Erythropoiesis-stimulating Agents Responsiveness Research Articles

A Systematic Literature Review of Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes.

Erythropoiesis-stimulating agents (ESAs) are the first-line treatment option for anemia in patients with lower-risk myelodysplastic syndromes (LR-MDS). A systematic literature review was conducted to identify evidence of the association between prognostic factors and ESA response/failure in LR-MDS. MEDLINE, Embase, and relevant conferences were searched systematically for studies assessing the association between prognostic factors and ESA response/failure in adult patients. Of 1566 citations identified, 38 were included. Patient risk status in studies published from 2000 onwards was commonly assessed using the International Prognostic Scoring System (IPSS) or revised IPSS. ESA response was generally assessed using the International Working Group MDS criteria. Among the included studies, statistically significant relationships were found, in both univariate and multivariate analyses, between ESA response and the following prognostic factors: higher hemoglobin levels, lower serum erythropoietin levels, and transfusion independence. Furthermore, other prognostic factors such as age, bone marrow blasts, serum ferritin level, IPSS risk status, and karyotype status did not demonstrate statistically significant relationships with ESA response. This systematic literature review has confirmed prognostic factors of ESA response/failure. Guidance to correctly identify patients with these characteristics could be helpful for clinicians to provide optimal treatment.

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

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

Outcomes and effect of somatic mutations after erythropoiesis stimulating agents in patients with lower-risk myelodysplastic syndromes.

Erythropoiesis stimulating agents (ESAs) are the first-line therapy in patients with lower-risk myelodysplastic syndromes (LR-MDS). Some predictive factors for ESAs response have been identified. Type and number of somatic mutations have been associated with prognosis and response to therapies in MDS patients. The objective was to evaluate the outcomes after ESAs in patients with LR-MDS and to address the potential predictive value of somatic mutations in ESAs-treated patients. Multi-center retrospective study of a cohort of 722 patients with LR-MDS included in the SPRESAS (Spanish Registry of Erythropoietic Stimulating Agents Study) study. Retrospective analysis of 65 patients with next generation sequencing (NGS) data from diagnosis. ESAs' efficacy and safety were evaluated in patients receiving ESAs and best supportive care (BSC). To assess the potential prognostic value of somatic mutations in erythroid response (ER) rate and outcome, NGS was performed in responders and non-responders. ER rate for ESAs-treated patients was 65%. Serum erythropoietin (EPO) level <200 U/l was the only variable significantly associated with a higher ER rate (odds ratio, 2.45; p = 0.036). Median overall survival (OS) in patients treated with ESAs was 6.7 versus 3.1 years in patients receiving BSC (p < 0.001). From 65 patients with NGS data, 57 (87.7%) have at least one mutation. We observed a trend to a higher frequency of ER among patients with a lower number of mutated genes (40.4% in <3 mutated genes versus 22.2% in ⩾3; p = 0.170). The presence of ⩾3 mutated genes was also significantly associated with worse OS (hazard ratio, 2.8; p = 0.015), even in responders. A higher cumulative incidence of acute myeloid leukemia progression at 5 years was also observed in patients with ⩾3 mutated genes versus <3 (33.3% and 10.7%, respectively; p < 0.001). This large study confirms the beneficial effect of ESAs and the adverse effect of somatic mutations in patients with LR-MDS.

Impact of Mutational Burden and IPSS-M on Response to ESAs in Lower Risk Myelodysplastic Neoplasms

INTRODUCTION Lower risk myelodysplastic neoplasms (LR-MDS), as defined by IPSS-R, are frequently presenting with anemia which is primarily treated with erythropoiesis stimulating agents (ESAs). However, response rates are suboptimal due to primary resistance or subsequent loss of response, leading to transfusion dependency and poor quality of life. In 2022 a new prognostic system has been developed considering number and type of somatic mutations in MDS (IPSS-M), showing a stronger prognostic power in MDS. AIMS We aimed to assess whether IPSS-M risk score could predict ESA response in IPSS-R LR-MDS patients. METHODS In this multicentric European study we evaluated baseline IPSS-M score in 397 LR-MDS cases from 14 different centers (Italy, Germany, France and Spain) and correlated with ESA response assessed with IWG criteria. Mutational data were obtained by different next generation sequencing (NGS) panels targeting genes recurrently mutated in myeloid neoplasia and necessary to calculate IPSS-M. RESULTS Median age of patients was 74 years with male preponderance (54.5%). Serum EPO levels (sEPO) were available in 277/397 cases (mean 157U/L, &amp;lt;200 U/L in 80% of the cases). When transfusion history (TH) was known (252/397), 44.6% of cases were transfusion dependent (TD). The majority of the cases received erythropoietin-α and darbepoetin-α with response rate of 52.6% (HI-E) according to IWG criteria and a median duration of response of 30 months (data from 165 responders with follow up information). We observed that IPSS-M score, but not the number of mutations, was significantly lower in ESA responders compared to non-responders (median -1,08 vs -0,63 respectively , p&amp;lt;0.0001). The very low (VL) IPSS-M risk group was enriched in ESA responders (74 vs 26% p=0.036), while groups from moderate low (ML) to very high (VH) were more enriched with non-responders (37.5 vs 62% p=0.001; 45.4 vs 54.6% p=0.045; 29.6 vs 70,4% p=0.0017; 25 vs 75% p=0.021 respectively, Fig.1). In cases with known TH (n=252), non-TD (NTD) ESA responders had lower IPSS-M scores (mean -1,17) compared to i) NTD ESA non-responders (mean -0,61 , p&amp;lt;0.0001), ii) TD ESA responders (mean -0,93, p=0,025) and iii) TD ESA non-responders (mean -0,54, p&amp;lt;0.0001). As observed in other settings, 17% of the cases (n=67) were re-stratified to higher risk IPSS-M categories (8%, 13,4% and 44,3% of IPSS-R very low, low and intermediate risk respectively). Among upstaged cases, most were ESA non-responders especially in the moderate high (MH, 67%), high (H, 61%) and very high-risk (VH, 100%) groups. Only 4% of cases (n=17) were down-staged, all from IPSS-R intermediate risk group, and showed response rates similar to IPSS-R intermediate cases who remained ML or MH. Finally, IPSS-M score, sEPO and TD correlated with response in multivariate logistic regression analysis ( p=0.005, p=0.004 and p=0.014 respectively), but only IPSS-M score and TD were predictive (OR 0.51 and 0.34 respectively). Based on this model, we designed a ROC curve (AUC 0.79) where a cut-off of 0.46 showed a sensitivity of 0.9 and specificity of 0.67 in discriminating responders from non-responders (Fig.2). CONCLUSIONS To our knowledge, this is the first report correlating IPSS-M with ESA response in a large number of LR-MDS cases. IPSS-M scores exhibited predictive power, with lower values in ESA responders compared to non-responders and in NTD compared to TD cases. We also observed that higher IPSS-M categories were inversely correlated with ESA response. A fraction of cases with scarce ESA response was upstaged to IPSS-M higher risk groups. The number of mutations did not correlate with ESA response, while IPSS-M score, which considers the prognostic weight of specific mutations, showed predictive significance. In the multivariate analysis IPSS-M score and TD were strong predictors of ESA response, irrespective of baseline sEPO, potentially defining at diagnosis LR-MDS for whom novel agents like luspatercept could be considered as first line therapeutic option.

Impact of Genomic Landscape and Mutational Burden on Primary Endpoint Responses in the COMMANDS Study

Background: Myelodysplastic syndromes (MDS)-related anemia leads to significant morbidity, due to impaired oxygen transport and red blood cell transfusion (RBCT)-related iron overload. Erythropoiesis-stimulating agents (ESAs) are used to treat anemia and decrease transfusion burden and are effective in ~ 35% of patients (pts) with lower-risk (LR)-MDS. Luspatercept is approved for pts with LR-MDS refractory/intolerant to ESAs who need regular RBCTs. Primary resistance to ESAs is frequent, and ~ 70% of responders relapse in &amp;lt; 2 years. Baseline (BL) erythropoietin level ≤ 200 U/L and ≤ 2 somatic mutations are prognostic factors for better ESA response. An association of driver gene mutations with deteriorating clinical outcomes is well established in LR-MDS (Papaemmanuil E, et al. Blood 2013;122:3616-3627; Bersanelli M, et al. J Clin Oncol 2021;39:1223-1233; Nazha A, et al. J Clin Oncol 2021;39:3737-3746). The Molecular International Prognostic Scoring System (IPSS-M; Bernard E, et al. NEJM Evidence 2022;1(7):EVIDoa2200008) was developed to improve upon the shortcomings of the Revised IPSS (IPSS-R) and restratified ~ 46% of pts by adding genomic profiling to existing hematologic and cytogenetic parameters. Pts with LR-MDS typically harbor a median of 2-3 driver mutations in genes involved in MDS pathogenesis. Methods: Individual pt bone marrow samples were prepared for sequencing using the Illumina ® DNA prep with enrichment and the xGen™ hybridization capture of DNA libraries. Exon coverage was ≥ 400X for 3% sensitivity. Sequencing libraries were run on the NovaSeq6000 (Illumina ®) system and statistical analyses were conducted using R. A targeted panel of 82 genes was used. Results: At BL, 322/363 pts enrolled in the COMMANDS trial had somatic mutations in ≥ 1 gene; 11 pts did not have mutation data. Most mutations had a variant allele frequency of 3%-50%. In the intent-to-treat (ITT) population, the luspatercept arm did not show any significant differences in BL mutational burden (MB, defined as the number of gene mutations from the myeloid gene panel) between responders (R) and non-responders (NR). Interestingly, R in the ESA arm trended ( P = 0.065) towards lower MB compared with NR. Subgroup analysis revealed that ring sideroblast (RS)− pts in the ESA arm had lower MB at BL (median 1 gene mutation) compared with RS+ pts (2 gene mutations; P = 0.0004). However, no significant difference was observed in the luspatercept arm. In the ITT population (and the RS+ subgroup), compared with ESAs, luspatercept showed robust responses (Figure A) in pts with 1 (63% vs 40%; Fisher's P = 0.040), 2 (70% vs 27%; Fisher's P &amp;lt; 0.001), and 3 (72% vs 40%; Fisher's P = 0.018) gene mutations. However, in the RS− subgroup, luspatercept and ESAs had similar response rates independent of MB. Interestingly, more RS− pts in the luspatercept arm had ≥ 4 gene mutations (12/47 pts [26%]) versus the ESA arm (only 3 pts [6.4%]). Furthermore, these ≥ 4 mutations were in genes associated with shorter leukemia-free survival, overall survival, and progression-free survival. Of the RS− pts in the luspatercept arm, 9/12 were NR, compared to 2/3 in the ESA arm. Luspatercept showed superior clinical benefit in pts with difficult-to-treat mutations (such as ASXL1, TET2 DNMT3A ZRSR2) and favorability in pts with mutations in SRSF2 EZH2, TP53, DTA.SF3B1.n and IDH2. Primary endpoint analysis by IPSS-M (Figure B) also showed superior clinical benefit of luspatercept across risk groups compared with ESAs: Low (75% vs 38%); Moderate low (61% vs 38%); Moderate high (44% vs 21%); and High (36% vs 24%). Conclusion: In pts in the COMMANDS trial,BL MB impacted response to ESAs but not to luspatercept. In both ITT and RS+ pts, luspatercept showed either superior or comparable clinical benefit in pts with LR-MDS with various BL MB. Interestingly, both luspatercept and ESAs had similar clinical benefit across various MB in the RS− subgroup. However, lower MB favored higher responses to ESAs in the RS− subgroup, and higher MB in genes associated with poor prognosis significantly impacted response rates in the luspatercept arm. Despite the presence of these imbalances in BL MB, RS− pts had similar response rates to luspatercept as to ESAs. Pts with LR-MDS with difficult-to-treat mutations also showed superior or favorable clinical benefit with luspatercept. Finally, luspatercept showed superior clinical benefit to ESAs in pts with LR-MDS across all IPSS-M risk groups.

The Associations between Erythropoietic Response with Inflammation Markers and Perfluorinated Chemicals in Hemodialysis Patients.

Erythropoiesis-stimulating agents (ESA) are used to treat anemia in hemodialysis (HD) patients. We investigated the role of inflammation and accumulation of environmental toxins (perfluorinated chemicals (PFCs), such as perfluorooctanoic acid and perfluorooctane sulfonate) in the erythropoietic response of HD patients who receive a fixed monthly continuous erythropoietin receptor activator (CERA) dosage. Forty-five patients underwent three successive phases of ESA treatment for two months each (phase one: 100 µg CERA once monthly; phase two: 50 µg CERA twice monthly; phase three: 100 µg CERA once monthly). Patient data were collected to determine the association of various factors with erythropoietic response (change in hematocrit). Liquid chromatography-tandem mass spectrometry was used to analyze perfluorinated chemicals. Twenty-eight patients exhibited a poor erythropoietic response that was significantly associated with: age > 80 years, initial hematocrit > 36%, glucose > 200 mg/dL, alanine aminotransferase > 21 U/L, c-reactive protein > 1 mg/dL, interleukin-6 > 10 ng/mL, lactate dehydrogenase ≤ 190 U/L, and chloride ≤ 93 mEq/L. There was also a borderline significant association between inflammation and PFCs, although PFCs failed to show any impact on ESA response. Age, glucose, chloride, liver function, and inflammation may be associated with cost-effective fixed CERA dosage administered at an increased frequency.

Mechanisms of hemoglobin cycling in anemia patients treated with erythropoiesis-stimulating agents.

Patients with renal anemia are frequently treated with erythropoiesis-stimulating agents (ESAs), which are dynamically dosed in order to stabilize blood hemoglobin levels within a specified target range. During typical ESA treatments, a fraction of patients experience hemoglobin 'cycling' periods during which hemoglobin levels periodically over- and undershoot the target range. Here we report a specific mechanism of hemoglobin cycling, whereby cycles emerge from the patient's delayed physiological response to ESAs and concurrent ESA dose adjustments. We introduce a minimal theoretical model that can explain dynamic hallmarks of observed hemoglobin cycling events in clinical time series and elucidates how physiological factors (such as red blood cell lifespan and ESA responsiveness) and treatment-related factors (such as dosing schemes) affect cycling. These results show that in general, hemoglobin cycling cannot be attributed to patient physiology or ESA treatment alone but emerges through an interplay of both, with consequences for the design of ESA treatment strategies.

Not baseline but time-dependent erythropoiesis-stimulating agent responsiveness predicts cardiovascular disease in hemodialysis patients receiving epoetin beta pegol: A multicenter prospective PARAMOUNT-HD Study

BackgroundResponsiveness to erythropoiesis-stimulating agents (ESAs) has been reported to be associated with increased cardiovascular disease (CVD) and mortality in patients undergoing hemodialysis (HD). However, the association between hyporesponsiveness to the long-acting ESA, epoetin beta pegol (CERA), and CVD remains unknown. MethodsThis multicenter prospective study included 4034 patients undergoing maintenance HD. After shifting from prior ESA to CERA, we studied the association between erythropoietin resistance index (ERI) at six months and outcomes, including cardiac events, major adverse cardiovascular events (MACE), and all-cause mortality, using Cox proportional hazards models (Landmark analyses) and marginal structural models to adjust for time-dependent confounding factors, including iron-containing medications and hemodiafiltration (HDF). ResultsThe median dialysis vintage and the observational period were 5.0 years and 22.1 months, respectively. The landmark analyses revealed that the highest tertile of baseline ERI (T3) was associated with a significantly higher all-cause mortality than the lowest tertile (T1) (hazard ratio [HR]: 1.48, 95% CI: 1.03–2.13). Furthermore, marginal structural models revealed that time-dependent ERI T3 was significantly associated with increased cardiac events (HR: 1.59, 95% CI: 1.14–2.23), MACE (HR: 1.60, 95% CI: 1.19–2.15), all-cause mortality (HR: 1.97, 95% CI: 1.40–2.77), and heart failure (HF) (HR: 2.05, 95% CI: 1.23–3.40) compared to T1. A linear mixed effects model showed that iron-containing medications and HDF are negatively associated with time-dependent ERI. ConclusionsBaseline ERI at six months predicted only all-cause mortality; however, time-dependent ERI was a predictor of cardiac events, all-cause mortality, MACE, and HF. The widespread use of iron-containing medications and HDF would ameliorate ESA hyporesponsiveness.

Responsiveness to an erythropoiesis-stimulating agent is correlated with body composition in patients undergoing chronic hemodialysis.

Resistance to erythropoiesis-stimulating agents (ESA) is associated with adverse outcomes in patients undergoing chronic hemodialysis. However, the impact of body composition on ESA response remains uncertain. This study retrospectively investigated whether there is an association between the ESA resistance index (ERI) and body composition in patients undergoing chronic hemodialysis. Multifrequency bioelectrical impedance analysis was used to measure body composition every six months. The ERI was calculated by dividing the weekly body weight-adjusted erythropoietin dose by the hemoglobin concentration. The ERI values were recorded every three months. A total of 123 patients were followed up for 24 (interquartile range 5, 75) months. The ERI was negatively correlated with body mass index, arm circumference, arm muscle circumference, body fat percentage, and visceral fat area (P = 0.057, 0.001, 0.017, 0.063, and 0.041, respectively). Patients with a higher mean ERI during the study period had an increased risk of all-cause mortality, cardiovascular events, and infection requiring hospitalization than those with a lower mean ERI (P = 0.027, 0.021, and 0.037, respectively). We also evaluated the association between the slope of body composition parameters and the ERI trend over time and found that the ERI increased over time in patients who had an increased ratio of extracellular water to total body water (P = 0.002) as well as decreased arm circumference, arm muscle circumference, visceral fat area, and phase angle (P = 0.001, P < 0.001, P = 0.036, and 0.002). ESA responsiveness appears to be associated with body composition in patients undergoing chronic hemodialysis. Therefore, measures improving body composition, such as nutrition and exercise, may have a favorable effect on the response to ESA.

Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes: Systematic Literature Review

Introduction: Patients with lower-risk myelodysplastic syndromes (LR-MDS) commonly experience chronic progressive anemia, which is initially treated with erythropoiesis-stimulating agents (ESAs). However, many patients do not respond to ESAs, thereby putting them at risk of earlier disease progression, which can require invasive and/or costly treatments, including blood transfusions or hypomethylating agents. A systematic literature review (SLR) was conducted to assess quantitative associations between prognostic factors and response to treatment with ESAs in patients with LR-MDS. Methods: An electronic search for relevant literature was conducted on February 25, 2022, across Embase and MEDLINE via OvidSP. Also, proceedings from the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, Academy of Managed Care Pharmacy, and European Society for Medical Oncology meetings from 2019 to 2022 were searched via OvidSP or manually if not indexed in databases. Articles written in languages other than English were excluded. Adult patients with LR-MDS were included in the analysis. Studies reporting measures of effect between prognostic factors and ESA response were included, as were studies reporting quantitative data pertaining to differences in patient characteristics between ESA responders and non-responders. Studies reporting both univariate and multivariate analyses were included. No geographic or temporal limits were applied to the search strategy, except for congress proceedings, which were limited to 2019 onwards. Results: In total, 38 studies were eligible for inclusion in this SLR, and 8 prognostic factors of interest were most frequently reported: baseline serum erythropoietin (EPO), hemoglobin (Hb), transfusion independence, bone marrow blast count, ferritin levels, International Prognostic Scoring System (IPSS) risk status, age, and karyotype status. Regarding study design, most were retrospective cohort studies (N = 15) or single-arm trials (N = 12), and were conducted in Europe (N = 24). Within the identified publications, ESA response was often assessed using the International Working Group (IWG) MDS 2000 or 2006 criteria in publications after 2000. Studies published prior to 2000 did not use a standardized method of refining response, but still classified patients according to changes in Hb levels or transfusion requirements. The literature available in LR-MDS demonstrated statistically significant relationships suggesting that patients with low serum EPO levels (vs higher EPO levels), high Hb levels (vs lower levels), and transfusion independence (vs transfusion dependent) are more likely to respond to ESA treatment (Table). This relationship was consistent across both univariate and multivariate analyses. The evidence for bone marrow blasts and ferritin levels was inconclusive, but could potentially be influenced in the future by the publication of studies with larger patient populations. There was no published evidence that ESA response was related to IPSS risk status, age, and karyotype status. The associated data for these prognostic factors in responders versus non-responders showed similar patterns. Conclusion: All studies assessing quantitative associations between ESA response and prognostic factors were published after 2000, hence ESA response was assessed according to IWG 2000 or 2006 criteria. The studies demonstrate a clear link between response to ESA treatment and lower serum EPO levels, higher Hb levels, and transfusion independence. The other prognostic factors were either not significant or inconclusive, and more research is needed to clarify whether they have a prognostic impact on ESA response in patients with LR-MDS. Some of the studies comparing prognostic factors for responders versus non-responders to ESA treatment were published before 2000 and did not use standardized methods to describe response. Due to changes in ESA treatment response definitions over time, some patients in the included studies may be classified differently with a more recent version of the IWG MDS criteria. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Distribution of Erythroid Progenitors and Precursors Correlate with Erythropoiesis Stimulating Agents (ESAs) Response in Lower Risk Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are an heterogenous group of clonal myeloid disorders characterized by dysplastic ineffective hematopoiesis, peripheral blood cytopenias and a variable risk of progression to acute myeloid leukemia (AML) evaluated by IPSS-R score. Early stage erythropoiesis is dependent on growth factors like EPO, whereas late erythroid differentiation is iron-dependent. The entire process requires a fine regulation between apoptosis and cell survival. Anemia is the most common cytopenia in IPSS-R lower risk MDS (LR-MDS) and the mechanism underlying dyserythropoiesis is multifactorial, leading to apoptosis of erythroid progenitors and precursors. LR-MDS anemia is mainly treated with ESAs (e.g., Erythropoietin or EPO), but response is not optimal and eventually patients will suffer from chronic anemia and transfusion dependence. Moreover, the only strong predictor of ESAs treatment is the endogenous concentration of serum EPO (sEPO). The primary aim of this study was to detect quantitative and qualitative flow cytometry (FC) alterations of erythroid populations in the bone marrow (BM) of LR-MDS patients associated with resistance or response to ESAs and compared them with age-matched non cytopenic BM controls (CTRLs, 6). Secondly, we wanted to investigate if different WHO diagnostic MDS subgroups displayed specific pattern of erythroid maturation and/or FC abnormalities. We selected 97 LR-MDS anemic patients treated with ESAs at MDS Unit, Hematology dpt. AOU Careggi (Florence) and divided them according to type of ESAs response (e.g., primary refractory, PR; long responders, LR, with DOR longer than 24 months and secondary refractory, SR, with DOR shorter than 24 months). Baseline BM FC analysis was performed using an erythroid panel containing antibodies for CD33, CD34, CD36, HLA-DR, CD45, CD71, CD105, CD117. We also measured the coefficient of variance (CV) of CD71 and CD36 to assess qualitative FC abnormalities within the erythroid populations. We then identified all stages of erythroid maturation from A) CD34+ committed erythroid cells (CD34+, CD45dim, CD117+, CD71+, CD33+, HLA-DR +), or erythroid progenitors (COM-E), expressed both as fraction of all CD34+ cells and all 117+ progenitor cells, to B) CD34- erythroid precursors (from proerythroblasts, PROE, to orthochromatic erythroblasts). CV CD71 was increased in PR patients compared to CTRLs (p=0,009) and to responders (p=0,008). COM-E/tot.CD34+ cells were increased in all response categories, but there was a significant trend of higher values in LR vs. PR (p=0,055). Finally, (COM-E + PROE)/tot.117+ progenitors were only enriched in LR compared to CTRLs (p=0,009). Regarding WHO subgroups, MDS 5q- displayed a decrease in COM-E/CD34+ cells and in (COM-E + PROE)/tot.117+ cells compared to MDS-RS (p=0,00094 and p=0,009 respectively) and to CTRLs for the latter population (p=0,03). Moreover, total erythroid precursors were significantly reduced compared to MDS-SLD, -MLD and -RS. MDS-RS showed a marked erythroid hyperplasia and elevation of CV CD71 compared to CTRLs (p=0,0079 and p=0,024 respectively). Taken together, these results show that in LR-MDS, the increase of CV CD71 in erythroid cells is associated with resistance to ESAs, whereas response to ESAs is present in cases with enriched EPO sensitive COM-E and PROE populations compared to CTRLs, especially for LR vs PR (p=0,055). Finally, MDS-5q- and MDS-RS were the WHO subgroups with the highest rate of PR in our cohort (46% and 59% respectively), irrespective of sEPO. These 2 subgroups of MDS exhibited different repartition of erythroid subpopulations with characteristics associated with ESAs resistance. In 5q- COM-E and PROE were depauperate and, consequently, erythroid precursors reduced, while MDS-RS displayed an expansion of erythroid precursors and higher CV of CD71 compared to CTRLs. Finally, these FC parameters, easily and rapidly assessed at baseline BM evaluation in MDS patients, correlate with response to ESAs and with different WHO subgroups. FC erythroid abnormalities could partly explain the complex pathobiology underlying dyserythropoiesis and its treatment. The different repartition of erythroid progenitors observed could lead to molecular and transcriptome analyses focused on these altered subpopulations in order to investigate the exact mechanism of anemia in LR-MDS(s). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Investigation of the Relationship between Lean Muscle Mass and Erythropoietin Resistance in Maintenance Haemodialysis Patients: A Cross-Sectional Study.

Each patient undergoing maintenance haemodialysis (MHD) has a different response to erythropoiesis-stimulating agents (ESAs). Haemodilution due to fluid overload has been shown to contribute to anaemia. Body mass index (BMI) has been shown to influence ESA response in dialysis patients; however, BMI calculation does not distinguish between fat and lean tissue. The association between lean muscle mass and erythropoietin hyporesponsiveness is still not well-known among MHD patients. We designed a cross-sectional study and used bioimpedance spectroscopy (BIS) to analyse the relationship between body composition, haemoglobin level, and erythropoietin resistance index (ERI) in MHD patients. Seventy-seven patients were enrolled in the study group. Compared with patients with haemoglobin ≥ 10 g/dL, those with haemoglobin < 10 g/dL had higher serum ferritin levels, malnutrition–inflammation scores (MIS), relative overhydration, ESA doses, and ERIs. In multivariate logistic regression, higher ferritin levels and MIS were the only predictors of lower haemoglobin levels. The ERI was significantly positively correlated with age, Kt/V, ferritin levels, and MIS and negatively correlated with albumin levels, BMI, and lean tissue index (LTI). Multivariate linear regression analysis revealed that ferritin levels, BMI, and LTI were the most important predictors of ERI. In MHD patients, using BIS to measure body composition can facilitate the development of early interventions that aim to prevent sarcopenia, support ESA responsiveness, and, consequently, improve anaemia management.

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients

IntroductionImpaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients.MethodsIn this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index.ResultsOf the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (β = −0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 μg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables.ConclusionSerum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.

Prognosis of Lower Risk Patients with Myelodysplastic Syndromes without Isolated Del(5q) after Failure of Erythropoiesis-Stimulating Agents. a Multicenter Study By the Hellenic MDS Study Group

INTRODUCTIONMost anemic non-del(5q) lower risk myelodyplastic syndromes (MDS) patients are treated with erythropoiesis stimulating agents (ESAs). Second-line treatments, including hypomethylating agents (HMA), lenalidomide (LEN) and other drugs, may be used after ESA failure in some countries, but their effect on disease progression, transformation to acute myeloid leukemia (AML), and overall survival (OS) is unknown. We analyzed MDS patients' outcome after primary or secondary failure of treatment with ESAs as a first-line treatment option. METHODSThis retrospective study included 1065 non-del(5q) lower risk (low or intermediate-1 IPSS risk) MDS patients, registered in the Hellenic National MDS Registry, treated with ESAs. Extensive biostatistical analysis performed in this study included Kaplan-Meier survival analysis. The level of statistical significance was set at a probability value of less than 0.050 (P <0.050). RESULTSBaseline patient characteristics are presented in Table 1. 848 (79.6%) of 1065 MDS patients included in this study were first treated with ESAs. Erythroid response (HI-E) to ESAs was 26.3%, and the median response duration was 21 months. Stable disease (SD) was achieved by 139 (19.4%) MDS patients, while 204 (28.4%) patients receiving ESA had progression of disease (PD) or primary treatment failure. Moreover, 353 (41.6%) MDS patients relapsed after an initial response. Primary failure to ESA was associated with a higher risk of transformation to AML, as well as poorer prognostic outcome regarding OS. The 5-year cumulative incidence of AML transformation in patients with primary and secondary failure was 32.2% and 16.1% respectively (P <0.001). In a median follow-up time period of 28 months, the mean survival from ESA failure was 40 and 80 months for primary refractory patients and relapsing patients, respectively (P <0.001). The estimated mean time to transformation to AML patients with primary failure to ESA treatment was 71.2 months (95% confidence interval [CI] = 63.0-79.3) vs. 104.6 months (95% CI = 99.6-109.6) for those having a secondary failure (P <0.001) (Figure 1a). The estimated mean OS for patients with primary failure to ESA treatment was 40.1 months (95% CI = 34.5 - 45.6) vs. 79.9 months (95% CI = 73.9-85.9) for those having a secondary failure (P <0.001) (Figure 1b). Out of 412 patients who received a second-line treatment, 48 received HMAs, 22 were treated with LEN and 176 had other treatments. CONCLUSIONSThe data of this large, multicenter, retrospective cohort of non-del(5q) lower-risk MDS patients, treated with ESAs, show that patients not responding to ESAs, as first-line treatment, are at a higher risk of transformation to AML and have poorer OS, compared to those who initially respond to ESAs but lose response thereafter. This information combined with other parameters, predictive a worse outcome (eg IPSS-R, duration of ESAs response) can be used in future clinical studies, distinguishing candidate patients for a more intensive treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Oxidative Stress Parameters Can Predict the Response to Erythropoiesis-Stimulating Agents in Myelodysplastic Syndrome Patients.

Oxidative stress has been implicated in the development of several types of cancer, including myelodysplastic syndromes (MDS), as well as in the resistance to treatment. In this work, we assessed the potential of oxidative stress parameters to predict the response to erythropoiesis-stimulating agents (ESAs) in lower-risk MDS patients. To this end, we analyzed the systemic levels of reactive species (peroxides and NO), antioxidant defenses (uric acid, vitamin E, vitamin A, GSH, GSSG, TAS, as well as GPX and GR activities], and oxidative damage (8-OH-dG and MDA) in 66 MDS patients, from those 44 have been treated with ESA. We also calculated the peroxides/TAS and NO/TAS ratios and analyzed the gene expression of levels of the redox regulators, NFE2L2 and KEAP1. We found that patients that respond to ESA treatment showed lower levels of plasma peroxides (p < 0.001), cellular GSH (p < 0.001), and cellular GR activity (p = 0.001) when compared to patients who did not respond to ESA treatment. ESA responders also showed lower levels of peroxides/TAS ratio (p < 0.001) and higher levels of the expression of the NFE2L2 gene (p = 0.001) than those that did not respond to ESA treatment. The levels of plasmatic peroxides shown to be the most accurate biomarker of ESA response, with good sensitivity (80%) and specificity (100%) and is an independent biomarker associated with therapy response. Overall, the present study demonstrated a correlation between oxidative stress levels and the response to ESA treatment in lower-risk MDS patients, with the plasmatic peroxides levels a good predictive biomarker of drug (ESA) response.

Serum trace metal association with response to erythropoiesis stimulating agents in incident and prevalent hemodialysis patients

Alterations in hemodialysis patients’ serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients’ chromium and antimony levels exceeded established accepted upper limits of normal.

Initial responsiveness to darbepoetin alfa and its contributing factors in non-dialysis chronic kidney disease patients in Japan

BackgroundHyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN.MethodsOf 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed.ResultsThe mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15–900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein–creatinine ratio were independently associated with better initial response to DA (P = < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively).ConclusionsNon-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.

Clinical and Economic Outcomes of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Post-Bundling Era

Rationale & ObjectiveSince the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences.Study DesignRetrospective observational cohort study.Setting & ParticipantsUS Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014.PredictorsErythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic.OutcomesAssociations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups.Analytical ApproachBaseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model.ResultsOf 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days.LimitationsOnly US Medicare patients were included and different hyporesponder definitions may have influenced the results.ConclusionsThis study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

Inflammation and Erythropoiesis-Stimulating Agent Response in Hemodialysis Patients: A Self-matched Longitudinal Study of Anemia Management in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Rationale & ObjectivePrevious studies of inflammation and anemia management in hemodialysis (HD) patients may be biased due to patient differences. We used a self-matched longitudinal design to test whether new inflammation, defined as an acute increase in C-reactive protein (CRP) level, reduces hemoglobin response to erythropoiesis-stimulating agent (ESA) treatment.Study DesignSelf-matched longitudinal design.Setting & Participants3,568 new inflammation events, defined as CRP level > 10 mg/L following a 3-month period with CRP level ≤ 5 mg/L, were identified from 12,389 HD patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018) in 10 countries in which CRP is routinely measured.Predictor“After” (vs “before”) observing a high CRP level.OutcomesWithin-patient changes in hemoglobin level, ESA dose, and ESA hyporesponsiveness (hemoglobin < 10 g/dL and ESA dose > 6,000 [Japan] or >8,000 [Europe] U/wk).Analytical ApproachLinear mixed models and modified Poisson regression.ResultsComparing before with after periods, mean hemoglobin level decreased from 11.2 to 10.9 g/dL (adjusted mean change, −0.26 g/dL), while mean ESA dose increased from 6,320 to 6,960 U/wk (adjusted relative change, 8.4%). The prevalence of ESA hyporesponsiveness increased from 7.6% to 12.3%. Both the unadjusted and adjusted prevalence ratios of ESA hyporesponsiveness were 1.68 (95% CI, 1.48-1.91). These associations were consistent in sensitivity analyses varying CRP thresholds and were stronger when the CRP level increase was sustained over the 3-month after period.LimitationsResidual confounding by unmeasured time-varying risk factors for ESA hyporesponsiveness.ConclusionsIn the 3 months after HD patients experienced an increase in CRP levels, hemoglobin levels declined quickly, ESA doses increased, and the prevalence of ESA hyporesponsiveness increased appreciably. Routine CRP measurement could identify inflammation as a cause of worsened anemia. In turn, these findings speak to a potentially important role for anemia therapies that are less susceptible to the effects of inflammation.

A Brief Review for Clinicians of Iron Metabolism and the Safety, Efficacy, and Rationale for Use of Intravenous Iron Products

Iron is an abundant element that is essential for multiple biologic processes. Iron metabolism is not entirely understood, but since the discovery of hepcidin, much progress has been made especially in the last five years. This article is intended to enhance clinician understanding of iron metabolism which may inform decisions about parenteral iron use in iron-restricted erythropoiesis (IResE). This article briefly discusses intravenous (IV) iron utilization in iron deficiency, anemia of chronic inflammation (ACI), functional iron deficiency (FID), and anemia associated with chronic kidney disease, heart failure, pregnancy, inflammatory bowel disease and cancer. Oral iron therapy is valuable in mild to moderate pure iron deficiency. Intravenous iron is required when a prompt response is needed in severe pure iron deficiency. ACI is a hypoferremic state resulting from altered iron metabolism. In ACI, IV iron is needed to overcome the blocking effects of hepcidin on intestinal absorption. ESAs stimulate erythropoiesis increasing iron utilization. This surge in iron requirement can result in FID, especially when ESAs are used in patients with ACI. Intravenous iron is required to treat or avoid iron deficiency in FID when inflammation is present. Parenteral iron maximizes ESA response and can make using erythropoiesis-stimulating agents (ESAs) safer by being ESA sparing. The complex and seemingly ubiquitous nature of iron in humans and the inadequate methods of assessment of iron status in inflammatory states means clinical and laboratory monitoring and individualization of care remain essential. The decision to administer intravenous iron is complex as it often lacks robust consensus guidelines; despite this we can expect utilization of these products to increase as they are safe, effective and necessary.