Erythropoiesis-stimulating Agents Exposure Research Articles

Real-World Impact of Luspatercept on Patients with Myelodysplastic Syndromes Requiring Red Blood Cell Transfusions and with Prior Exposure to Erythropoietin-Stimulating Agents: A United States Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are among the most common hematologic cancers in older US adults. MDS are characterized by abnormal bone marrow function leading to impaired production of blood cells, persistent cytopenia, and variable risk of progression to acute myeloid leukemia (AML). Since anemia is a common complication of MDS, many patients (pts) become dependent on red blood cell transfusions (RBCTs) and erythropoiesis-stimulating agents (ESAs) are the standard of care for patients with lower-risk MDS. In a randomized, double-blind, placebo-controlled phase 3 MEDALIST clinical trial, luspatercept, a first-in-class erythroid maturation agent, was shown to reduce the severity of anemia among transfusion-dependent (TD) pts with lower-risk MDS with ring sideroblasts (RS) status and who were refractory to prior ESA treatment (Fenaux P, et al. N Engl J Med 2020; 382:140-151). However, real-world evidence regarding the effect of luspatercept on transfusion burden among pts with MDS requiring RBCTs and with prior ESA exposure is currently limited. Aim: To describe clinical outcomes and MDS-related treatment patterns before and after the initiation of luspatercept among real-world pts with lower-risk MDS in the USA who required RBCTs before luspatercept initiation and were previously exposed to ESAs. Methods:In this retrospective claims-based cohort study, data from Symphony Health, a nationally representative database, (Jan 1, 2010 to June 30, 2022) were used to identify adults with ≥1 claim with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Pts were considered TD at luspatercept initiation if they had ≥1 claim for RBCT in the 8 weeks before index date, and ESA-exposed if they had ≥1 ESA claim at any point before or at luspatercept initiation. Pts with chemotherapy treatments, with a diagnosis for refractory anemia with excess blasts, or with AML during the study period were excluded as they were presumed to have higher-risk MDS. Pts were also excluded if they had prior use of hypomethylating agents (HMAs) or a diagnosis for β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months prior to index date (baseline period). Pt demographics and clinical characteristics were assessed during the baseline period. Pts' RBCT status (transfusion independent [TI] or TD) was measured in the 6 months after index date. A pt was considered 8-week TI if they had 0 RBCT in ≥1 rolling 8-week period in the 6 months after index date. 12-week, 16-week, and 24-week TI pts were defined similarly, using increasingly longer periods without RBCT. Pts' use of MDS-related treatment classes (ie, chemotherapy, ESAs, granulocyte-colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD] agent) was measured before and after index date until end of data availability or clinical activity (follow-up). Results:The population comprisedof240 pts with MDS who were TD and had ESA exposure before luspatercept initiation. The mean (standard deviation [SD]) age was 75.4 (5.4) years and 56.7% were male. About one fifth of pts received ≥2 treatment classes before luspatercept initiation (2: 17.5%; 3+: 1.7%). Most pts (64.2%) achieved 8-week TI in the 6 months after luspatercept initiation. Similarly, 53.8%, 43.3%, and 29.6% of pts achieved 12-, 16-, and 24-week TI in the 6 months after luspatercept initiation, respectively (Figure 1). The percentage of pts achieving 8-, 12-, 16-, and 24-week TI was numerically higher among pts with positive RS status than those with negative/unknown RS status (Figure 1). Most pts (64.2%) did not require any additional MDS-related treatments during the study follow-up period (mean (SD) 15.6 (7.3) months). The most common treatment classes used after luspatercept initiation were ESA (22.5%) and HMA (16.3%; Figure 2). Conclusions:The findings of this real-world study strongly corroborate clinical trial results, showing that luspatercept is highly effective in reducing transfusion dependence among ESA-exposed pts with lower-risk MDS who were TD before luspatercept initiation. In this study, over half of pts achieved 8-week and 12-week TI status during the follow-up period, and more than a quarter did not require any RBCT over a 24-week period. Further, most pts treated with luspatercept did not require any additional MDS-related treatments during the follow-up period.

Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review.

Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion.

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.

Association of erythropoiesis-stimulating agents and the incidence risk of cancer diagnosis among chronic dialysis patients: a nested case-control study.

Erythropoiesis-stimulating agents (ESAs) are the cornerstone of the treatment for anemia in end-stage renal disease (ESRD) patients. Although a correlation has been established between ESAs and increased tumor growth among patients with cancer-related anemia, an association with a higher incidence of cancer among chronic dialysis patients remains relatively unclear. We completed a nested case-control study in a cohort of 4574 patients who began chronic dialysis treatment between 1 January 2001 and 31 December 2007 in Quebec, Canada, utilizing dialysis registry and administrative databases exclusively to extract our data. We excluded patients with a prior diagnosis of cancer. Eligible cases were identified by the time of initial cancer diagnosis obtained from either the hospital's discharge or physician billing form. We then randomly selected up to 10 controls for each case. ESA exposure was evaluated between 6 and 9 months prior to the initial cancer diagnosis. The mean weekly exposure was used to categorize ESA usage as either a low dose (<30 µg/week), moderate dose (30-70 µg/week) or high dose (>70 µg/week). We estimated the association between ESAs and the risk of developing cancer using a multivariable conditional logistic regression. We identified 419 cases of cancer and 3895 matched controls during the study period. The use of ESAs was associated with a higher risk of cancer {odds ratio [OR] 1.04 [95% confidence interval (CI) 1.02-1.07]}. Specifically, patients in the high exposure group (>70 µg/week) had an increased risk of developing cancer [OR 1.77 (95% CI 1.18-2.66)] compared with patients in the unexposed group. High-dose ESA was associated with an increased incidence risk of new cancer diagnosis among chronic dialysis patients.

Factors precipitating erythropoiesis-stimulating agent responsiveness in a European haemodialysis cohort: case-crossover study.

PurposeHyporesponsiveness to erythropoiesis‐stimulating agents (ESAs) is clinically and economically important in the treatment of anaemia in chronic kidney disease (CKD) patients. Previous studies focused on baseline predictors of ESA hyporesponsiveness, rather than factors associated with the transition to this state. Reversibility of ESA hyporesponsiveness has also not been studied previously.MethodsCase‐crossover methodology was applied to a cohort of 6645 European CKD patients undergoing haemodialysis and prescribed ESAs. Ninety‐day ESA exposure periods were defined, haemoglobin (Hb) response was calculated using the last 30 days of one period and the first 30 days of the next, and periods were classified based on a median ESA dose (80.8 IU/kg/week) and a 10 g/dL Hb threshold. Clinical, dialysis and laboratory data from patients' first hyporesponsive ‘case’ period was compared with the preceding responsive ‘control’ period using conditional logistic regression. A similar approach was applied to hyporesponsiveness reversal.ResultsOf the patients, 672 experienced hyporesponsiveness periods with preceding responsive periods; 711 reversed to normality from hyporesponsiveness periods. Transition to hyporesponsiveness was associated with hospitalization, vascular access changes or worsening inflammation, with these factors accounting for over two‐thirds of transitions. Findings were largely insensitive to alternative ESA doses and Hb thresholds. Continued hospitalization, catheter insertion and uncontrolled secondary hyperparathyroidism were associated with a lack of regain of responsiveness.ConclusionsTransition to hyporesponsiveness is linked to the development of conditions such as hospitalization events, vascular access issues or episodes of systemic inflammation. However, a third of hyporesponsive episodes remain unexplained. © 2015 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.

Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer

Erythropoiesis-stimulating agents (ESAs) increase red blood cell (RBC) production in bone marrow by activating the erythropoietin receptor (EpoR) on erythrocytic-progenitor cells. Erythropoiesis-stimulating agents are approved in the United States and Europe for treating anaemia in cancer patients receiving chemotherapy based on randomised, placebo-controlled trials showing that ESAs reduce RBC transfusions. Erythropoiesis-stimulating agent-safety issues include thromboembolic events and concerns regarding whether ESAs increase disease progression and/or mortality in cancer patients. Several trials have reported an association between ESA use and increased disease progression and/or mortality, whereas other trials in the same tumour types have not provided similar findings. This review thoroughly examines available evidence regarding whether ESAs affect disease progression. Both clinical-trial data on ESAs and disease progression, and preclinical data on how ESAs could affect tumour growth are summarised. Preclinical topics include (i) whether tumour cells express EpoR and could be directly stimulated to grow by ESA exposure and (ii) whether endothelial cells express EpoR and could be stimulated by ESA exposure to undergo angiogenesis and indirectly promote tumour growth. Although assessment and definition of disease progression vary across studies, the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients, and preclinical data indicate a direct or indirect effect of ESAs on tumour growth is not strongly supported.

Venous thromboembolism (VTE) and erythropoiesis-stimulating agents (ESAs) in breast cancer: a single tertiary care center experience from the University of Arkansas for Medical Sciences (UAMS).

Abstract Abstract #6137 Introduction: ESAs have been associated with increased rates of death, myocardial infarction, stroke and venous thromboembolism(VTE) in dialysis patients especially when targeted to higher hemoglobin levels. VTE and progression of cancer have also been reported in cancer patients receiving ESAs with chemo- and/ or radiotherapy, without a strict correlation with hemoglobin levels. ESAs are the subject of intense scrutiny by the FDA and the center for Medicare and Medicaid Services. We conducted a retrospective cohort study of a relatively homogeneous group of breast cancer patients. The objectives were to detect any increased risk of VTE with ESA exposure, and to correlate it with the hemoglobin/hematocrit levels.&amp;#x2028; Methods: Data were extracted from Logician, an electronic medical record database used in the Medical Oncology Clinic at UAMS. The study cohort included breast cancer patients treated at UAMS with chemotherapy between July 1, 2004 and July 1, 2007. Patients with prior history of VTE were excluded. The patients were followed until September 9, 2007 for ESA(Erythropoietin/Darbepoietin) exposure and development of VTE. The association between ESA exposure and VTE development was assessed using Cox regression with ESA exposure as a time-dependent covariate, and the results were reported as the hazard ratio (HR) along with associated chi-square statistic and p value.&amp;#x2028; Results: 483 patients (482 female, 1 male) met the study inclusion criteria. Median (range) age was 56 yrs (27-89). 107 (22%) were African American, 361 (75%) were Caucasian, and 15 (3%) in other categories. 9 out of the total 483 pts (1.86%) developed a VTE [7 Deep Vein Thromboses (DVTs) and 2 pulmonary embolism (PE)]. 63 subjects (13%) were exposed to ESAs during the study period, and 1 of them developed a DVT. The mean Hgb/Hct in the 62 patients exposed to ESAs who did not develop VTE was 11.34/35.26; the 1 patient exposed to ESA with DVT had a Hgb/Hct of 12.5/37.9. Among the 420 patients not exposed to ESAs, 6 developed a DVT; their mean Hgb/Hct was 12.95/39.4. The 414 pts without a DVT had mean Hgb/Hct of 12.66/38.55. Comparisons of the Hgb/Hct values in the various groups with or without VTE and, with or without ESA exposure showed no significant differences between any of the groups. Cox regression showed little evidence of increased risk with ESA use for either VTEs in general (HR=1.83; X21=0.57, P=0.45) or DVT in particular (HR=1.08; X21=0.005, P=0.94).&amp;#x2028; Conclusions: The number of VTEs in the study patients was very small, and much lower than previous reports. There was no evidence of increased risk of VTE from ESA exposure. However, due to the small number of events, this study lacked the power to detect an ESA effect unless the effect was huge. On the other hand, the very small number of VTEs in the ESA- exposed patients to may reflect our conservative ESA usage in breast cancer patients, and is reassuring that when used appropriately, ESA use is safe. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6137.

Intravenous iron as standard of care in oncology: Opportunity lost

<h2>Abstract:</h2> In the past 4 months, the Centers for Medicare & Medicaid Services (CMS) has imposed restrictions on the use of eryth- ropoiesis-stimulating agents (ESAs) in oncology. ESAs can no longer be used to treat patients with hemoglobin (Hb) levels of more than 10 grams/dL or patients with cancer-related anemia who are not on chemotherapy. New recommendations to deny coverage of patients receiving curative (adjuvant) chemotherapy and patients with metastatic breast and head and neck cancer have been made by the Oncology Drug Advisory Committee (ODAC) to the Food and Drug Administration (FDA). ESAs are contraindicated in patients with untreated absolute iron deficiency. No International Statistical Classification of Diseases and Related Health Problems, 9th revision, code exists for iron-restricted erythropoi- esis (functional iron deficiency). This omission is particularly important, as aptly pointed out by Shord and Cuellar¹ in this issue of JAPhA, because five of five recent publications in the oncology literature (see article by Shord and Cuel- lar) have shown a markedly improved Hb response, decreased time to target Hb, decreased ESA exposure for equivalent benefit, and huge cost savings when intravenous (I.V.) iron was added to ESA therapy. These benefits, in all five papers, were independent of the baseline iron parameters, serum iron, total iron binding capacity, and serum ferritin. Adverse events with I.V. iron were negligible in all of the studies.

Intravenous iron improves efficacy and results in substantial savings in cost for patients receiving erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia

20664 Background: Annually approximately 800,000 patients receiving chemotherapy experience anemia. Of these approximately 380,000 are treated with ESAs, and many require transfusions. We conducted a retrospective review of anemia management in cancer patients receiving chemotherapy in an oncology practice in Maryland to assess the effectiveness of low molecular weight (LMW) iron dextran in reducing ESA exposure, cost of treatment, and decreasing transfusions. Methods: Living patients who recently received IV iron were screened for inclusion criteria: anemic, diagnosis of cancer <3 years prior, received chemotherapy, and ≥1 dose IV iron, with data for ≥12-weeks from first dose. Data were analyzed and compared to pooled transfusion rates from phase III epoetin trials and to published per patient per week costs of ESA and oral/no iron. Results: Forty patients met inclusion criteria: 58% received platinum-containing chemotherapy, most common cancer diagnoses were lung (38%) and breast (28%). Fifteen percent ...

Should Intravenous Iron Be the Standard of Care in Oncology?

Should Intravenous Iron Be the Standard of Care in Oncology?

Erythropoietin Therapy Does Not Benefit Transfusion-Dependent Primary Myelofibrosis Patients and Treatment Response Is Infrequent with a Baseline Hemoglobin Level ≥ 10 g/dL.

BACKGROUND: The potential risks of tumor growth promotion and thromboembolism associated with erythropoietin (Epo) therapy warrant cautious use of erythropoiesis stimulating agents (ESA). Recent data suggest a surprising and significant association between ESA use and increased incidence of leukemic transformation in primary myelofibrosis (PMF) (data from an analysis separately submitted for American Society of Hematology meeting, 2007). It is prudent, therefore, to avoid unnecessary ESA exposure in PMF, especially in patients with low likelihood of treatment response.METHODS: Diagnosis of PMF was based on World Health Organization criteria. Study inclusion required availability of treatment history with ESA and adequate follow-up. We excluded patients who were receiving hemoglobin-improving agents concomitantly with an ESA, such as prednisone, androgens, danazol, or thalidomide. Transfusion dependency was defined by a history of minimum 2 units of red blood cell transfusions in a 1-month period for a hemoglobin < 8.5 g/dL, not associated with bleeding. An adequate treatment response was defined as a minimum 2.0 g/dL increase in hemoglobin level or becoming transfusion-independent over a minimum 1-month period.RESULTS: A master database of PMF patients seen at the Mayo Clinic from 1976 through 2006 was queried to identify 43 patients (median age 67 years; 35% females) treated with ESAs and in whom adequate follow-up was available to determine response. Prior to ESA treatment, median hemoglobin was 9.2 g/dL (range 7.0–11.9), and 16 (37%) were red blood cell transfusion-dependent. In 25 patients, pre-treatment serum Epo level was available (median 34 mU/mL; range 2–323). Among the 43 study patients, 16 (37%) were previously treated with other PMF-specific therapies, and 18 (42%) were receiving cytoreductive treatment concurrent with an ESA. Overall, 23% of patients (10 of 43) responded to treatment with ESA. The response rate was 0% (0 of 16) in the transfusion-dependent group compared to 37% (10 of 27) in the transfusion-independent group (p=0.007). Among the transfusion-independent patients, the proportion of ESA responders was significantly higher in the presence of a baseline hemoglobin level < 10 g/dL prior to treatment (p=0.009). ESA response was not correlated with baseline serum Epo level in the context of either all 43 study patients (p=0.68) or the 27 transfusion-independent patients (p=0.39). ESA response was not affected by PMF-specific treatment history (p=0.46), use of concurrent cytoreductive therapy (p=0.28), cytogenetic findings (p=0.62), JAK2V617F presence (p=0.69) or its allele burden at time of initial PMF diagnosis (p=0.16).CONCLUSIONS: Clear benefit of ESAs in PMF is limited to red blood cell transfusion-independent patients and those with baseline hemoglobin levels less than 10 g/dL.