;gt; 5% pts. In both tx arms, rates of on-tx deaths (8.2% for luspatercept and 7.2% for epoetin alfa) and post-tx deaths (13.2% and 13.4%) were similar. Conclusions: Results of this full analysis confirm the findings from the interim analysis; RBC-TI duration and erythroid responses achieved with luspatercept are superior compared with epoetin alfa. Luspatercept safety results were consistent with previous MDS studies. These data show that luspatercept could represent a new standard of care for pts with TD LR-MDS.

Nanoengineered injectable hydrogels derived from layered double hydroxides and alginate for sustained release of protein therapeutics in tissue engineering applications

Chronic Kidney Disease (CKD) which involves gradual loss of kidney function is characterized by low levels of a glycoprotein called Erythropoietin (EPO) that leads to red blood cell deficiency and anemia. Recombinant human EPO (rhEPO) injections that are administered intravenously or subcutaneously is the current gold standard for treating CKD. The rhEPO injections have very short half-lives and thus demands frequent administration with a risk of high endogenous EPO levels leading to severe side effects that could prove fatal. To this effect, this work provides a novel approach of using lamellar inorganic solids with a brucite-like structure for controlling the release of protein therapeutics such as rhEPO in injectable hydrogels. The nanoengineered injectable system was formulated by incorporating two-dimensional layered double hydroxide (LDH) clay materials with a high surface area into alginate hydrogels for sustained delivery. The inclusion of LDH in the hydrogel network not only improved the mechanical properties of the hydrogels (5–30 times that of alginate hydrogel) but also exhibited a high binding affinity to proteins without altering their bioactivity and conformation. Furthermore, the nanoengineered injectable hydrogels (INHs) demonstrated quick gelation, injectability, and excellent adhesion properties on human skin. The in vitro release test of EPO from conventional alginate hydrogels (Alg-Gel) showed 86% EPO release within 108 h while INHs showed greater control over the initial burst and released only 24% of EPO in the same incubation time. INH-based ink was successfully used for 3D printing, resulting in scaffolds with good shape fidelity and stability in cell culture media. Controlled release of EPO from INHs facilitated superior angiogenic potential in ovo (chick chorioallantoic membrane) compared to Alg-Gel. When subcutaneously implanted in albino mice, the INHs formed a stable gel in vivo without inducing any adverse effects. The results suggest that the proposed INHs in this study can be utilized as a minimally invasive injectable platform or as 3D printed patches for the delivery of protein therapeutics to facilitate tissue regeneration.

Prognostic impact of elevated erythropoietin levels in patients with severe aortic stenosis receiving trans-catheter aortic valve implantation

BackgroundElevated endogenous erythropoietin (EPO) levels are associated with worse clinical outcomes in patients with heart failure (HF). The clinical implication of endogenous EPO levels in patients undergoing trans-catheter aortic valve implantation (TAVI) beyond other conventional risk factors remains unknown. MethodsConsecutive patients with EPO measurements who underwent TAVI for the treatment of their severe aortic stenosis at our institute between May 2015 and December 2020 were included. The association between the endogenous EPO levels and the primary outcome consisting of all-cause mortality and HF hospitalization was evaluated. ResultsA total of 263 patients (85.1 ± 5.1 years old, 74 men) were included and tertiled according to the baseline EPO levels. The high EPO group had more advanced anemia, renal impairment, and hypoalbuminemia than the other two tertiled groups (p < 0.05 for both). Patients with high EPO had a significantly higher cumulative incidence of the primary outcomes compared to the other two groups (p = 0.002) with an adjusted hazard ratio of 6.0 (95 % confidence interval 1.9–18.1) in its logarithmic value (p < 0.001). ConclusionsElevated baseline EPO levels were independently associated with mortality and morbidity following TAVI. The clinical implication of aggressive intervention on the elevated EPO levels in this cohort remains the next concern.

Practical aspects of the use of erythropoiesis-stimulating agent in patients with hematological malignancy

Anemia is one of the most common symptoms of hematological malignancy and, on the other hand, a common complication of myelosuppressive anticancer therapy. Iron, vitamin B12, folate, biological analogs of human erythropoietin (EPO), and new targeted drugs (lenalidomide, luspatercept, roxadustat, etc.) are used in clinical practice to correct anemic syndrome in cancer patients. All these activators of erythropoiesis are combined into a single group called erythropoiesis-stimulating agents (ESAs). Issues of physiological regulation of erythropoiesis, historical information on the creation of recombinant human erythropoietin (rh-EPO), structural and biological characteristics of this group of drugs are covered in this literature review. In accordance with ESMO guidelines (2018), rh-EPO is indicated for patients receiving myelosuppressive chemotherapy with symptomatic anemia with Hb &lt; 100 g/L and asymptomatic anemia with Hb &lt; 80 g/L. ESAs are not used in patients not receiving chemotherapy, similarly to ASCO/ASH (2019) guidelines. Iron replacement therapy in patients receiving rh-EPO should be used regardless of whether there is an initial iron deficiency or not, since its functional deficiency occurs during treatment. The low-risk MDS is exception, where rh-EPO may be the mainstay of therapy. Low-risk MDS patients with endogenous EPO levels &lt; 500 mIU/mL and a low transfusion load of less than 2 RBCs per month are optimal candidates for rh-EPO therapy. The article is illustrated by clinical observation of a patient with R-IPSS intermediate-risk MDS treated with epoetin alfa. The problems of prevention of thromboembolic complications associated with the use of ESA are also discussed.

Targeting the innate repair receptor axis via erythropoietin or pyroglutamate helix B surface peptide attenuates hemolytic-uremic syndrome in mice.

Hemolytic-uremic syndrome (HUS) can occur as a systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli and is characterized by microangiopathic hemolytic anemia and acute kidney injury. Hitherto, therapy has been limited to organ-supportive strategies. Erythropoietin (EPO) stimulates erythropoiesis and is approved for the treatment of certain forms of anemia, but not for HUS-associated hemolytic anemia. EPO and its non-hematopoietic analog pyroglutamate helix B surface peptide (pHBSP) have been shown to mediate tissue protection via an innate repair receptor (IRR) that is pharmacologically distinct from the erythropoiesis-mediating receptor (EPO-R). Here, we investigated the changes in endogenous EPO levels in patients with HUS and in piglets and mice subjected to preclinical HUS models. We found that endogenous EPO was elevated in plasma of humans, piglets, and mice with HUS, regardless of species and degree of anemia, suggesting that EPO signaling plays a role in HUS pathology. Therefore, we aimed to examine the therapeutic potential of EPO and pHBSP in mice with Stx-induced HUS. Administration of EPO or pHBSP improved 7-day survival and attenuated renal oxidative stress but did not significantly reduce renal dysfunction and injury in the employed model. pHBSP, but not EPO, attenuated renal nitrosative stress and reduced tubular dedifferentiation. In conclusion, targeting the EPO-R/IRR axis reduced mortality and renal oxidative stress in murine HUS without occurrence of thromboembolic complications or other adverse side effects. We therefore suggest that repurposing EPO for the treatment of patients with hemolytic anemia in HUS should be systematically investigated in future clinical trials.

Causes of anemia in patients with gastric cancer during the perioperative period

The OBJECTIVE of the study was to reveal the causes of anemia in patients with gastric cancer in the perioperative period.METHODS AND MATERIALS. The object of the study were 700 patients with gastric cancer who underwent surgical treatment. All patients underwent clinical and biochemical blood test, indicators characterizing iron metabolism in the body (serum iron, ferritin, transferrin), and the level of endogenous erythropoietin during the perioperative period. The comparison group included 20 patients with gastric bleeding of non-neoplastic etiology. Both groups were comparable in age (median was 60 and 62 years old) and hemoglobin level (median Hb 95.3 g/l and 94.5 g/l).RESULTS. Anemia was diagnosed in 15 % of patients (n=105) in the perioperative period. Mild anemia was more often detected (hemoglobin level 95–110 g/l) – in 47.6 % of patients. Moderate anemia (80–94 g/l) was observed in 24.0 % of patients, severe anemia (65–79 g/l) – in 18.1 % of patients, severe (hemoglobin level below 65 g/l) – in 10.3 % of patients. A strong correlation (r=0.89; P&lt;0.05) was observed between the stage at the tumor process and the severity of anemia. At the same time, no connection was found between the macroscopic form of a stomach tumor and the severity of anemia. The analysis of the indicators of iron metabolism allowed to confirm the true iron deficiency in this category of patients, which was characterized by a decrease in the level of serum iron in patients with gastric cancer to (7.8±1.6) μmol/L (from 4.7 to 8.2 μmol/L). Comparative analysis of the level of endogenous erythropoietin in the group of patients with gastric cancer (n=20) and patients with gastrointestinal bleedings of non-neoplastic etiology (n=20) showed significantly lower values with a difference of 27.7 % in the first group of patients ((66.9±28.2) mIU/ml versus (95.6±36.7) mIU/ml; P&lt;0.05), which indicated inadequate production of erythropoietin in patients with gastric cancer.CONCLUSION. The main causes of anemia in patients with gastric cancer in the perioperative period should be considered a true iron deficiency, as well as inadequate production of endogenous erythropoietin.

Association of Endogenous Erythropoietin Levels and Iron Status With Cognitive Functioning in the General Population.

BackgroundEmerging data suggest that erythropoietin (EPO) promotes neural plasticity and that iron homeostasis is needed to maintain normal physiological brain function. Cognitive functioning could therefore be influenced by endogenous EPO levels and disturbances in iron status.ObjectiveTo determine whether endogenous EPO levels and disturbances in iron status are associated with alterations in cognitive functioning in the general population.Materials and MethodsCommunity-dwelling individuals from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a general population-based cohort in Groningen, Netherlands, were surveyed between 2003 and 2006. Additionally, endogenous EPO levels and iron status, consisting of serum iron, transferrin, ferritin, and transferrin saturation were analyzed. Cognitive function was assessed by scores on the Ruff Figural Fluency Test (RFFT), as a reflection of executive function, and the Visual Association Test (VAT), as a reflection of associative memory.ResultsAmong 851 participants (57% males; mean age 60 ± 13 years), higher endogenous EPO levels were independently associated with an improved cognitive function, reflected by RFFT scores (ß = 0.09, P = 0.008). In multivariable backward linear regression analysis, EPO levels were among the most important modifiable determinants of RFFT scores (ß = 0.09, P = 0.002), but not of VAT scores. Of the iron status parameters, only serum ferritin levels were inversely associated with cognitive function, reflected by VAT scores, in multivariable logistic regression analysis (odds ratio, 0.77; 95% confidence interval 0.63–0.95; P = 0.02 for high performance on VAT, i.e., ≥11 points). No association between iron status parameters and RFFT scores was identified.ConclusionThe findings suggest that endogenous EPO levels and serum ferritin levels are associated with specific cognitive functioning tests in the general population. Higher EPO levels are associated with better RFFT scores, implying better executive function. Serum ferritin levels, but not other iron status parameters, were inversely associated with high performance on the VAT score, implying a reduced ability to create new memories and recall recent past. Further research is warranted to unravel underlying mechanisms and possible benefits of therapeutic interventions.

New Approaches to Myelodysplastic Syndrome Treatment.

The treatment of myelodysplastic syndromes (MDS) begins with risk stratification using a validated tool such as the International Prognostic Scoring System (IPSS) or its revised version (IPSS-R). This divides patients into lower- and higher- risk categories. Although treatment objectives in lower-risk MDS (LR-MDS) have traditionally been directed at improving cytopenias (usually anemia) as well as quality of life, recent data supports a potential role for early intervention in delaying transfusion dependency. In addition, careful individualized risk stratification incorporating clinical, cytogenetic, and mutational data might help identify patients at higher-than-expected risk for progression. Given the need for supportive care with red blood cell (RBC) transfusions leading to iron overload, iron chelation should be considered for patients with heavy transfusion requirements at risk for end-organ complications. For patients with LR-MDS and isolated anemia, no high-risk features, and endogenous erythropoietin (EPO) levels below 500 U/L, erythropoiesis-stimulating agents (ESAs) can be attempted to improve anemia. Some LR-MDS patient subgroups may also benefit from specific therapies including luspatercept (MDS with ring sideroblasts), lenalidomide (MDS with deletion 5q), or immunosuppressive therapy (hypocellular MDS). LR-MDS patients failing the above options, or those with multiple cytopenias and/or higher-risk features, can be considered for oral low-dose hypomethylating agent (HMA) therapy. Alternatively, these patients may be enrolled on a clinical trial with promising agents targeting the transforming-growth factor beta (TGF-β) pathway, the hypoxia-inducible factor (HIF) pathway, telomerase activity, inflammatory signaling, or the splicing machinery. In higher-risk MDS (HR-MDS), therapy seeks to modify the natural history of the disease and prolong survival. Eligible patients should be considered for curative allogeneic hematopoietic stem cell transplantation (aHSCT). Despite promising novel combinations, the HMAs azacitidine (AZA) or decitabine (DAC) are still the standard of care for these patients, with intensive chemotherapy-based approaches being a potential option in a small subset of patients. Individuals who fail to respond or progress after HMA experience dismal outcomes and represent a major unmet clinical need. Such patients should be treated as part of a clinical trial if possible. Experimental agents to consider include venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies (directed towards CD47, TIM3, or CD70), interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor. In this review, we extensively discuss the current landscape of experimental therapies for both LR- and HR-MDS.

Treatment of lower-risk myelodysplastic syndrome

Introduction. We present the recommendations for treatment of the lower-risk myelodysplastic syndromes on behalf of the Serbian myelodysplastic syndromes group. Material and Methods. A literature review was conducted using the following bibliographic databases: Google Scholar, MEDLINE and Kobson. The recommendations for treatment of lower-risk myelodysplastic syndromes are based on expert opinion based on review of the literature and contemporary recommendations for treatment of lower risk myelodysplastic syndromes. Recommendations. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk myelodysplastic syndromes, and may be treated successfully with erythropoietic stimulating agents, with or without granulocyte growth factor, provided a careful selection is performed on the basis of Revised International Prognostic Scoring System, endogenous erythropoietin levels, and transfusion independence. In case a patient fails erythropoietic stimulating agents treatment, the available options may include lenalidomide, hypomethylating agents, and a rather large number of experimental agents. Chelation therapy is recommended in patients who have received or are anticipated to receive &gt; 20 red blood cell transfusions and those with serum ferritin levels &gt; 2500 ng/mL. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Severe neutropenia is targeted symptomatically with growth factor supportive care. The immunosuppressive treatments are indicated mainly for pancytopenia, hypoplastic lowerrisk myelodysplastic syndromes. Finally, hematopoietic stem cell transplantation is the curative option for younger, good performance (fit) lower-risk patient with poor risk features, according to European Blood and Marrow Transplantation/European Leukemia Net International expert panel and myelodysplastic syndrome-RIGHT group. Conclusion. Treatment of myelodysplastic syndromes is mainly based on resolution of symptoms due to particular cytopenia(s).

Updated recommendations on the use of ruxolitinib for the treatment of myelofibrosis

ABSTRACT Objectives Myelofibrosis is a rare bone marrow disorder associated with a high symptom burden, poor prognosis, and shortened survival. While allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis, the only approved and reimbursed pharmacotherapy for non-HSCT candidates in Belgium is ruxolitinib. Methods These updated recommendations are based on a consensus reached during two meetings and provide guidance for ruxolitinib administration in myelofibrosis patients considering the particularities of Belgian reimbursement criteria. Results and Discussion In Belgium, ruxolitinib is indicated and reimbursed for transplant-ineligible myelofibrosis patients from intermediate-2- and high-risk groups and from the intermediate-1-risk group with splenomegaly. Our recommendation is to also make ruxolitinib available in the pre-transplant setting for myelofibrosis patients with splenomegaly or heavy symptom burden. Before ruxolitinib initiation, complete blood cell counts are recommended, and the decision on the optimal dosage should be based on platelet count and clinical parameters. In anemic patients, we recommend starting doses of ruxolitinib of 10 mg twice daily for 12 weeks and we propose the use of erythropoiesis-stimulating agents in patients with endogenous erythropoietin levels ≤500 mU/mL. Increased vigilance for opportunistic infections and second primary malignancies is needed in ruxolitinib-treated myelofibrosis patients. Ruxolitinib treatment should be continued as long as there is clinical benefit (reduced splenomegaly or symptoms), and we recommend progressive dose tapering when stopping ruxolitinib. Conclusion Based on new data and clinical experience, the panel of experts discussed ruxolitinib treatment in Belgian myelofibrosis patients with a focus on dose optimization/monitoring, adverse events, and interruption/rechallenge management.

Iron deficiency contributes to resistance to endogenous erythropoietin in anaemic heart failure patients.

Abnormal endogenous erythropoietin (EPO) constitutes an important cause of anaemia in chronic diseases. We analysed the relationships between iron deficiency (ID) and the adequacy of endogenous EPO in anaemic heart failure (HF) patients, and the impact of abnormal EPO on 12-month mortality. We investigated 435 anaemic HF patients (age: 74 ± 10 years; males: 60%; New York Heart Association class I or II: 39%; left ventricular ejection fraction: 43 ± 17%). Patients with EPO higher than expected for a given haemoglobin were considered EPO-resistant whereas those with EPO lower than expected - EPO-deficient. ID was defined as serum ferritin <100 µg/L or 100-299 µg/L with transferrin saturation <20%. EPO-resistant patients (22%) had more advanced HF whereas those with EPO deficiency (57%) were more frequently females and had worse renal function. Lower serum ferritin (indicating depleted body iron stores) was related to higher EPO observed/predicted ratio when adjusted for significant clinical confounders, including C-reactive protein. One year all-cause mortality was 28% in patients with EPO resistance compared to 17% in patients with EPO deficiency and 10% in patients with adequate EPO (log-rank test for the comparison EPO resistance vs. adequate EPO: P=0.02). When adjusted for other prognosticators, there was still a trend towards increased 12-month mortality in patients with higher EPO level. Anaemic HF patients with endogenous EPO deficiency vs. resistance have different clinical and laboratory characteristics. In such patients, ID contributes to EPO resistance independently of inflammation.

Role of Erythropoietin in the Late Anemia of Patients with Chronic Myeloid Leukemia Treated Frontline with Imatinib

Background Late occurrence of moderate/severe anemia in patients with Chronic Myeloid Leukemia (CML) during long-lasting treatment with imatinib has been reported in a sizeable rate and seems to be more common in elderly patients. Treatment of such complication is subjective and the possible role of erythropoietin (EPO) still unclear.Methods To highlight this issue, we revised retrospectively 37 CML patients treated at 10 Institutions in Italy with frontline imatinib for at least 24 months and in stable complete cytogenetic response (CCyR) who developed a late chronic anemia and were treated with EPO. Late chronic anemia was defined as the presence of persistent (> 3 months) and otherwise unexplained (creatinine level < 2 mg/dl, normal iron balance, bilirubin level < 2 mg/dl, folate and Vitamin B12 in the normal range) Hb levels < 11 g/dl which occurred > 6 months from imatinib start. The main clinical features of the patients at diagnosis were as follows: male/female 21/16 (56.8%/43.2%), median age 69.4 years [interquartile range (IQR) 62.7 - 74.8], median Hb 12.2 g/dl (IQR 10.9 - 13.5), median WBC 50.3 x 109/l (IQR 28.7 - 87.2), median PLTS 384 x 109/l (IQR 277 - 645). According to Sokal risk classification, available in 35 patients, 7 (20.0%) were low risk, 24 (68.6%) intermediate risk and 4 (11.4%) high risk.Results Median time from imatinib start to EPO treatment was 44.2 months (IQR 21.6 - 100.2). At baseline of EPO treatment, all patients were in stable CCyR and 31/37 (83.7%) were also in stable MR 3.0. Median Hb value at baseline was 9.9 g/dl (IQR 9.2 - 10.2): four out 37 patients (10.8%) needed packed red cell transfusions before the starting of EPO treatment. Endogenous EPO level at baseline was available in 22 patients, with a median value of 21.5 mU/ml (IQR 13.6 - 35.7). Alpha-EPO (40,000 UI weekly) was employed in 31 cases, beta-EPO (30,000 UI weekly) in 4 cases and darbopoietin (150 mcg/weekly) in 2 patients. On the whole, 29 patients (78.3%) achieved an erythroid response, defined as a stable (> 3 months) increment > 1.5 g/dl of Hb levels, and 8 patients (21.7%) were resistant to treatment: median HB values at different time-points during EPO treatment are reported in the figure 1. Among responding patients, 3 had a relapse of anemia after 8, 24 and 96 months from EPO start, respectively, and stopped EPO, 4 died while in response from CML unrelated causes, 2 stopped EPO while in response: the remaining 20 responding patients are still alive in response and still in treatment with EPO. No EPO-related toxicity was observed. 5-year overall survival from EPO treatment of the entire cohort was 81.0% (95%CI 65.7 - 96.3).Conclusions Results with EPO in the treatment of late chronic anemia which occurs during long-lasting imatinib treatment are encouraging, with a high rate of response and an excellent safety profile: however, larger prospective studies are warranted to define more precisely the role (when to start EPO?, at what dosage?, for how long?) of such an approach in the treatment of this common late complication of prolonged imatinib therapy. [Display omitted] DisclosuresBocchia:Celgene: Other: Travel grant; Novartis: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Galimberti:Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Breccia:Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Pane:Novartis: Honoraria, Speakers Bureau.

Refining Hellström-Lindberg Score: Which Patients Could Benefit from Standard Dose EPO?

BackgroundHellström-Lindberg score (HLS-1997) is a useful tool to predict the probability of response to erythropoietin (EPO) treatment in anemic MDS patients. HLS response criteria was not assessed according to the IWG criteria published by Cheson et al. in 2006. To date, international guidelines suggest a front-line therapy with high doses of EPO (80000 U/week) in MDS anemic patients with Hb <10 g/dL and endogenous EPO levels <500 mU/mL. In our previous report, we validated the HLS in a single center cohort according to the IWG criteria of response (Molteni et al. Int J Hematol 2013). Of note, observing the response rate of the “good” responders group (score 3 or 4), a significant difference between patients with a score 3 vs 4 was detected (p= 0.004), identifying two new categories (“good” and “very good”) with different probability of response. The high likelihood of responding with patients with a “very good” score was such as to suggest that even standard therapy doses (40000 U/week) would be effective for this group.AimTo validate our previous report on a new cohort of MDS patients treated with erythropoietin.Patients and methodsHellström-Lindberg score variables considered were: erythropoietin serum levels in pre-treatment (<100, 100-500 or >500 mU/mL) and RBC transfusion requirements (≥2 or <2 RBC per month). We decided not to consider the patients with “poor” HLS (EPO >500 mU/mL and ≥2 RBC per month) on the basis of our previous report and on the evidence of the very modest efficacy of EPO in these cases. Therefore, we applied a “revised HLS” (figure 1), that distinguishes three prognostic groups: “very good” response (score 4), “good” (score 3) and “intermediate” response (score -1 to +1). With this premise, we retrospectively evaluated 57 “low” or “intermediate-1” IPSS risk MDS patients treated with a standard dose of EPO between 2005 and 2017. According to our score: 15 of them were “intermediate”, 12 “good” and 30 “very good”. Response to EPO therapy was based on the revised IWG criteria (2006). Statistical analysis was conducted using Fisher's exact test and ordinal logistic regression followed by Wald's test. Then the quality of the response with the different scores was compared using the Bonferrion - Adjusted for multiple comparison test.ResultsAmong the 57 patients 14 were transfusion dependent before treatment. Initial EPO dose was 40000 U/week. Dose was modulated in relationship to response from a maximum of 40000 U every 5 days to a minimum of 40000 U every two weeks. Response rate observed was 76% (64% in the previous series described) in “good” + “very good” group and 33% (33% in the previous series) in “intermediate” group. Scoring “very good” patients had a higher response rate (80%) than scoring good patients (67%). In the previous experience the results were 79% and 33% respectively. The difference in response rate between “very good” and “intermediate” scoring was statistically significant (p=0.009). No difference was instead noticed between “good” and “very good” scoring (p=0.187) and between “good” and “intermediate” scoring (p=0.384). Furthermore, scoring “very good” patients showed a 700% (it was 667% in the previous report) increase in odds of response compared to scoring “intermediate” patients (p=0.004), meanwhile a not significant difference in odds of response between scoring “good” and scoring “intermediate” was found, just as in the previous described series.Conclusion:These data confirm our previous report which describes a very high probability of responding to standard EPO dose (40000 U/week) in the “very good” group and suggests a “standard” starting dose in these patients. “High” initial doses (80000 U/week) have to be recommended for the “intermediate” group. Considering the “good” group, the difference between the two analysis suggests that it would be appropriate to expand the sample in order to assess whether these patients may benefit from high doses of therapy or may also be candidate, in the first instance, for the standard doses. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

MO560IS SERUM ERYTHROPOIETIN CORRELATED WITH IRON METABOLISM AND INFLAMMATION IN NON-DIALYSIS CHRONIC KIDNEY DISEASE PATIENTS WITH ANEMIA?

Abstract Background and Aims Both the relative erythropoietin (Epo) deficiency and its relationship with serum hemoglobin (Hb) are widely postulated in chronic kidney disease (CKD), but the influence of chronic inflammation and iron status on serum Epo levels is still a matter of debate, with yet divergent reported results. Therefore, we aimed to assess the determinants of serum Epo in non-dialysis CKD patients. Method Fifty-two adults with CKD and anemia (defined as Hb &amp;lt;12g/dL), in stable clinical condition, never treated with erythropoiesis-stimulating agents (ESA) entered this cross-sectional, single-center study. Diabetes mellitus, active infectious and inflammatory diseases, malignancy, anemia of other causes than CKD, current immunosuppressive therapy, iron supplementation and blood transfusions in the previous six months were exclusion criteria. The subjects were mostly men (56%), elderly (two thirds over 60 years), with advanced CKD [71% in CKD stages G4-G5, median estimated glomerular filtration rate – eGFR 14.5 (95%CI 16 to 25) mL/min], moderate anemia [Hb 9.8 (95%CI 9.2 to 9.9) g/dL], and mild to moderate inflammation [C-reactive protein 6 (95%CI 9.2 to 18.4) mg/L]. Serum Epo was assessed by ELISA (Abcam® 119522). Complete blood count, reticulocyte index, peripheral blood smear, bone marrow aspiration (Perls’ stain), serum ferritin, and transferrin saturation, were used to investigate anemia and iron metabolism. Parameters of kidney disease (CKD etiology, eGFR and proteinuria), demographic data (age, gender), C-reactive protein, serum albumin, and serum hepcidin-25 (Hep-25, Bachem® commercial ELISA kit) were also analyzed. Results The median serum Epo of the whole cohort was 4.8 (95%CI 5.1 to 9.9) mU/mL. According to median Epo, subjects were clustered in Group 1 (below median, G1) and Group 2 (above median, G2). Estimated GFR and serum Hep-25 were lower in G1 than in G2 [10.6 (95%CI 9.7 to 20.8) vs. 26 (95%CI 19.1 to 32.8) mL/min, p=0.004, and 62.6 (95%CI 51.0 to 85.1) vs. 95.4 (95%CI 77.0 to 108.5) ng/mL, p=0.03, respectively]. All the other investigated parameters were similar in the two groups. In bivariate analysis (Spearman rank correlation), serum Epo was positively associated only with eGFR (rs=0.40, p=0.003). Marginal associations with the percentage of bone marrow sideroblasts, as marker of the iron available for erythropoiesis (rs=0.25, p=0.08), erythrocyte mean corpuscular hemoglobin concentration (rs=−0.26, p=0.07), and reticulocyte index (rs=0.24, p=0.09) were observed. Conversely, serum Epo was not related to hemoglobin, indices of iron stores (e.g. serum ferritin and iron content in bone marrow macrophages), inflammation and nutritional status (e.g. C-reactive protein and serum albumin). In a model of multiple linear regression which explained 14% of serum Epo variation, eGFR was the only determinant: Beta 0.14 (95%CI 0.05 to 0.23), p=0.004. Also, a binary logistic multiple regression model predicting serum Epo lower or higher than the median retained the eGFR as an independent predictor, while serum hepcidin showed only borderline significance: Conclusion Kidney function is the main determinant of endogenous erythropoietin level in moderately anemic patients with advanced CKD, ESA or iron naive, while serum hepcidin-25 seems to exert a limited influence.

FC 074POOLED EFFICACY AND CARDIOVASCULAR SAFETY RESULTS OF 3 PLACEBO-CONTROLLED AND 1 DARBEPOETIN ALFA-CONTROLLED STUDIES OF ROXADUSTAT FOR TREATMENT OF ANAEMIA IN PATIENTS WITH NON-DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE

Abstract Background and Aims Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, induces a coordinated erythropoietic response by increasing endogenous erythropoietin levels and improving iron metabolism. This analysis was performed to examine the consistency of efficacy and cardiovascular safety results for roxadustat vs placebo or darbepoetin alfa (DA) in patients with non-dialysis-dependent (NDD) chronic kidney disease (CKD). Method Results from three phase 3, double-blind studies comparing roxadustat with placebo (ALPS, ANDES, OLYMPUS) with anaemia and stage 3-5 NDD CKD were pooled and assessed for consistency with results of an open-label study comparing roxadustat with DA (DOLOMITES) in predominantly European patients. The primary efficacy endpoint was haemoglobin (Hb) response, defined as (a) Hb ≥11.0 g/dL that changed from baseline (CFB) by ≥1.0 g/dL in patients with Hb &amp;gt;8.0 g/dL or (b) Hb CFB by ≥2.0 g/dL in patients with Hb ≤8.0 g/dL irrespective of and without rescue therapy for placebo-controlled (assessed for superiority) and DA-controlled (assessed for non-inferiority) studies, respectively. The secondary efficacy endpoint was Hb CFB to Weeks 28-36 using least squares mean difference (LSMD) without rescue therapy. The key safety endpoints of major adverse cardiovascular event (MACE, comprising death, myocardial infarction, and stroke) and MACE+ (MACE plus hospitalization with heart failure or unstable angina) were adjudicated in all studies. MACE and MACE+ for roxadustat vs placebo or DA were compared in the intention-to-treat sample using a Cox proportional hazards model. Results In total, 4886 patients were randomised in placebo-controlled (2386 roxadustat, 1884 placebo) and DA-controlled (323 roxadustat, 293 DA) studies. Baseline characteristics of patients treated with roxadustat vs placebo and roxadustat vs DA were similar: baseline Hb (placebo, 9.10 vs 9.10 g/dL; DA, 9.55 vs 9.55 g/dL) and iron repletion (placebo, 59.9% vs 59.8%; DA, 56.3% vs 51.9%). Roxadustat was superior to placebo for Hb response without rescue therapy (80.2% vs 8.7%; difference of proportion [DOP], 71.50%; 95% CI, 69.40-73.51) and noninferior to DA (89.5% vs 78.0%; DOP, 11.51%; 95% CI, 5.66-17.36). Mean Hb CFB (Weeks 28-36) achieved superiority in pooled analysis vs placebo (LS mean, 1.91 vs 0.14; LSMD, 1.77; 95% CI, 1.69-1.84; P&amp;lt;0.0001) and noninferiority vs DA (LS mean, 1.85 vs 1.84; LSMD, 0.02; 95% CI, -0.13 to 0.16). Risk for MACE or MACE+ was similar for roxadustat vs placebo (MACE, 480 [20.1%] vs 350 [18.6%]; HR, 1.10; 95% CI, 0.96-1.27; MACE+, 578 [24.2%] vs 432 [22.9%]; HR, 1.07; 95% CI, 0.94-1.21) and vs DA (MACE, 38 [11.8%] vs 41 [14.0%]; HR, 0.81; 95% CI, 0.52-1.25; MACE+, 54 [16.7%] vs 43 [18.1%]; HR, 0.90; 95% CI, 0.61-1.32). Conclusion Roxadustat corrected Hb more effectively than placebo and comparably to DA in patients with anaemia and stage 3-5 NDD CKD. Cardiovascular safety was comparable between roxadustat and DA and placebo.

Plasma erythropoietin level and heart failure in patients undergoing peritoneal dialysis: a cross-sectional study

BackgroundRenal anemia is the important complication in patients undergoing peritoneal dialysis (PD), and heart failure (HF) is the important complication in patients on dialysis. Decreasing endogenous erythropoietin (EPO) in patients with chronic kidney disease is a major cause of renal anemia. On the other hand, high levels of EPO have been associated with the prognosis of patients with chronic HF. The association between plasma EPO and HF in patients on PD remains unclear. This study was designed to test our hypothesis that the plasma EPO level in patients on PD was associated with the markers of HF.MethodsWe investigated 39 patients undergoing PD at our hospital. We measured plasma EPO before erythropoiesis-stimulating agent (ESA) administration at the regular outpatient visits and then at 2 weeks after the final dose of ESA was administered and investigated the clinical factors. We estimated the correlations between the plasma EPO and the other parameters, and constructed univariate and multivariate logistic regression models for the risk for HF to estimate the effectiveness of plasma EPO and other factors on HF treatment in patients undergoing PD.ResultsThe plasma EPO concentration was positively correlated with the ESA dose and negatively correlated with serum ferrum, transferrin saturation, and body mass index and showed no correlation with other factors, such as the New York Heart Association (NYHA) classification and ferritin level. In univariate analysis, the factors significantly associated with HF risk were N-terminal pro-brain natriuretic peptide (NT-pro BNP), cardiothoracic ratio (CTR), serum creatinine (Cr), serum beta 2 microglobulin, dialysate dose, left ventricular mass index, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and weekly Kt/V. We performed a multivariate analysis with NT-pro BNP, Cr, and CTR, and all three factors were significant in the analysis.ConclusionThe plasma EPO level in patients undergoing PD was positively correlated with the monthly ESA dose and was not significant as a marker of HF, as judged with the NYHA classification. Therefore, the plasma EPO level may not be a useful marker for HF in patients undergoing PD.

Оценка эффективности препарата Гамавит при коррекции ренальной анемии у кошек с ХБП: контролируемое рандомизированное исследование

Renal anemia is one of the most common complications of chronic kidney disease (CKD) in cats, which significantly reduces their life quality. Most often, the mechanism of renal anemia development is associated with insufficiency of endogenous erythropoietin (EPO), or with a reduction in the life of red blood cells caused by uremic intoxication. Since anemia increases the severity of renal hypertension and other CKD symptoms, the search for effective drugs that can stimulate erythropoiesis in CKD and do not have nephrotoxic properties is particularly relevant. The aim of the work was to study the effectiveness of Gamavit in the treatment regimen for cats with CKD compared with the standard treatment protocol. Active ingredients of Gamavit are sodium nucleinate and denaturated placenta extract. The study included 20 cats of different breeds aged from 5 to 16 years with CKD stage III-IV according to the IRIS classification, accompanied by anemia and a decrease in hematocrit in the range from 25 to 16%. Patients were randomly divided into 2 equal groups - control (n=10) and experimental (n=10) using the block randomization method. In the control group a standard nephroprotective therapy regimen was used. In the experimental group Gamavit was added to the standard regimen. Gamavit was administered at a dose of 0.5 ml/kg 1 time per day, at the same time, during 14 consecutive days (7 days i/v and 7 days s/c). The conditions for feeding and keeping animals of the experimental and control groups were identical. For feeding, we used a standardized serial diet ― Purina CatChow Adult with chicken/turkey/salmon. Access to drinking water ― ad libitum. The initial number of red blood cells, as well as the hematocrit index and hemoglobin level in the experimental and control groups were at the lower limit of the norm or below the reference values. During the study, in the experimental group of the patients, these indicators returned to normal after 2 weeks, while in the control group there were no significant changes. The statistically significant difference between the experimental and control groups remained until the end of the observation (p=0.001). Levels of creatinine and urea in the blood serum of the patients of both groups consistently high throughout the study, but in the experimental group a significant decrease in these indicators was found. The initial level of EPO in both groups was significantly lower than in healthy cats. During the experiment, it was not possible to reach the lower limit of the normal value, which allows us to conclude that the stimulation of erythropoiesis indicators in the experimental group, observed under the influence of Gamavit, is not associated with the stimulation of endogenous EPO production. Thus, the study revealed that Gamavit stimulates erythropoiesis in cats with CKD stage III-IV, significantly increasing the number of red blood cells, and the levels of hematocrit and hemoglobin. This effect, combined with a decrease in uremic intoxication values (creatinine and urea levels), lead to an improvement in the general condition of patients and regression in a number of important clinical manifestations. Since no nephrotoxic effects and undesirable interactions with drugs of standard nephroprotective therapy were detected in the process of this study, Gamavit can be recommended for widespread use in cats as one of the pathogenetic, symptomatic, and therapeutic and prophylactic drugs in the complex therapy of CKD at the preclinical and clinical stages of the disease.

The Commands Trial: A Phase 3 Study of the Efficacy and Safety of Luspatercept Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low-, Low-, or Intermediate-Risk MDS in Erythropoiesis Stimulating Agent-Naive Patients Who Require RBC Transfusions

The Commands Trial: A Phase 3 Study of the Efficacy and Safety of Luspatercept Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low-, Low-, or Intermediate-Risk MDS in Erythropoiesis Stimulating Agent-Naive Patients Who Require RBC Transfusions