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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.

8230 Background: The aim of this study was to determine whether epoetin treatment in solid tumor patients receiving platinum (Pt)-based chemotherapy (CT) might prevent anemia and improve patients’ ...

8141 Background: Many patients with metastatic breast cancer are treated with anthracycline and/or taxane-based chemotherapy; such therapies produce a high incidence of anemia. The aim of the BRAVE...

5102 Background: Recent meta-analyses in anemic patients with cancer have shown that epoetins do not have a negative impact on survival and show a trend towards reducing the risk of disease progres...

5121 Background: Patients with advanced cervical cancer frequently suffer from anaemia. Additionally, concomitant anaemia is aggravated by radiochemotherapy (RCT). Study Objectives: This study aime...

BACKGROUND: Epoetin beta (NeoRecormon®) 30 000 IU/week raises hemoglobin levels, reduces transfusion need and improves quality of life in patients with cancer. Recent studies have also suggested that epoetin therapy may impact upon outcomes in these patients. A meta-analysis was performed to investigate the effects of epoetin beta on survival, tumor progression and thromboembolic events in patients with hematological malignancies receiving chemotherapy. METHODS: Data were pooled from all five randomized, controlled (placebo or standard care) clinical trials of epoetin beta that included anemic patients with hematological malignancies receiving chemotherapy. The study that showed epoetin beta once weekly to be as effective with the same safety profile as a three times weekly regimen was excluded from this analysis because of the lack of a non-epoetin-treated group. These studies were not designed to assess duration of survival and in all except one there was no follow-up beyond the duration of study treatment plus an additional 4-week period. Deaths reported during the study plus 4 weeks were therefore recorded in this analysis. All adverse event reports were assessed for evidence of disease progression or thromboembolism. Data were analyzed by standard Kaplan-Meier methods, Cox regression and log-rank tests. RESULTS: A total of 791 patients with hematological malignancies were included (epoetin beta, n=461; control, n=330) (the difference in number was due to two of the five studies containing multiple epoetin beta treatment groups versus one control group). The majority was diagnosed with lymphoma (56%) or multiple myeloma (42%); the remaining patients (2%) were diagnosed with acute myeloid leukemia. Treatment groups were well balanced with regard to baseline demographic characteristics. There were no obvious differences in baseline tumor stage between treatment groups, although these data were not consistently collected across studies. The median weekly dose of epoetin beta was 30 000 IU. Death rates were similar in both the epoetin beta and control groups (0.39 vs 0.37 deaths/patient year). There was no indication of a difference in survival with epoetin beta compared with control (relative risk 1.04, 95% CIs 0.69, 1.55, p=0.86). The rate of disease progression was lower in the epoetin beta group compared with the control group (0.69 vs 0.81 events/patient year). The results from Kaplan-Meier estimates and Cox regression did not indicate an increased risk of disease progression with epoetin beta compared with control (relative risk 0.84, 95% CIs 0.62, 1.13, p=0.25). In fact, the hazard rate of 0.84 indicated a 16% reduction in the risk of an event when treated with epoetin beta. Thromboembolic event rates were also similar in the epoetin beta and control groups (0.17 vs 0.14 events/patient year), corresponding to crude rates of 5.4% and 4.8% (observation times: 147 and 112 patient years). These event rates are well within the range of those reported in the literature. CONCLUSIONS: Epoetin beta has no effect on short-term survival, tumor progression or thromboembolic events when used to treat anemic patients with hematological malignancies, and the risk-to-benefit ratio of epoetin beta therapy remains favorable.

Background: With the recent reporting of 191 cases of epoetin induced PRCA (Bennett CL, NEJM 2004), information is needed about the long-term follow-up of individuals with this diagnosis. While 47 cases from France, Germany, and England have been reported recently (Verhelst D, Lancet 2004), these data are limited by short follow-up and absence of information from other regions. Methods: RADAR investigators identified cases of epoetin-associated PRCA from the Food and Drug Administration MEDWatch database and proprietary reports from both the manufacturers epoetin alpha (Epogen from AMGEN, and Eprex from Johnson and Johnson) and epoetin beta (Neorecormon from Roche). Patients exposed to more than one epoetin form were excluded. PRCA recovery was operationally defined as transfusion independence, clearance of anti-erythropoietin antibody, and/or normalization of reticulocyte count. Results: See table. Conclusions: The overall recovery rate of 82% following transplantation versus 40% following immunosuppression suggests that transplantation might be the optimal therapy for epoetin-associated PRCA. Almost half of the patients rechallenged with epoetin developed recurrent PRCA, raising concern over the benefits of rechallenge. Eprex (N=82) Neorecormon (N=11) Epogen (N=5) Origin: US 60% 64% 100% Europe 60% 64% – Pacific Rim/Asia 21% 36% – Canada 19% – – Subcutaneous delivery 99% 100% 60% Recovery with Immunosuppression 37% 73% 0% Recovery with renal Transplant 11% – – No recovery with renal transplant 1% – 20% No Recovery 41% 18% 40% Unknown Recovery 10% 9% 40% Male gender 68% 73% 40% Rechallenged with epoetin N=12 – – Response rate 50% Median age 68 years 47 years 51 years

8206 Background: The dose of Erythropoietin for chemotherapy-induced anemia in cancer patients is considerably higher than the one used for anemia due to renal failure. However, limited number of reports on pharmacokinetics (PK) with higher dose are available. We carried out the PK and pharmacodynamic study of epoetin beta (EPOCH) in lung cancer (LC) patients with chemotherapy-induced anemia. Methods: Fifteen LC patients with chemotherapy-induced anemia [hemoglobin (Hb) level of 11 g/dL or less] received EPOCH 9000, 18000 or 36000 IU subcutaneously (SC), weekly for 8 weeks. We estimated the PK parameters following the first administration of EPOCH and also measured the trough level of Erythropoietin and Hb level over 7 weeks. Results: Cmax and AUC rose in proportion to the dose given, and T\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \({1}/{2}\) \end{document}, Vd, and CL appeared almost stable ...

8169 Background: Administering epoetin beta (EPO) to anemic cancer patients receiving chemotherapy has been reported to improve their anemia and quality of life (QOL). We conducted a randomized, do...

6523 Background: Although anemia of IPSS low and int-1 (LR) MDS initially responds to erythroid stimulating agents (ESA) in 40-50% of patients (pts), response is generally transient. Anemia recurrence with RBC cell transfusion dependency (RBC-TD) is an indicator of poor prognosis, even in absence of progression to higher risk MDS. AZA leads to RBC transfusion independence (RBC-TI) in 30–40% of LR-MDS (Lyons, JCO, 2009), but it has not been prospectively tested in LR-MDS patients resistant to ESA. It also remains unknown if the addition of ESA to AZA would be useful in such pts. Methods: In this randomized phase-II trial (GFMAzaEpo-2008-1 trial, NCT01015352), the Groupe Francophone des Myélodysplasies (GFM) compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) to the same treatment plus EPO 60000U/week (AZA+EPO arm). Inclusion criteria were LR-MDS resistant to at least 12 weeks of ESA, with RBC-TD ≥ 4 RBC units in the previous 8 weeks. Responders in both arms were eligible for maintenance up to 12 monthly cycles, unless progression or loss of erythroid response occurred. The primary endpoint was RBC-TI (HI-E major using IWG 2000 criteria) after 6 courses. Results: Between 2009 and 2010, the 98 planned pts were included: M/F 65/28; median age 71y (41-84); 5 pts were excluded (one consent withdrawal, 2 early unrelated events and 2 with exclusion criteria). In the remaining 93 pts, IPSS risk was low in 69 and int-1 in 23 pts, with no imbalance between arms. Five pts received < 4 cycles and 16 received only 4 or 5 cycles, mainly due to toxicity or progression. RBC-TI after 6 courses was observed in 16.7% (8/48) in the AZA arm and 18 % (8/45) in the AZA+EPO arm (P=1), and in 19.5% (8/41) and 26 % (8/31) respectively, in the 72 pts who received ≥ 6 cycles (P=.57). Overall best response rate (at least HI-E minor using IWG 2000 criteria) was 35 and 33% in the AZA and AZA+EPO arms, respectively (P=0.99). Of note, only 9 pts in the AZA+EPO arm required at least one hospitalization for a SAE, compared to 22 pts in the AZA arm (P=0.015). Conclusions: Erythroid response to AZA, in LR MDS with demonstrated ESA resistance, appears lower than expected, with no improved outcome when combined with an ESA. The latter may however improve tolerance of AZA in LR MDS.

The impact of erythropoiesis stimulating agents (ESAs) on clinical outcomes among breast cancer patients is debatable. Current review is aimed to ascertain the efficacy of ESAs among breast cancer patients. Randomised controlled trials (RCTs) were electronically searched. Primary outcomes were mortality, blood transfusion requirements and thromboembolic events (TEEs); whereas, secondary outcomes were safety, tumor progression, anemia treatment, hemoglobin levels and quality of life (QOL). Out of 11 RCTs including 6,849 participants, 9 RCTs reported 2,312 deaths with overall mortality of 33.7%. Mortality reported for epoetin alfa (EA), epoetin beta (EB) and darbepoetin alfa (DA) was 41.24%, 73.1% and 8.99% respectively. TEEs reported for EA, EB and DA were 5.88%, 9.28% and 2.85%, respectively. Serious adverse events were 39.04%, 36.29%, 1.53% for EA, EB and DA, respectively. Tumor progression for EA and EB was 37.53% and 95.46%, respectively. No tumor progression was reported with DA. Erythropoietin reported no mortality, TEEs, serious ADRs and tumor progression. About 9% patients required transfusions during ESA therapy. Current evidence suggests that use of ESA reduces transfusion need but increases mortality and risks of TEEs.

Background: Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp™) is an erythropoiesisstimulating glycoprotein that has been shown, in dosefinding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy. Methods: In this multicenter, doubleblind, placebo-controlled study, 320 anemic patients (hemoglobin 11.0 g/dL) were randomly assigned to receive darbepoetin alfa or placebo injections weekly for 12 weeks. The 297 patients who completed at least the first 28 days of study were assessed for red blood cell transfusions, the primary endpoint. Patients were also assessed for hemoglobin concentration (i.e., hematopoietic response), adverse events, antibody formation to darbepoetin alfa, hospitalizations, Functional Assessment of Cancer Therapy (FACT)–Fatigue score, and disease outcome. Efficacy endpoints were assessed using Kaplan–Meier analyses, Cox proportional hazards analyses, and chi-square tests where appropriate. All statistical tests were two-sided. Results: Patients receiving darbepoetin alfa required fewer transfusions (27% versus 52%; mean difference = 25%; 95% confidence interval [CI] = 14% to 36%; P

Erythropoietin (EPO) has been suggested to promote cardiac repair after MI. However, the randomized, double-blind, placebo controlled REVIVAL-3 trial showed that short term high dose EPO in timely reperfused myocardium does not improve left ventricular ejection fraction after 6 months. Moreover, the study raised safety concerns due to a trend towards a higher incidence of adverse clinical events as well as a increase in neointima formation after treatment with EPO. The present study therefore aimed to assess the 5-year clinical outcomes. After successful reperfusion 138 patients with STEMI were randomly assigned to receive epoetin beta (3.33×104 U, n = 68) or placebo (n = 70) immediately, 24 and 48 h after percutaneous coronary intervention. The primary outcome of the present study- the combined incidence of MACE 5 years after randomization - occurred in 25% of the patients assigned to epoetin beta and 17% of the patients assigned to placebo (RR 1.5; 95% CI 0.8-3.5; p = 0.26). Target lesion revascularization was required in 15 patients (22.1%) treated with epoetin-s and 9 patients (12.9%) treated with placebo (p = 0.15). Analysis of patients in the upper and lower quartile of baseline hemoglobin as an indirect estimate of endogenous erythropoietin levels revealed no significant impact of endogenous erythropoietin on efficiency of exogen administered epoetin-s in terms of death and MACE. These long-term follow-up data show that epoetin beta does not improve clinical outcomes of patients with acute myocardial infarction. URL www.clinicaltrials.gov ; Unique identifier NCT00390832; trial registration date October 19th 2006

Lenalidomide (Len) is the reference treatment of anemia in patients with del(5q) MDS with half of them being responders. An erythroid response is also achieved in ~25% of non del(5q) low-risk or int-1 MDS patients. The mechanisms of resistance are still unclear although the molecular target of Len, Cereblon, a receptor for several substrates including Ikaros, Aiolos and the casein kinase 1 in the E3 ubiquitin ligase Cul4A-DDB1-Roc1, had been identified. Biomarkers are needed to avoid inappropriate exposure to the risk of severe neutropenia or thrombocytopenia. In this study, we investigated biomarkers of response to Len treatment in a cohort of 132 non del(5q) MDS patients, non-responders to erythropoiesis-stimulating agent (ESA) and enrolled in the GFM-LenEpo 08 clinical trial (NCT01718379). Patients were randomized to Len 10mg/day (L-arm) or Len 10 mg/day plus Epoetin beta (60,000 units/w) (LE-arm) and evaluated after 4 cycles. The biological studies were conducted in 99/132 patients including 41 responders and 58 non responders. According to IWG2006, HI-E was significantly higher in LE-arm (52%) vs. L-arm (31%) (p=0.031). Extensive genotyping study of 29 genes (ASXL1, CBL, CSNK1A, DNMT3A, ETV6, EZH2, FLT3, IDH1, IDH2, IKZF1, IKZF3, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PHF6, PTPN11, RIT1, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR2) was conducted in the 99 patients by NGS or Sanger approaches. Found all along the coding sequence of the genes and with variable VAF, mutations in SF3B1 (73%), TET2 (46%), ASXL1 (20%) and DNMT3A (20%) genes did not influence the response in the L-arm or LE-arm. Previously identified in myeloma cells resistant to Len treatment, an IKZF1 mutation located in the exon 5 of the gene and affecting the binding domain of the protein has been reported during Len treatment in one patient with del(5q) MDS and was associated with a loss of efficacy of the Len treatment in vivo. In this cohort, we did not find any mutation in the exon 5 of IKZF1 or IKZF3 or in the exons 3 and 4 of CSNK1A which are described as affecting their domain of interaction with Cereblon. A A>G polymorphism in the 5’UTR region of CRBN gene (rs1672753) was significantly associated with HI-E in the whole cohort (41.5% in responders vs. 22.4% in non-responders; p=0.048). A gene expression profiling (GEP) study was conducted on BMMC of 50 at inclusion and 24 paired samples before and after 4 cycles of treatment. Using a Gene Set Enrichment Analysis (GSEA), the comparison of GEP in 24 paired samples linked the response in L-arm or LE-arm to a signature of 32 up-regulated genes exclusively involved in the immune response. A supervised GSEA analysis combined with a Pam R strategy of GEP before treatment identified a predictive signature of 36 up-regulated genes mainly involved in translation, epigenetic regulation of transcription, cell division and DNA repair. Slight variations of CRBN gene expression level were not correlated to the response. However, the resistance in L-arm and LE-arm was predicted by a low expression level of NPM1 (P In conclusion, resistance to Lenalidomide or Lenalidomide plus EPO seems not be associated with a particular mutational profile nor with mutations in recently identified Cereblon targets. By contrast, a low expression level of NPM1 associated with a A/A polymorphism of CRBN is highly predictive of a treatment failure by Lenalidomide or Lenalidomide plus EPO non del(5q) MDS patients. Disclosures Chesnais: celgene: Research Funding. Sardnal:Celgene: Research Funding. Passet:Celgene: Research Funding. Gauthier:Celgene: Research Funding. Kosmider:Celgene: Research Funding. Fontenay:Celgene: Research Funding.

Subsequent entry biologics (SEBs) may soon be a reality in Canadian nephrology practice. Understanding the worldwide experience with these agents will be valuable to Canadian clinicians.To compare the efficacy and safety data between SEBs used in nephrology practice and their reference biologic.Systematic review.Ovid MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Review of Effects, Cochrane Central Register of Controlled Trials.Adult patients with chronic kidney disease (CKD).Our systematic review follows the process outlined by Cochrane Reviews. For efficacy data, all randomized controlled trials (RCTs), quasi-RCTs and observational trials in nephrology practice were included. For safety data, case series, case reports, review articles in nephrology practice and pharmacovigilance programs were included as well.Only epoetin SEBs trials were published in the literature. Ten studies involving three different epoetin SEBs (epoetin zeta, HX575 and epoetin theta) were included. The mean epoetin dose used did not differ significantly between the SEBs and the reference product. For epoetin zeta and epoetin theta, the mean hemoglobin levels achieved in the studies were similar between the SEBs and the reference epoetin. The HX 575 studies reported a mean absolute change in hemoglobin within the predefined equivalence margin, when compared with the reference biologic. In terms of safety data, 2 cases of pure-red-cell aplasia were linked to the subcutaneous administration of HX 575. Otherwise, the rate of adverse drug reactions was similar when epoetin SEBs were compared with the reference biologic.Our analysis is limited by the paucity of information available on SEB use in nephrology with the exception of epoetin SEBs. Methodological flaw was found in one of the epoetin zeta studies which accounted for 45% of pooled results.Little clinical difference was found between epoetin SEBs and the reference product. Although not deemed clinically important, the financial implication of a possible dose difference between epoetin zeta and reference product should be considered in pharmacoeconomic studies. Ongoing trials are expected to address the risk of pure-red-cell aplasia with HX 575.Il est possible que les produits biologiques ultérieurs (PBU) soient bientôt utilisés en néphrologie. Afin de guider la pratique en néphrologie au Canada, il est important de comprendre l’ensemble des expériences produites, à l’échelle mondiale, en matière d’efficacité et d’innocuité de ces agents.Comparer les données relatives à l’efficacité et l’innocuité entre les PBU utilisés en néphrologie et leurs médicaments biologiques de référence.Revue systématique.La recherche en vue de la revue de littérature a été effectuée en interrogeant les bases de données suivantes : Ovid Medline, Embase, la base de données de revues systématiques Cochrane Reviews, la Database of Abstracts of Reviews of Effects, et la Cochrane Central Register Controlled Trials.Les patients d’âge adulte atteints de néphropathie chronique.Notre revue systématique suit la méthode suggérée par la Collaboration Cochrane (Cochrane Reviews). Pour les données se rapportant à l’efficacité, l’ensemble des essais randomisés contrôlés (ERC) et des modèles quasi expérimentaux et des études observationnelles du domaine de la néphrologie ont été comptabilisés. Pour les données se rapportant à l’innocuité, tous les ERC, les modèles quasi expérimentaux, les études observationnelles, les études ou séries de cas, ainsi que les revues d’articles en néphrologie clinique et de programmes en pharmacovigilance ont été comptabilisés.Nous nous sommes attardés à l’époétine biologique ultérieure, puisqu’aucune documentation sur d’autres produits biologiques ultérieurs (PBU) n’était disponible. Nous avons utilisé dix études présentant trois époétines biologiques ultérieures différentes (époétine zeta, époétine HX575 et époétine thêta). Il n’existait pas de différence significative entre les doses moyennes des PBU et d’époétine biologique de référence. La dose moyenne d’époétine utilisée ne variait pas de façon significative entre les PBU et le produit de référence. Pour les époétines zeta et thêta, les taux moyens d’hémoglobine obtenus dans les diverses études entre les PBU et les époétines de référence étaient similaires. Les études se rapportant à l’époétine HX575 montraient un changement absolu du taux moyen d’hémoglobine à l’intérieur de l’intervalle d’équivalence prédéfini, lorsque comparé au médicament biologique de référence. En ce qui concerne les données d’innocuité, deux cas d’érythroblastopénie chronique acquise ont été liés à l’administration sous-cutanée de l’époétine HX575. Sinon, les taux d’effets indésirables recensés pour l’époétine biologique ultérieure et son médicament biologique de référence étaient similaires.Notre analyse est limitée par la rareté de l’information accessible sur l’utilisation des PBU en néphrologie, à l’exception de l’époétine biologique ultérieure. Une faille sur le plan méthodologique a été retrouvée dans une des études sur l’époéine zeta. Celle-ci se rapportait à 45 % des résultats regroupés.Peu de différences sur le plan clinique ont été trouvées entre l’époétine biologique ultérieure et l’époétine de référence. Même si elles ne sont pas cliniquement significatives, les répercussions financières qui sont entraînées par la possible différence de dose entre l’époétine zeta et le produit de référence devraient être considérées dans les études pharmacoéconomiques. Il existe certaines préoccupations entourant les risques d’érythroblastopénie chronique acquise et l’époétine HX575, mais des essais présentement en cours tentent de faire le tour de la question.SEBs pertinent to nephrology practice are available commercially in other countries. Epoetin SEBs have been compared with reference epoetins in clinical studies involving CKD patients.This systematic review summarizes the efficacy data comparing epoetin SEBs to the reference epoetins in patients with CKD and provides an overview of the European experience in terms of safety data for epoetin SEBs. No other SEBs pertinent to nephrology practice have published data as yet.