Erythropoietic-stimulating Agents Research Articles

A Cross-Sectional Study on The Prevalence of Anemia in Maintenance Hemodialysis and Peritoneal Dialysis Patients and Its Related Factors

Objective: To study the prevalence of anemia, the proportion of hemoglobin (Hb) levels, the treatment methods, and the influencing factors of Hb levels in maintenance hemodialysis (MHD) and peritoneal dialysis patients. Methods: In this study, 602 patients with maintenance hemodialysis and continuous ambulatory peritoneal dialysis were enrolled from December 2020 to December 2022 in our hospital, and their medical records were collected and summarized. The main contents included the patient’s gender, age, primary disease, dialysis duration, dialysis method, the use of erythropoietic stimulating agents (ESA), intravenous iron, and laboratory tests. A Hb index exceeding 110 g/L was set as the standard for the prevalence of anemia. Results: The rate of anemia in patients undergoing blood purification was 83%. The proportion of ESA use was 84.1%, and the proportion of iron use was 76.7%, of which the proportion of intravenous iron used was 17.0%, and the proportion of folic acid used was 28.3%. Conclusion: The incidence of anemia in MHD patients was relatively high, with a low proportion of patients reaching the standard Hb levels. Risk factors include albumin (ALB) levels, iron storage, white blood cells, C-reactive protein, cholesterol, etc. Nutritional support, iron supplementation, and prevention of micro-inflammatory reactions can effectively promote the improvement of Hb indicators in dialysis patients to prevent anemia.

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.

Clinical and economic effects of technology updates to the electronic health record for the management of erythopoetic stimulating agents and MDS-associated anemia.

509 Background: NCCN Guidelines recommend erythropoietic stimulating agents (ESAs) to manage symptomatic anemia in patients with lower-risk myelodysplastic syndrome (MDS) and serum EPO ≤500 mU/mL. Epoetin alfa and darbepoetin alfa have been used with a variety of dosing strategies in clinical practice, and patients often require dose adjustments to achieve an optimal clinical response, including transfusion independence. The objective of this study was to increase concordance with guidelines supported initial and subsequent doses of ESAs in The US Oncology Network (The Network). Methods: The Network developed a dosing guidance tool to standardize ESA dosing for anemia associated with MDS. These updates were made to the electronic health record (eHR) in October 2022 and included creation of an MDS-specific ESA regimen. The primary endpoint of initial dose concordance was evaluated in a retrospective chart review of patients with MDS, initiating treatment with an ESA, and randomly selected prior to and after implementation of the eHR changes. Secondary endpoints included subsequent ESA dose concordance at 4-weeks and 8-weeks post-implementation, percent of patients who reached hemoglobin (Hb) goal ≥10 g/dL by week 12, number of ESA orders using the MDS-specific regimen, and number of patients with transfusions after start of ESA. Fisher’s exact test was used to analyze the primary endpoint, and descriptive statistics were used for secondary endpoints. Darbepoetin claims data from five practices was also used to evaluate changes in payment denials during the intervention period. Results: The analysis included 50 patients (25 pre and 25 post). The primary outcome of overall initial dose concordance was 36% and 48% pre- and post-implementation periods respectively. The initial dose concordance was 73% vs. 29% (P=0.0472) in the group of patients who received an ESA using the new MDS-specific regimen (n=11) vs. non-MDS specific (n=14). Additionally, any ESA dose concordance (initial, 4-week post-, or 8-week post-ESA) using MDS-specific regimen vs. non-MDS specific occurred in 91% and 43% of patients post-implementation. The secondary outcome of Hb goal reached and percent transfused was 32% and 48% vs. 44% and 32% pre- and post-implementation respectively. During the study post-implementation period, first denial claims for darbepoetin decreased by 41%. Conclusions: Modification of ESA regimens to include MDS-specific dosing guidance resulted in a 12% increase in the initial dose concordance. A 48% increase in any dose concordance was noted when using MDS-specific ESA regimens vs. non-MDS specific ESA regimens. Based on these findings, additional eHR changes were implemented to increase the use of MDS-specific ESA regimens, and impact data are pending.

Patient Blood Management in Microsurgical Procedures for Reconstructive Surgery.

Introduction: The main purpose of reconstructive surgery (RS) is to restore the integrity of soft tissues damaged by trauma, surgery, congenital deformity, burns, or infection. Microsurgical techniques consist of harvesting tissues that are separated from the vascular sources of the donor site and anastomosed to the vessels of the recipient site. In these procedures, there are some preoperative modifiable factors that have the potential to influence the outcome of the flap transfer and its anastomosis. The management of anemia, which is always present in the postoperative period and plays a decisive role in the implantation of the flap, covers significant importance, and is associated with clinical and laboratory settings of chronic inflammation. Methods: Chronic inflammatory anemia (ACD) is a constant condition in patients who have undergone RS and correlates with the perfusion of the free flap. The aim of this treatment protocol is to reduce the transfusion rate by maintaining both a good organ perfusion and correction of the patient's anemic state. From January 2017 to September 2019, we studied 16 patients (16 males, mean age 38 years) who underwent microsurgical procedures for RS. Their hemoglobin (Hb) levels, corpuscular indexes, transferrin saturation (TSAT) ferritin concentrations and creatinine clearance were measured the first day after surgery (T0), after the first week (T1), and after five weeks (T2). At T0, all the patients showed low hemoglobin levels (average 7.4 g/dL, STD 0.71 range 6.2-7.4 g dL-1), with an MCV of 72, MCH of 28, MCHC of 33, RDW of 16, serum iron of 35, ferritin of 28, Ret% of 1.36, TRF of 277, creatinine clearance of 119 and high ferritin levels (range 320-560 ng mL-1) with TSAT less than 20%. All the patients were assessed for their clinical status, medical history and comorbidities before the beginning of the therapy. Results: A collaboration between the two departments (Department of Transfusion Medicine and Department of Reconstructive Surgery) resulted in the application of a therapeutic protocol with erythropoietic stimulating agents (ESAs) (Binocrit 6000 UI/week) and intravenous iron every other day, starting the second day after surgery. Thirteen patients received ESAs and FCM (ferric carboxymaltose, 500-1000 mg per session), three patients received ESAs and iron gluconate (one vial every other day). No patients received blood transfusions. No side effects were observed, and most importantly, no limb or flap rejection occurred. Conclusions: Preliminary data from our protocol show an optimal therapeutic response, notwithstanding the very limited scientific literature and data available in this specific surgical field. The enrollment of further patients will allow us to validate this therapeutic protocol with statistically sound data.

Serum Erythroferrone in End Stage Renal Disease Patients: Relation to Iron Status, Anaemia and Erythropoiesis Stimulating Agents

Abstract Background Anaemia is a hallmark of chronic kidney disease (CKD), where erythropoietin deficiency and reduced iron availability by the negative iron regulator, hepcidin, are principal causes of the anaemia. Erythroferrone (ERFE), a hormone synthesized by erythroblasts, is a hepcidin inhibitor and increases iron absorption and mobilization, resulting in erythropoiesis stimulation. Thus, ERFE could be considered as one of potential clinical biomarkers for assessing erythropoiesis. Moreover, it has been found that ERFE is produced in response to erythropoietic stimulating agent (ESA) in CKD and thus could have a role in cure from anaemia in those patients. However, few studies focused on understanding the role of this hormone in the regulation of iron homeostasis. Aim of the Work To study the correlation between ERFE level and iron parameters and its response to iron/ESA in end stage renal disease (ESRD) patients with iron deficiency anaemia. Study design and methods A case-control study was carried out on 40 ESRD patients (GFR &amp;lt; 15 ml/min/1.73 mm3) with evidence of iron deficiency anaemia. Patients were further subdivided into 2 subgroups, where subgroup I included patients who received both iron and ESA (Erythropoietin) (n = 28) and subgroup II patients who were treated with iron only (n = 12). Ten age &amp; sex matched normal healthy subjects were included in the study as a control group. The studied parameters (ERFE, Hb, HCT%, MCV, MCH, serum iron, TSAT% and TIBC) were measured at baseline and then revaluated three months later after iron/ESA therapy. Erythroferrone was measured (baseline and post iron/ESA treatment) by ELISA. Results The present study was conducted on 40 ESRD patients with male to female ratio 1:1.5. Their mean age was 51.03±11.22 years and mean dry weight 73.4±13.08 Kg. The commonest risk factor was hypertension (32.5%). Treatment with iron ± EPO results in significant increase of Hb and serum iron in both patients' subgroups (p ˂ 0.001). Baseline and post treatment ERFE levels were higher in patients’ groups than in the control group with significant statistical difference (p = 0.016 &amp; 0.023 respectively). The highest level was in those patients treated with both iron and EPO (212.31±106.33 ng/L at baseline &amp; 520.00±255.26 post treatment). Positive correlation of ERFE level with both Hb and serum Iron (p-value &amp;lt;0.05) was detected. Conclusion Managing anaemia in ESRD patients remain a significant unmet challenge in those patients. Insight into iron homeostasis is important in order to develop new diagnostic as well as therapeutic modalities. Our study proved that ERFE is associated with iron/EPO therapy and positively correlated with hemoglobin and serum iron levels. Thus, ERFE could play a key role in the assessment of erythropoietic activity, as well as, in the treatment process among those patients in status of iron deficiency or iron overload.

Carbon dots for the treatment of cancer-related anemia.

Carbon dots for the treatment of cancer-related anemia.

Targeting Stress Erythropoiesis Pathways in Cancer.

Cancer-related anemia (CRA) is a common multifactorial disorder that adversely affects the quality of life and overall prognosis in patients with cancer. Safety concerns associated with the most common CRA treatment options, including intravenous iron therapy and erythropoietic-stimulating agents, have often resulted in no or suboptimal anemia management for many cancer patients. Chronic anemia creates a vital need to restore normal erythropoietic output and therefore activates the mechanisms of stress erythropoiesis (SE). A growing body of evidence demonstrates that bone morphogenetic protein 4 (BMP4) signaling, along with glucocorticoids, erythropoietin, stem cell factor, growth differentiation factor 15 (GDF15) and hypoxia-inducible factors, plays a pivotal role in SE. Nevertheless, a chronic state of SE may lead to ineffective erythropoiesis, characterized by the expansion of erythroid progenitor pool, that largely fails to differentiate and give rise to mature red blood cells, further aggravating CRA. In this review, we summarize the current state of knowledge on the emerging roles for stress erythroid progenitors and activated SE pathways in tumor progression, highlighting the urgent need to suppress ineffective erythropoiesis in cancer patients and develop an optimal treatment strategy as well as a personalized approach to CRA management.

Treatment of Lower Risk Myelodysplastic Syndromes

Purpose of review: Management and Optimization of therapy for lower-risk myelodysplastic syndromes will be reviewed here. Recent findings: Lower-risk MDS typically present with clinical manifestations of anemia, which is the most frequently encountered cytopenia in this setting. While therapy with erythropoietic stimulating agents (ESAs) is used in the vast majority of cases, if correctly selected, some patients do not respond, or become irresponsive to ESAs. Novel agents with very different modes of action show promising clinical results in anemic LR-MDS refractory/relapsed after ESAs. Luspatercept, a TGFbeta family ligand trap, induces nearly 50% of transfusion independence in LR MDS. Another investigational agent showing efficacy and possibly disease modifying activity is the telomerase inhibitor imetelstat. Modulation of dose and schedule of hypomethylating agents, both injectable and oral, is currently being explored, and preliminary results are positive. There is still no standard therapeutic approach for thrombocytopenic and neutropenic LR MDS, although they do represent a smaller proportion of cases. Immunosuppressive treatments, as well as TPO mimetics, could represent a good option in selected MDS cases. Summary: At present, the availability of novel active agents allows the planning of sequential therapy, especially for anemic LR MDS. Better diagnosis and prognostic stratification may allow a more precise and personalized treatment.

Advances in myelodysplastic syndrome.

In this review, the focus is on the most recent improvements in diagnosis, prognostication and therapy of myelodysplastic syndromes (MDS) and on their relevance for clinical management. Analytical methods to refine cytogenetic and molecular assessment of MDS have been proposed, improving prognostic stratification obtained from integration of clinical and genomic data. Novel agents with very different mode of action, as single drugs or added to HMA backbone, show promising clinical results in LR-MDS and HR-MDS. Luspatercept has obtained approval given the fact that in transfusion-dependent erythropoietic-stimulating agent resistant/relapsed LR-MDS induced nearly 50% of transfusion independence. Another investigational agent showing efficacy and possibly disease modifying activity in the same setting is the telomerase inhibitor imetelstat. Results from phase II study with azacytidine and pevonedistat indicate the concrete possibility to enhance durable responses compared with azacitidine single drug. In the same direction are the preliminary results of other agents with different mode of action: magrolimab, venetoclax, sabatolimab, as well as the targeted therapy with enasidenib and ivosidenib. New posttransplant maintenance strategies may concur to prolong response. Better diagnosis and prognostic stratification may allow a more precise and personalized treatment of MDS with novel agent combinations leading to improved therapeutic algorithms.

MDS-223: Response to Erythroid Stimulating Agents (ESA) and Flow Cytometric Characteristics of Bone Marrow Erythroid Precursors in IPSS-R Lower-Risk Myelodysplastic Syndrome Patients

Context: Standard treatment of anemia in lower-risk myelodysplastic syndromes (LR-MDS) is based on erythropoietic-stimulating agents (ESAs), but some patients are primary refractory (PR) or lose response (secondary refractory, SR). High serum erythropoietin (sEPO) is the main negative predictor, and treatment of ESA-resistant anemia is challenging, so more predictors are needed. EPO promotes differentiation of committed erythroid cells (COMe) into erythroid precursors (EP), constituted by early (EEP) and late (LEP) precursors. Flow cytometry (FC) can characterize COMe and EP. RED score is an FC parameter that assesses dyserythropoiesis. Objective: We aimed to correlate COMe, EP, and RED score with response to ESAs, WHO category, and sEPO in 44 anemic LR-MDS patients. Design: We evaluated 10 negative controls, 17 PR patients, 17 SR patients, and 10 long responders (LR, response duration >24 months). Fifty-nine percent had sEPO 500 mU/mL(H-EPO); 23% had single lineage dysplasia (MDS-SLD), 34% multilineage dysplasia (MDS-MLD), 23% ring sideroblasts (MDS-RS), and 20% deletion of 5q (MDS-5q-). FC analysis was performed on bone marrow aspirates for all subgroups at diagnosis and within SR subgroup at loss of response to ESA (SRII). We used anti-CD34, CD36, CD105, CD117, CD33, CD71, and CD45 antibodies to identify COMe, total erythroid cells (TOTe), and EP. Coefficients of variance of CD71 and CD36 were used to calculate RED score. Results: TOTe and COMe were increased in LR-MDS compared to controls (p=0.013 and p=0.04, respectively), with the exception of MDS-5q- cases. In the PR subgroup, LEP were increased and COMe were reduced compared to LR. In the SRII group, COMe were lower than at diagnosis (p=0.039). RED score was higher in PR compared to responders (p=0.011). MDS-5q- cases showed reduced TOTe (p=0.047), while MDS-RS cases had higher LEP and RED score (p=0.008 and p=0.012, respectively). Finally, LEP were increased in the H-EPO group compared to L-EPO (p=0.023). Conclusions: These data suggest that COMe seem to be positively associated with ESA response, whereas higher LEP and RED score are negatively associated and also correlate with MDS-RS and H-EPO. Finally, MDS-5q- cases displayed fewer TOTe and COMe, suggesting premature apoptosis of erythroid precursors.

Anemia Clinic Treatment and Pre-Operative Management of Cardiovascular Surgery Patients

Introduction:The efficacy of an Anemia Clinic in medically optimizing cardiovascular surgery (CVS) patients preoperatively has not yet been examined. A retrospective chart review was performed to explore whether such an intervention might minimize resource utilization, improve outcomes and decrease health system cost.Methods:Twenty five patients with a history of anemia (defined as hemoglobin ≤ 13.5 in men and 12.0 in women) undergoing cardiac surgeries - inclusive of Coronary Artery Bypass Graft (CABG), valvular (mitral or aortic) surgery, or a combination of the two - were referred to the Department of Hematology's Anemia Clinic at Pennsylvania Hospital by cardiovascular surgeons throughout the University of Pennsylvania Health System between January 01, 2016 and June 01, 2017. Three patients had comorbidities that precluded surgery and one with normal hemoglobin was referred for further optimization. Twenty one anemic CVS patients met criteria for evaluation and nineteen were treated in the preoperative setting, receiving erythropoietic-stimulating agents (ESA) and/or IV iron. Eleven of nineteen received both ESA and IV iron, while eight received only the latter. Three of the patients in the treatment cohort preemptively refused blood products at time of presentation on account of religious convictions.Results:Special attention was paid to patients' hemoglobin at initial encounter, final hemoglobin prior to surgery, post-operative hemoglobin, doses of ESA and/or IV iron, number of subsequent transfusions, and 30-day hospital readmissions with comparison to the standard of care. Four of the sixteen patients (25%) managed pre-operatively with ESA and/or IV iron who were willing to accept blood products following CVS ultimately required transfusion, as compared to transfusion rates that typically near 50% for patients undergoing cardiac surgery (Mehta et al., 2009; Murphy et al., 2015). Two of these four had received both ESA and parenteral iron, while two had received iron alone. Zero of the nineteen patients treated pre-operatively in the Anemia Clinic were readmitted within 30 days of their discharge from the hospital, as compared to a state-specific 30-day readmission rate of 11.7% for patients undergoing CVS between 01/2014 and 03/2016 (Martin, 2017).Conclusion:The medical optimization of cardiovascular surgery patients pre-operatively via an Anemic Clinic platform decreases post-operative transfusions and may play a prominent role in preventing 30-day hospital readmissions. A potential improvement in patient outcomes at decreased cost to the health system advocates strongly for further cost-benefit analysis as well as examination of this model's validity in larger data sets and across other healthcare specialties. DisclosuresNo relevant conflicts of interest to declare.

Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes.

Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPNs) are clonal diseases that differ in morphologic diagnostic criteria but share some common disease phenotypes that include cytopenias, propensity to acute myeloid leukemia evolution, and a substantially shortened patient survival. MDS/MPNs share many clinical and molecular features with MDS, including frequent mutations involving epigenetic modifier and/or spliceosome genes. Although the current 2016 World Health Organization classification incorporates some genetic features in its diagnostic criteria for MDS and MDS/MPNs, recent accumulation of data has underscored the importance of the mutation profiles on both disease classification and prognosis. Machine-learning algorithms have identified distinct molecular genetic signatures that help refine prognosis and notable associations of these genetic signatures with morphologic and clinical features. Combined geno-clinical models that incorporate mutation data seem to surpass the current prognostic schemes. Future MDS classification and prognostication schema will be based on the portfolio of genetic aberrations and traditional features, such as blast count and clinical factors. Arriving at these systems will require studies on large patient cohorts that incorporate advanced computational analysis. The current treatment algorithm in MDS is based on patient risk as derived from existing prognostic and disease classes. Luspatercept is newly approved for patients with MDS and ring sideroblasts who are transfusion dependent after erythropoietic-stimulating agent failure. Other agents that address red blood cell transfusion dependence in patients with lower-risk MDS and the failure of hypomethylating agents in higher-risk disease are in advanced testing. Finally, a plethora of novel targeted agents and immune checkpoint inhibitors are being evaluated in combination with a hypomethylating agent backbone to augment the depth and duration of response and, we hope, improve overall survival.

MO802DOES ETELCALCETIDE REVERSE MYELOFIBROTIC BONE CHANGES DUE TO HYPERPARATHYROIDISM? A CASE REPORT

Abstract Background and Aims A 21 year old boy with a diagnosis of Autosomal Recessive Polycystic Kidney Disease and Caroli disease reached a final stage of chronic kidney disease (CKD) and started haemodialysis. Method After 3 years in haemodialysis he underwent a kidney transplant from a cadaveric donor. His transplanted kidney worked fairly well until the patients was 31 year old when he developed graft dysfunction (serum creatinine from 2.7 to 5 mg/dL in a very short period). There was a concomitant increase in serum phosphate levels (8.3 mg/dl) and iPTH that progressively increased to 1032 pg/ml despite a traditional therapy. Results At age 32, the patient returned to haemodialysis treatment thrice weekly with a concomitant a progressive worsening of hyperparathyroidism with bone pain . Cinacalcet at a dosage of 30 mg daily treatment was initiated, then it was increased to 120 mg daily without any benefit. Two years later, being the clinical situation without any improvement and being the patient scarcely compliant to the therapy and because a further enlargement of parathyroid glands was observed, a Parathyroidectomy (PTX) was advised. Nevertheless, PTX was not performed because of patient’s refusal. Furthermore, despite Erythropoietic Stimulating Agent (ESA) therapy, he developed severe anemia that required regular and frequent blood transfusions. iPTH increased to 4500 pg/ml [Fig.1] with a parallel rise in alkaline phosphatase &amp;gt;600 UI/L [Fig.2]. A Computed Tomography scan showed multiple bone-thickening lesions. He thus initiated Etelcalcetide 5 mg e.v. 3 times a week, after the HD session but without any benefit. The dosage was then increased to 7.5 mg but the patient gradually became frail and developed pancytopenia and low-grade fever. Hematological evaluation with bone marrow biopsy was performed in December 2019. Bone marrow histology showed severe fibrosis [Myelofibrosis (MF) grade 3] with normal bone marrow cytogenetics. Blood samples for mutations in JAK-2, CALR, and MPL and BCR-ABL rearrangement were negative. There was no evidence for a myeloproliferative neoplasm (MPN) or metastatic lesions. During the following months, while on a 7,5 mg dose of etalcalcetide, there was a gradual reduction in iPTH [Fig.1] and serum alkaline phosphatase [Fig.2], up to 500 pg/dl and 200 IU/L respectively. The patient developed asymptomatic, often severe, hypocalcemia which was managed with therapy. The patient’s clinical conditions gradually improved, anemia responded to lower doses of ESAs. A bone marrow biopsy was repeated after one year (December 2020) and it showed a reduction in fibrosis (MF grade varying from 1-2). Then etelcalcetide dosage was reduced while serum calcium and phosphate levels were in the normal limit. Conclusion Myelofibrosis secondary to renal osteodystrophy is an uncommon complication. It has been rarely reported and usually is associated with primary hyperparathyroidism. Marrow fibrosis and pancytopenia is related to the excessive iPTH that upregulates production of cytokines and paracrine factors in the bone marrow (IL-1a, IL-6, FNF-a, TGF–b, and platelet-derived growth factor) and it has an important stimulatory effect on fibroblast proliferation. It is known that surgical parathyroidectomy is associated with a reduction of bone marrow fibrosis in primary hyperparathyroidism. To our knowledge, this is probably the first case of tertiary hyperparathyroidism in which the effect of etelcalcetide is comparable to parathyroidectomy as far as on calcium-phosphate balance, and a significant improvement in bone marrow fibrosis and hemoglobin. In conclusion, etelcalcetide at least in this patient seems as effective as PTX on bone balance, bone marrow and anemia.

Harnessing the Biologics and Biosimilars Collective Intelligence Consortium to Evaluate Patterns of Care.

As clinical trials test efficacy rather than effectiveness of medications, real-world effectiveness data often vary from clinical trial data. Given the recent market entry of multiple biologics and biosimilars, a dedicated assessment of these diverse agents is needed to build the evidence base regarding efficacy and safety of innovator biologics and biosimilars. The Academy of Managed Care Pharmacy's Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) was convened to address the lack of real-world, postmarket outcome evidence generation for innovator biologics and corresponding biosimilars. The BBCIC is a multistakeholder scientific research consortium whose participants prioritize topics and collaboratively conduct research studies. The BBCIC conducts a wide range of analyses, including population characterization, epidemiologic studies, and active observational studies, and develops best practices for conducting large-scale studies to provide real-world evidence. Over the past 3 years, we undertook multiple descriptive analyses with the goal of characterizing data availability and demonstrating the feasibility and efficacy of using the BBCIC distributed research network (DRN), which includes commercial claims data from 2008-2018 covering approximately 100 million lives, with approximately 20 million active members in 2017 from 2 major U.S. health plans and 3 regional integrated delivery networks. We analyzed 4 medication classes of particular interest to biologics and biosimilars development: insulins, granulocyte colony-stimulating factors, erythropoietic-stimulating agents, and anti-inflammatories. We were able to identify exposures and user characteristics in all 4 categories. Herein we describe the successes and challenges of conducting some of our analyses, specifically among insulin users with type 1 diabetes mellitus. Our results demonstrate the BBCIC DRN's ability to identify and characterize exposures, cohorts, and outcomes that can contribute to more sophisticated comparative surveillance of biosimilars and innovator biologics in the future. Additional linkages to laboratory data and a wider range of insurance carriers will further strengthen the BBCIC DRN. This study was coordinated and funded by the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) and represents the independent findings of the BBCIC Insulins Principal Investigator and the BBCIC Insulins Research Team. Lockhart is employed by the BBCIC; Eichelberger was employed by the BBCIC at the time of this study. McMahill-Walraven is employed by Aetna, a CVS Health business. Panozzo, Marshall, and Brown are employed by Harvard Pilgrim Healthcare Institute. Aetna receives external funding through research grants and subcontracts with Harvard Pilgrim Healthcare Institute, which are funded by the FDA, NIH, PCORI, BBCIC, Pfizer, and GSK; the Reagan-Udall Foundation for IMEDS; and PCORI for the ADAPTABLE Study. Aetna was reimbursed for data and analytic support from Harvard Pilgrim Healthcare Institute and the Reagan Udall Foundation for the U.S. Food and Drug Administration. This work was presented as a poster at AMCP Nexus 2018; October 22-25, 2018; in Orlando, FL.

The Impact of Anemia Treatment on Health-Related Quality of Life in Patients With Chronic Kidney Disease in the Contemporary Era.

The treatment of anemia with erythropoietic-stimulating agents is now part of the routine care of patients with CKD with guidelines for anemia management carefully outlined by Kidney Disease Improving Global Outcomes. The treatment of anemia impacts the health-related quality of life of CKD patients, primarily affecting the domains of energy/vitality and physical functioning. Improvements in these domains occur, in general, most noticeably when hemoglobin levels are raised from below 9 g/dL to the 10-12 range, with limited improvements occurring when hemoglobin levels are increased above 12 g/dL. Importantly, individual patient responses to anemia treatment vary depending on a variety of factors and it is important to assess the impact of treatment on each patient, particularly as nephrology care moves to a patient-centered care model.

Impact of Preoperative Erythropoietin on Allogeneic Blood Transfusions in Surgical Patients: Results From a Systematic Review and Meta-analysis.

Erythropoietic-stimulating agents such as erythropoietin have been used as part of patient blood management programs to reduce or even avoid the use of allogeneic blood transfusions. We review the literature to evaluate the effect of preoperative erythropoietin use on the risk of exposure to perioperative allogeneic blood transfusions. The study involved a systematic review and meta-analysis of randomized controlled trials evaluating the use of preoperative erythropoietin. The primary outcome was the reported incidence of allogeneic red blood cell transfusions during inpatient hospitalizations. Secondary outcomes included phase-specific allogeneic red blood cell transfusions (ie, intraoperative, postoperative), intraoperative estimated blood loss, perioperative hemoglobin levels, length of stay, and thromboembolic events. A total of 32 randomized controlled trials (n = 4750 patients) were included, comparing preoperative erythropoietin (n = 2482 patients) to placebo (n = 2268 patients). Preoperative erythropoietin is associated with a significant decrease in incidence of allogeneic blood transfusions among all patients (n = 28 studies; risk ratio, 0.59; 95% CI, 0.47-0.73; P < .001) as well as patients undergoing cardiac (n = 9 studies; risk ratio, 0.55; 95% CI, 0.37-0.81; P = .003) and elective orthopedic (n = 5 studies; risk ratio, 0.36; 95% CI, 0.28-0.46; P < .001) surgery compared to placebo, respectively. Preoperative erythropoietin was also associated with fewer phase-specific red blood cell transfusions. There was no difference between groups in incidence of thromboembolic events (n = 28 studies; risk ratio, 1.02; 95% CI, 0.78-1.33; P = .68). Preoperative erythropoietin is associated with a significant reduction in perioperative allogeneic blood transfusions. This finding is also confirmed among the subset of patients undergoing cardiac and orthopedic surgery. Furthermore, our study demonstrates no significant increase in risk of thromboembolic complications with preoperative erythropoietin administration.

Anemia and Iron Deficiency in Cancer Patients: Role of Iron Replacement Therapy.

Anemia in cancer patients is quite common, with remarkable negative impacts on quality of life and overall prognosis. The pathogenesis is complex and typically multifactorial, with iron deficiency (ID) often being a major and potentially treatable contributor. In turn, ID in cancer patients can be due to multiple concurring mechanisms, including bleeding (e.g., in gastrointestinal cancers or after surgery), malnutrition, medications, and hepcidin-driven iron sequestration into macrophages with subsequent iron-restricted erythropoiesis. Indeed, either absolute or functional iron deficiency (AID or FID) can occur. While for absolute ID there is a general consensus regarding the laboratory definition (that is ferritin levels <100 ng/mL ± transferrin saturation (TSAT) <20%), a shared definition of functional ID is still lacking. Current therapeutic options in cancer anemia include iron replacement, erythropoietic stimulating agents (ESAs), and blood transfusions. The latter should be kept to a minimum, because of concerns regarding risks, costs, and limited resources. Iron therapy has proved to be a valid approach to enhance efficacy of ESAs and to reduce transfusion need. Available guidelines focus mainly on patients with chemotherapy-associated anemia, and generally suggest intravenous (IV) iron when AID or FID is present. However, in the case of FID, the upper limit of ferritin in association with TSAT <20% at which iron should be prescribed is a matter of controversy, ranging up to 800 ng/mL. An increasingly recognized indication to IV iron in cancer patients is represented by preoperative anemia in elective oncologic surgery. In this setting, the primary goal of treatment is to decrease the need of blood transfusions in the perioperative period, rather than improving anemia-related symptoms as in chemotherapy-associated anemia. Protocols are mainly based on experiences of Patient Blood Management (PBM) in non-oncologic surgery, but no specific guidelines are available for oncologic surgery. Here we discuss some possible approaches to the management of ID in cancer patients in different clinical settings, based on current guidelines and recommendations, emphasizing the need for further research in the field.

Does G6PD-Deficiency Related Oxidative Stress and Hemolysis Affect Erythroid Response to Erythropoietic Stimulating Agents (ESA) in Myelodysplastic Patients?

Background: Anemia is the most frequent cytopenia in Myelodysplastic Syndrome (MDS). Epoetin alfa, Epoetin beta and Darbepoetin alfa (ESA) have been investigated in several studies as useful to treat anemia in this category of patients. Available preclinical data support oxidative stress and hemolysis contributing to ESA resistance but not clinical data is today available. G6PD deficiency is an X-linked condition characterized by a markedly reduced capability to protect red blood cells from oxidative stresses. In the island of Sardinia the prevalence is reported to be as high as 12%. Patients and Methods: We retrospectively analyzed all MDS patients who had received ESA in our centre. Diagnosis of MDS was made according to WHO criteria. Patients were stratified based on International Prognostic Scoring System (IPSS). At diagnosis baseline EPO level and G6PD quantitative estimation were detected. G6PD deficiency was defined as an enzyme dosage of less than 0.96 UI/g of Hb in the peripheral blood. Red blood cell (RBC) transfusions requirement before starting treatment was evaluated. Erythroid hematologic improvement (HI-E) was evaluated according to the International Working Group (IWG) response criteria ( Cheson et al JCO 2006). Results: Thirty patients met the above specified criteria. Table 1 showed patients’ characteristics. Of them 7 were G6PD-defiecient and 23 had normal G6PD level values. Twenty four patients (80%) achieved an HI-E (14 major and 10 minor). In the G6PD-deficient group HI-E was observed in 7 over 7 patients ( major in 4 and minor in 3). In the control group HI-E was observed in 17 over 23 patients (major in 10 minor in 7). (P= 0.29). Conclusions: We evaluated 30 MDS lowrisk and Int I IPSS patients who received ESA in the last 20 years in our centre. Despite the common belief that oxidative stress and hemolysis may contribute to ESA resistance, no statistically significant difference to potentially resistance to ESA treatment in G6PD deficiency have been observed. We conclude that G6PD-deficiency does not contraindicate the use of ESA in this setting of patients.

ITACA: A new validated international erythropoietic stimulating agent-response score that further refines the predictive power of previous scoring systems.

In 'real-life', the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower-risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. To validate existing ESA predictive scores and develop a new score that identifies non-responders. ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, and MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS-CAN, and IPSS-R-based ESA scores were calculated and documented ESA responses compared. 996 ESA-treated patients were identified. Overall response rate (ORR) was 59%. The database was randomly divided into balanced derivation (n = 463) and validation (n = 462) cohorts. By multivariate analysis, transfusion independence, erythropoietin (EPO) level <100 IU/L, and IPSS low-risk were independently predictive of response. Assigning a score of 1 to each resulted in a scoring system of 0-3 with response rates of 23%, 43%, 67%, and 85%. ORR was concordant in the validation cohort. The 'ITACA' score had the highest discriminating power of response. ITACA is an internally-validated predictive SS of ESA response in real-life 'good risk' MDS patients derived from a large international dataset that surpasses others. The incorporation of biologic markers to better identify non-responders is still needed.

Treatment of low-risk myelodysplastic syndromes

New progress of treatment of low-risk myelodysplastic syndromes (MDS) reported in the 58th American Socienty of Hematology (ASH) Annual Meetings was reviewed. Anemia is a single common symptom of low-risk MDS, and erythropoietic-stimulating agents (ESA) may be effective. The dose and duration of erythropoietic-stimulating agents (ESA) are critical to determine efficacy. If the treatment of ESA failed, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents and a rather large number of experimental agents. The choice for the second-line treatment must consider the biologic, cytogenetic and molecular-identified characteristics of individual patient, as well as frailty and comorbidities. Other cytopenias rarely appear alone. Thrombomimetic agents for thrombocytopenia has been proposed in clinical trials, but there were some safety issues. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive therapy is indicated mainly for pancytopenic and hypoplastic low-risk MDS. Finally, hematopoietic stem cell transplantion is the curative option also for low-risk MDS, but it should be carefully evaluated to balancing toxicity and the possibility of survival advantage. Key words: Myelodysplastic syndromes; Low-risk; American Society of Hematology Annual Meeting