Erythropoiesis-stimulating Agents Initiation Research Articles

Clinical Outcomes and Healthcare Resource Utilization for Patients With Lower-Risk Myelodysplastic Syndromes Treated With Erythropoiesis-Stimulating Agents

IntroductionReal-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States. Patients and MethodsThis retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019. The primary analysis assessed patient demographic and clinical characteristics, treatment patterns, clinical outcomes (hematologic response, transfusion requirements, disease progression), and HCRU (medical encounters, laboratory tests, and medication use). Subgroup analyses of patients repeatedly treated with ESA therapy evaluated selected clinical outcomes and primary ESA failure by SF3B1 mutational status, per recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines©). ResultsA total of 142 patients were included with a median follow-up time of 17 months (interquartile range [IQR], 7-33). Median age at ESA initiation was 79 years (IQR, 73-85). Patients were predominantly male (54%), overweight or obese (32% and 23%, respectively), of White race (96%) and non-Hispanic ethnicity (89%). Overall, 57% patients were initially treated with darbepoetin alfa and 43% with epoetin alfa. Clinical outcomes were poor, and there was a significant burden on both the health system and individual patients treated with ESA therapies. Hematologic improvement- erythroid was only seen in 26% of 142 patients treated with ESAs, and 65% of 82 retreated patients experienced primary ESA failure. ConclusionOur results indicate that primary ESA failure is largely unrecognized and that many patients should be considered for alternative treatments.

Real-Life Anemia Management Among Patients with Non-Dialysis-Dependent Chronic Kidney Disease in Three European Countries.

Anemia is prevalent among patients with chronic kidney disease (CKD), yet current evidence indicates that treatment may not adhere to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. We aimed to document the management of patients with non-dialysis-dependent (NDD)-CKD receiving erythropoiesis-stimulating agent (ESA) therapy in Europe. This retrospective, observational study extracted information from medical records in Germany, Spain, and the UK. Eligible patients were adults with NDD-CKD stages 3b-5 who initiated ESA therapy for anemia between January and December 2015. Anemia was defined as hemoglobin (Hb) <13.0 g/dL (males) or <12.0 g/dL (females). Data regarding ESA treatment, treatment response, concomitant iron therapy and blood transfusions were extracted up to 24 months post-ESA initiation, and data on CKD progression until abstraction date. Eight hundred and forty-eight medical records were abstracted. Approximately 40% received no iron therapy prior to ESA initiation. At ESA initiation, mean ± standard deviation Hb level was 9.8 ± 1.0 g/dL. Most patients received darbepoetin alfa, and switching between ESAs was rare (8.5% of patients). Concomitant intravenous and oral iron therapy was prescribed for 36% and 42% of patients, respectively, during initial ESA therapy. Mean Hb levels reached the target level (10-12g/dL) within 3-6 months of ESA initiation. Hb, transferrin saturation, and ferritin levels were infrequently monitored from 3 months post-ESA initiation. Rates of blood transfusion, dialysis, and diagnosis of end-stage renal disease were 16.4%, 19.3%, and 24.6%, respectively. Rates of kidney transplant and death were 4.8% and 8.8%, respectively. Among ESA-treated patients, ESA initiation was in accordance with KDIGO guidelines, but subsequent monitoring of Hb and iron deficiency were suboptimal.

Treatment Patterns and Outcomes in Lower-Risk, Non-Del(5q) Myelodysplastic Syndromes: Findings from a Global Real-World Medical Record Review Study

Background: Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell malignancies defined by ineffective hematopoiesis and peripheral blood cytopenias. Patients often present with anemia and frequently require red blood cell transfusions (RBCTs), which may lead them to become transfusion-dependent (TD). This results in poor quality of life and reduced survival. In patients with non-del(5q) lower-risk (LR)-MDS, the standard of care includes erythropoiesis-stimulating agents (ESAs) ± granulocyte colony-stimulating factor as first-line (1L) therapy; however, although clinical trials have demonstrated efficacy, there is little evidence from real-world settings. This study aimed to assess real-world data to investigate treatment patterns and prevailing hematologic outcomes in patients with non-del(5q) LR-MDS. Methods: In this retrospective medical record review, eligible patients ≥ 18 years of age diagnosed with non-del(5q) LR-MDS between July 1, 2013 and September 30, 2018 were identified by participating hematologist-oncologists in the US, Canada (CAN), UK, and EU (France, Germany, Spain). Demographics, clinical characteristics, treatment patterns, and hematologic outcomes data were abstracted (June-November 2021) and reported descriptively. Aggregated analyses were performed using pooled US/CAN and UK/EU data sets for the overall cohort and for patient subgroups treated with clinician-defined 1L and second-line (2L) ESA-containing regimens. Results: Medical record data were abstracted for 119 patients with non-del(5q) LR-MDS in US/CAN (median age, 61.5 years; 71.4% male) and 245 patients in UK/EU (median age, 67.3 years; 71.4% male). Median follow-up duration from MDS diagnosis was 50.5 months (US/CAN) and 67.8 months (UK/EU). At initial diagnosis, 50.4% (US/CAN) and 53.5% (UK/EU) of patients had Low-risk MDS (per Revised International Prognostic Scoring System). Of the 71 patients in US/CAN and 123 patients in UK/EU who were tested successfully for the SF3B1 mutation, 16.9% (US/CAN) and 15.5% (UK/EU) were positive. Most of the patients initiated 1L therapy (US/CAN: 109 [91.6%]; UK/EU: 225 [91.8%]) and more than one-third initiated a 2L therapy (US/CAN: 45 [37.8%]; UK/EU: 89 [36.3%]). In 1L, 2.8% patients in US/CAN and 2.2% in UK/EU received treatment with lenalidomide. Most patients were treated with ESA-containing regimens in 1L, with a median duration of therapy of ≥ 2 years (US/CAN: 97 [89.0%], of which 86.6% was ESA monotherapy; UK/EU: 203 [90.2%], of which 85.7% was ESA monotherapy). Treatment characteristics and hematologic outcomes for patients treated with ESAs are presented in the Table. Among patients who were TD before 1L ESA treatment (36 [37.1%] US/CAN; 104 [51.2%] UK/EU), a small proportion (2.8% US/CAN; 14.4% UK/EU) became transfusion independent (TI) during 1L; RBCT reduction threshold (≥ 50%) was met by 41.7% in US/CAN (median duration, 23 months) and 52.9% in UK/EU (median duration, 13 months). Among patients treated with ESA-containing regimens in 2L (12 [26.7%] US/CAN; 26 [29.2%] UK/EU), most had been treated with ESA in 1L (US/CAN: 10 [83.3%]; UK/EU: 22 [84.6%]). The most frequently reported reasons for reinitiating treatment with ESAs in 2L were overall health status (54.6% US/CAN; 40.9% UK/EU), treatment efficacy (45.5% US/CAN; 63.6% UK/EU), and disease characteristics (36.4% US/CAN; 45.5% UK/EU). In the subgroup of patients who reinitiated ESA in 2L, the most frequently reported reasons for discontinuation of 1L ESA were patient decision (45.5% US/CAN; 22.7% UK/EU), completion of planned course of therapy (45.5% US/CAN; 18.2% UK/EU), and progressive disease (36.4% US/CAN; 68.2% UK/EU). Conclusions: In this real-world study, the most frequently used treatments for the management of anemia in patients with non-del(5q) LR-MDS were ESA-containing regimens. A considerable proportion of patients were TD before initiating 1L ESA therapy. For those who were re-treated with ESAs in 2L, the most common reasons for treatment reinitiation were health status, disease characteristics, and reported treatment efficacy, although only a small fraction of patients who were TD at 1L ESA initiation became TI. These findings highlight an unmet need in anemia management among patients with non-del(5q) LR-MDS, and a requirement for new and more effective treatment options. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P781: CLINICAL OUTCOMES AND HEALTHCARE RESOURCE UTILIZATION (HCRU) IN PATIENTS WITH LR-MDS REINITIATING ESAS FOLLOWING PREVIOUS ESA TREATMENT

Background: The median survival for patients with lower-risk myelodysplastic syndromes (LR-MDS) is estimated to be 5–10 years. Erythropoiesis-stimulating agents (ESAs) are utilized as first-line treatment for anemia in LR-MDS; however, real-world treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) for patients with LR-MDS who reinitiated ESAs following previous discontinuation are not well-established. Aims: To examine treatment patterns, clinical outcomes, and HCRU in patients with LR-MDS who reinitiated treatment with ESAs. Methods: This was a retrospective study of patients with LR-MDS in a network of US community health systems who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019 and were followed through June 30, 2021. Patients were required to have discontinued (had a ≥ 3-week gap between treatment with epoetin alfa, or a ≥ 6-week gap between treatment with darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Outcomes included failure to achieve transfusion independence (TI), progression to acute myeloid leukemia (AML), overall survival (OS), number and type of health system visits, and medication use. TI was defined per IWG 2006 criteria in the subset of patients who had received ≥ 1 transfusion in the 8 weeks prior to ESA initiation. Results: There were 108 patients with confirmed LR-MDS who initiated ESA-based therapy. Patients had a median age of 79 years at diagnosis (interquartile range [IQR] 73–85), were predominantly male (58%), White (97%), and overweight or obese (52%). The median follow-up period was 17.0 months (IQR 7.2–34.7). The most used ESA was darbepoetin alfa (60%), followed by epoetin alfa (38%) and epoetin alfa-epbx (2%). Of the 33 patients who received a baseline transfusion, 52% did not achieve TI; 53% and 43% failed to achieve TI at 6 and 12 months, respectively. The majority of patients were repeatedly treated with ESAs (n = 61, 56%). Among these patients, 2% progressed to AML and 48% died during follow-up; median OS was 45 months. The median number of health system visits per patient-month was 3.2 (IQR 0.6–4.9); 89%, 62%, and 72% of pts had ≥ 1 outpatient, emergency department, or inpatient visit respectively, with median length of hospitalization of 12 days (IQR 4.8–27.8). Most patients (54%) received an antibiotic at least once during follow-up; overall, use of immunosuppressive therapy (2%) or iron chelation (3%) was rare. Summary/Conclusion: In this real-world study of community practice in the USA, reinitiation of ESA treatment after prior discontinuation in LR-MDS was prevalent. In these patients, poor clinical outcomes and frequent health system visits were observed. This study highlights the need to consider alternative treatment options for patients with LR-MDS.

Clinical outcomes and healthcare resource utilization (HCRU) in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) reinitiating erythropoiesis-stimulating agents (ESAs) following previous ESA treatment.

e19067 Background: The median survival for pts with LR-MDS is estimated to be 5–10 years. ESAs are utilized as first-line treatment for anemia in LR-MDS; however, real-world treatment patterns, clinical outcomes, and HCRU for pts with LR-MDS who reinitiated ESAs following previous discontinuation are not well-established. Methods: This was a retrospective study of pts with LR-MDS in a network of US community health systems who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019 and were followed through June 30, 2021. Pts were required to have discontinued (had a ≥ 3-week gap between treatment with epoetin alfa, or a ≥ 6-week gap between treatment with darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Outcomes included failure to achieve transfusion independence (TI), progression to acute myeloid leukemia (AML), overall survival (OS), number and type of health system visits, and medication use. TI was defined per IWG 2006 criteria in the subset of pts who had received ≥ 1 transfusion in the 8 weeks prior to ESA initiation. Results: There were 108 pts with confirmed LR-MDS who initiated ESA-based therapy. Pts had a median age of 79 years at diagnosis (interquartile range [IQR] 73–85), were predominantly male (58%), White (97%), and overweight or obese (52%). The median follow-up period was 17.0 months (IQR 7.2–34.7). The most used ESA was darbepoetin alfa (60%), followed by epoetin alfa (38%) and epoetin alfa-epbx (2%). Of the 33 pts who received a baseline transfusion, 52% did not achieve TI; 53% and 43% failed to achieve TI at 6 and 12 months, respectively. The majority of pts were repeatedly treated with ESAs (n = 61, 56%). Among these patients, 2% progressed to AML and 48% died during follow-up; median OS was 45 months. The median number of health system visits per patient-month was 3.2 (IQR 0.6–4.9); 89%, 62%, and 72% of pts had ≥ 1 outpatient, emergency department, or inpatient visit respectively, with median length of hospitalization of 12 days (IQR 4.8–27.8). Most pts (54%) received an antibiotic at least once during follow-up; overall, use of immunosuppressive therapy (2%) or iron chelation (3%) was rare. Conclusions: In this real-world study of community practice in the USA, reinitiation of ESA treatment after prior discontinuation in LR-MDS was prevalent. In these pts, poor clinical outcomes and frequent health system visits were observed. This study highlights the need to consider alternative treatment options for pts with LR-MDS.

Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program.

Risk evaluation and mitigation strategy (REMS) programs are intended to improve safe use of US Food and Drug Administration-approved drugs. However, controversy exists over whether they consistently accomplish this goal. We aimedto assess how initiation of the erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin alfa changed following implementation and enforcement (following a 1-year post-implementation grace period) of a prominent REMS program warning physicians against use in cancer patients with hemoglobin above 10g/dL. Using claims data from a large US commercial insurance company, we conducted interrupted time-series analyses of darbepoetin alfa and epoetin alfa initiation among adult cancer patients in the 12 months before REMS program implementation, after REMS program implementation, and after REMS program enforcement. We also evaluated differences in inappropriate initiation (hemoglobin tests all above 10g/dL in the prior month) between the periods. In total, we identified 3456 darbepoetin alfa initiators and 2632 epoetin alfa initiators. Over the study period, the monthly number of initiators per 100,000 patients with cancer fell from 119 to 32 for darbepoetin alfa and from 82 to 34 for epoetin alfa. However, non-significant post-REMS program implementation level and slope changes per 100,000 adult patients with cancer were observed for darbepoetin alfa (level0.03 [95% confidence interval (CI) -14.98 to 15.05]; slope 1.94 [95% CI -0.22 to 4.10]) and epoetin alfa (level -4.10 [95% CI -16.85 to 8.65]; slope -0.52 [95% CI -2.35 to 1.32]). Non-significant post-REMS program enforcement level and slope changes were also seen for both drugs (darbepoetin alfa level 1.58 [95% CI -0.58 to 3.74,slope -0.28 [95% CI -15.29 to 14.73]; epoetin alfa level 1.58 (95% CI -0.26 to 3.42],slope 5.74 [95% CI -7.01 to 18.49]). Finally, non-significant changes in inappropriate darbepoetin alfa (60% vs. 53% vs. 57%, p = 0.68) and epoetin alfa (53% vs. 53% vs. 46%, p = 0.41) initiation were observed between the three study periods. REMS program implementation and enforcement were not associated with significant changes in ESA initiation, adding to concerns over the degree to which certain REMS programs enhance patient safety.

End of an era for erythropoiesis-stimulating agents in oncology.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration. We evaluated ESA utilization from 2003 to 2012 and obtained private health insurer claims data for persons with lung, colorectal, or breast cancer from 2001 to 2012. ESA use for CIA was determined by an ESA claim after chemotherapy, up to 6 months after treatment. We identified 839,948 commercially insured patients, including 24,785 patients with ESA-treated CIA (3.2%). Darbepoetin use increased 3.9-fold from 2003 to 2007 (12.3% to 48.7%) and then decreased 95% to 2.6% by 2012. Epoetin use decreased 90% from 2003 to 2012 (30.3% to 3.1%). Between 2003 and 2012, mean epoetin dosing decreased 0.8-fold (244,979 in 2003 vs. 196,216 units in 2012), but increased 1.8-fold for darbepoetin-treated CIA (262 in 2003 to 467 μg in 2012). Among CIA patients, transfusions were low (4.5%) in 2002-2007, then increased 2.2-fold between 2008 and 2012. Safety initiatives between 2007 and 2010 facilitated reductions in ESA use combined with changes in coverage. These data show the efficacy of regulatory efforts, publication of adverse events and changes in reimbursement in reducing use of ESAs. Future studies are warranted to optimize deimplementation strategies to improve patient safety.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs. To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence. We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin. Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%). Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants.

Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs. To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence. We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin.Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Statin therapy and erythropoiesis-stimulating agent hyporesponsiveness in patients with nondialysis chronic kidney disease: A retrospective study in Beijing, China.

Erythropoiesis-stimulating agents (ESAs) are frequently used among patients with renal anemia, while a significant proportion of patients exhibit ESA hyporesponsiveness despite adequate dosing. Previous studies have suggested an inverse association between ESA hyporesponsiveness and statin use among patients receiving dialysis therapy. However, studies based on predialysis patients are extremely limited.Based on electronic medical records of a tertiary hospital in Beijing, China between April 2010 and April 2015, we investigated the association between statin use and ESA hyporesponsiveness among patients with predialysis-chronic kidney disease (CKD).Altogether 232 patients with CKD initiating ESA therapy and with hemoglobin levels monitored for at least 6 months were included in our analyses. Among them, 77 (38.5%) were long-term statin users (regular statin treatment for more than 3 months) before ESA initiation. Overall, 6.5% of the statin users and 17.1% of nonusers were considered to have ESA hyporesponsiveness. Long-term statin therapy was significantly associated with a lower proportion of ESA hyporesponsiveness in fully adjusted model (odds ratio 0.15, 95% confidence interval: 0.03–0.64).We found that long-term statin therapy was inversely associated with ESA hyporesponsiveness among predialysis patients with CKD. Further studies are needed to validate our observations, and to explore the potential mechanisms between ESA resistance and statin therapy.

Changes in the use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in patients with cancer amidst regulatory and reimbursement changes.

Evaluate changes in use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in cancer patients receiving myelosuppressive chemotherapy following regulatory and reimbursement actions. Calendar year patient cohorts (2005-2013) with breast, colorectal, lung, multiple myeloma, non-Hodgkin lymphoma, ovarian, or prostate cancer and receiving myelosuppressive chemotherapy were identified within the Marketscan database. Incidence of ESA treatment and transfusion were estimated in each year, as was median number of ESA administrations. Clinical characteristics associated with ESA administration and transfusions were evaluated by using multivariable logistic regression. Additionally, annual new ESA user cohorts within the Oncology Services Comprehensive Electronic Records database (2011-2014) were examined to assess hemoglobin levels at ESA initiation. Across all tumor types, ESA use decreased substantially (breast cancer: 53.7 to 3.2%; lung cancer: 66.0 to 13.3%, non-Hodgkin lymphoma: 39.8 to 3.8%), transfusion use increased (2 to 5.5%, 5.5 to 18.2%, and 4.5 to 9.1%, respectively), and median number of ESA administrations declined. Across all tumor types, proportion of patients initiating an ESA with hemoglobin >10g/dL was <10% from 2011 onward. In recent years, cancer patients who are older, female, and have chronic kidney disease or moderate or severe liver disease were most likely to receive ESAs. Subsequent to important regulatory and reimbursement ESA-related actions, total ESA exposure among cancer patients receiving myelosuppressive chemotherapy declined substantially. Today, fewer patients receive ESA therapy, and among those treated, more are initiated at hemoglobin levels <10g/dL and are exposed for a shorter duration, consistent with current product labeling.

Initiation of erythropoiesis-stimulating agents and outcomes: a nationwide observational cohort study in anaemic chronic kidney disease patients.

In 2012, new clinical guidelines were introduced for use of erythropoiesis-stimulating agents (ESA) in chronic kidney disease (CKD) patients, recommending lower haemoglobin (Hb) target levels and thresholds for ESA initiation. These changes resulted in lower blood levels in these patients. However, there is limited evidence on just when ESA should be initiated and the safety of a low Hb initiation policy. In this observational inception cohort study, Swedish, nephology-referred, ESA-naïve CKD patients (n = 6348) were enrolled when their Hb dropped below 12.0 g/L, and they were followed for mortality and cardiovascular events. Four different ESA treatments were evaluated applying dynamic marginal structural models: (i) begin ESA immediately, (ii) begin ESA when Hb <11.0 g/dL, (iii) begin ESA when Hb <10.0 g/dL and (iv) never begin ESA in comparison with 'current practice' [the observed (factual) survival of the entire study cohort]. The adjusted 3-year survival following ESA begun over a range of Hb (from <9.0 to 12.0 g/dL) was evaluated, after adjustment for covariates at baseline and during follow-up. Overall, 36% were treated with ESA. Mortality during follow-up was 33.4% of the ESA-treated and 27.9% of the non-treated subjects. The adjusted 3-year survival associated with ESA initiation improved for subjects with initial Hb <9.0 to 11 g/dL and then decreased again for those with Hb above 11.5 g/dL. Initiating ESA at Hb <11.0 g/dL and <10.0 g/dL was associated with improved survival compared with 'current practice' [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.79-0.89 and 0.90; 95% CI 0.86-0.94, respectively] and did not increase the risk of a cardiovascular event (HR 0.93; 95% CI 0.87-1.00). In non-dialysis patients with CKD, ESA initiation at Hb < 10.0-11.0 g/dL is associated with improved survival in patients otherwise treated according to guidelines.

Abstract P5-15-18: Hemoglobin levels and quality of life in patients with breast cancer and symptomatic chemotherapy-induced anemia enrolled in the eAQUA study

Abstract Background: Fatigue associated with chemotherapy-induced anemia (CIA) is common in patients with breast cancer, and can have adverse effects on quality of life (QoL). Erythropoiesis-stimulating agents (ESAs) reduce the need for transfusions and may improve QoL in patients with symptomatic CIA. Information on hemoglobin (Hb) levels and effects of fatigue on QoL in patients with breast cancer and CIA in real-world clinical practice is limited. Methods: The Electronic Assessment of Quality of Life in Patients With Symptomatic CIA (eAQUA) study evaluated improvements in QoL for patients with CIA receiving ESAs who had an increase in Hb of ≥1 g/dL by week 9. This phase 4, international, longitudinal, prospective, observational study enrolled patients with solid tumors who received chemotherapy and had symptomatic anemia. Patients received ESA therapy for up to 13 weeks based on European indication. The primary outcome was the proportion of patients with increase in Hb ≥1 g/dL and improvement in fatigue-related QoL based on the Functional Assessment of Cancer Therapy-Fatigue (FACT-F; scale = 0 to 52 with lower scores indicating worse fatigue) subscale scores and fatigue Visual Analog Scale (VAS; scale = 0 to 100 with higher scores indicating worse fatigue) from baseline to week 9. FACT-F change scores were anchored to VAS change scores to determine the minimally important difference (MID) for improvements in QoL. Patients with a FACT-F change score that was ≥ the MID were considered to have an improvement in QoL. For Hb and QoL outcomes, week 9 data were those assessed closest to on-treatment day 57 (after initiation of ESA) and within on-treatment days 43 to 70 inclusive, to account for different ESA dosing schedules and the observational nature of the study. Secondary outcomes included rates of red blood cell (RBC) transfusions or iron supplementation during the study. Results: Of 1262 patients enrolled in eAQUA, 289 had breast cancer and were included in the full analysis set (FAS; had at least one ESA dose); of these, 152 patients were eligible to be included in the primary analysis set (PAS; had QoL and Hb data available at baseline and week 9). At baseline, mean (standard deviation [SD]) Hb was 9.4 (0.6) g/dL; mean (SD) FACT-F and VAS scores were 27.1 (10.5) and 52.7 (22.8), respectively, in the FAS. Mean (SD) change from baseline at week 9 was 1.3 (1.3) g/dL for Hb; 4.1 (10.8) score change for FACT-F; and 4.7 (25.9) score change for VAS in the FAS. A total of 54 (18.7%) patients in the FAS required an RBC transfusion and 79 (27.3%) received iron supplementation. At week 9, 77 of 152 patients in the PAS had achieved improvement in fatigue-related QoL (50.7%; 95% confidence interval [CI] = 42.7%, 58.6%); 93 patients had increased Hb ≥1 g/dL (61.2%; 95% CI = 53.4%, 68.9%); and 59 patients (38.8%; 95% CI = 31.1%, 46.6%) had achieved both improvement in fatigue-related QoL and increased Hb ≥1 g/dL. Conclusions: In this exploratory subgroup analysis, patients with breast cancer and symptomatic CIA treated with ESAs achieved clinically meaningful improvements in fatigue-related QoL and Hb levels. Citation Format: Mario Airoldi, Dominique Spaeth, Joan Van den Bosch, Charalambos Christofyllakis, Laura Belton, Chet Bohac, Jan-Henrik Terwey, Giuseppe Tonini. Hemoglobin levels and quality of life in patients with breast cancer and symptomatic chemotherapy-induced anemia enrolled in the eAQUA study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-18.

Sompas: a Prospective, Non-Interventional Study (Nis) of the Management of Symptomatic Chemotherapy (Ct)-Induced Anemia (Cia) in Patients (Pts) with Colorectal (Crc), Breast (Bc) or Lung Cancer (Lc) in Austria (At) and Switzerland (Ch)

ABSTRACT Aim: SOMPAS investigated the clinical practice of symptomatic CIA management in AT and CH. Methods: Design: multi-center, prospective NIS. Eligibility: adults with CRC, BC or LC and ≥3 cycles of planned CT in combination with an erythropoiesis-stimulating agent (ESA). 1° objective: adherence to EORTC guidelines and ESA label. 1° outcome: Hb threshold at ESA initiation; 2° outcomes: Hb trajectory, ESA treatment patterns, red blood cell transfusions (RBCTs), iron supplementation. Hb values within 28 days after RBCTs were excluded. Results: 270/273 enrolled pts were analyzed (3 received no ESA). Median age at baseline (BL) was 64.0 yrs (range 33-86) and 67% of pts were female and 12% had ECOG ≥2. Tumors: 47% BC, 37% LC, 21% CRC; 81% stage III-IV disease. CT use: 36% platinum, 22% taxane, 15% anthracycline, 58% other; 77% palliative intent. Most frequent anemia symptoms at BL: 72% fatigue, 19% pallor, 16% respiratory distress, 15% depression, 29% other. Indications for ESA use by Hb target ( Hb outcomes: Hb range at ESA initiation 9-11 g/dL (EORTC)a ≤10 g/dL (label) 71% (n = 191) 49% (n = 132) Mean Hb (95% CI) ESA initiation (n = 270) ESA end of treatmentb (n = 241) 10.2 g/dL (10.1-10.3)c 10.9 g/dL (10.7-11.1)c Hb >10 g/dLd 90% (n = 243) aexcludes pts with Hb >11-11.9 g/dL and declining Hb trend; blast available Hb value; cdifference statistically significant [non-overlapping CIs]; din ≥1 cycle Conclusions: ESAs were used as per EORTC guidelines in 71% of pts, 51% of pts were initiated at Hb >10g/dL. Pts achieved a significant increase in Hb during ESA treatment; 90% had a Hb >10 g/dL. A large proportion of pts avoided RBCTs while treated with an ESA. Disclosure: G. Delmore: declares to be a member of the Amgen advisory board; C. Jaeger, C. Bast and I. Pezzani: declares to be an Amgen employee and to hold Amgen stock; M. Schmid: declares to be a member of the Amgen advisory board. All other authors have declared no conflicts of interest.

Effect of erythropoiesis-stimulating agent policy decisions on off-label use in myelodysplastic syndromes.

Erythropoiesis-stimulating agents (ESAs) are widely used to treat anemia associated with myelodysplastic syndromes (MDS) as an off-label indication. In early 2007, the U.S. Food and Drug Administration (FDA) released safety alerts and mandated label changes, and the Centers for Medicare & Medicaid Services (CMS) implemented a National Coverage Determination (NCD) in August 2007, dramatically restricting ESA coverage based on specific clinical parameters in non-MDS patients. We sought to determine the effect on ESA use in MDS, examining both treatment initiation and concordance with guidelines designed to target patients most likely to benefit from therapy. We determined receipt of ESA within 6 months of diagnosis. For ESA recipients, we operationalized three National Comprehensive Cancer Network guidelines: serum erythropoietin determination before ESA initiation, transfusion-independent at ESA initiation, and initial ESA treatment episode of >= 8 weeks. Logistic regression models tested the effect of time (half-year increments pre-post the August '07 CMS NCD implementation), controlling for demographics and health status. 17,491 (61.1%) of 28,627 beneficiaries with MDS received ESAs. ESA use increased prior to the reference period (Jan.-July 2007), but declined beginning in August 2007, the date of NCD implementation (marginal probability =-0.05, p-value<0.01). Concordance with treatment guidelines changed during the observation period, with increased rates of serum erythropoietin levels, but declined in the other two guidelines. These results suggest a mixed pattern of change in the face of the FDA safety warnings and CMS NCD in MDS and highlight the importance of monitoring for unintended consequences of policy changes.

Patterns of erythropoiesis-stimulating agent use among Medicare beneficiaries with myelodysplastic syndromes and consistency with clinical guidelines

Erythropoiesis-stimulating agents (ESA) are used commonly to reduce symptomatic anemia in patients with myelodysplastic syndromes (MDS). We assessed population-based patterns of ESA use relative to treatment guidelines using data from the Surveillance, Epidemiology, and End Results (SEER) registries, with linked Medicare claims providing detailed treatment data from 2001 through 2005.The study found widespread use (62%) of ESA in Medicare beneficiaries with MDS. Similar ESA use rates regardless of risk status, low frequency (45%) of serum erythropoietin determination prior to ESA initiation, and high prevalence (60.4%) of short-duration ESA episodes suggest clinically important discrepancies between actual practice and guideline-recommended therapy.

Management of Anemia in Advanced Breast and Lung Cancer Patients in Daily Practice: Results of a French Survey

The purpose of this French survey was to evaluate the adherence to the guidelines (European Organisation for Research and Treatment of Cancer [EORTC]; American Society of Clinical Oncology [ASCO]; French Standards, Options, and Recommendations [SOR]; European Society of Medical Oncology [ESMO]; Food and Drug Administration [FDA]; and National Comprehensive Cancer Network [NCCN]) for the use of erythropoiesis-stimulating agents (ESAs) in the management of chemotherapy- induced anemia for patients with advanced breast and lung cancers. Two-hundred patients were recruited for each malignancy. The collected items were characteristics of ESA initiation, treatment, adjustment, and discontinuation. Metastatic breast cancer and stage IIIb/IV lung cancer patients who had received chemotherapy were eligible. The endpoint was to compare French daily practices with national and international guidelines. From November 2010 to December 2010, 185 breast cancer and 227 lung cancer files were collected. The main reason of ESA initiation was the correction of anemia (49% and 44%, respectively). The median baseline value of hemoglobin was 9.5 g/dL, and the median target value was 12 g/dL. The mean duration of treatment was 12 and 14 weeks, respectively. The mean gain of hemoglobin was 2.3 g/dL and 1.9 g/dL, respectively. In the breast cancer population, two patients (1%) developed a thromboembolic event, which is lower than what has been described in the literature. An iron supplement was prescribed in 55% of patients with breast cancer and 49% of those with lung cancer, with about one-third administered intravenous iron. The interruption of ESA and chemotherapy was synchronous in about 20% of cases, and was earlier in lung cancer patients than in breast cancer patients. The quality and the rigor of the sampling represent one of the key points of this survey. The French and international guidelines for the use of ESA were well respected by the physicians. Overall, the management of chemotherapy-induced anemia was improved compared with what was described in the historical surveys (European Cancer Anaemia Survey [ECAS], French Anaemia Cancer Treatment [F-ACT]).

Transfusion risk in cancer patients with chemotherapy-induced anemia when initiating darbepoetin alfa therapy at a baseline hemoglobin level of &lt;9 g/dL versus 9 to &lt;10 g/dL versus ≥10 g/dL: an exploratory analysis of a phase 3 trial

Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia (CIA). Safety concerns have prompted changes to the ESA-product information, which now recommends initiating ESAs at hemoglobin (Hb) levels < 10 g/dL (US) or ≤ 10 g/dL (EU). The present exploratory analysis of a DA trial examined how baseline-Hb levels at ESA initiation affect transfusion rates, Hb response, and safety outcomes in CIA patients. Data were retrospectively analyzed from a phase 3 trial of CIA patients randomised to 500 mcg DA every 3 weeks (Q3 W) or to 2.25 mcg/kg DA weekly (QW) for 15 weeks. In the current analysis, data were reanalyzed by baseline-Hb categories of <9 g/dL (n = 126), 9 to <10 g/dL (n = 225), and ≥ 10 g/dL (n = 354). The Q3 W and QW groups were combined. Transfusion rates were highest in the <9 g/dL baseline-Hb group in all time periods examined. The Kaplan-Meier percentage (95% CI) of patients achieving Hb ≥ 10 g/dL was 68% (59, 78) and 88% (82, 92) in the <9 g/dL and 9 to <10 g/dL baseline-Hb groups, respectively. With lower baseline-Hb, incidence of a ≥ 1 g/dL-Hb rise in 14 days progressively decreased. Incidence of venous thromboembolic events was similar in all baseline-Hb groups and similar between patients with or without a ≥ 1 g/dL-Hb rise in 14 days. Overall, transfusion risk increased and Hb response decreased at lower baseline-Hb levels in this exploratory analysis. When following ESA-product information to initiate ESAs at Hb ≤ 10 g/dL, the greatest benefit may be achieved when initiating close to 10 g/dL. Prospective studies are needed to further examine this hypothesis.

Rate of hemoglobin (Hb) decline from less than 10 g/dl to less than 9 g/dl in placebo-treated patients (pts) receiving chemotherapy: A pooled analysis of data from six randomized darbepoetin alfa trials.

e19637 Background: Cancer pts often develop chemotherapy-induced anemia (CIA), which can be treated with erythropoiesis-stimulating agents (ESAs). Controlled trials have shown that ESAs reduce transfusion needs in CIA pts. Recent changes to the ESA product labels restricted ESA use in CIA (i.e., ESAs are now initiated in the US at Hb < 10 g/dL and in the EU at Hb ≤ 10 g/dL). Some evidence suggests pts with low Hb (< 9 g/dL) at ESA initiation are at higher risk for transfusion. Understanding how quickly CIA pts transition from Hb < 10 g/dL to < 9 g/dL may therefore help optimize ESA use. Methods: An exploratory, pooled analysis was performed in a subset of placebo-treated pts from 6 randomized darbepoetin alfa CIA trials. Pts had baseline Hb ≥ 10 g/dL and Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of pts with transfusions, Hb < 9 g/dL, and Hb < 8 g/dL (or transfusion) by week 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Results: Of 411 pts analyzed, 59% were men, 97% were white, 72.3% had lung cancer, 87.8% had known ≥ stage III cancer, and 79.3% had an ECOG status ≤ 1. The mean (Q1, Q3) age was 62.5 (56, 70) years, and mean (Q1, Q3) baseline Hb was 11.26 (10.47, 12.00) g/dL. Median time (95% CI) to Hb < 9 g/dL was 5 weeks (4, 7). Time-to-event analyses indicated that over half (54%) of pts transitioned from Hb < 10 g/dL to < 9 g/dL by 6 weeks (Table). Incidence of transfusion from Hb < 10 g/dL and incidence of Hb < 8 g/dL (or transfusion) from Hb < 10 g/dL are shown (Table). Conclusions: This exploratory analysis suggests pts receiving chemotherapy transition quickly from Hb < 10 g/dL to Hb < 9 g/dL. As evaluating the suitability of ESAs for CIA pts may take time, doing so early could mitigate some risk of pts requiring transfusions or reaching low Hb levels. Incidence of events from Hb < 10 g/dL for 411 placebo-treated pts receiving chemotherapy. Transfusion Hb < 9 g/dL Hb < 8 g/dL or transfusion Events, n (%) 178 (43%) 244 (59%) 196 (48%) K-M% of events (95% CI) By week 0 3% (2, 6) 13% (10, 16) 4% (3, 7) By week 3 20% (16, 24) 40% (35, 45) 23% (20, 28) By week 6 32% (27, 36) 54% (49, 59) 37% (33, 42) By week 9 39% (35, 44) 58% (53, 63) 45% (40, 50)

Outcomes of erythropoiesis-stimulating agents in cancer patients with chemotherapy-induced anemia

PurposeTo assess the clinical and economic outcomes among patients with chemotherapy-induced anemia (CIA) treated with United States Food and Drug Administration-approved fixed dosing regimens of erythropoiesis-stimulating agents (ESA).MethodsData were employed from the Dosing and Outcomes Study of Erythropoiesis-Stimulating Therapies (DOSE) registry to evaluate CIA patients who were initiated on either epoetin alfa (EPO) 40,000 Units (U) or darbepoetin alfa (DARB) 500 micrograms (mcg) between January 1, 2006 and May 8, 2009. Study measurements included ESA treatment dose and dose ratio, changes in hemoglobin (Hb) levels from baseline, and cumulative ESA costs.ResultsFive hundred forty patients treated in 44 clinical centers were evaluated, of which 420 were initiated on EPO 40,000 U and 120 were initiated on DARB 500 mcg. Both cohorts had similar baseline characteristics, although EPO patients were less likely than DARB patients to have received iron supplementation before ESA initiation (11.4% EPO vs. 20.0% DARB, p = 0.015). The EPO-to-DARB dose ratio based on cumulative ESA dose was 169:1 (U EPO: mcg DARB). EPO patients showed statistically greater Hb improvement compared to DARB patients, and compared to EPO patients, a greater proportion of DARB patients required a blood transfusion (13.9% EPO vs. 22.5% DARB, p = 0.026). Mean cumulative ESA cost was significantly lower for EPO patients than DARB patients ($4,261 EPO vs. $8,643 DARB, p < 0.0001).ConclusionsThese findings reported that patients with CIA achieved more favorable clinical and economic outcomes if initiated with EPO 40,000 U vs. DARB 500 mcg.