Epoetin Beta Treatment Research Articles

Treating Posttransplant Anemia With Erythropoietin Improves Quality of Life but Does Not Affect Progression of Chronic Kidney Disease.

Posttransplant anemia affects 30% to 45% of kidney transplant recipients and is associated with increased morbidity. However, there is lack of evidence about safe hemoglobin levels after erythropoietin treatment. Studies are needed to better understand the potential benefits and risks, as well as to define safe target hemoglobin ranges in these patients. In this single-center exploratory, open-label randomized controlled trial, kidney trans-plant recipients with anemia 3 months posttransplant were either treated with epoetin beta to a hemoglobin target level of 11.5 to 13.5 g/dL (n = 28) or given no treatment (n = 27). Treatment effects on graft function and health quality of life were assessed. After 2 years, hemoglobin concentrations were significantly higher in the epoetin beta treatment group than in the no treatment group (12.3 ± 0.18 vs 9.99 ± 0.22 g/dL; P < .0001). Estimated glomerular filtration rate, calculated by Modified Diet in Renal Disease 7, declined by 1.7 mL/min (interquartile range, -6 to 4.24) in the epoetin treatment group and by 4.16 mL/min (interquartile range, -12.42 to 2.78) in the no treatment group (P = .32). Rate of progression, determined by estimated glomerular filtration rate slope, was not significantly different between groups (-0.09 ± 0.1 vs -0.12 ± 0.15 mL/min for treated vs not treated; P = .78). Moreover, we observed no significant differences in proteinuria and blood pressure. Treated patients had greater improvements in the vitality and mental health domains of the Medical Outcomes Short Form Health Survey quality of life scores. Treatment of anemia in kidney transplant recipients to a hemoglobin level of 11.5 to 13.5 g/dL with erythropoietin improves some quality of life scores. The treatment was safe and not associated with adverse outcomes. There were no changes in rate of decline of graft function.

Low Hemoglobin Levels and Hypo‐Responsiveness to Erythropoiesis‐Stimulating Agent Associated With Poor Survival in Incident Japanese Hemodialysis Patients

Although erythropoiesis-stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi-center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10,310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three-year survival rate of patients with <9 g/dL Hb levels after 6 months was 74.1%, which was significantly lower than 89.3% for patients with Hb levels 10 to 11 g/dL; the adjusted hazard ratio (HR) was 2.08 (95% CI, 1.57-2.77; P < 0.0001). Moreover, the 3-year survival rate for poor responders defined by Hb levels <10 g/dL and weekly epoetin beta doses ≥ 9000 IU during the induction phase was 71.6%, which was significantly lower than 89.4% for the group, which had Hb levels 10 to 11 g/dL excluding poor responders and those with excursion; the HR was 1.71 (95% CI, 1.13-2.60; P = 0.0118). Adverse events related to the treatment were reported in 71 of 10,310 patients (0.69%). These findings suggest that the achieved low Hb levels and poor response to ESA therapy are significantly associated with high mortality.

Changes in Hepcidin and Reticulocyte Hemoglobin Equivalent Levels in Response to Continuous Erythropoietin Receptor Activator Administration in Hemodialysis Patients: A Randomized Study

Inadequate iron availability limits the response to erythropoiesis-stimulating agents (ESA) and hepcidin is a key regulator of iron metabolism. However, there is little information concerning time-dependent changes in hepcidin in response to the change of accelerated iron demand due to ESA-induced erythropoiesis. In this study, iron-related parameters, including hepcidin levels, were explored in comparison to patients receiving continuous erythropoietin receptor activator (CERA) and epoetin beta (EPO) treatment. Ninety-four patients were randomized to receive monthly CERA (N = 47) or EPO three times/week (N = 47). After the titration period, hemoglobin levels and iron-related parameters were examined. Data for 71 patients were evaluated (CERA, N = 34; EPO, N = 37). Compared with EPO treatment, CERA treatment caused significant decreases within 1 week in hepcidin (-93.5 ± 46.9 vs. -1.3 ± 38.3 ng/mL, P < 0.01), reticulocyte hemoglobin equivalent (Ret-He) (-4.03 ± 2.64 vs. -1.13 ± 1.41 pg, P < 0.01), ferritin (-58.9 ± 30.5 vs. -12.2 ± 23.8 ng/mL, P < 0.01) and transferrin saturation (-13.2 ± 9.1 vs. 1.0 ± 11.9%, P < 0.01) and significant increases within 2 weeks in the levels of hemoglobin (0.42 ± 0.38 vs. -0.02 ± 0.48 g/dL, P < 0.01). In conclusion, hepcidin, Ret-He, ferritin and transferrin saturation levels decreased within 1 week and hemoglobin increased within 2 weeks after CERA administration. Time course of iron-related parameters including hepcidin demonstrated accelerated iron utilization appropriately according to ESA-induced erythropoiesis.

Meta‐analysis of epoetin beta and darbepoetin alfa treatment for chemotherapy‐induced anemia and mortality: Individual patient data from Japanese randomized, placebo‐controlled trials

Erythropoiesis-stimulating agents (ESA) reduce the need for transfusions and improve the quality of life in patients receiving chemotherapy, but several clinical trials have suggested that ESA might have a negative impact on survival. To evaluate the efficacy and safety of ESA, epoetin beta and darbepoetin alfa, including their impact on overall survival and thromboembolic events, we conducted an individual data-based meta-analysis of three randomized, placebo-controlled trials studying Japanese patients with chemotherapy-induced anemia. All trials were conducted in compliance with Good Clinical Practice. A total of 511 patients with solid tumor or lymphoma (epoetin beta or darbepoetin alfa, n=273; placebo, n=238) were included. The ESA significantly reduced the risk of transfusion (relative risk, 0.47; 95% confidence interval, 0.29-0.76). No significant effect of the ESA on overall survival was observed (unadjusted hazard ratio, 1.00; 95% confidence interval, 0.75-1.34). A prespecified subgroup analysis showed no strong interaction between the baseline hemoglobin concentration and the effect of ESA on overall survival. Among the ESA-treated patients, the highest hemoglobin achieved during the treatment period in each patient had no impact on mortality. No increase in thromboembolic events was observed in the ESA-treated patients (0.7% vs 1.7% placebo). The ESA reduced the risk of transfusion without a negative impact on the survival of patients with chemotherapy-induced anemia.

Continuous Erythropoietin Receptor Activator Enhances Iron Metabolism by Hepcidin Down-Regulation and Maintains Stable Hemoglobin Levels by Controlling Maturation Rate of Erythroid-Lineage Cells

Abstract 1031 Background and aims.Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a chemically synthesized erythropoiesis-stimulating agents (ESA) and differs from epoetin-beta (EPO) through the integration of an amide bond between an amino group of EPO and a specific, linear methoxy polyethylene glycol. Hematopoietic progenitor cells are known to show dynamic changes after ESA administration through erythropoietin signaling. It is also well known that C.E.R.A. increases the number of red blood cells and hemoglobin (Hb) levels and provides stable control of Hb levels in clinical and nonclinical studies, but the effects of C.E.R.A. on the maturation of erythroid-lineage cells and iron metabolism are still unclear. In the present study, we analyzed these effects to extract features of C.E.R.A. against EPO, existing ESA. Methods.C.E.R.A. was administered intravenously into male 8-weeks old C57BL/6 mice at 2 (C2) or 10 (C10) μg/kg in a single injection, and EPO was also administrated intravenously into the same conditioned mice at 0.8 (E0.8) or 2 (E2) μg/kg with 5 day continuous injection. Mice sera and bone marrow cells were collected on 0, 2, 5, 8, 11, and 14 days after first administration. Hematological parameters and serum iron concentrations were analyzed, and mouse serum hepcidin concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. We also analyzed the maturation of erythroid-lineage cells in bone marrow by flow cytometry technique, staining TER-119, transferring receptor (CD71), 7-Amino-Actinomycin D (7-AAD) and annexin V. Results.While Hb levels reached a maximum level on 5th day after first administration and then decreased in C2, E0.8 and E2 groups, high Hb levels were maintained after 5th day in C10 group. In this C10 group, mouse serum hepcidin concentrations were effectively down-regulated until 8th day after first administration, and serum iron concentrations also dropped to the lowest level on 5th day and then recovered. Interestingly, relatively-small erythroid-lineage cells were detected according to forward scatter (FSC) data by flow cytometry on 5th day in C10, which reflects transient iron-insufficient condition. TER-119 and CD71 were expressed on the surface of these small cells, and 7-AAD and annexin V were not. The percent of these TER-119(+) and CD71(+) cells which are at intermediate stage of erythroid-lineage cells maturation was increased and maintained continually in C10 group. Additionally, the percent of TER-119(+) and CD71 (−) cells which are at late stage of erythroid-lineage cells maturation in bone marrow was elevated sustainably and moderately. Discussion and Conclusions.These results strongly indicate that C.E.R.A. maintains stable Hb levels by enhancing iron metabolism and controlling maturation rate of erythroid-lineage cells with fewer administrations than EPO. Our previous study showed that EPO treatment mainly down-regulated serum hepcidin concentrations by indirect mechanisms through the involvement of bone marrow cells. Furthermore the present study suggests that C.E.R.A. down-regulates serum hepcidin concentrations more effectively than EPO, and promotes more effective use of iron storage for hematopoiesis. It is revealed that C.E.R.A. controls maturation rate of erythroid-lineage cells in association with enhancement of iron metabolism and provides stable control of Hb levels. It is possible to functional iron-insufficient state undermines the efficacy of C.E.R.A. treatment, but further investigation is needed. Disclosures:No relevant conflicts of interest to declare.

Red blood cell aggregation changes are depended on its initial value: Effect of long-term drug treatment and short-term cell incubation with drug

This study was designed to investigate whether the red cell aggregation depends on its initial level under drug therapy or cell incubation with bioactive chemical compounds. Sixty six subjects were enrolled onto this study, and sub-divided into two groups: the first group of patients (n = 36) with cerebral atherosclerosis received pentoxifylline therapy (400 mg, thrice daily) for 4 weeks. The patients of the second group were initially treated with Epoetin beta 10,000 units subcutaneously thrice a week, for 4 weeks. The second group - adult anemic patients (n = 30) with the confirmed diagnosis of solid cancer (Hb < 100 g/L). After 4 weeks of pentoxifylline treatment the red cell aggregation increased (p < 0.05) in the patients with initially low RBCA. On the other hand in the patients with initially high RBCA treatment with pentoxifylline reduced it markedly (p < 0.01). In vitro experiments with pentoxifylline RBC incubation resulted in a decrease of the initially high RBCA by 47% (p < 0.01), whereas in the sub-group with initially low RBCA it increased. It was observed that after 4 weeks of epoetin-beta treatment 75% the anemic patients with initially high RBCA had an aggregation lowering. The drop of aggregation was about 34% (p < 0.01). At the same time 25% of the study patients had a significant RBCA increase (p < 0.05) after treatment. The initially low red cell aggregation after incubation with epoetin-beta was markedly increased by 122% (p < 0.05). On the contrary initially high RBCA was reduced by 47% (p < 0.05). When forskolin (10 μM) was added to the RBC suspensions the RBCA was increased in sub-group of subjects with initially low aggregation and it was decreased in sub-group with initially high one. The similar RBCA changes were observed when RBC suspensions were incubated with vinpocetine, calcium ionophore (A23187), Phorbol 12-myristate 13-acetate (PMA) as a protein kinase C (PKC) stimulator. A major finding of this study is that the red cell aggregation effects of some drugs depend markedly on the initial, pre-treatment aggregation status of the patients. These results demonstrate that the different red blood cell aggregation responses to the biological stimuli depend strongly on the initial, pre-treatment status of the subject and the most probably it is connected with the crosstalk between the adenylyl cyclase signaling pathway and Ca2+ regulatory mechanism.

Anemia response and safety to epoetin-beta treatment in patients with neoadjuvant therapy prior to primary digestive tract tumor surgery

Anemia is common during anticancer treatment. This study aimed to evaluate the response and safety of treatment with epoetin-beta (EB) in patients with neoadjuvant therapy prior to primary digestive tract tumor surgery. In this open-label, single-arm study, patients (n = 22) with hemoglobin (Hb) levels below 11 g/dl who received epoetin-beta 450 IU/kg (30,000 IU) weekly until the hemoglobin level reached 12 g/dl. After treatment with EB, a mean absolute increment of 2.6 g/dl was attained. The mean hemoglobin values during the study were pretreatment 10.1 g/dl, half-way through treatment 12.3 g/dl, 4 weeks after concomitant radiochemotherapy 12.7 g/dl, the week prior to surgery 12.5 g/dl, and after surgery 10.9 g/dl. No patient required transfusion before or after surgery. The probability or risk of postoperative complications was 27.3%, and included one rectovaginal fistula, one parastomal hernia, one case of ileus and two surgical wound infections. In this series, downstaging was observed in 81.8% of patients, and downsizing in 90.9%. Most interestingly, histopathological complete response rate was achieved by 18.2%. Epoetin-beta (EB) treatment in our series of patients with digestive malignancies subjected to neoadjuvant radiochemotherapy proved effective and safe, avoiding the need for transfusion during surgery.

Multicenter open label study of epoetin beta prevention and treatment for anaemia in non-small cell lung cancer patients treated with chemotherapy prone to induce anaemia

20743 Background: To determine the efficacy and safety of epoetin beta in the prevention and treatment of anaemia in non-small cell lung cancer (NSCLC) patients treated with chemotherapy. Methods: It is a multicenter, open-label, single-arm study. All eligible patients receive treatment of epoetin beta subcutaneously 3 times weekly at the initial dose of 150 IU/kg for 16 weeks. Primary efficacy parameter is the percentage of patients with increase in haemoglobin values by ≥ 2 g/dl compared to baseline without blood transfusion in previous 6 weeks (defined as response rate). Secondary efficacy parameters are increase in haemoglobin,number and volume of blood transfusion per patient and red cell count. Safety includes blood pressure, adverse events and serious adverse event. Median progression-free survival (mPFS) is calculated only for the advanced NSCLC patients in the first line setting.Statistical computations are performed with SPSS13.0. Results: 26 male and 24 female NSCLC patients treated with chemotherapywere enrolled in this study from October 12, 2006 to December 8, 2006. Response rate of epoetin beta is 74% for intent-to-treatment (ITT) analysis population but 86% for Per-Protocol (PP) analysis population; haemoglobin has increased significantly since the 4th week and is significantly different among different duration of epoetin beta treatment, and change of red cell count is similar to that of haemoglobin. Fewer patients (4%, 2/50) need blood transfusion. After epoetin beta treatment, blood pressure shows no significant difference compared to the baseline. Safety of epoetin beta is good. Grade 3/4 adverse events: neutropenia 14%, diarrhea 2%, vomitting 2%, palpitation 2%, anemia 2%, oral ulcers 2% and arrhythmia (serious adverse events) 2%, all of which were not related to epoetin beta. When epoetin beta is used, mPFS was 152.0 days, 95% CI (115.9∼188.1) for those in the first line setting. Conclusions: Epoetin beta may prevent and treat anaemia in non-small cell lung cancer (NSCLC) patients treated with chemotherapy. No significant financial relationships to disclose.

Epoetin Beta with Intravenous Iron Results in Overall Cost Savings in a Population of Anemic Patients with Lymphoid Malignancies Not Receiving Chemotherapy.

Erythropoiesis-stimulating agents (ESAs) provide effective treatment for anemia in patients with cancer, but studies suggest that response rates can vary from 50 to 80%. One major reason why a patient may fail to respond to an ESA is functional iron deficiency (FID), defined as a failure to provide iron rapidly enough to meet the needs of erythropoiesis, despite the presence of sufficient iron stores. Consequently, concomitant intravenous (IV) iron supplementation has the potential to improve response to ESAs, thereby, allowing a decrease in dose requirements. A recent study of 67 anemic (hemoglobin [Hb] 9–11 g/dL) patients with lymphoid malignancies not receiving chemotherapy evaluated the Hb response (defined as an increase in Hb of ≥2 g/dL without transfusion up to Week 15) to epoetin beta 30 000 IU Once Weekly with or without IV iron sucrose (Hedenus et al. Leukemia. 2007; 21:627–632). Patients were iron replete at baseline, as shown by the presence of stainable iron in the bone marrow. This analysis aimed to investigate whether use of epoetin beta and IV iron is cost-effective compared with epoetin beta without IV iron, based on the results of this study. The analysis was performed from a Swedish societal perspective based on differences in overall costs (drug costs, laboratory tests and resource use) and differences in effect (Hb increase) during 16 weeks' treatment with epoetin beta with or without IV iron. All costs are presented in 2006 Swedish Kronor (SEK). In normal practice in Sweden, IV iron is administered by a nurse in an outpatient setting. Therefore, resource costs in this analysis included an estimate of costs of nurse time and all materials required for administration of IV iron, as well as the cost of travel to the clinic for the patient. Since 20% of patients attend with a companion, an estimate of the cost of loss of companion work time for 20% of visits was also included. In contrast, epoetin beta is usually self-administered in Sweden; thus, no resource costs for epoetin beta administration were included. In the intention-to-treat population (n=67), the Hb increase (mean 2.76 g/dL versus 1.56 g/dL, respectively; p=0.0002) and Hb response rate (87% versus 53%, respectively; p=0.0014) were significantly greater in patients receiving epoetin beta with IV iron compared with patients receiving epoetin beta without IV iron. Total cumulative dose of epoetin beta over the course of the study was lower in the epoetin beta with IV iron group (532 000 IU) than in the epoetin beta without IV iron group (629 000 IU; p=0.059). Overall mean cost per patient in the epoetin beta with IV iron group was SEK 56 411 and in the epoetin beta without IV iron group was SEK 60 666. Despite the additional costs of iron administration, epoetin beta treatment with IV iron resulted in overall cost savings of ∼7% compared with epoetin beta without IV iron, mainly due to reduced ESA dosages. Treatment of anemic patients with lymphoid malignancies not receiving chemotherapy with epoetin beta and IV iron resulted in better outcomes at lower cost compared with epoetin beta without IV iron. This suggests that epoetin beta with IV iron is a dominant (or superior) therapy at least from a Swedish perspective.

Epoetin Beta (Neorecormon®) Treatment for Anemia of Patients with Non-Myeloid Hematological Malignancy under Chemotherapy: Results of a Large Prospective Cohort Study.

Background: The efficacy of epoetin beta (E) is well documented in clinical trials in anemic cancer patients (pts). This study was conducted to assess E use, efficacy, safety and effect on quality of life in cancer pts, in usual practice.Methods: This prospective, multicenter, longitudinal, observational French study assessed a 4-month follow-up of informed consent cancer pts (including both solid tumors (ST) and non-myeloid hematological malignancies (H)) treated with E for chemotherapy-related anemia. Data were collected between January 2005 and March 2006. We only present here the results of the H subgroup.Results: Among 2809 pts, 675 had an H including 325 non-Hodgkin lymphoma (NHL), 181 multiple myeloma (MM) and 80 chronic lymphocytic leukemia (CLL). 52% of pts received their first line of chemotherapy, 24% their second one. At inclusion, Hb levels were distributed as follows: < 9 g/dl: 32%, [9–11[ g/dl, 56%, [11–13[ g/dl, 11%. At inclusion, endogenous erythropoietin rate was monitored for only 8% of pts, ferritin was available for 32%, transferrin saturation for 17% and reticulocytes for 24%. At initiation, pts received a median dose of 30000 U/week of E on a once weekly regimen schedule for 98% of pts. E was associated with iron supplementation in 20% of pts (1% IV). The mean Hb level increased from 10 g/dl [5 – 14] at baseline to 13 g/dl [7 – 17] in the entire cohort of H pts, from 10 g/dl [5 – 14] to 12 g/dl [7 – 16] in NHL pts, from 10 g/dl [6 – 13] to 13 g/dl [8 – 17] in MM pts and from 10 g/dl [6 – 13] to 13 g/dl [7 – 17] in CLL pts. Hb response rate (RR) was 56% (CI95: 51 – 61) in H pts, 53% (CI95: 46 – 60) in NHL pts, 57% (CI95: 48 – 66) in MM pts and 56% (CI95: 41 – 70) in CLL pts. 41% of patients were transfused at inclusion or during the study. Good performance status (PS≤1) (OR=1.6, CI95: 1.1–2.5), non platinum-based regimen (OR=2.4, CI95: 1.2–4.9) and iron supplementation (OR=2.6, CI95: 1.4–5.1) are identified both in univariate and multivariate analysis as predictive factors of Hb response. The mean of FACT score improved from 29 (CI95: 26–31) at initiation to 36 (CI95: 34–38) at the end of study (p<0.0001). Thromboembolic events were reported in 2% of patients.Conclusion: These results confirm the efficacy and safety of epoetin beta in routine practice for anemic patients with a non-myeloid hematological malignancy receiving chemotherapy. Epoetin beta improves the quality of life measured by FACT score.

About the infrequent thrombotic events during erythropoietin therapy of anemic ovarian cancer patients with chemotherapy

Thrombotic events are infrequently observed in erythropoietin treatments for the anemia in tumorous patients with chemotherapy. The manufacturers call attention to this possible side effect of all kind of such drugs. To estimate the amount of thrombotic events in erythropoietin administrations during epoetin treatments for ovarian cancer patients treated with antineoplastic drugs. 275 ovarian cancer patients were treated with erythropoietin in the Gynecologic Department at the National Institute of Oncology, Budapest, in the period between 2000 and 2006: 52 of them were given epoetin-alfa, 157 of them epoetin-beta and 66 of the patients received darbepoetin-alfa. Median age of the patients was 60 (ranges 22 and 84) years. Thrombotic events were detected in 3 patients out of the 275: one with epoetin-alfa and two times with epoetin-beta treatment (3/275 = 1,1%). No definite causal relationship was confirmed between the thrombotic events and the erythropoietin drugs. Thrombosis was infrequently monitored among the authors' patients similarly to the literature data.

P1-252: Epoetin beta treatment for anemia in lung cancer patients under chemotherapy: results of a large prospective cohort study

P1-252: Epoetin beta treatment for anemia in lung cancer patients under chemotherapy: results of a large prospective cohort study

Erythropoetin (epoetin beta) once weekly in anemic patients with advanced cancer of the stomach or gastroesophageal junction: Interim results of a randomized German AIO phase II trail

15133 Background: Tumor-related or chemotherapy-induced anemia is common in gastrointestinal cancer patients and results in reduced quality of life and worse prognosis. Thus, the effectiveness of erythropoetin (epoetin beta) treatment (EB) to achieve and maintain a target haemoglobin (Hb) level of ≥ 11 g/dl was assessed within a randomised German AIO phase II study to assess efficacy of irinotecan/capecitabine versus cisplatin/capecitabine in advanced gastric or lower esophageal cancer. Methods: Patients (pts) with untreated locally advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction (KPS ≥ 60%, &gt; one measurable lesion, adequate organ functions) were randomized to receive 3-weekly cycles of either irinotecan 250 mg/m2 d1 (arm A) or cisplatin 80 mg/m2 d1 (arm B). Capecitabine was administered at 2000 mg/m2 for 14 days in both arms. In both arms, EB (30,000 I.E. once weekly) was given at Hb of &lt; 11 g/dl and continued until Hb ≥ 12 g/dl. If after 4 treatment weeks, Hb increase was &lt; 0.5 g/dl, EB was increased to 30,000 I.E. twice weekly. FACT-An questionnaires were completed at each cycle. Results: At time of abstract submission, 81 pts were randomized to A (37 pts) or B (44 pts). 23 pts received at least 3 EB injections (A: 10 pts, B: 13 pts). Median Hb prior to EB was 10.5 g/dl (A: 10.4 g/dl, B: 10.5 g/dl) and median Hb at end of EB was 11.6 g/dl (A: 11.5 g/dl, B: 11.75 g/dl). During EB, 80 % of A and 77 % of B achieved target Hb of ≥ 11 g/dl with a median rise in Hb of 2.0 g/dl (A: 1.4 g/dl, B: 2 g/dl). 5 pts in A and 7 pts in B responded with a ≥ 1 g/dl rise in Hb during first 4 weeks. FACT-An questionnaires showed no change from baseline to end of EB. Among evaluable pts with EB (20 pts) versus without EB (34 pts), response (CR + PR) and tumor control rates (CR + PR + SD) were 60% vs 35% and 85% vs 70%, respectively. Conclusions: EB is effective in raising Hb levels in advanced or metastatic gastric cancer. Patients receiving EB tend to show a better response to chemotherapy. No significant financial relationships to disclose.

Once-weekly epoetin beta treatment in anemic patients with breast cancer receiving chemotherapy: Interim analysis of a multicenter, single arm study

19605 Background: Epoetin beta administered three times weekly is effective in the treatment of anemia in patients with malignancy. This study investigated the efficacy and safety of a more convenient and reduced frequency administration of epoetin beta 30,000 IU sc once weekly in anemic patients with early or metastatic breast cancer receiving chemotherapy (CT). Methods: Patients &gt;18 years with early or metastatic breast cancer receiving CT with hemoglobin (Hb) &lt;11 g/dL were enrolled in this open-label, single-arm, multicenter study. Patients received epoetin beta until Hb was = 12 g/dL. The primary endpoint was the proportion of patients with an Hb increase =2 g/dL from baseline or achievement of Hb =12 g/dL after 12 weeks of treatment in the absence of transfusion. Other endpoints included: median time to response, median change in Hb level after 12 weeks of treatment from baseline and proportion of patients with a Hb increase =1 g/dL at week 4. Adverse events (AEs), vital signs, and laboratory safety were recorded. Results: Interim data are presented for 101 patients (out of 200 patients enrolled) who had completed treatment to date. Patients’ characteristics were: median age 58 years (33–81), PS 0–1 88%, metastatic disease 49%, median baseline Hb 10.1 g/dL (7.8–11.7). Overall, 46% (95% CI: 35.5–57.6) of patients responded according to the primary end point, the median time to response was 42 days (95%CI: 15–103). Secondary objectives: median Hb increase after 12 weeks was 1.7 g/dL (CI95%: -1.6 to +5.4), at week 4 an Hb rise =1 g/dL was observed in 44% of patients (CI95%: 33.0–57.4). Overall, 13/101 (13%) patients required red blood transfusions, the median number of transfusion was 2. The incidence of treatment-related AEs (6.9%) was consistent with the current label for epoetin beta. Conclusions: These preliminary results indicate that Epoetin beta 30,000 IU once weekly is effective and well tolerated in patients with early or advanced breast cancer receiving CT. [Table: see text]

Epoetin beta treatment of chemotherapy induced anemia in cancer patients: Results of a large prospective cohort study

19582 Background: The efficacy of epoetin beta (E) is well documented in clinical trials in anemic cancer patients (pts). This study was conducted to assess E use, efficacy, safety and effect on quality of life in cancer pts, in usual practice. Methods: This prospective, multicenter, longitudinal, observational French study assessed a 4-month follow-up of informed consent cancer pts (including both solid tumors (ST) and hematological malignancies (H)) treated with E for chemotherapy-related anemia. Data were collected between January 2005 and March 2006. Results: Among 3100 pts enrolled by 423 specialists, 2810 were analysed. Pts’ characteristics were: mean age 63±13 yrs, male 50%, performance status 0 (13%), 1 (46%), =2 (41%). 74% of pts suffered from a ST and 26% from a H. The most frequent cancer types were lung (22%), breast (15%), non-Hodgkin lymphoma (12%), colon (9%), multiple myeloma (7%), ovary (7%), prostate (3%), head and neck (3%) and chronic lymphocytic leukemia (3%). The mean time from diagnosis to inclusion was 2 yrs. 52% of pts received their first line of chemotherapy, 25% their second one. 55% and 10% of ST and H pts received platinum based regimen, respectively. At inclusion, hemoglobin levels were distributed as follows: &lt; 9 g/dl (ST 14%, H 32%), [9–11 [g/dl (ST 70%, H 56%), [11–13 [g/dl (ST 16%, H 11%). Regarding pre-treatment biological tests, endogenous erythropoietin rate was controlled for only 3% of pts (ST 1% and H 7%, median 37 IU/ml [0; 388]), ferritin was available for 15% of pts (ST 11% and H 28%), transferrin saturation for 12% of pts (ST 10% and H 17%) and reticulocytes for 11% of pts (ST 7% and H 24%). At initiation, pts received a median dose of 30000 U/week of E on a once weekly regimen schedule for 98% of pts. E was associated with iron supplementation in 49% and 13% of ST and H pts, and with blood transfusion in 5% and 15% of ST and H pts. Conclusion: These preliminary results describe baseline characteristics of cancer patients treated with epoetin beta. The study suggests very few biological controls before initiation of E in routine practice. Final analyses of hemoglobin evolution and quality of life will be presented. [Table: see text]

Evaluation of beta globin mRNA as an early marker of haemoglobin response to epoetin treatment

Approximately 60% of anaemic cancer patients respond to epoetin treatment. An early marker of response would be valuable in order to avoid ineffective treatment. We have previously shown that beta globin mRNA increases rapidly after epoetin beta treatment of healthy controls. In the present study we have evaluated whether a change of this marker during the first 2 weeks of epoetin treatment could predict later Hb response in anaemic cancer patients. Twenty cancer patients with Hb <11 g/dl received epoetin beta (NeoRecormon) 10,000 IU three times weekly during 6 weeks. Hb, reticulocytes and beta-globin mRNA were followed. The latter was measured quantitatively using PCR via the 5' nuclease assay. Eleven patients responded with a Hb increase of >1 g/dl, nine were nonresponders. All responders increased in beta-globin mRNA within 2 weeks, mean 7.7 x base-line. With a cut-off of an increase of 3 x base-line value, we obtained a specificity of 45% and a sensitivity of 91% for the prediction of a later increase of Hb >1 g/dl. With a cut-off of 4x base-line, the specificity increased to 66%, but the sensitivity decreased to 82%. Beta globin mRNA increases before Hb in all responding patients. However, some non-responding patients also show an increase, and there is a trade-off between specificity and sensitivity as the cut-off level is set at different levels. Compared to reticulocyte count, beta-globin mRNA is more reliable in the individual patient, but the clinical usefulness of the assay needs to be evaluated in further studies.

Warning Flags for Erythropoiesis-Stimulating Agents and Cancer-Associated Anemia

A recent U.S. Food and Drug Administration (FDA) alert has raised further concerns about potential adverse effects of erythropoiesis-stimulating agents (ESAs) in anemic cancer patients who are not receiving chemotherapy [1]. The warning was issued following interim analysis of an investigator-led phase III trial of 989 patients with head and neck cancers randomized to receive darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) or placebo (Danish Head and Neck Cancer Group [DAHANCA] 10 study, http://www. dahanca.dk). The enrolled patients were anemic but were not receiving chemotherapy. The trial data showed that darbepoetin alfa was associated with a higher mortality than with placebo (hazard ratio, 1.25; confidence interval [CI], 1.04–1.51) and, furthermore, darbepoetin alfa did not reduce the need for blood transfusion [2]. Hard on the heels of the darbepoetin alfa alert, Roche announced that it had temporarily suspended recruitment into its phase II dose-finding study with Continuous Erythropoietin Receptor Activator (CERA) in anemic patients with advanced nonsmall lung cell cancer (NSCLC) receiving chemotherapy [3]. Very recently, an unplanned safety analysis resulted in closure of a randomized placebo-controlled trial of epoetin alfa in NSCLC patients with disease-related anemia [4]. This analysis suggested poorer overall survival in patients with NSCLC treated with erythropoietin (Epo) [4]. Anemia in cancer patients has a multifactorial etiology. Anemia may develop secondary to impaired production of Epo or a blunted response of erythroid precursors to Epo [5]. Anemia may be exacerbated by chronic blood loss from tumor sites or be secondary to chemotherapy and radiotherapy. Debilitating fatigue, if it is secondary to anemia, can be managed by blood transfusions or ESAs to improve the quality of life (QOL) for anemic cancer patients. Interestingly, the effect of Epo therapy on QOL as a prospective outcome is not entirely consistent [6, 7]. Darbepoetin alfa is a hyperglycosylated Epo analog with an extended serum half-life [8] compared with available recombinant human Epos (epoetin alfa [Procrit, Ortho Biotech, Bridgewater, NJ; Epogen, Amgen; or Eprex, Janssen-Cilag Ltd, High Wycombe, U.K.] and epoetin beta [NeoRecormon, Roche, Basel, Switzerland]). CERA incorporates methoxy-polyethylene glycol polymers, which increase its mass to 60 kDa, twice that of Epo, and substantially prolong its half-life to about 135 hours. Darbepoetin alfa and CERA therefore have the therapeutic advantage of requiring less frequent administration for anemia management. Previous reports have suggested that ESA therapy may be harmful to some groups of cancer patients. Henke and colleagues [9] described the outcome of epoetin beta treatment in a randomized trial of 351 anemic head and neck cancer patients undergoing radiotherapy. The therapeutic goal was normalization of hemoglobin to 14 g/dl in men and 13 g/dl in women. Unexpectedly, locoregional progression-free survival was worse in the Epo treatment arm compared with placebo. In the same year, another random-

Evaluation of beta Globin mRNA as an Early Marker of Hb Response to Epoetin Treatment.

BackgroundAnaemia is a very common complication of cancer, and treatment with erythropoietic stimulating agents (ESA) is an important part of the supportive care. However, only about 60% of cancer patients respond to ESA treatment. An early marker of ESA response would be very valuable in order to avoid ineffective treatment. So far, predictors and early markers of response are unreliable in individual patients. We have previously shown that beta globin mRNA increases rapidly after epoetin beta treatment of healthy controls. In the present study we have evaluated whether the level of expression of this marker during the first two weeks of ESA treatment could predict later Hb response in patients with anemia of cancer.Patients and methodsTwenty patients with malignant disease and Hb <10.5 g/dl, who had no change in anti-tumoral therapy within 6 weeks before entering or during the study, were treated with epoetin beta (NeoRecormon®) 10000 IU s.c. three times per week during 6 weeks. Other causes of anaemia than the cancer itself were excluded by normal levels of S-B12, S-folate, S-ferritin, S-haptoglobin, S-Fe, S-Transferrin (Tf) and Tf saturation. Microcytosis was not allowed and two F-Hb samples were negative. The diagnoses included 4 biliary, 5 pancreatic, 3 gynecologic, 2 breast-, 1 gastric and 1 prostate cancer, 3 multiple myelomas and 3 myelodysplastic syndrome patients.Samples were then taken twice weekly during the first two weeks of treatment, once weekly during week 3–6 for measurement of Hb, reticulocytes and β-globin mRNA, which was measured quantitatively using PCR via the 5′ nuclease assay.ResultsEleven patients responded with a Hb increase of >1 g/dL, 9 were nonresponders. All responders increased in beta globin mRNA within two weeks, mean 7.7 × baseline (range 1.4–13.8). However, 6/9 non-responders also increased (2.2–8 × baseline). There was no correlation between the degree of Hb elevation and increase in beta globin mRNA. With a cut-off of an increase of 3 times the baseline value, 1 responder was missed and there were 5 false positives, which means a specificity of 45% and a sensitivity of 91% for the prediction of a later increase of Hb> 1g/dL. If the cut-off was set at 4 × baseline, the specificity increased to 66%, but the sensitivity decreased to 82%.The reticulocyte count increased in 7/11 responders and in 3/9 non-responders. There was no correlation between the Hb increase and the elevation in reticulocytes and no correlation between increase in beta globin mRNA and reticulocytes.ConclusionsBeta globin mRNA increases before Hb after epoetin treatment in all responding patients. However, some non-responding patients also show an increase, and there is a trade-off between specificity and sensitivity as the cut-off level for prediction is set at different levels. Compared to reticulocyte count, beta globin mRNA is more reliable in the individual patient, but the clinical usefulness of the assay needs to be evaluated in larger studies.

Once-weekly epoetin beta (30,000 IU) in anemic patients with lung cancer receiving chemotherapy

Anemia occurs frequently in patients with lung cancer receiving chemotherapy and has a negative impact on quality of life (QoL). Erythropoietic proteins effectively increase hemoglobin (Hb) levels, reduce transfusion requirements and improve QoL in anemic patients with a range of malignancies. This prospective, observational study evaluated epoetin beta 30,000 IU once weekly in patients with lung cancer in a real-life, clinical-practice setting. Forty patients (72.5% with NSCLC and 27.5% with SCLC) were treated with epoetin beta during any cycle of chemotherapy when Hb decreased to <12 g/dL. Hb levels were assessed at regular intervals and transfusion needs were monitored throughout the study. In total, 72.5% of patients required epoetin treatment by the second cycle of chemotherapy. Epoetin beta treatment duration ranged from 1 to >9 (median 4) weeks. Mean (+/-S.D.) baseline Hb was 10.4+/-1.2 g/dL. Epoetin beta was associated with a rapid increase in Hb levels, with a mean increase of 1.3 g/dL by week 4. Most patients (95%) remained transfusion-free throughout the study. Epoetin beta was well tolerated. This early intervention strategy with epoetin beta 30,000 IU once weekly is an effective and well-tolerated therapy for anemia in patients with lung cancer.

Efficacy and Safety of Epoetin beta 30 000 IU Once Weekly in Anemic Patients with Non-Myeloid Malignancies Receiving Chemotherapy.

Background: Once weekly (QW) epoetin beta (NeoRecormon®) 30 000 IU rapidly increases hemoglobin (Hb) levels and prevents transfusions in patients with lymphoid malignancies (Cazzola et al 2003). The aim of this study was to evaluate the efficacy and safety of epoetin beta 30 000 IU QW in patients with non-myeloid malignancies.Methods: Adult anemic patients (Hb 8–12 g/dl) with non-myeloid malignancies, WHO performance status 0–2 and who were scheduled to receive chemotherapy (CT) entered into this multicenter, open-label, single-arm study. Patients received epoetin beta 30 000 IU QW for 16 weeks. Primary efficacy endpoint was the % of Hb responders during epoetin beta therapy. Hb response was defined to account for the Hb level at baseline: Hb level of 13 g/dl achieved in patients with baseline Hb 11–12 g/dl or Hb increase of 2 g/dl and/or Hb level of 12 g/dl achieved in those with baseline Hb < 11g/dl.Results: This analysis reports data of the first 98 patients (mean age 63.4 ± 12.4 years; 61% solid; 39% hematological malignancies). Overall, 67% of patients responded to epoetin beta treatment, with a greater number of patients with hematological malignancies (78.9%) obtaining a Hb response. Median time to response was 43 days. Mean Hb level at baseline was 10.1 ±1.04 g/dl. Hb levels increased to a mean of 12.8 ±1.75 g/dl over a median treatment period of 14 weeks with epoetin beta. Median Hb increase of 1.5 g/dl and 2 g/dl at 7 and 10 weeks, respectively, were recorded. A greater number of patients receiving non-platinum (Pt)-based CT responded (73.5%) than those receiving Pt-based CT (51.7%). At least one thromboembolic event (TEE) was observed in 5% of the patients. Only one TEE was considered to be related to the study treatment.Conclusions: Epoetin beta 30 000 IU QW is an effective and safe treatment of anemia in patients with non-myeloid malignancies, regardless of CT type and appears particularly effective in patients not receiving Pt-based CT or with hematological malignancies.