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Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. In Phase 3 trials, roxadustat increased hemoglobin (Hb) levels and reduced the number of red blood cell (RBC) transfusions vs placebo in patients with anemia of non-dialysis-dependent chronic kidney disease (CKD). In anemia of dialysis-dependent CKD, roxadustat achieved greater mean Hb increase vs epoetin alfa, and reduced IV iron use and RBC transfusions (Coyne, et al. Poster SA-0228 American Society of Nephrology (ASN) 2019; Charytan, et al. Poster SA-0227 ASN 2019) Low-risk myelodysplastic syndrome (LR-MDS), characterized by symptomatic anemia, is treated with RBC transfusion, erythropoiesis-stimulation agents (ESAs), or luspatercept. Suboptimal response and response durability across MDS subpopulations demonstrates an unmet medical need in LR-MDS. We report a 52-week update of the open-label (OL) phase of a study of roxadustat in anemia in primary MDS patients that determined the starting dose of the ongoing double-blind study phase (NCT03263091). Methods: The OL phase (N=24) used 3 sequential dose cohorts (1.5, 2.0, and 2.5 mg/kg) thrice weekly (TIW). Eligible patients had very low- to intermediate-risk primary MDS patients per International Prognostic Scoring System-Revised classification, with < 5% bone marrow blasts; baseline Hb < 10.0 g/dL; had low transfusion burden, defined as receiving 1-4 RBC units within 8 weeks before randomization; endogenous EPO levels ≤ 400 mIU/mL; and no 5q(del) cytogenetic abnormality. Red blood cell transfusion was allowed per institutional criteria. Roxadustat doses were titrated every 8 weeks based on Hb response and RBC transfusions. The primary endpoint was transfusion independence (TI) for ≥ 56 consecutive days during the first 28 treatment weeks; follow-up was at 52 weeks. Secondary endpoints included TI ≥ 56 consecutive days anytime during the study, proportion of patients who achieved ≥ 50% reduction in number of RBC transfusion over any 8 weeks vs baseline (BL), cumulative number of patient-exposure-week of TI, cumulative number of pRBC packs transfused, proportion of patients who achieved TI for > 20 weeks. Safety was assessed via adverse events monitoring and patients (%) who progressed to acute myeloid leukemia (AML). Patients with and without ring sideroblasts (RS+/RS-) and BL EPO ≤ 200 mIU/ml and > 200 mIU/ml were assessed for the primary endpoint. Results: In the OL phase, 24 transfusion-dependent LR-MDS patients were enrolled in 3 starting dose cohorts (Table). Nine patients (38%) achieved TI for ≥ 56 consecutive days within the first 28 and 52 weeks, 3 in cohort 1 (1.5 mg/kg), 1 in cohort 2 (2.0 mg/kg), and 5 in cohort 3 (2.5 mg/kg). When TI was achieved, 78% were receiving 2.5 mg/kg dose, 11% were receiving 2.0 mg/kg dose (started with 1.5 mg/kg) and 11% were receiving 1.5 mg/kg. Four patients (16.7%) remained TI for > 20 weeks (1 at 1.5 mg/kg dose level and 3 at 2.5 mg/kg dose-level) at 52 weeks. The 50% reduction in number of transfusion compared with BL occurred in 13 patients (54.2%) at 28 weeks and 14 (58.3%) at 52 weeks. In patients with TI duration ≥ 56 days (n = 9), the mean (SD) TI duration was 182.9 (153.66) days. In patients with TI duration ≥ 140 days (n = 4), the mean (SD) TI duration was 324.5 (121.22) days. Subgroups met the primary endpoint at week 28 (23.1% and 54.5% MDS-RS+ and -RS-, respectively, and 38.9% and 33.3% BL EPO ≤ 200 mIU/ml and > 200 mIU/ml, respectively); all subgroups maintained TI response to week 52. The overall safety profile was consistent with this patient population. Eight patients reported 8 treatment-emergent serious AEs; none were fatal. No patient progressed to AML. Conclusion: In this 52-week update, roxadustat 2.5 mg/kg TIW was effective in LR-MDS patients, based on observed response (TI and transfusion reduction), safety profile, and durable 52-week response. The ongoing, 156-patient, double-blind study phase uses a 2.5 mg/kg starting dose. Preliminary data in OL subgroups RS-/RS + and BL EPO ≤ 200 mIU/ml and >200 mIU/ml suggest roxadustat may be effective in these subgroups. These data await confirmation in the ongoing double-blind, placebo-controlled study. Table 1 Disclosures Carraway: Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bradley:FibroGen, Inc.: Current Employment. Saha:FibroGen, Inc.: Current Employment. Bartels:FibroGen, Inc.: Current Employment. Leong:FibroGen Inc.: Current Employment, Current equity holder in private company. Yu:FibroGen, Inc.: Current Employment.

Despite the establishment of a specific approval pathway, the issuance of detailed scientific guidelines for the development of similar biological medicinal products (so-called “biosimilars”) and the approval of several biosimilars in the European Union, acceptance of biosimilars in the medical community continues to be low. This is especially true in therapeutic indications for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. This article addresses the concerns frequently raised in the medical community about the use of biosimilars in such extrapolated indications and explains the underlying scientific and regulatory decision making including some real-life examples from recently licensed biosimilars.

Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin 2 units/month) with serum Epo >500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a >2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients ( Results: Among 205 patients randomized, 14 were excluded from the primary analysis due to a 4 month interruption in drug supply. Among the 195 evaluable patients, 96 were assigned to Arm A and 99 to Arm B. Baseline characteristics were well balanced between arms with 85% of patients heavily TD, receiving a median of 4 units/8 weeks. Overall, 93% of patients received prior treatment with Epo and 18% azanucleosides. In an intent to treat analysis, 28/99 patients (28.3%) in Arm B achieved MER compared to 11/96 (11.5%) in Arm A (P=0.004). Among 136 patients who completed 16 weeks of study treatment, 28/72 (38.9%) and 10/64 (15.6%) achieved MER, respectively (P=0.004). Forty-four Arm A non-responders crossed over to combination-therapy with 11 patients (25%) experiencing a MER. Multivariable logistic regression analysis identified only treatment with LEN + EA as an independent covariate for erythroid response (P=0.01). Responses were durable with MER median duration of 23.8 months in Arm B compared to 13 months in Arm A. There was no significant difference in the frequency or distribution of >Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1–risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)–sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858.

ABSTRACT: Anemia resulting from cancer, or its treatment, is an important clinical problem increasingly treated with the recombinant hematopoietic growth factor erythropoietin. To address uncertainties regarding indications and efficacy, the American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical circumstances. Good evidence from clinical trials supports the use of subcutaneous epoetin thrice weekly (150 U/kg tiw) for a minimum of 4 weeks. Less strong evidence supports an alternative weekly (40,000 U/wk) dosing regimen, based on common clinical practice. With either administration schedule, dose escalation should be considered for those not responding to the initial dose. In the absence of response, continuing epoetin beyond 6 to 8 weeks does not appear to be beneficial. Epoetin should be titrated once the hemoglobin concentration reaches 12 g/dL. Evidence from one randomized controlled trial supports use of epoetin for patients with anemia associated with low-risk myelodysplasia not receiving chemotherapy; however, there are no published high-quality studies to support its use for anemia in other hematologic malignancies in the absence of chemotherapy. Therefore, for anemic patients with hematologic malignancies, it is recommended that physicians initiate conventional therapy and observe hematologic response before considering use of epoetin.

This randomized, placebo-controlled trial was designed to assess the efficacy and safety of therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (epoetin alfa) in anemic, neutropenic patients with myelodysplastic syndrome. Sixty-six patients were enrolled according to the following French-American-British classification: refractory anemia (20), refractory anemia with excess blasts (35), refractory anemia with ringed sideroblasts (9), and refractory anemia with excess blasts in transformation (2). Patients were stratified by their serum erythropoietin levels (less than or equal to 500 mU/mL, n = 37; greater than 500 mU/mL, n = 29) and randomized, in a 2:1 ratio, to either GM-CSF (0.3-5.0 microg/kg.d) + epoetin alfa (150 IU/kg 3 times/wk) or GM-CSF (0.3-5.0 microg/kg.d) + placebo (3 times/wk). The mean neutrophil count rose from 948 to 3831 during treatment with GM-CSF +/- epoetin alfa. Hemoglobin response (increase greater than or equal to 2 g/dL, unrelated to transfusion) occurred in 4 of 45 (9%) patients in the GM-CSF + epoetin alfa group compared with 1 of 21 (5%) patients with GM-CSF + placebo group (P = NS). Percentages of patients in the epoetin alfa and the placebo groups requiring transfusions of red blood cells were 60% and 92%, respectively, for the low-endogenous erythropoietin patients and 95% and 89% for the high-endogenous erythropoietin patients (P = NS). Similarly, the average numbers of units of red blood cells transfused during the 12-week study in the epoetin alfa and the placebo groups were 5.9 and 9.5, respectively, in the low-endogenous erythropoietin patients and 9.7 and 8.6 in the high-endogenous erythropoietin patients (P = NS). GM-CSF +/- epoetin alfa had no effect on mean platelet count. Treatment was well tolerated in most patients, though 10 withdrew from the study for reasons related predominantly to GM-CSF toxicity. (Blood. 2000;95:1175-1179)

Background: Anemia of unknown etiology (AUE) is a common category of anemia in the elderly where investigations cannot identify a specific cause. We have previously shown that AUE patients exhibit lower erythropoietin (EPO) levels which may be associated with either decreased EPO production or a blunted EPO response to anemia. Erythropoiesis-stimulating agents (ESAs) mimic the effect of endogenous EPO and may play a role in treating AUE. In this study, we investigated the response to ESA treatment in patients with AUE compared to other causes of anemia. We also examined the effect of ESAs on cardiovascular outcomes in our cohort. To our knowledge, no previous study has specifically assessed ESAs in AUE. Patients and methods: We conducted a retrospective cohort study including all consecutive hematology patients referred to our centre and who had EPO levels determined between 2005 and 2013. We included patients 60 years or older who met the World Health Organization criteria for anemia (hemoglobin [Hb] Results: The inclusion criteria were met by 570 of 1511 potentially eligible patients. Of the 113 patients treated with an ESA, data was adequate to assess treatment response in 101 patients. Of the patients treated with an ESA, the mean age was 75.1 years and 60% were male. The mean pretreatment hemoglobin was 88.5 g/L. Inter-observer agreement for diagnostic categories was adequate. Eighty-two patients were treated with epoetin alfa and 19 patients received darbepoetin alfa. Treatment response was better in the CKD and AUE groups (54% and 47%, respectively) compared to the other groups. Compared to the group of other etiologies logistic regression analysis showed a 3.6 and 3.3 adjusted odds ratio (OR) for response for CKD and AUE respectively, although this was not statistically significant (Table 1). A baseline EPO level Conclusion: Our results suggest that ESAs can be used to treat anemia of unknown etiology, and responses may be similar to those in chronic kidney disease. This supports the notion that a relative EPO deficiency is probably related to the pathogenesis of AUE. Although treatment may be associated with increased cardiovascular events, this was not found to be significant in our cohort. Limitations of this study include its retrospective nature and a relatively small sample size. Further studies exploring the safety and efficacy of ESAs in the treatment of AUE are warranted. Table 1 Odds ratio of treatment response in unadjusted and adjusted logistic regression models Table 1. Odds ratio of treatment response in unadjusted and adjusted logistic regression models Table 2 Hazard ratios for cardiovascular outcomes in patients receiving ESAs in unadjusted and adjusted Cox regression models Table 2. Hazard ratios for cardiovascular outcomes in patients receiving ESAs in unadjusted and adjusted Cox regression models Disclosures Xenocostas: Janssen Inc.: Research Funding. Lazo-Langner:Daiichi Sankyo: Research Funding; Pfizer: Honoraria; Bayer: Honoraria.

Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin 2 units/mo) with serum Epo >500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers. Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (< median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of >Grade 3, non-hematologic AEs. Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. Disclosures Bennett: Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.

Introduction: Patients with chronic kidney disease who progress to end stage renal disease (ESRD) require renal replacement therapy to assume some functions of the diseased kidney and sustain life. Hemodialysis (HD) is the most common option for renal replacement therapy in ESRD patients and includes routine treatments 3 times per week to filter uremic toxins and remove excess fluid from the blood. The prevalence of anemia is high in the ESRD population with about 80% of HD patients being treated with an erythropoietin stimulating agent (ESA) for management of anemia (United States Renal Data System. 2015 USRDS annual data report: Epidemiology of Kidney Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2015). Until recently, there had only been a few of choices for ESA therapies in the United States, epoetin alfa, which is considered short-lasting (dosing generally greater than once per week), and darbepoetin alfa, which is middle-lasting (dosing generally once per week). Methoxy polyethylene glycol-epoetin beta is a long lasting ESA (dosing once per 2-4 weeks) that has been recently approved and permitted to be used for treatment of patients with anemia in the United States. At Fresenius Medical Care North America (FMCNA), we began the conversion from use of short- or middle-lasting ESAs to Methoxy polyethylene glycol-epoetin beta in our HD facilities in December of 2014. In this analysis, we aimed to determine the profiles of hemoglobin (Hgb) levels in this large national population of anemic HD patients treated with methoxy polyethylene glycol-epoetin beta. Methods: We retrospectively studied data on HD patients treated at FMCNA facilities that converted from epoetin alfa or darbepoetin alfa to using methoxy polyethylene glycol-epoetin beta for the standard of care treatment of anemia. Data for the weekly Hgb levels that were used to conduct anemia management using the ESAs was analyzed for comparisons. The target goal for ESA treatment at FMCNA is to maintain patient Hgb levels between 10 to 11 g/dL. We computed the 3 months profiles of mean Hgb levels associated with the routine clinical use of methoxy polyethylene glycol-epoetin beta in all (n=118,681) HD patients receiving the long-lasting ESA therapy at FMCNA during May to July of 2016. Additionally, evaluations of mean Hgb levels before and after the conversion to the long-lasting ESA was performed using patient data from September 2014 to July of 2015; this analysis included 24,223, 7,494, and 1,345 anemic HD patients who received methoxy polyethylene glycol-epoetin beta for maintenance of anemia for at least 2, 4 and 6 months, respectively. Results: We found that treatment of anemia in HD patients with methoxy polyethylene glycol-epoetin beta maintained Hgb levels steady at a mean value of 10.7g/dL for the population from May to July of 2016. In an evaluation of Hgb levels before and after the conversion from epoetin alfa or darbepoetin alfa to methoxy polyethylene glycol-epoetin beta, we observed a slight increase of 0.18, 0.17, and 0.15 g/dL in mean Hgb levels after 2, 4, and 6 months of patients receiving the long-lasting ESA for maintenance of anemia (Figures 1-3). There was a slight nadir mean Hgb level of 10.2 g/dL that occurred 1 week prior to conversion to the long-lasting ESA. This was a result of anemia protocols that had patients with higher Hgb values wait until the level had decreased before converting to the long-lasting ESA. Conclusions: The findings of this retrospective investigation indicate that the long-lasting ESA methoxy polyethylene glycol-epoetin beta maintains Hgb levels in target range for HD patients. The conversion from a short- or middle-lasting ESA to the long-lasting ESA methoxy polyethylene glycol-epoetin beta may be associated with overall a minor increase in mean Hgb levels that are on average within normal limits. Disclosures Stennett: Fresenius Medical Care North America: Employment. Ofsthun:Fresenius Medical Care North America: Employment, Equity Ownership. Larkin:Fresenius Medical Care North America: Employment. Reviriego-Mendoza:Fresenius Medical Care North America: Employment. Usvyat:Fresenius Medical Care North America: Employment, Equity Ownership. Maddux:American National Bank & Trust (NASDAQ: AMNB): Membership on an entity's Board of Directors or advisory committees; Fresenius Medical Care North America: Employment, Equity Ownership, Other: Founder: Scholarships Expanding Education 501c3 non profit, Research Funding; Kidney Care Partners: Membership on an entity's Board of Directors or advisory committees; Pacific Renal Care Foundation: Membership on an entity's Board of Directors or advisory committees; Specialty Care: Membership on an entity's Board of Directors or advisory committees; Sound Physicians: Membership on an entity's Board of Directors or advisory committees; Mid Atlantic Renal Coalition: Membership on an entity's Board of Directors or advisory committees. Hymes:Nephroceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Fresenius Medical Care North America: Employment, Equity Ownership.

Background: Erythropoiesis-stimulating agents (ESAs) increase hemoglobin, reduce transfusion requirements and improve quality of life in myelodysplastic syndromes (MDS), but many patients do not respond to treatment. Various scoring systems have been developed to predict which patients with MDS will respond to ESAs. The Nordic score derived by Hellstrom-Lindberg et al. stratifies patients based on the erythropoietin (EPO) level and transfusion frequency. Houston et al. have proposed another score which is based on EPO and the International Prognostic Scoring System (IPSS) risk group. The latter score has not yet been validated. We assessed the validity of these scoring systems in an independent cohort of patients with MDS. Patients and methods: We conducted a retrospective cohort study including all patients with confirmed MDS based on bone marrow biopsy, aspirate or cytogenetic findings who were treated with ESAs at our institution from 2005 to 2013 and who had available follow-up information. Both the International Working Group (IWG) 2006 criteria and the Nordic study response criteria were used to assess treatment response. Statistical significance of both scores was assessed using Pearson's chi-squared test. Analysis was repeated with the score by Houston et al. dichotomized to low (0 or 1) or high (2 or 3). Results: Of 180 patients diagnosed with MDS, 44 patients met our inclusion criteria. Forty patients were treated with epoetin alfa and 4 were treated with darbepoetin alfa. The mean age was 76.4 years and 61% were male. The mean pretreatment hemoglobin was 85.3 g/L. There was a significant difference in the treatment response between the Nordic score groups using the Nordic response criteria but the difference was insignificant using the IWG criteria (Table 1). We found no difference in treatment response between the scores by Houston et al. using either response criteria, however a low score (0 or 1) predicted a significantly better response than a high score (2 or 3). An EPO level less than 100 IU/L was a statistically significant predictor of treatment response but the IPSS designation was not. Conclusion: Our results have validated the Nordic score using the same response criteria as the original study, but our population size was not adequate to validate the Nordic score using IWG criteria. We have confirmed that patients with EPO levels below 100 IU/L respond to treatment significantly better than patients above 100 IU/L. Our data does not support the use of the IPSS risk group in predicting treatment response, but this result may be limited by the relatively small number of patients. Further studies exploring the predictive variables in MDS treatment with ESAs are warranted. Table 1. ESA Response in MDS Scoring Systems Score N Nordic criteriaa IWG criteriab ResponseN (%) p-valuec Response N (%) p-valuec Nordic Score Good (> +1) 19 10 (53) 0.033d 9 (47) 0.141 Int. (-1 to +1) 24 4 (17) 5 (21) Poor (< -1) 1 0 (0) 0 (0) Score by Houston et al. 0 8 3 (38) 0.347 3 (38) 0.080 1 15 7 (47) 8 (53) 2 4 1 (25) 0 (0) 3 17 3 (18) 3 (18) Dichotomized Score by Houston et al. Low (0 - 1) 23 10 (43) 0.082 11 (48) 0.017d High (2 - 3) 21 4 (19) 3 (14) EPO < 100 IU/L 23 - - 11 (48) 0.017d ≥ 100 IU/L 21 - 3 (14) IPSS Risk Group Low 12 - - 3 (25) 0.552 Int-1 or Int-2 32 - 11 (34) a Increase in hemoglobin to >115 g/L, increase in hemoglobin of >15 g/L, or 100% decrease in transfusion requirements b Increase in hemoglobin of ≥15 g/L, or ≥4 less transfusions (for hemoglobin ≤90 g/L) in 8 weeks compared to 8 weeks pretreatment c Group comparison using Pearson's chi-squared test d p < 0.05 Disclosures Lazo-Langner: Pfizer: Honoraria; Bayer: Honoraria.

Background. OncoBOS is a prospective, non-interventional study conducted in France to describe modalities of treatment with Binocrit® in routine clinical practice setting, for the correction of hemoglobin (Hb) in patients with CIA receiving chemotherapy (CT) for solid tumors, lymphoma or myeloma. This analysis focuses on patients with lymphoid malignancies (LM). Patients & methods. Patient ≥18 years old with LM, CIA and eligible for treatment with Binocrit® were included. This analysis reports patients characteristics along with anemia-related data such as Hb outcomes, Binocrit® treatment characteristics and concomitant treatments received, at baseline, 3-4 weeks and 12 (± 1) weeks later. Factors associated with a Hb increase ≥2 g/dL in patients with LM were analyzed by means of univariate and multivariate analyses. Results. 563 evaluable patients (302 males (53.6%), mean age 67.9 (SD 14.0) years were recruited from 34 sites, between September 2011 and July 2014. Non-Hodgkin lymphoma (NHL) (281 patients; 49.9%) and multiple myeloma (165 patients; 29.3%) were most prevalent. Among patients with NHL, 46.0% had a diffuse large B cell lymphoma, 11.5% a follicular lymphoma and 11.1% a mantle cell lymphoma. 62.5% of patients with NHL had a stage IV disease and bone marrow was involved by NHL in 45.2% of patients. A vast majority of patients (84.3%) suffering from multiple myeloma had a Durie-Salmon stage III myeloma. Mean baseline Hb was 9.5 (SD 1.0) g/dL, which increased by an average of 0.9 (SD 1.4) g/dL and 1.9 (SD 1.7) g/dL after 1 and 3 months, respectively. A Hb increase ≥1 g/dL was achieved by 51.3% of patients after 3-4 weeks of treatment with Binocrit®. About half of patients (53.0%) achieved a Hb increase ≥2 g/dL at week 12 (± 1). Patients received a mean Binocrit® dose of 31252.4 ± (SD 5815.9; median: 30000) UI once-weekly, over an average time span of 10.8 (SD 3.2; median: 13) weeks. Iron status (serum ferritin and transferrin saturation coefficient) was assessed in 29.1% of subjects at baseline. In total, 2.8% and 1.4% of patients concomitantly received oral or intravenous iron, respectively, during the follow-up period. 12.1% and 11.6% of patients received a folate supplementation at week 3-4 and 12, respectively. Moreover, 16.2% and 15.0% of patients received red blood cells transfusion over the 3-4 first weeks, and over the next 2 months, respectively. Over the treatment period, no treatment‐related adverse reaction was recorded. Factors negatively/positively associated with a Hb increase ≥2 g/dL (p Conclusions. This study indicates that in real-life clinical conditions Binocrit® increases effectively Hb, without any adverse drug reaction, in anemic patients with lymphoid malignancies, whatever chemotherapy received. The effect of treatment with Binocrit® is rapid, with mean hemoglobin increase of 0.9 (SD1.4) g/dL seen as early as 3 or 4 weeks following the start of therapy. Disclosures Karlin: Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Metges:Sandoz: Consultancy. Khobta:Sandoz: Membership on an entity's Board of Directors or advisory committees. Boschetti:Sandoz: Membership on an entity's Board of Directors or advisory committees. Toledano:Sandoz: Membership on an entity's Board of Directors or advisory committees. Aubron-Olivier:Sandoz: Employment. Fernet:Sandoz: Employment. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees.

Background Recommendations on erythropoiesis-stimulating agents (ESAs) for the management of chemotherapy-induced anemia (CIA) are well established (Schrijvers D et al. Ann Oncol 2010;21[suppl 5]:v244-7). Iron supplementation can further improve treatment response of CIA, particularly in the case of iron deficiency (Pedrazzoli P et al. J Clin Oncol 2008;26:1619-25; Auerbach M et al. J Clin Oncol 2004;22:1301-7), but is under-used. Objective To evaluate the effect of epoetin alfa biosimilar, with or without iron, on CIA in current oncology and hematology practice. Methods SYNERGY was an observational, longitudinal, prospective, multicenter study conducted in France, from a representative, random sample of oncologists and hematologists. Patients of these clinicians were aged ≥18 years with solid tumors, lymphoma and/or myeloma and CIA, eligible for treatment with epoetin alfa biosimilar and followed for 12-16 weeks. A subanalysis describing the treatment response to epoetin alfa biosimilar in patients with/without iron supplementation and their target hemoglobin (Hb) levels is presented here. Results Overall, 2167 patients were enrolled by 195 French oncologists/hematologists during June 2012-December 2014. The analysis included 2076 patients, of whom half were male. At inclusion, mean age ± standard deviation (SD) was 67±12 years and 75.7% (n=1517) of patients had a World Health Organization performance status of 0 or 1. Most patients had not received any blood transfusions (90.0%, n=1867) or ESAs (93.1%, n=1932) in the year before the inclusion visit. A total of 31.6% (n=655) patients received iron supplementation, of whom 58.9% (n=386) received intravenous (IV) iron, 40.5% (n=265) had oral iron and 0.6% (n=4) were prescribed both oral and IV iron. An iron status assessment was more common in patients who were given iron supplementation, while over a third of patients who did not have an iron status were prescribed iron (Table). At follow-up, over 70% of patients had a maximum Hb level above 11 g/dL, regardless of iron status (Table). For patients with and without added iron, the mean change in Hb level was 2.26 g/dL and 2.22 g/dL at maximum during the study and 1.71±1.52 g/dL and 1.59±1.60 g/dL at final visit, respectively. Iron status results were used to define patients as having absolute iron deficiency (coefficient of saturation of transferrin [CST] Conclusions Overall, these results provide real-life evidence that epoetin alfa biosimilar was effective in treating anemia. Iron supplementation improved the response to epoetin alfa biosimilar in patients with an absolute iron deficiency, suggesting that iron status can be used to optimize treatment of patients with CIA with ESAs and iron supplementation. Disclosures Scotté: Hospira SAS: Research Funding. Laribi:Hospira SAS: Research Funding. Gisselbrecht:Bertram Glass: Research Funding; Chugai Pharmaceutical: Research Funding; Baxter: Research Funding; Roche: Consultancy, Research Funding; Hospira SAS: Research Funding. Spaeth:Hospira SAS: Research Funding. Kasdaghli:Hospira: Employment. Albrand:Hospira: Employment. Leutenegger:GECEM: Employment; Hospira SAS: Research Funding. Ray-Coquard:PharmaMar: Consultancy, Other: Paid instructor; Roche: Consultancy, Other: Paid instructor; Amgen: Consultancy, Other: Paid instructor; Hospira SAS: Research Funding.

Introduction: Erythropoiesis-stimulating agents (ESAs) have been used in treating anemic MDS patients to improve erythropoiesis and reduce the risk of red blood cell (RBC) transfusion. Two previous systematic reviews found that ESA use was efficacious, but these reviews focused on short-acting epoetin alfa (EA). Since then, the results of a number of prospective interventional trials of DA have been reported. We present an updated systematic review and meta-analysis to estimate the efficacy of DA in the treatment of MDS-related anemia. Methods: We conducted a systematic review of the medical literature to identify prospective interventional trials of DA in patients with MDS. The main inclusion-exclusion (IE) criteria were: that studies had to be prospective and interventional in nature; have at least 10 adult subjects with MDS reporting either World Health Organization (WHO), French-American-British (FAB) criteria, or International Prognostic Scoring System (IPSS) status; and report results for the pre-specified primary outcome (proportion of patients with erythroid response) or one of the secondary outcomes (which included major hemoglobin response, changes from baseline in hemoglobin levels, transfusion status, and quality of life (QoL) measures). We recorded and collated all reported adverse events. Two independent reviewers identified the studies and abstracted the information and a third reviewer adjudicated. Clinical and methodological heterogeneity across studies were evaluated with respect to the study population and participant selection method (e.g. MDS diagnosis, history of ESA use, baseline erythropoietin (EPO), hemoglobin, and creatinine levels, transfusion status, and other factors), the intervention (e.g. initial and maintenance ESA dose), and the endpoints of interest including the response criteria. Forest plots with formal testing using Cochran's Q-statistic was also used to assess the heterogeneity across the studies. We used random effects methodology to generate combined estimates when warranted by the data. Subgroup analyses and/or meta-regressions were conducted by dose level, ESA-naïve status, baseline EPO level, hemoglobin level, transfusion status, and other factors. Results: Ten studies (9 single-arm, 1 randomized controlled trial [RCT]) with a total of 647 patients were included in the systematic review, with response rates ranging from 38% to 72%, and the median duration of response varying from 5 to 12 months. The overall response rate for the nine studies that used IWG 2000 response criteria could not be evaluated because of heterogeneity. However, among studies that stratified response rates by baseline endogenous EPO levels, patients with EPO 100 IU/L. Across the studies that reported response stratified by prior ESA use, ESA-naïve patients had a median response rate of 75% compared to 53% for patients previously treated with an ESA. Baseline mean hemoglobin was significantly associated with response (p=0.0204), with higher baseline levels associated with improved response. We also found that response tended to improve with dose (p=0.2; Figure 2): the estimated response for a mean initial dose of 150 μg once weekly (QW) was 57% (95% CI: 49-66%) compared to 64% (95% CI: 55-74%) for 300 μg QW. Baseline transfusion independence (6 studies), and low-risk IPSS status (2 studies) were reported to be significantly associated with better response in several studies. Treatment with DA tended to show an improvement in the quality of life (QoL) measures, transfusion rates, and hemoglobin levels, but the number of studies that reported these outcomes was small. Hypertension, thromboembolism, and progression to acute myeloid leukemia were respectively reported in 2%, 1%, and 1% of the patients. Conclusions: Published studies suggest that treatment with DA yielded high hemoglobin response (38-72%) in MDS patients with anemia. The response was strongest in patients with lower baseline serum EPO level, and ESA naïve patients. Disclosures Park: Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Mehta:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Callaghan:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Kim:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Tomita:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Xu:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership.

Background Recommendations on erythropoiesis-stimulating agents for the management of chemotherapy-induced anemia (CIA) are well established (Schrijvers D et al. Ann Oncol 2010;21[suppl 5]:v244-7). Iron supplementation can further improve treatment response of CIA, particularly in the case of iron deficiency (Pedrazzoli P et al. J Clin Oncol 2008;26:1619-25; Auerbach M et al. J Clin Oncol 2004;22:1301-7), but is under-used. Objective To evaluate the effect of epoetin alfa biosimilar, with or without iron, on CIA in current oncology and hematology practice. Methods SYNERGY was an observational, longitudinal, prospective, multicenter study conducted in France, from a representative, random sample of oncologists and hematologists. Patients of these clinicians were aged ≥18 years with solid tumors, lymphoma and/or myeloma and CIA, eligible for treatment with epoetin alfa biosimilar and followed for 12-16 weeks. A subanalysis of patients with lymphoma or multiple myeloma is presented here. Results Overall, 2167 patients were enrolled by 195 French oncologists and hematologists during June 2012-December 2014. Of these patients, 12.7% (n=264) had lymphoma and 6.6% (n=136) had multiple myeloma and were included in the analysis population, where the disease categories were non-exclusive; 84.5% (n=223) of patients with lymphoma were diagnosed with non-Hodgkin's lymphoma. Half of the patients with lymphoma and multiple myeloma were male. The majority of patients were ≥70 years old (60.6% of patients with lymphoma and 69.1% with multiple myeloma) and had a performance status of 0 or 1 (72.9% [n=180] of patients with lymphoma and 71.8% [n=94] with multiple myeloma). Baseline mean ± standard deviation (SD) hemoglobin (Hb) levels of patients with lymphoma and multiple myeloma were 9.5±0.8 g/dL and 9.5±0.9 g/dL; 40.2% (n=106) and 39.0% (n=53) of these patients had moderate anemia (Hb 8.0-9.5 g/dL), while 2.3% (n=6) and 4.4% (n=6) had severe or very severe anemia (Hb ≤8.0 g/dL), respectively. Iron status assessment was available for 60.2% (n=159) of patients with lymphoma and for 59.6% (n=81) with multiple myeloma. Concomitant iron supplementation was not prescribed with epoetin alfa biosimilar for the majority of patients. A total of 11.4% (n=30) of patients with lymphoma and 6.6% (n=9) of patients with multiple myeloma received iron, of whom 63.3% (n=19) and 77.8% (n=7) were prescribed oral iron formulations, respectively. Patients who reached their target Hb level (increase of ≥1 g/dL since enrollment or an increase of ≥2 g/dL, with no transfusions in the three previous weeks) was 79.1% (n=201) of patients with lymphoma and 84.6% (n=104) of patients with multiple myeloma, higher than the overall analyzed population (74.2%, n=1390). The response rate to epoetin alfa biosimilar (epoetin alfa biosimilar discontinued as Hb > target level, with no transfusions in the three previous weeks) was lower in patients with lymphoma given iron supplementation versus those not given iron; 66.7% (n=20) of the iron supplementation group were responders, compared with 75.4% (n=169) of patients without iron. Response to epoetin alfa biosimilar was similar in patients with multiple myeloma regardless of the iron supplementation status (85.7% [n=6] of patients with iron supplementation and 81.0% [n=94] of patients without). The response to epoetin alfa biosimilar translated into an improvement in patient perception of fatigue (66.7% [n=20] of patients with iron supplementation and 72.5% [n=161] of patients without who had lymphoma; 71.4% [n=5] of patients with iron supplementation and 81.3% [n=91] of patients without who had multiple myeloma). Conclusions These results indicate that epoetin alfa biosimilar was effective in treating patients with CIA and lymphoma/myeloma in France and agrees with previous studies (Michallet M et al. BMC Cancer 2014;14:503). Iron supplementation did not appear to increase the response to epoetin alfa treatment in this population; however, confirmatory studies in larger patient cohorts are required. Disclosures Scotté: Hospira SAS: Research Funding. Laribi:Hospira SAS: Research Funding. Gisselbrecht:Hospira SAS: Research Funding; Roche: Consultancy, Research Funding; Baxter: Research Funding; Chugai Pharmaceutical: Research Funding; Bertram Glass: Research Funding. Spaeth:Hospira SAS: Research Funding. Kasdaghli:Hospira: Employment. Albrand:Hospira: Employment. Leutenegger:GECEM: Employment; Hospira SAS: Research Funding. Ray-Coquard:Hospira SAS: Research Funding; Amgen: Consultancy, Other: Paid instructor; PharmaMar: Consultancy, Other: Paid instructor; Roche: Consultancy, Other: Paid instructor.

Introduction: Most myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol for the treatment of anemia in MF demonstrate responses in anemia. In prior randomized-controlled studies, ruxolitinib demonstrated improvements in splenomegaly, symptom burden, and even survival yet improvements in cytopenias were uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This was a Simon optimum two-stage phase II trial. Eligible subjects received ruxolitinib, a JAK 1/JAK2 inhibitor, at 10mg (plat >75 x10x9) BID or 5mg (plat Results: Patients: Fourteen pts enrolled (9 Mayo Arizona, 5 Mount Sinai). Median (Med) age 70.5 (range 43-78), M:F ratio 1.8:1. Ten primary MF, 2 post-essential thrombocythemia MF, and 2 post-polycythemia vera MF. JAK2 V617F positive in 42.9%. DIPSS Low in 1 pt, Int-1 in 1pt, Int-2 in 8 pts, High in 2 pts, and unknown in 2pts. Transfusion dependence in 35.7% at baseline. Med baseline hemoglobin (hgb) was 9.0 g/dL (R: 8.3 - 12.4), platelet (plt)157 x109/L (R:143 - 520). Thirteen pts received prior therapy, with 9 pts (64.2%) on a JAK inhibitor within 3 months of study entry. Tolerability: Nine pts (64.2%) ended active treatment, due to progression of disease in 2 pts (22.2%), adverse event (AE) in 2, pt preference in 2, stem cell transplant in 1, unrelated death in 1, and comorbidity in 1. Med duration of therapy: 91 days (range 24-287). AEs regardless of attrition included: hematologic grade 3 or >: anemia in 7 pts (50%), neutropenia in 2 (14.3%), leukopenia in 1 (7.1%), and thrombocytopenia in 2 (14.3%). Non-hematologic grade 3 or >: electrolyte abnormalities in 3 pts (21.4%), infection in 2 (14.3%), edema in 1(7.1%), hypertension in 1 (7.1%), and intracranial hemorrhage in 1 (7.1%). Efficacy: Of the 5 JAK inhibitor naïve pts, 4 had stable or increasing hgb levels with therapy despite new ruxolitinib therapy. Of the 9 pts on prior JAK inhibitor (5 ruxolitinib, 4 other), 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels, respectively. See Table #1. Four pts (28.6%) had at least 50% improvement from baseline on MPN-SAF TSS (95% CI 8.4%-58.1%). Overall treatment response: (IWG-MRT) stable disease (SD) in 10 pts (71.4%), clinical improvement (CI) in 3 (21.4%) all of which were spleen responses, and progressive disease (PD) in 1 (7.1%). Trial was halted secondary to lack of anemia response. Table 1. Patient Specific Response Patient IWG-MRT Response: Study Cycles (N): Prior therapy (within 3 mo) Hemoglobin Response*: (initial, final g/dL) Platelet Response*: (initial, final 10(9)/L) Ruxolitinib 1 CI-Spleen 5 D (8.8, 7.6) S (221,212) 2 SD 4 D (10.3,7.9) S (54,46) 3 SD 2 S (8.8,8.9) S (82,101) 4 SD 3 I (8.9,9.8) S (441,458) 5 SD 3 S (9.6, 9.5) I (161, 231) JAK Inhibitor: 6 SD 5 Momelotinib S (9.0, 9.2) S (132,113) 7 SD 1 NS-018 D (8.3, 7.1) D (120,43) 8 SD 3 NS-018 D (10.1,9.0) D (138,111) 9 SD 2 LY2784544 S (8.7,9.1) S (56,21) Other: 10 CI-Spleen 9 Procrit I (10.5,11.9) S (153,198) 11 CI-Spleen 7 None I (8.9,10.2) D (338,133) 12 PD 1 Hydroxyurea S (12.4, 12.2) D (310, 82) 13 SD 1 Procrit D (10.1, 8.6) D (192, 71) 14 SD 1 Hydroxyurea S (9.1,8.9) D (346,119 *S=stable (Hgb +/- 0.5g/dL, Plt +/- 50x109, D=decreasing, I=increasing. Conclusions: Although overall well tolerated, the addition of danazol to ruxolitinib therapy has modest incremental efficacy by IWG-MRT criteria. Clinical improvement was observed in 21.4% of treated patients, however responses were limited to spleen reduction. The degree to which danazol may stabilize expected cytopenias is interesting and may require further investigation. Disclosures Hoffman: Promedior: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding.

Introduction Chemotherapy-induced anaemia (CIA) is a frequent complication of patients (pts) with cancer, associated with fatigue and impaired quality of life, and may have serious medical consequences that can lead to discontinuation or interruption of chemotherapy (CT). Guidelines from the European Organisation for Research and Treatment of Cancer (EORTC) recommend epoetin treatment of CIA to increase haemoglobin (Hb) levels and to help to prevent red blood cell transfusions and related complications. Several epoetin alpha biosimilars are currently approved for use in the EU for the treatment of CIA. The ORHEO study (place of biOsimilaRs in the therapeutic management of anaemia secondary to chemotherapy in HaEmatology and Oncology) was a prospective, observational, non-interventional, longitudinal, national, multicentre study conducted in France that evaluated the changes in Hb level in pts with solid tumours, lymphoma or myeloma, treated with an epoetin alfa biosimilar (EAB). In this subanalysis of the ORHEO study, we compare the usage of EAB in relation to the dosage recommendations of the EORTC guidelines, with respect to efficacy and safety. Methods Pts >18 years with CIA (Hb Results Data from 2310 pts (mean age ± standard deviation 66.5±11.8 years) from 232 centres were included in the study analysis. Overall, 79.6% of pts had solid tumours, 13.0% had lymphoma and 7.4% myeloma. Of those pts with solid tumours, 30.1% of pts had a stage III and 21.6% had a stage IV tumour. Mean baseline Hb level across all pts was 9.6 g/dL, with 35.6% of pts having moderate anaemia (Hb 8–9.5 g/dL). Almost all pts (99.9%) received the epoetin alpha biosimilar (Retacrit™, Hospira UK Ltd., median dose 30,000 IU/week). Overall, 43.8% of pts received the recommended dose of EAB (as determined by their weight) throughout the study. The proportion of pts receiving the recommended dose showed little variation between malignancies (lymphoma: 43.6%; myeloma: 40.9%; breast: 39.3%; lung: 48.3%; colorectal: 39.5%). Overall, the percentage of responders was 81.6% at M3 and 86.5% at M6. The overall mean change in Hb level was 1.5±1.6 g/dL at M3 and 1.72±1.61 g/dL at M6. Responses to treatment at M6 were similar whether or not EAB was prescribed at the recommended dose throughout the study. A similar proportion of pts receiving the recommended dose of EAB reported adverse events (AEs) at M6 compared with pts who did not receive the recommended dose (9.9 vs 9.0%). Overall, transfusion rates were 9.4% and 5.8%, while the rate of thromboembolic events was 2.4% and 1.5%, at 3 and 6 months respectively. Conclusion In the ORHEO study, 44% of pts received the EORTC recommended dose of EAB over the 6-month course of the study. However, the response to therapy was similar regardless of dose. Furthermore, the frequency of overall AEs at M6 did not vary depending on dose. In conclusion, the EAB Retacrit™ was effective and well tolerated in the management of CIA in pts with solid tumours, lymphoma and myeloma and provides an alternative therapeutic option for the treatment of CIA. Disclosures Michallet: MSD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hospira: Consultancy, Honoraria. Soubeyran:Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria; Hospira: Honoraria. Kurtz:Hospira: Coverage of travel expenses/congress fees Other. Albrand:Hospira: Employment.

Background: OncoBOS is a national, prospective, non-interventional, longitudinal, observational study describing biosimilar epoetin alfa (Binocrit®) use in routine practice in France in patients receiving chemotherapy treatment (CT) for solid tumors, lymphoma or myeloma. This sub-analysis focuses on the management of CIA in patients with MM. Patients and methods: Patients ≥18 years with MM, CIA and eligible for treatment with Binocrit® were included in this analysis. Patients characteristics, data on CIA and its management and predominant factors considered by the physician in prescribing Binocrit® were recorded at baseline, 3-4 weeks and 12 (± 1) weeks later. Hemoglobin (Hb) outcomes assessed included the proportion of patients achieving a Hb increase ≥1 and ≥2 g/dL, and the mean Hb change from baseline. Results: 99 patients with MM (mean age 71.1 years) from 20 sites were recruited from September 2011 to April 2014. 54.5% of subjects were male. Mean and median baseline Hb levels were 9.4 g/dL and 10 g/dL, respectively. The mean increase in Hb level was 1.1 g/dL after 1 month and 2.2 g/dL after 3 months (p Conclusion: This sub-analysis indicates that Binocrit®, used in routine practice, is effective and well tolerated for the treatment of CIA in patients with MM receiving CT. Disclosures Voronina: Sandoz: Investigator Other. Ojeda-Urib:Sandoz: Honoraria. Dauriac:Sandoz: Investigator Other. Voillat:Sandoz: Investigator Other. Aubron-Olivier:Sandoz: Employment. Fernet:Sandoz: Employment. Karlin:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fitoussi:Sandoz: Honoraria.

Background Epoetin and intravenous iron are used at St. Bartholomew's Hospital (Barts Health NHS Trust) for the treatment of patients with non-myeloid malignancy and chemotherapy-induced anemia. Modified American Society of Hematology/American Society of Clinical Oncology guidelines are used to guide epoetin use. This is combined with a systematic approach to iron supplementation based on iron status markers, including zinc protoporphyrin (ZPP). Using this approach, we have previously reported very high hemoglobin response rates of up to 92% with epoetin beta (Agrawal et al. Blood 2005; 106: Abs 588). Biosimilar versions of epoetin alfa are now approved in Europe to treat chemotherapy-induced anemia in patients with cancer. These agents offer potentially substantial cost savings to healthcare payers, and their greater affordability may increase patient access to treatments. We performed a pilot study of the effectiveness of biosimilar epoetin alfa (Sandoz, Germany) in our protocol for the management of chemotherapy-induced anemia in patients with hematological malignancies. Methods Patients with chronic lymphocytic leukemia (CLL), myeloma or lymphoma, receiving chemotherapy and with Hb2 g/dL, respectively. Iron support was given in the form of intravenous (i.v.) iron sucrose 200 mg weekly if indicated based on iron status markers (serum ferritin, transferring saturation [TSAT], mean corpuscular Hb [MCH] and ZPP). Results Nineteen patients treated with biosimilar epoetin alfa were included in this analysis (9 with CLL, 7 with myeloma, 3 with lymphoma). Ages ranged from 25 to 84 years. 18 patients had a response to biosimilar epoetin alfa (95%); of these, 12 had a major response and 6 a minor response. Only one patient required an epoetin dose increase. Four patients were transfusion-dependent at baseline, 3 of whom became transfusion-independent on epoetin therapy. Seven of the 19 patients were ineligible for iron supplementation because of a serum ferritin >1000 μg/L. Of the remaining 12 patients, five (43%) received i.v. iron support based on their iron status markers at baseline and during epoetin therapy. In all five, the trigger for iron support was a raised ZPP in combination with a low/normal serum ferritin; TSAT was low in only 2/5and the MCH was normal in 5/5. All five patients achieved a response to epoetin. In contrast, five other patients who had a raised ZPP did not receive iron support because of markedly raised serum ferritin (>750 μg/L) with raised TSAT. Conclusions This pilot study indicates that biosimilar epoetin alfa is effective for the treatment of chemotherapy-induced anemia in patients with hematological malignancies. Although this is a small data set, response rates using biosimilar epoetin alfa in our epoetin/iron supplementation protocol (95%) are very high and similar to historical data using epoetin beta (92%). While ZPP appears to be a useful parameter to guide iron support in patients with hematological malignancies, it cannot be used in isolation and must be correlated with serum ferritin. Appropriate use of iron support, based on assessment of readily available laboratory parameters, may increase response rates to epoetin therapy. Disclosures: Agrawal: Sandoz Biopharmaceuticals: Consultancy, Honoraria, Research Funding. Turner:Sandoz Biopharmaceuticals: Employment.

Abstract 2838 Background: Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 COMFORT studies in MF patients (pts). Consistent with rux's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable leading to discontinuation in only 1 pt. In clinical practice, anemia can be managed with ESAs, which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of rux in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of rux. This post hoc analysis evaluated the safety and efficacy of rux in pts receiving concomitant ESA in COMFORT-II. Methods: COMFORT-II is an open-label, randomized, multicenter study. Pts were randomized (2:1) to receive rux 15 or 20 mg bid or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa, epoetin nos), although not prohibited, was discouraged for pts randomized to rux because ESAs can increase spleen size, which could confound efficacy analyses. Spleen volume was assessed by MRI or CT every 12 wk. The rate of transfusions was calculated as the number of units transfused per exposure duration (typically 12 wk). Results: Concomitant use of ESA was reported for 13 (PMF, n = 10; PET-MF, n = 2; PPV-MF, n = 1) of the 146 pts who were treated with rux (darbepoetin alfa, 2% [n = 3]; epoetin alfa, 6% [n = 9]; epoetin nos, < 1% [n = 1]). The median exposure to rux was similar for pts who received an ESA (+ESA group; 500 d) vs those who did not receive ESA (468 d), and the median dose intensity of rux was the same for each group (30 mg/d). As shown in the table, 8 pts (62%) had no change, 2 pts (15%) had a decrease, and 3 pts (23%) had an increase in the rate of packed red blood cell (PRBC) transfusions per mo after the first administration of ESA compared with 12 wk before ESA use. Six wk prior to the first administration of ESA, 10/13 pts (77%) had grade 3/4 hemoglobin abnormalities; however, 6 wk after the administration of ESA, most pts' conditions improved to grade 2 (7/13 [54%]). The majority of pts (77%) did not have any change in their reticulocyte counts within the 6 wk before and after the administration of ESA; 1 pt (8%) had a marked increase; for 2 pts (15%), the data were not available. The AEs reported in pts who received ESA were similar to those previously reported with rux. Serious AEs were reported for 8 pts in the +ESA group (3 events in 2 pts that were possibly related to study drug). Within the last assessment prior to and the first assessment after the first administration of ESA, 7/9 evaluable pts (78%) had spleen volume reductions. Conclusions: In this analysis, although the sample size is small, rux was generally well tolerated in pts who received ESA, and the tolerability profile of rux was similar to that reported in previous studies. Rux-treated pts who received ESA generally did not have any change in their transfusion rates, but the rate of grade 3/4 hemoglobin abnormalities decreased within 6 wk of the first administration of ESA, suggesting that the use of ESA in combination with rux was beneficial in some pts. ESA did not appear to affect the efficacy of rux concerning spleen size reduction. The use of ESA for the treatment of anemia is common in clinical practice, and further analyses in combination with rux in this pt population are warranted. Disclosures: McMullin: Bristol Myers Squibb: Honoraria; Shire: Honoraria; Novartis: Honoraria. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. Recher:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, travel to ASH, travel to ASH Other; sunesis: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Gisslinger:Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; AOP Orphan Pharma AG: Consultancy, Speakers Bureau. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Al- Ali:Sanofi Aventis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria.

Abstract 4194 For the past 20 years, management of hemoglobin (Hb) level via erythropoiesis-stimulating agents (ESAs), such as epoetin alfa (EPO) has been the norm in the care of end-stage renal disease (ESRD) patients. Recently, questions about patient safety and new economic bundling rules have brought renewed focus on appropriate Hb targets and how they relate to the use of EPO. Important issues related to Hb control are the frequency of Hb measurements, Hb value, the frequency of changes in EPO dose (titrations), and total EPO dose. Current practice aims to achieve greater control of Hb by more frequent measurement and finer EPO dose titrations. No studies have definitively shown that levels of titration and measurement frequency lead to better clinical outcomes or more efficient use of EPO. One large retrospective analysis found increasing Hb measurements and EPO dose titration frequency decreased patient variability around the facility-level Hb mean (Khan et al, 2011). However, a second study found that frequent titrations have been shown to be the most important driver of Hb cycling—potentially dangerous large fluctuations in Hb levels (Fishbane and Berns, 2005). The issue remains controversial. We conducted a retrospective database analysis in order to quantify the frequency of Hb dose titrations and measurements, and to evaluate their relationship to ESA dose and the ability to keep patients within a Hb range of 10–12 g/dL. Data from prevalent (≥ 120 days), adult (>18 years old) hemodialysis patients dialyzing at DaVita dialysis clinics ≥ 3 times per week between January 1, 2009 and December 31, 2010 were included. For every session, patients' stable dosing periods were defined as any series of at least 3 doses during which the dose did not change more than 10% from first dose in the series. Dose holds were defined as ≥ 3 consecutive sessions with 0 EPO dose. An EPO dose of 0 lasting 10% between any of the following: the mean dose of 2 consecutive stable periods; the mean dose of stable period and next/previous dose in transition period; and 2 consecutive doses within a transition period. Transitions involving a dose hold were counted as 1 titration if the patient then returned to a dose within 10% of the mean of the prior period; or 2 titrations otherwise. Similar rules were developed for the minority of patients who received EPO once or twice per week. Correlations among measures (titrations/patient-month and Hb measurements/patient-month with mean monthly EPO dose and time with Hb in range) were assessed using Pearson product-moment correlation and linear regression (adjusted for racial composition, percentage of dialysis vascular access types, percentage with comorbidities, and mean age, vintage, and BMI) at the physician and the facility levels. Time in range was defined as total patient time in range/total patient-time. Facility level analyses were weighted by facility load (minimum of 300 patient-months) and are reported here. Information from 81,464 patients at 1,336 facilities was assessed. The mean number of titrations was 13.6 ± 2.83 (mean ± SD) per patient per year and the mean number of Hb measurements was 36.3 ± 8.24 per patient per year. The mean percent of patient-time in range among these facilities was 57.1% ± 5.8%. At the facility level, after adjustment for case mix factors (mean age, vintage, and BMI at facility, access types, and racial composition) the annual number of dose titrations per patient and Hb measurements per patient were not associated with the percent of patient-months within a 10–12 g/dL Hb range (p=0.12 and p=0.47; respectively). An analysis of ESA utilization showed that an increase of 1 titration per patient at the facility level was associated with an extra 18,000 U (p In this retrospective study of >80,000 US dialysis patients over 2 years, neither increased Hb measurements nor increased EPO titrations were associated with improving patient-time in Hb range. However, increased EPO titrations were associated with significantly increased EPO utilization. Although these associations do not demonstrate causality (or the direction of potential causality), they do underscore the need to assess titration practices. Disclosures: Bond: DaVita Clinical Research: Employment; Affymax Inc: Research presented in this study was paid for by Affymax. Rubin:DaVita Clinical Research: Employment; Affymax: The research presented in this abstract was paid for by Affymax. Wang:DaVita Clinical Research: Employment; Affymax: The research presented in this abstract was paid for by Affymax. Yang:Affymax: Employment.

Abstract 2092 Background: Erythropoiesis-stimulating agents (ESAs) are indicated for the management of chemotherapy induced anemia in oncology. However, increased risks of cardiovascular events, inferior survival, and poorer tumor outcomes are linked to ESAs when used to achieve a target hemoglobin ≥12 g/dL. Due to these serious safety concerns, the FDA has recommended more conservative dosing guidelines whereby the lowest possible dose of ESAs should be used to gradually increase hemoglobin concentration to the lowest level sufficient to avoid blood transfusion. The currently ASCO/ASH recommended and FDA approved starting dose for epoetin is 150 U/kg three times weekly (TIW) or 40,000 U weekly, and the dose should be increased to 300 U/kg or 60,000 U in nonresponsive patients. Objectives: This study evaluated the effectiveness of a fixed lower dose (4000 unit, TWI) of Epoetin alfa (Epo a) in comparison with transfusion support alone in anemic solid tumor patients (Hb< 9 g/dl) who were administered concomitant chemotherapy. Methods: This was a prospective, single-centered, randomized, controlled study. The period of enrollment began in June 2009 and ended in December 2010. A total of a hundred and two solid tumor patients with chemotherapy induced anemia (Hb < 9 g/dl) and Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–3 were enrolled and randomized into two groups; forty five patients (treatment arm) received 4000 unit of Epo a three times weekly plus oral iron, whereas fifty seven patients were randomized to control group (control arm). Both groups received RBC transfusion when needed. Epo dose was not increased in patients deemed nonresponsive. The primary endpoints were the changes in hemoglobin (Hb) concentrations, transfusion needs, and QoL. The follow-up period was twelve weeks. Results: Mean age of 102 patients was 53.6 ±12.7 years (mean ± SD), mean weight was 63.86 ±12.05 kg (mean ± SD), mean hemoglobin was 8.22 ± 0,55 g/dl (mean ± SD), 32.4% were male, and 60.8% were on platinum based chemotherapy. After excluding patients who died, were lost to follow up, withdrew consent, or were ineligible, 81, 59, and 50 patients were assessed at weeks 4, 8, and 12 respectively. At each of these time points, Epo at low dose (4000 unit, TWI) significantly decreased transfusion needs, increased hemoglobin concentrations, and improved QoL. At week 12, the mean hemoglobin increase was 2.4 g/dL in the EPO group (n=28) versus 0.97 g/dL in the control group (n=22) (P < 0.001). In Epo-responders (17/28), Hb increase was 2.87 g/dl, and Hb concentrations were > 12 g/dl in 5/17 (29.4%), 11–12 g/dl in 3/17 (17.64%), and 10–10.9 in 3/17 (17.64%). EPO evaded blood transfusion in 19/28 patients (67.87%) in the EPO arm. 9/28 (32.14%) of patients in the EPO arm were transfused a total of 18 units (0.65 unit per patient), versus 21/22 (95.45%) in the control group who received a total of 53 units, resulting in a significantly higher average transfused units per patient (2.41 units per patient) (p < 0.001). Based on ECOG PS score, QoL was significantly better in Epo treatment group in comparison with control group (p< 0.05). Conclusions: Administration of EPO in a low dose (4000 U, TIW) is effective in alleviating anemia, evading RBC transfusions, and improving QoL in a considerable proportion of anemic cancer patients receiving chemotherapy. Our findings highlight a great variation in responsiveness to low dose of EPO in anemic cancer patients and suggest the existence of high EPO responders. Lowering the starting dose of Epo may represent a more physiologic and effective alternative that better corresponds to FDA recommendations. Disclosures: No relevant conflicts of interest to declare.

Abstract 4798 Objectives: The role of steroids in mammalian erythropoiesis has not well defined. We have previously reported our observation on three human cases in which there was a synergism and accelerated response to the Erythropoietic Stimulating Agents (ESA) with simultaneous low and physiologic dose administration of glucocorticoids. In the current study, we investigated the additive effects of different dose schedules of steroids on hematopoietic effects of ESA in animal modules. Methods: A total of 74, four-weeks old male Sprague-Dawley rats were randomized to 6 groups; (A) control, (B) therapeutic doses of either erythropoietin, [Procrit Epoetin Alfa, 100 UI/kg], or (C) dexamethasome (300 mcg/kg), as well as combination of erythropoietin (Epoetin Alfa, 100 UI/kg) with (D) low, [25 mcg/kg], (E) physiologic, [300 mcg/kg], and (F) high, [2.5 mg/kg] doses of dexamethasone through abdominal hypodermal injection three times a week for a total of four weeks. At the conclusion of the study, peripheral blood sample, and Bone marrow mononuclear cells were collected through femur flushing. The samples were lysed and stored in RNA denaturation buffer at –80°C until use. Expressions of multiple hematopoietic major genes were assessed by real-time RT-PCR. Amplification data were processed using ΔΔCt method. Hemoglobin concentration and other CBC parameters were measured at the reference lab. Results: Mean hemoglobin concentrations were significantly higher in groups D (20.76 g/dl, 95% CI 20.08–21.45), E (20.45 g/dl, 95% CI, 19.97–20.94), and F (20.99 g/dl, 95% CI 20.55–21.42), compared to the controlled groups A, B, C (14.57, 15.68, 19.23 g/dl respectively) with two-tailed p-value of Conclusion: The findings in this study is suggestive that simultaneous administration of ESAs with glucocorticoids is associated with significant additive elevation of the hemoglobin concentration; however, higher dose of dexamethasone is associated with more frequent adverse side effects such as significant weight loss. It is also suggested that the erythropoietic effect of steroid is concerted by up-regulation of the multiple erythropoietic gene expressions, such as JAK2, GATA-1, c-Kit, and NFkB1, while down regulations of EPOR is uniformly seen in the Epo-treated groups. This novel finding could be clinically utilized to accelerate the erythropoietic response of the ESA in selected cases. Disclosures: No relevant conflicts of interest to declare.

Abstract 5147 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life in 2 phase 3 studies (the COMFORT studies) in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), and post-essential thrombocythemia-MF (PET-MF). Consistent with ruxolitinib's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable and led to discontinuation in only one patient. In clinical practice, anemia can be managed with erythropoietic-stimulating agents (ESAs), which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of ruxolitinib in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of ruxolitinib. Methods: COMFORT-II is an open-label, randomized, multicenter study in patients with MF. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa), although not prohibited, was discouraged for patients randomized to ruxolitinib because they can increase spleen size, which could confound the efficacy analyses. This post hoc analysis evaluates the safety and efficacy of ruxolitinib in patients receiving concomitant ESAs in the COMFORT-II study. Results: Use of ESAs was reported for 9 (PMF, n=6; PET-MF, n=2; PPV-MF, n=1) of the 146 patients who were treated with ruxolitinib (darbepoetin alfa, 1.4% [n=2]; epoetin alfa, 4.8% [n=7]), with a median duration of exposure to ESAs of 22.1 weeks. The median dose intensity of ruxolitinib was numerically higher for patients who received ESAs (+ESA group; 39.2 mg/day) compared with those who did not receive ESAs (–ESA group; 30.0 mg/day). The mean change from baseline in spleen volume at week 48 was similar in both groups (+ESA, –29.8%; –ESA, –30.1%); 44.4% of the +ESA group (4 of 9 patients) and 27.0% of the –ESA group (37 of 137 patients) achieved ≥ 35% reduction in spleen volume from baseline at week 48. The mean number of packed red blood cell units received per month while on treatment was similar in both groups (+ESA, 0.78; –ESA, 0.86). The AEs reported in the +ESA group were similar to those reported in the –ESA group; serious AEs (SAEs) were reported for 4 patients in the +ESA group (patient 1: fracture of the distal radius after a fall; patient 2: urinary tract infection, abdominal pain, and anemia; patient 3: herpes zoster; patient 4: respiratory infection, decrease in general condition, and acute renal insufficiency). SAEs determined to be possibly related to study medication (respiratory infection and decrease in general condition) occurred in 1 patient who discontinued the study; this patient died from respiratory infection. At baseline, patients in the +ESA and –ESA groups had median creatinine levels of 70.2 and 75.4 μmol/L, respectively. Median changes from baseline at week 48 were similar for reticulocytes (+ESA, –13.6%; –ESA, –9.1%) and hemoglobin (+ESA, –5.8%; –ESA, –5.7%). The +ESA group had higher median levels of erythropoietin (39.0 and 7.0 pg/mL) at baseline and a larger increase at week 48 (485.0% and 185.2%). Conclusions: In the COMFORT-II study, ruxolitinib resulted in significant reduction in spleen size compared with BAT in patients with PMF, PPV-MF, or PET-MF. In these analyses, although the sample size is small, the use of ESAs did not appear to affect the efficacy of ruxolitinib concerning spleen size reduction, and no substantially different AEs were reported between patients receiving ESAs and those who did not. Additionally, concomitant use of ESAs may have allowed for an increased dose of ruxolitinib. The use of ESAs for the treatment of anemia is common in clinical practice, and further analyses in combination with ruxolitinib in this patient population are warranted. Disclosures: McMullin: Novartis: Honoraria; Amgen: Honoraria; Bristol Myers: Honoraria. Harrison:Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment. Wearver:Novartis Pharma AG: Employment. Stalbovskaya:Novartis Pharma AG: Employment. Kiladjian:Novartis: Honoraria; Celgene: Honoraria.

Abstract 4002 Background. In lower-risk MDS, anemia is the main therapeutic challenge. ESAs can frequently correct anemia, but not all pts respond and median response duration to ESAs is only about 2 years. LEN yields RBC transfusion-independence (TI) in 65% of lower risk MDS with del(5q)] and about 25% of lower risk MDS without del 5q (Raza A, et al, Blood, 2008, 111, 1). However, in the last study, pretreatment with ESAs was not always documented, and the efficacy of LEN on anemia of non-del(5q) MDS refractory to ESAs remains unknown. Patients and Methods: 31 consecutive lower-risk non-del(5q) MDS with anemia refractory to ESAs were treated with LEN through a compassionate program. Pts wn@ere from 7 centers of the Groupe Francophone des Myélodysplasies. They had previously received an ESA during at least 12 weeks, including epoetin alfa (80,000 U qw, n= 17), epoetin beta (60,000 qw, n=3), darbepoetin (500 μg q2 w, n=11), and GCSF was added in 20 patients. Results: At inclusion in the program, median age was 69 (range 41–87), including RA (n=3), RAEB-1 (n=2), RARS (n=11), RCMD (n=12), and RCMD-RS (n=3). Karyotype was fav (n=27), int (n=2), and unfav (n=2). IPSS was low (n=15), int-1 (n=16). Median ESAs treatment duration was 3 months (3-36+). According to IWG 2006 criteria, 18 pts were primary resistant to ESAs while 13 relapsed after a 12 months median duration of erythroid response (range 3–36). At onset of LEN, median Hb level was 8.9 g/dl (range 6.3–9.9), median endogenous EPO level 172 UI/l (48-1092 UI/l). The starting doses of LEN were 5 (n=10) or 10 mg (n=21), daily (n=26) or daily × 3 wks q28d cycle (n=5). 20 pts also received ESAs including EPO alone (n=6) and EPO+GCSF (n=14). Deep vein thrombosis (DVT) prophylaxis was made in 22 pts (71%) with aspirin (n=20), heparin (n=1) or warfarin (n=1). With a median follow-up of 16 months (range 3–27), 13 (42%) pts obtained an erythroid response (IWG 2006 criteria). All responses occurred within the first 3 months of treatment. 4 of the responders (31%) relapsed at 4, 9, 15, and 16 months whereas 9 (69%) were still responding after 3+ to 24+ months. Median response duration was 12 months. Of the 24 RBC-TD patients, 10 (42 %) achieved RBC-TI of 12 months median duration (range 3+-22+). The most common drug-related grade 3/4 adverse events were neutropenia (n=6, 19%) and thrombocytopenia (n=6, 19%). No pt developed DVT. One pt with RCMD and complex karyotype developed AML and died at 3.1 months from treatment onset, 2 additional pts who resisted to LEN died 5 and 6 months after LEN interruption. According to IWG 2006 criteria, the proportion of erythroid responses was significantly lower in the 8 patients who had developed neutropenia or thrombocytopenia: 1/8 vs 12/23, p = 0.038. Among the 24 RBC-TD patients, the proportion of RBC-TI was significantly lower in the 8 patients who had developed neutropenia or thrombocytopenia: 1/8 vs 9/16, p = 0.05. Median RBC-TI duration was significantly lower in the 8 patients who had developed neutropenia or thrombocytopenia: 0 vs 9 months, p=0.05. Other factors such as age, sex, WHO classification, time between diagnosis and treatment, response to ESAs, interval between ESAs and REV, WBC count, hemoglobin level, platelet count, LEN dose, combination to ESAs, did not significantly influence response to LEN, and RBC-TI duration. Conclusion: In this cohort of lower-risk non-del(5q) MDS refractory to ESAs LEN yielded RBC transfusion independence in more than 40% of the pts and was well-tolerated. Treatment-induced cytopenia was associated with fewer erythroid responses and shorter response duration. Disclosures: No relevant conflicts of interest to declare.

Abstract 395 Background: Racial/ethnic variations in utilization of cancer care services and outcomes are well documented with African Americans (AAs) almost uniformly shown to have lower utilization rates than Whites. This issue is especially important with respect to use of the supportive care agents, erythropoiesis stimulating agents (ESAs) during time-periods where ESAs were perceived as being associated with high benefit-risk ratios as well as with low benefit-risk ratios. We evaluated ESA utilization among Medicaid patients in South Carolina with anemia and lung cancer (LC), non-Hodgkins lymphoma (NHL) or breast cancer (BC). Three time-points were selected; 2002 nearly 10 years after epoetin alfa received an indication for anemia associated with chemotherapy and the first full year following the approval of darbepoetin, 2006 the year prior to ESA safety notifications and 2009 the most recent full year of data following the implementation of a black box warning. Methods: The analysis utilizes South Carolina Medicaid fee-for-service paid claims. AA and White patients diagnosed with LC=162.xx; NHL=201.xx and 202.xx; or females with BC=174.xx plus anemia (ICD-9-CM=284.xx, 285.xx) were evaluated. Utilization rates were calculated annually as a percent of patients within each racial group with at least one prescription claim or procedure code for an ESA (i.e. epoetin/darbepoetin). Fisher's exact test was used to test for utilization rate differences. Results: The number of SC Medicaid patients diagnosed with anemia and one of the three cancers ranged from 442 to 655 annually. The average age of the study population in 2002 (55.6 years), 2006 (55.3 years) and 2009 (57.7 years) did not vary significantly between AAs and Whites. Among all cancer patients, ESA utilization increased from 2002 peaking in 2006 (prior to safety notifications and CMS National Coverage Decision). Following publication of the black box warning, utilization rates decreased 60% for AAs and 67% for Whites, in 2009. Initially (2002) utilization rates were 15% lower among AAs than Whites. However, by 2006 utilization rates were 13% higher in AAs compared to Whites. Following the black box warning, utilization rates were 30% greater in AAs versus Whites among all cancer patients (LC, BC or NHL). More specifically, ESA utilization rates were 47% greater among AAs compared to Whites with BC, and 280% greater among AA versus White patients with NHL. In contrast, ESA utilization rates were 9% lower in AAs compared to Whites with LC. (Table) Conclusions: Following the approval of darbepoetin in 2002, utilization of ESAs were lower among AA patients with LC, BC or NHL compared to Whites. However, by 2006 when these agents were perceived to have high benefit-risk profiles utilization rates were greater among anemic AA versus White cancer patients. The utilization rates remained higher for AAs during 2009 when ESAs were perceived to have lower benefit-risk profile. Our findings indicate that disparities in the utilization of ESA changed overtime. Counter to results reported in prior studies of racial/ethnic disparities, among the insured poor in South Carolina in recent years, rates of ESA utilization were greater for AAs versus Whites. Additional analyses will evaluate if these differences were associated with differences in outcomes and toxicity. Disclosures: Bennett: Pfizer: Consultancy.

Abstract 4892 Introduction In multiple myeloma (MM), hemoglobin (Hb) levels have long been part of staging of the disease and an important determinant in assessing treatment options, response to therapy and prognosis. The causes of a low Hb level are complex, but reflect in part the extent of myeloma cell infiltration in the bone marrow. Changes in the level of the monoclonal immunoglobulin protein in the blood and/or urine (M protein) serve as the main surrogate marker for response to treatment and progression of disease in the majority of patients (pts). This analysis explores the longitudinal relationship between treatment response (using M protein levels from serum protein electrophoresis [SPEP] results) and Hb levels. Methods This retrospective chart review included all pts who initiated drug treatment for relapsed/refractory MM between Jan-06 and Dec-07, inclusive, at Princess Margaret Hospital, Toronto, ON. Hb and M protein (SPEP) results were collected before the start of each treatment cycle. These results were then plotted over time to explore the association between these 2 variables. Results 136 of 281 (48.4%) of pts treated for relapsed/refractory MM had at least one simultaneous measurement of Hb and serum M protein levels and were included in the analysis. Mean age was 66 (SD±9.7) years, 65% of pts were male. More than half (63.2%) of the pts were receiving treatment for 1st MM relapse. Treatments for relapsed/refractory MM included cyclophosphamide ± steroids (33.1%), bortezomib-based regimens (20.6%), thalidomide-based regimens (26.5%), steroid monotherapy (15.4%), and other regimens (4.4 %). Patients received between 1 and 17 cycles of therapy (mean = 2.5 ± 2.9 cycles). Supportive care measures included erythropoiesis stimulating agents (ESAs) in 33.8% [mean dose was 488 (SD±23) μg q3 weeks and 42,343 (SD±7,768) IU weekly for darbepoetin alfa and Epoetin alfa, respectively], RBC and/or platelet transfusions in 17% (14.1% RBC and 6.7% platelets), and G-CSF in 7.4% of pts. The plot below (Figure 1) demonstrates a decrease in serum M protein levels over time and an inverse relationship between Hb and serum M protein levels. Both the decrease of serum M protein levels (p-value Conclusion There was a statistically significant improvement in disease burden across all treatments as evidenced by the drop in serum M protein levels over the cycles of therapy, which was accompanied by a decrease in the level of anemia. A statistically significant inverse relationship between Hb and serum M protein levels was observed in this exploratory analysis. Further studies are required to assess the relevance of Hb change as a viable clinical surrogate marker of response in MM and its potential predictive impact on outcome over time. This research was funded by an unrestricted grant from Ortho Biotech (a division of Janssen-Ortho, Inc.), Toronto, ON, Canada. Disclosures Reece: Ortho Biotech: Honoraria, Research Funding. Teixeira:Ortho Biotech: Employment. Yoong:Janssen Ortho Inc: Employment. Camacho:Janssen Ortho Inc: Consultancy. Plante:Janssen Ortho: Employment.

Abstract 1399 Poster Board I-421 Purpose: Anemia, a common hematologic complication of cancer and myelosuppressive chemotherapy, is often treated with ESAs, which include darbepoetin alfa (DA) and epoetin alfa (EA). Since 2007, the use of ESAs in CIA has been increasingly restricted in product labels, reimbursement, and practice guidelines. Prior analyses have indicated increasing transfusion rates over this period among CIA patients in the community setting. Little is known about the trajectory (or time path) of Hb levels prior to and after initiation of ESA therapy in real world practice. In particular, it is unknown whether recent ESA utilization restrictions have affected the change in Hb levels that chemotherapy patients experience prior to and after ESA initiation. This study analyzed Hb trajectories in CIA patients receiving ESAs from 2006 - 2008. Methods: ESA episodes of care (ESA EOCs) within episodes of chemotherapy care (EOCCs) were identified from 2006 to 2008 in an oncology electronic medical records database of approximately 250,000 cancer patients receiving care from 111 practice sites across 25 states. An EOCC was identified by a gap of ≥90 days with no evidence of chemotherapy use. An ESA EOC was identified by a gap of ≥42 days without ESA therapy. To measure Hb trajectory over time, the difference between Hb at ESA initiation (baseline Hb) and mean Hb in each of the 6 weeks before and 6 weeks after ESA initiation was computed. Differences in means were compared by t-tests. Analysis of variance was done to test whether the differences differed by calendar year. Results: From 2006 to 2008, 22,357 ESA episodes were identified (EA: n=6,117, DA: n=16,420). Compared to 2006 (mean Hb=10.7 g/dL), ESAs were initiated at progressively lower baseline Hb levels overtime, 0.3 g/dL lower in 2007 (p Conclusions: In patients with CIA treated with ESAs between 2006 and 2008, Hbs at ESA initiation progressively declined likely in response to the changes in product labels, reimbursement and practice guidelines. There were no clinically significant differences in the rates of Hb changes observed from 2006 to 2008 before and after ESA initiation. Further research is needed to determine if earlier initiation of ESA therapy may help maintain Hb levels, improve patient's clinical outcomes and/or offset other health services such as the use of transfusions. Disclosures: Hill: Amgen, Inc.: Research Funding. Cong: Amgen, Inc.: Employment. Hess: Amgen, Inc.: Research Funding. Nordyke: Amgen Inc.: Employment.

Abstract 3008 Poster Board II-984 Introduction: The erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients (pts) with cancer chemotherapy-associated anemia (CAA). Extended-interval ESA dosing (i.e., administration less than once weekly) is a common practice with DA, which is FDA approved for dosing once every 3 weeks (q3wks); a previous study of the North Central Cancer Treatment Group suggested that EA can also be given less often than the FDA-approved once weekly schedule (Steensma DP et al, J Clin Onc 2006; 24:1079). The present study compared 2 different q3wks extended-interval EA regimens with weekly fixed-dose EA and with q3wks DA in pts with CAA. Patients and Methods: Eligible pts were receiving chemotherapy for a non-myeloid malignancy and had Hb 20 ng/mL, weight >40 kg and 12 g/dL and restarted at a lower dose when Hb fell to '11.5 g/dL. All pts received ferrous sulfate 325 mg orally once daily, if tolerated. Quality of life (QOL) was measured using the Symptom Distress Scale (SDS), Brief Fatigue Inventory (BFI), FACT-An, and Linear Analogue Self Assessment (LASA) tools. The primary endpoint was the proportion of pts achieving Hb≥11.5 g/dL or increment of Hb>2.0 g/dL from baseline. Secondary endpoints included RBC transfusion requirements, adverse events (AEs), and QOL. Results: 239 pts (236 evaluable) enrolled at 10 MCCRC sites between Feb. 2007 and Dec. 2008; 62% of pts completed all study interventions. The median age of enrolled pts was 66 years; 42.4% were men, 91.5% had solid tumors, 26.7% had severe anemia (Hb 0.41 for all comparisons), but the median Hb increment from baseline was higher in the 40K and DA arms compared to the 2 extended dosing EA arms (40K-2.8 g/dL, 80K-2.0 g/dL, 120K-2.1 g/dL, DA-2.6 g/dL; p=0.005 for 40K vs 80K). Hb response was achieved more quickly in the weekly EA arm, but the difference was not significant (40K-32 days, 80K-50 days, 120K-49 days, DA-49 days; p>0.13). The proportion of patients transfused was similar between arms (40K-27.9%, 80K-33.3%, 120K-22.4%, DA-29.8%; p>0.49). There were no significant differences in QOL changes. Deaths were also similar between arms (40K-5 pts, 80K-7 pts, 120K-7 pts, DA-1 pt, p>0.10) and were primarily due to disease progression. AEs and serious AEs were comparable between study groups; grade 3/4 AEs were observed in 22% of pts in the 40K arm, 22% on 80K, 17% on 120K, and 13% on DA; p>0.56. The median total dose of EA used was highest in the 120K arm (40K-265,000 U; 80K-240,000 U; 120K-360,000 U; p=0.0009 for 40K vs 120K), while pts on the 40K arm were more likely to omit a dose due to a high Hb (40K-63.9% of pts omitted at least one dose; 80K-30.0%; 120K-34.5%; DA-43.6%, p Conclusion: Although there was no significant difference in the proportion of responding pts (the primary endpoint), Hb increments from baseline were moderately higher with the 2 FDA-approved regimens – weekly EA 40,000 Units, and q3wk DA 500 mcg – than with the extended dosing regimens. This study was supported by a grant from Centocor Ortho Biotech, Inc. to the MCCRC. Disclosures: No relevant conflicts of interest to declare.

Background: The erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) are treatments for chemotherapy-induced anemia. Therapy choice depends on many factors, including cost. Previous analyses have demonstrated differences in the characteristics of patients receiving EA vs. DA. We estimated cost differences between DA and EA in patients with cancer receiving chemotherapy using a propensity score matched analysis of baseline patient characteristics with and without hemoglobin (Hb) values. Methods: Data were extracted from electronic medical records in two US databases between January 2004 and December 2006. The study sample included 6743 patients receiving chemotherapy, with ≥ 1 visit during the study period, who received an ESA during a chemotherapy episode. Episodes of chemotherapy care were constructed using a 90 day gap in administration to identify the start and end. Patients receiving both, or neither, DA and EA during their initial chemotherapy episode, or with missing descriptive data were excluded. Drug costs were calculated from cumulative dose multiplied by 106% of the average sales price (ASP) for DA or EA. Two propensity score matches were conducted: first using variables available in administrative billing claims systems, then adding the baseline Hb test result. Regression-adjusted cost differences were estimated with and without baseline Hb, using generalized linear models. Results: Using baseline Hb as a variable resulted in a better match of the baseline characteristics for the EA and DA treatment groups compared to the original sample or the matched sample without baseline Hb. Mean ESA costs for the original sample were $4171 for EA and $3811 for DA (mean difference: $360; P Conclusions: Addition of baseline Hb as a variable in propensity score and ESA cost models affects ESA treatment cost estimates in patients with cancer receiving chemotherapy. Cost comparisons based on observational data should use analytical methods that account for differences in clinical variables between treatment groups.

Background: The treatment of newly diagnosed low/intermediate-1 (low/int-1) myelodysplastic syndromes (MDS) varies significantly from observation only (until the patient develops transfusion dependence) to using specific agents like erythropoiesis-stimulating (ESA), demethylating, or immunomodulatory (IMiD) agents. To date no prospective comparative clinical trial has been conducted to evaluate relative efficacy of these agents. In the present literature meta-analysis, we compared the erythroid response (ER) rates achieved with epoetin alfa (EPO)-based therapy (monotherapy or in combination with other growth factors or non-ESAs) versus single agent/combination non-ESA therapies for the treatment of anemia in patients with MDS and specifically in low/int-1 risk category. Methods: Data extraction was performed on studies from PubMed and ASCO/ASH proceedings in MDS patients treated with EPO ± granulocyte-/granulocyte-macrophage colony stimulating factor (G/GM-CSF) or other non-ESAs (search cutoff date 9/30/07). To allow cross comparison, only studies using IWG or IWG-like ER criteria and treatment-naïve patients were selected. Patients were further stratified according to risk and non-ESA therapy. Pooled estimates of ER rates were calculated using random-effect (R-E) meta-analysis methods. Results: Of 790 studies identified, 37 were included in the present analysis. Among the 23 studies that included low/int-1 MDS patients, a majority of the patients in both the EPO-based (82.4%) and non-ESA (74.4%) groups had refractory anemia or refractory anemia with ringed sideroblasts, and baseline transfusion dependency rates were lower in the EPO-based (52.4%) than in the non-ESA (91.7%) groups. As shown in the Table, among all MDS patients regardless of risk category, EPO-based regimens had a higher ER rate when compared to IMiD-based therapies (p=0.0328), or demethylating agent-based therapies (p=0.1660). In the patients with low/int-1 risk disease, EPO-based therapy had a significantly better ER rate when compared to single-agent/combination non-ESA-based therapies (p=0.0015) and specifically, IMiD-based therapies (p=0.0231). The studies with demethylating agent-based therapies in the present analysis did not include low/int-1 MDS patients. Conclusions: These results suggest that, for appropriately selected treatment-naïve patients with low/int-1 MDS, among the currently available therapies, EPO-based regimens may yield a higher erythroid response than non-ESA therapies, with lenalidomide in del 5q patients being the only exception. Further prospective clinical trials are needed to determine relative clinical benefits with different agents in different MDS risk groups. Non-ESA based therapy MDS Study Group EPO-based therapy All mono + combination therapies IMiD-based therapy Demethylating agent-based therapy NA: not available No. of Studies All 19 18 9 2 Low/Int-1 Risk 14 9 4 NA Evaluable patients, n All 849 866 635 85 Low/Int-1 Risk 620 403 291 NA Overall ER, R-E% (95% CI) All 56.7 (49–65) 33.6 (23–44) 39.3 (26–53) 37.6 (12–63) Low/Int-1 Risk 53.8 (46–62) 35.1 (24–46) 42.4 (37–48) NA

Chemotherapy induced anemia patients who respond to ESA treatment have hemoglobin increases within 4–8 weeks. Patients with inadequate Hb response after several weeks treatment often have their ESA dose escalated.. We conducted an exploratory analysis to test the hypothesis that safety outcomes in randomized studies of epoetin alfa might differ depending on the Hb response after 4–8 weeks of treatment. Methods: The analysis compared the survival across subsets of epoetin-alfa treated patients. Specifically, a landmark analysis was used, which defines a hemoglobin responder at a pre-specified point in time (in this case 4 & 8 weeks post treatment), and then examines survival subsequent to that point in time.Patients were categorized as “Hb responder” when their Hb increased by >0.5 g/dL; “Hb stable” when Hb change within ≤ 0.5g/dL; “Hb non-responder” when the Hb decreased >0.5 g/dL, compared to the value prior to epoetin-alfa treatment. Survival was estimated using the Kaplan-Meier method and comparisons were made between the responders and non-responders versus the stable group. Cox’s proportional hazards model was used to adjust for the following baseline covariates: hemoglobin prior to treatment, baseline performance status, and advanced disease at baseline. All analyses were stratified by study to account for any differences in the study populations and study conduct. Results: These exploratory findings suggest the possibility that patients identified as non-responders to ESAs after 4 or 8 weeks of ESA treatment may be at increased risk of death, and that this effect is most pronounced in the studies that treated patients beyond the correction of anemia. Although these analyses were adjusted for several key baseline covariates, it is unclear whether these effects result from treatment, or whether patients who fail to respond to epoetin alfa are inherently at increased risk of death (e.g., due underlying malignancy), regardless of their treatment status.

Background: Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients; however, there are concerns that ESAs increase mortality in some patients. Within the framework of an international collaboration we thus conducted a patient-level meta-analysis to assess the effects of ESAs on mortality in cancer patients. Methods: We performed a meta-analysis, based on the intention-to-treat principle, of cancer patients enrolled in randomized controlled trials comparing epoetin alfa, epoetin beta or darbepoetin alfa plus red blood cell transfusions as needed versus transfusion alone, for prophylaxis or treatment of anemia while or after receiving anticancer therapy. Patient-level data were obtained and analyzed by independent statisticians at two academic departments. Primary endpoints were on-study mortality and overall survival in patients receiving chemotherapy, defined as all patients from studies in which =/> 70% of study population received chemotherapy, and in all cancer patients regardless of anticancer therapy. On-study mortality was defined as death from any cause between date of randomization and 28 days after end of active study phase. Overall survival was defined as death from any cause between date of randomization and longest follow up available. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated per study and meta-analyzed with fixed-effects and random-effects models. Stratified multivariable Cox-regression analyses were conducted to assess the impact of baseline imbalances. Tests for interactions were used to identify differences in effect across pre-specified subgroups. All analyses were pre-specified in a peer-reviewed protocol (Bohlius et al. 2008). An independent steering committee consisting of clinicians and methodologists agreed on all analyses and interpretations. Independent investigators and representatives from manufacturers contributing data offered advice, but had no decision-making authority. Results: Data from 13,933 cancer patients enrolled in 53 studies were included in the analysis; 38 trials including 10,441 patients used mainly chemotherapy. Including all cancer patients ESAs increased on-study mortality by 17% (HR 1.17; 95% CI 1.06–1.30), with little evidence for a difference between chemotherapy and other trials (p for interaction=0.42), and worsened overall survival by 6% (HR 1.06; 95% CI 1.00–1.12). In the chemotherapy population on-study mortality was increased by 10% (HR 1.10, 95% CI 0.98–1.24) and overall survival was worsened by 4% (HR 1.04; 95% CI 0.97–1.11). Adjusting for known prognostic factors had little effect on the overall estimates. There was no conclusive evidence for effect modification by patient level characteristics such as age, sex, Hb and Hct at baseline, Hb ceiling, type and stage of tumor or study level characteristics (anticancer treatment, ESA treatment schedules, study design and quality) for the outcomes tested. Conclusion: ESA treatment in cancer patients increased on-study mortality by 17% and worsened overall survival by 6%. For patients undergoing chemotherapy the increase was less pronounced, but could not be excluded. In clinical practice, risks of ESAs must be balanced against benefits of ESAs depending on the clinical circumstances of the individual patient.

Background: Epidemiological data on MDS is scarce in France, and registries from other countries do not provide data on the daily practice management of MDS in 2008. Methods: GFM centers were asked to collect characteristics of ongoing or recent treatments in all MDS patients (pts) seen at their clinic (as in or outpatients) during the Jan 28th–Feb 3rd, 2008 period (one week).Results: 919 pts from 74 centers were included, 57% males, mean age (+/− SD), 73 (±11) years, with 2.8%, 19% and 28% of pts aged 80 years, respectively (resp).13% of pts were hospitalized >24h (4.5% for infections or bleeding and 8.5 % for “active” treatments), 46% were seen in the day care facility (40% for transfusions), and 41% as consultations (for staging, follow up or ambulatory treatment). 93% of patients had PS ≤2. Median interval from diagnosis to survey was 29.2 months. FAB at time of survey was: 35.1% RA, 18.5% RARS, 39.1% RAEB, 7.4% CMML; WHO was: 17.4% RA, 13.3% RARS, 14% RCMD, 4.5% RCMD-RS, 18.5% RAEB-1, 15.9% RAEB-2, 7.7% CMML, 4.9% 5q-syndrome and 3.9% unclassifiable. Cytogenetic analysis had been performed at least once in 77.4 % pts: favorable (498 pts), intermediate (88 pts), unfavorable (96 pts). IPSS (determined in 75.4% of pts) was: 41.6% low, 33.3% Int-1, 16.4% Int-2 and 8.7% high. Significant differences between pts 65 years were, respectively, % of unfav karyotype (25.8% vs. 12.7%, p=0.0004), of isolated +8 (5.1% vs. 2.1%, p=0.04), of isolated −7 (6.2% vs. 1.1%, p=0.0003), and, with borderline significance, of CMML (4.5% vs. 9.5%, p=0.06), of 5q-syndrome (1.5% vs. 5%, p=0.07). EPO level, assessed in 359 (39.1%) of pts at diagnosis and 252 (27.4%) of pts at time of survey) was >200UI/l in 24.5% and 26.6% resp, and >500U/l in 13.5% and 14.7% pts resp and was significantly correlated with interval from diagnosis. At the time of survey, treatment received in the last 6 months (IPSS: high-int 2 vs low–int1) included: no active treatment 66.5% (IPSS: 42% vs. 72.9%), chemotherapy 12.8% (IPSS: 22.6% vs. 9.1%) including 2.7% intensive and 0.7% LD AraC, allogeneic SCT 1.7% (IPSS: 3.8% vs. 2.6 %) including 0.3% classical and 1.4% NMA, azacytidine 6.5%, (IPSS: 21.6% vs. 2.3%), decitabine 0.8%, lenalidomide 4%, thalidomide 0.5%, ATG 0.2 %, androgens 2.2% while 64.8% pts required RBC transfusions (IPSS: 81% vs. 61%) and 39.7% pts received an Erythropoiesis-Stimulating Agent (ESA) (IPSS: 40.3% vs. 37.2%), alone in 314 pts (epoetin alfa or beta in 92 pts, darbepoetin in 222 pts), and with G-CSF (61 pts). Response rates to ESAs were 58.6% and 33.8% in low int-1 and int-2-high risk MDS, resp (p=0.0009). Iron chelation therapy was administered in 17.6% pts (5.8% desferroxamine, 11% deferasirox) including 22.1% and 13.6% low-int-1 and int-2-high risk MDS, resp (p=0.009). Conclusions: Our survey provides a better knowledge of the characteristics and of the daily management of MDS in France. Of particular note are the more frequent unfavorable karyotypes in MDS pts

Background: Prevalent in the majority of patients at diagnosis, anemia associated with myelodysplastic syndromes (MDS) may increase in incidence and severity during the course of the disease. Red blood cell (RBC) transfusion support is often used to manage symptomatic anemia. Epoetin alfa (EPO) and darbepoetin alfa (DARB), two erythropoiesis-stimulating agents (ESAs), are frequently used as supportive care in the treatment of MDS-related anemia to reduce RBC transfusions. To date, limited information on dosing patterns and the associated costs of these agents for MDS patients in the hospital inpatient setting is available. This study examined cumulative ESA dosing and costs in MDS patients treated with ESAs in acute care hospitals. Methods: An analysis of electronic inpatient records from the Premier Perspective Comparative Hospital Database was conducted. The Premier database encompasses detailed inpatient services from patients admitted to more than 500 hospitals nationwide. A retrospective parallel-group design was used to compare two cohorts of MDS patients treated with EPO or DARB during their hospitalization. Study subjects were identified through hospitalization records between 4Q2006 and 1Q2008. Patients were ≥18 years of age, had an admitting diagnosis of MDS (ICD-9 codes: 238.72–238.75), and were treated with EPO or DARB during their hospital stay. Patients were excluded if they had cancer, received renal dialysis, or were treated with both ESAs. To minimize effect of outliers, 2% of patients, based on the upper and lower 1% patients with extreme doses in each group were excluded from the dosing analysis. Mean cumulative dose and July 2008 wholesale acquisition costs (EPO: $13.13/1,000 Units, DARB: $4.722/mcg) were used to calculate ESA costs. Results: A total of 3,312 inpatient stays were identified with a primary or secondary diagnosis of MDS (EPO: 2,719, DARB: 593). Mean age and gender distribution were comparable between groups (age: EPO 77.5 years, DARB 78.0 years; % women: EPO 49.4%, DARB 49.2%, p>.05 for both). Mean hospitalization length of stay was also similar for both groups (EPO: 8.8 days; DARB: 8.9 days; p>.05). The two groups were also comparable in terms of medical history at baseline, including hypertension, diabetes mellitus, cardiovascular disease, congestive heart failure, febrile neutropenia, chronic kidney disease, and sepsis. The mean cumulative dose per inpatient stay was 59,379 ± 66,002 Units for EPO and 230 ± 239 mcg for DARB, corresponding to a dose ratio of 258:1 (Units EPO: mcg DARB). Mean cumulative dose of EPO and DARB remained relatively stable over the period from 4Q2006 to 1Q2008. ESA treatment cost per inpatient stay was significantly lower in the EPO group, compared with DARB (EPO $780 vs. DARB $1,085; P Conclusions: The current study, based on recent real-life clinical practice data from an inpatient setting, observed a dose ratio of 258:1 (Units EPO: mcg DARB) in patients with MDS. Based on the cumulative dose administered during hospitalization, EPO was associated with a cost savings of 28% compared to DARB. These results are similar to those observed in MDS patients in the outpatient setting and consistent with reported findings in the chronic kidney disease and oncology populations both in outpatient and inpatient settings.

Safety signals raised in the recent oncology clinical trials have led to various regulatory restrictions including FDA black-box warning, National Coverage Determination (NCD), and updated ASCO/ASH guidelines in 2007. The purpose of this study was to determine the impact of these changes on the utilization of ESAs and on transfusion (Tx) of RBCs in 2006 (prior to changes) and 2007. We identified the total number of unique patients that received any treatment including chemotherapy, radiation, transfusions, or any treatment in the out-patient and in-patient settings during this 2 year time period. All the data on the ESA doses dispensed by the hospital pharmacy and all the RBC transfusions dispensed by the Blood bank were also analyzed. The ESA units were calculated by converting 40,000 units of epoetin alfa or 100 mcg of darbepoetin alfa to one unit of ESA. When comparing 2007 to 2006, the number of patients that received ESAs decreased by 26% and the total ESA units decreased by 30%. The overall usage of ESAs decreased by 55%, from 2398 units in 1/2006 to 1080 units in 12/2007. However, the number of pts that received RBC transfusions increased only by 6% and the total number of RBC units transfused by 2% (from 38,218 units in 2006 to 38,948 units in 2007). The median Hgb on the day of transfusion was same for each year (Hgb 8.2 g/dL for both 2006 and 2007), suggesting that the lack of impact on RBC Tx may not be due to a change in Tx threshold. The total number of unique patients referred and treated at MDACC during 2007 (24,356) increased by 13% from 2006 (21,619), not accounting for a lack of impact on transfusions. We therefore examined Hgb at the initiation of ESAs in a subset of pts (n=212) that had not received ESA for at least 3 months. The median Hgb/HCT values at the initiation of ESAs were 9.5 g/dL/27.4. The most frequent utilization of ESAs and transfusions was in patients with hematological malignancies. Conclusion: These findings indicate that the recent ESA safety concerns and related regulatory changes have significantly affected the ESA utilization. The lack of significant impact of reduced ESA usage on RBC transfusions may be related to a lower Hgb threshold used at initiation of ESAs and/or the targeted patient population (less likely to respond) treated with ESAs. Further research is needed to establish the factors contributing to the lack of correlation and to optimize the use of ESAs.

Introduction: Some patients treated with EPO and oral iron supplementation respond poorly to EPO, possibly due to inflammation-induced iron sequestration. In response to inflammation, hepcidin, a hormone secreted by the liver, binds to and downregulates ferroportin, the principal cellular iron exporter. In turn, ferroportin downregulation leads to sequestration of iron in absorption sites within duodenal enterocytes, hepatocytes, and in macrophages that break down senescent red blood cells and normally recycle iron back into circulation. This sequestration results in reduced amounts of plasma iron that is bio-available for erythropoiesis. Patients with rheumatoid arthritis (RA), malignancies, or infections frequently manifest inflammatory-associated anemia and elevated hepcidin levels. Objective: To assess the impact of EPO treatment on hepcidin levels in patients with RA. Methods: Serum hepcidin levels and iron status were analyzed from a randomized, double-blind, placebo-controlled, investigational study of 29 patients with RA treated with either EPO or Placebo for 20 weeks. Serum hepcidin levels were measured at baseline and at the end of study. Serum transferrin saturation, serum ferritin, serum transferrin receptor (sTfr) levels and hemoglobin (Hb) concentrations were also measured. Patients with baseline Hb ≤11 g/dL were treated with EPO starting doses of 20,000 U subcutaneously (SQ) once weekly (QW) that could be titrated up to 40,000 U SQ QW. Oral iron was administered to keep the sTfr index Results: Iron restriction was noted in 5/15 (33%) EPO-treated patients and in 2/14 (14%) receiving Placebo. Hepcidin levels were elevated in 10/15 (67%) EPO-treated patients and in 5/13 (38%) receiving Placebo. There was a strong correlation between baseline serum hepcidin and serum ferritin levels (R= 0.5598 P=0.0019), but not serum transferrin saturation. Eleven of 15 (73%) EPO-treated patients had a Hb response compared to one of 14 (7%) receiving Placebo. Mean hepcidin levels decreased significantly from baseline in the EPO-treated patients (−155.6±186.6 EPO, 90.28±83.1 Placebo, P Conclusion: EPO treatment may effectively elicit Hb response in patients with RA and may be associated with suppression of inflammation-induced serum hepcidin levels. Further study is warranted in conditions associated with inflammation, such as cancer and chronic renal failure, in which EPO is used to treat anemia. FIG 1. SERUM HEPCIDIN LEVELS (ng/mL) FIG 1. SERUM HEPCIDIN LEVELS (ng/mL) FIG 2. Change from Baseline to End of Study FIG 2. Change from Baseline to End of Study

BACKGROUND. The A.C.T. study has shown that in Europe more cancer patients (pts) with anemia are being treated with ESAs than 7 years ago. ESAs are indicated for multiple myeloma. Variability in treatment patterns, outcomes, and response rates in daily clinical practice need to be further investigated. OBJECTIVE. To examine anemia treatment patterns, outcomes, and response rates in the subsample of A.C.T. patients with multiple myeloma. DESIGN & PATIENTS. Multicenter, longitudinal retrospective study with at least 3 time points at approximately 1 month intervals, with visit 1 coinciding with start of ESA treatment. 111 centers in 10 European countries contributed 306 multiple myeloma pts who were anemic (hemoglobin [Hb] ≤11g/dL) and treated with an ESA (14.0% of total European sample). MEASUREMENTS. All data collected through retrospective chart review. Key variables reported here: age, chemotherapy regimen, Hb, WHO/ECOG performance status, ESA type, ESA dose incl. escalation, and iron supplementation. Response to ESA Rx: Hb rise ≥1g/dL, Hb rise ≥1g/dL within 8 weeks, hematopoietic response (Hb rise ≥2g/dL or Hb≥12g/dL achieved), Hb rise ≥2g/dL, and Hb target range of 12.0–12.9g/dL achieved by visit 3. RESULTS. Pts ranged in age from 26 to 91 years (66.6 11.0). 92.5% of pts were on chemotherapy, of which 94.6% on standard vs. 5.4% on high dose; and 6.7% on platinum vs. 93.3% on nonplatinum. Types of ESA prescribed included epoetin alfa (16.0%), epoetin beta (46.1%), darbepoetin alfa (37.9%). Results are summarized in Table 1. No severe adverse events were reported. Table 1. Treatment patterns & outcomes Visit 1 Visit 2 Visit 3 p Mean (SD) ESA dose (IU/wk) 30237 (7509) 30676 (8012) 30760 (8698) n.s. Median ESA dose (IU/wk) 30000 30000 30000 n.s. Mean (SD) Hb (g/dl) 9.2 (1.0) 10.3 (1.5) 11.0 (1.7) CONCLUSIONS. Mean and median dose did not change over time. Hb increased from visit 1 from visit 3 with a concomitant rise in performance status. Iron supplementation with, in particular, IV iron was consistently low. Dose escalation rates were low, perhaps reflecting that this be an individualized patient decision. An increase in Hb of ≥1g/dL over the course of treatment is an attainable goal in almost three-quarters of multiple myeloma pts with anemia. Adding time constraints, increasing the threshold level to ≥ 2g/dL, and/or setting an evidence-based target range of 12–12.9g/dL is associated with lower response rates. In multiple myeloma pts, the therapeutic Hb goal to be achieved may need to be determined under consideration of multiple factors, however the general effectiveness of ESAs in this population is evident.

BACKGROUND. The A.C.T. study has shown that in Europe more cancer patients (pts) with anemia are being treated with ESAs than 7 years ago. ESAs are indicated for hematological malignancies. Variability in treatment patterns, outcomes, and response rates in daily clinical practice need to be further investigated. OBJECTIVE. To examine anemia treatment patterns, outcomes, and response rates in the subsample of A.C.T. patients with hematological malignancies. DESIGN & PATIENTS. Multicenter, longitudinal retrospective study with at least 3 time points at approximately 1 month intervals, with visit 1 coinciding with start of ESA treatment. 152 centers in 13 European countries contributed 630 pts with hematological malignancies who were anemic (hemoglobin [Hb] ≤11g/dL) and treated with an ESA (14.8% of total European sample). MEASUREMENTS. All data collected through retrospective chart review. Key variables reported here: age, chemotherapy regimen, Hb, WHO/ECOG performance status, ESA type, ESA dose incl. escalation, and iron supplementation. Response to ESA Rx: Hb rise ≥1g/dL, Hb rise ≥1g/dL within 8 weeks, hematopoietic response (Hb rise ≥2g/dL or Hb ≥12g/dL achieved), Hb rise ≥2g/dL, and Hb target range of 12.0–12.9g/dL achieved by visit 3. RESULTS. Pts ranged in age from 18 to 92 years (62.4±15.3). 94.4% of pts were on chemotherapy, of which 89.1% on standard vs. 10.9% on high dose; and 12.8% on platinum vs. 87.2% on nonplatinum. Types of ESA prescribed included epoetin alfa (14.4%), epoetin beta (44.8%), darbepoetin alfa (40.8%). Results are summarized in Table 1.No severe adverse events were reported. Table 1 Treatment Patterns & Outcomes Visit 1 Visit 2 Visit 3 P Mean (SD) ESA dose (IU/wk) 31067 (7247) 32354 (9418) 32309 (9638) 0.001 Median ESA dose (IU/wk) 30000 30000 30000 n.s. Mean (SD) Hb (g/dL) 9.3 (1.0) 10.2 (1.5) 10.9 (1.7) CONCLUSIONS. The slight increase in ESA dose was not in accordance with the stable median ESA dose across the three visits. Hb increased from visit 1 from visit 3 with a concomitant rise in performance status. Iron supplementation with, in particular, IV iron was consistently low. Dose escalation rates were low, perhaps reflecting that this be an individualized patient decision. An increase in Hb of 1g/dL over the course of treatment is an attainable goal in over two-thirds of pts with hematological malignancies who are anemic. Adding time constraints, increasing the threshold level to 2g/dL, and/or setting an evidence-based target range of 12–12.9g/dL is associated with lower response rates. In pts with hematological malignancies, the therapeutic Hb goal to be achieved may need to be determined under consideration of multiple factors, however the general effectiveness of ESAs in this population is evident.

Glucocorticoids have either stimulatory or inhibitory effects on erythropoesis depending upon the timing and the dosage of their administration. We previously reported cases of enhanced hematopoetic recovery in response to erythropoietin (Epo; Procrit) in patients receiving prolonged treatment of glucocortcoids. To examine the differential roles of glucocorticoids on erythropoiesis in chronic settings, we use a murine model in current study and evaluate erythropoietic responses to Epo for rats receiving higher (loading) or lower (maintenance) dosages of dexamethasone(Dex) for a prolonged period of time. Commercially-obtained adult Sprague-Dawley rats were assigned randomly to DEX, EPO, DEX+EPO, or control groups, and maintained at conditions approved by the institutional Animal Care and Research Committee. Rats in the EPO or DEX+EPO groups received subcutaneous injection of Epo at 70 units/100 grams body weight, once a week, for five week. The animals in the DEX or DEX+EPO group were both divided into two subgroups receiving injection of Dex at either higher doses of 0.4mg/350 grams body weight, or lower doses of 0.02 mg/350 grams body weight, three times a week, for five weeks. The animals were sacrificed at the end of study and peripheral blood and bone marrow were used to evaluate levels of erythropoiesis. Weekly administration of Epo (70 units/100 grams body weight) for five weeks produced enhanced erythropoiesis in the EPO group, resulting in an increase of 10.6% in RBC, and 15.3% increase in hemoglobin (Hb), compared to control. Treatment of rats with higher dosage (0.4 mg/350 g, three times a week for five weeks) of dexamethasone increased RBC and Hb by 3% and 2%, respectively, when compared with controls. Combined treatment of Epo and dexamethasone at the higher dosage enhanced the erythropoiesis, and increased RBC and Hb by 20% and 23%, respectively. In contrast, treatment of rats with a lower maintenance dosage of 0.02 mg/350 g body weight, three times a week for five weeks, peripheral RBC and Hb levels were dropped by 7% and 6%, respectively. Combination of Epo and the lower dosage of dexamethasone could only generate an increase in RBC and Hb of 10% each, displaying suppressing effect of dexamethasone at lower dosage. Bone marrow biopsy revealed hypocellularity in all groups using dexamethasone. Marrow iron staining was performed and ruled out any iron deficiency in all groups. These results suggest that glucocorticoids modulate erythropoisis in two ways depending on concentrations, enhancing erythropoiesis greatly at loading dosage while suppressing it at lower maintenance doses. Our data, together with our clinical observations, present an interesting phenomenon of cross modulation of the two widely used medications, Epo and glucocorticoids. It certainly warrants further investigation of involving pathways at molecular levels. In Vivo Effects of Dexamethasone on Epo stimulated erythropoiesis In Vivo Effects of Dexamethasone on Epo stimulated erythropoiesis

Objective and Purpose: To understand current utilization patterns, this study examined real-world dosing and drug costs for erythropoiesis-stimulating agents (ESAs), epoetin alfa (EPO) and darbepoetin alfa (DARB) in cancer patients receiving chemotherapy. Methods: An analysis of ESA utilization in chemotherapy patients using adjudicated medical claims between 2004 and 2006 from seven health plans was conducted. Patients with ≥1 ESA claim, receiving concurrent chemotherapy identified through alphanumeric HCPCS codes, and newly initiated on EPO or DARB (no ESA administration within 90 days prior to initiation), and receiving chemotherapy were included. Those patients who received both EPO and DARB or who had myelodysplastic syndromes or end-stage renal disease were excluded. Treatment duration was defined as time from first to last ESA administration. Mean cumulative ESA dose was used to calculate drug cost (based on 1/2007 wholesale acquisition cost: EPO $12.52/1000 Units; DARB: $4.576/mcg) and dose ratio (Units EPO: mcg DARB). Results: 1,446 EPO and 2,729 DARB patients were included. Mean treatment duration was longer in the DARB-treated group by three days (EPO:49 days; DARB:52 days; p= 0.037). The EPO-treated group reported 5.8 administrations with a mean administered dose of 42,603 Units (median 40,000, interquartile range 40,000–45,714) corresponding to a mean cumulative dose of 247,097 Units. The DARB-treated group reported 5.0 administrations with mean administered dose of 262 mcg (median 250, interquartile range 200–300) corresponding to a mean cumulative dose of 1,310 mcg. Drug costs were $2,901 lower in the EPO group compared to the DARB group (EPO $3,094; DARB $5,995) and utilization reflected a dose ratio of 189:1 (Units EPO: mcg DARB). Conclusions: This observational study of over 4,100 cancer patients receiving chemotherapy found 48% lower drug cost in the EPO group compared to the DARB group. These findings provide greater understanding of current real-world ESA utilization and are consistent with other studies in the cancer chemotherapy population.

BACKGROUND: There are limited data from electronic medical record studies that provide a real-world view of practice patterns of epoetin alfa (EPO) as supportive therapy in patients with myelodysplastic syndrome (MDS). This retrospective, observational study was conducted to gain a better understanding of the demographics, real-world treatment patterns, and clinical outcomes for patients with MDS receiving EPO. METHODS: Electronic medical record data from a large oncology/hematology practice in the southeastern United States were collected from January 1, 2005 to September 30, 2006. Inclusion criteria consisted of patients receiving ≥ 2 doses of EPO with a diagnosis of MDS within 30 days prior to or during EPO treatment episode. All other cancer diagnoses were excluded. Baseline characteristics, EPO dosing, change in Hb levels, and response to EPO (attainment of Hb ≥ 11.0 g/dL at any point during the treatment episode from a baseline Hb < 11g.dL) were measured. EPO treatment episode was defined as continuous treatment with EPO and without EPO administration 35 days prior to or after the last administration. Weekly (QW) dosing was defined as ≤ 9 days, every 2 week dosing (Q2W) was defined as 9.1–18.0 days, and every 3 weeks (Q3W) was defined as > 18.1 days. RESULTS: A total of 166 patients were included in the analysis; 63.9% women, mean age was 76.2 ± 11.3 years. The mean starting dose was 44,518 ± 11,258 units (median = 40,000 units), and the mean administered dose (any dose of EPO) was 45,587 ± 10,351 units (median=40,000 units). The mean cumulative dose (sum of all EPO doses during the treatment episode) was 312,349 ± 453,551 units. Weekly dosing was administered in 38.0% of patients while 34.9% of patients received Q2W dosing and 27.1% received Q3W dosing. Mean Hb at baseline was 10.6 ± 1.1 mg/dL and increased to 11.3 ± 1.7 mg/dL after 12 weeks of EPO therapy. Fifty percent of the patients responded to treatment and the mean time to response was 33.2 days. DISCUSSION: This study provides insight into real-world treatment patterns and clinical outcomes for patients with MDS treated with EPO. Additional real-world studies may be warranted to validate these findings.

Recent investigational studies have explored the use of epoetin alfa for the treatment of cancer-related anemia in patients not receiving CT or RT. Previous studies in this patient population showed that EPO was effective in treating anemia at regimens of 40,000 U weekly, 60,000 U Q2W, and 80,000 U every 3 weeks. Because these patients do not experience the myelosuppressive effects of CT or RT, a lower cumulative dose of EPO may be efficacious. The current pilot study was designed to investigate two novel dosing regimens in this population. Based on recent safety concerns from studies with another ESA in cancer patients not receiving CT or RT, enrollment in this study was stopped prematurely. This prospective, randomized, open-label, multi-center study was to enroll 100 patients with an active non-myeloid malignancy, baseline (BL) hemoglobin (Hb) level ≤11 g/dL, and not receiving or planning to receive CT or RT during the course of the study. Non-cytotoxic antineoplastic therapy was allowed. Patients were randomized 1:1 to receive EPO subcutaneously either 80,000 U Q4W (maximum 13-week treatment period) or 40,000 U Q2W (maximum 15-week treatment period). Hb levels were obtained weekly in all patients. EPO was held for Hb level >13 g/dL; dose was reduced for Hb >12 g/dL or Hb increase >1 g/dL in any 2-week period. The primary efficacy endpoint was hematopoietic response (HR), defined as a ≥1 g/dL rise in Hb from BL. Enrollment was stopped at 60 patients (safety population; 29 Q4W, 31 Q2W). All received at least a partial planned cumulative dose of study drug. BL characteristics were similar: % female, 59% Q4W and 61% Q2W; mean age, 73 years Q4W and 71 years Q2W; ECOG 0–1 83% Q4W and 96% Q2W; mean BL Hb, 10.3 g/dL Q4W and 9.9 g/dL Q2W. Prostate was the most common tumor site in both the Q4W (n=6, 21%) and Q2W (n=10, 32%) groups. Efficacy was analyzed in 59 (28 Q4W, 31 Q2W) patients who also had at least one post-BL Hb value (mITT population). HR was achieved in 25 patients (89.3%; 95% CI 71.8, 97.7) in the Q4W group and 28 patients (90.3%; 95% CI 74.2, 98.0) in the Q2W group. The median time to achieve HR was 14 days in the Q4W group and 20 days in the Q2W group. Packed red blood cell transfusion rates for the period Day 29 through end of study were 10.7% (n=3) among Q4W patients and 3.2% (n=1) among Q2W patients. Fewer Q4W (n=20, 69%) vs. Q2W (n=27, 87%) patients required an EPO dose reduction or dose hold. Four patients in each group experienced a serious adverse event unrelated to study drug. No clinically relevant TVEs were reported among Q4W patients, while 2 events (myocardial ischemia and deep vein thrombosis) were reported in a single patient in the Q2W group. Two deaths (both attributed to disease progression) were reported in the Q2W treatment group. The two novel dosing regimens investigated in this study (80,000 U Q4W and 40,000 U Q2W) produced comparable efficacy (with approximately 90% response to either dose regimen) and safety outcomes. Although this study reinforces the dosing flexibility of epoetin alfa with dosing intervals of up to 4 weeks, current labeling warns against the use of ESAs in these types of patients with active malignant disease receiving neither CT or RT.

Venous thromboembolism (VTE) is a frequent complication of cancer and chemotherapy. Increased risk is associated with many factors including use of erythropoietic stimulating agents (ESA) and with increased platelet count (Khorana et al. Cancer 2005). The increase in platelet count observed with ESA use may be associated with functional iron deficiency as ESA therapy induces iron-restricted erythropoiesis, and iron deficiency can cause reactive thrombocytosis. VTE have been associated with thrombocytosis in iron deficient patients, and although occurance is extremely rare in otherwise-healthy individuals, patients who are already at high risk may be particularly susceptible. To explore this hypothesis we examined the association between VTE incidence and changes in platelet count in a post hoc analysis of our prospective, randomized, controlled, multicenter trial, which had compared effects of IV iron, oral iron, and no iron, on Hb response to ESA therapy in anemic cancer patients receiving chemotherapy (Henry et al. The Oncologist 2007). Major trial inclusion criteria: pt starting chemotherapy cycle, Hb 100 ng/mL or transferrin saturation >15%. Major exclusions: recent transfusion, ESA, or IV iron use, infection. All pts received epoetin alfa (40,000 U SQ/Wk for first 4 wks, then dose-adjusted per protocol). Pts were randomized to: No iron (ESA alone), PO FeSO4 325 mg tid, or IV ferric gluconate 125 mg IV weekly, for 8 weeks. Odds ratios (OR) for likelihood of occurrence of thromboembolic adverse events, and incident rate ratios (IRR) for their rate of occurrence were analyzed with logistic and Poisson regression, respectively. Nineteen of the 187 patients enrolled experienced 29 thromboembolic events (Table 1). The incidence of thromboembolism was fourfold greater among patients whose platelet counts increased from baseline to values ≥350,000 cells/μL at any time during the study (IRR 4.4, P=0.001). These patients were approximately three times more likely to experience at least one thromboembolic event than other patients (OR 2.9, P=0.036). Patients randomized to receive IV iron were significantly less likely to experience a post baseline platelet count of ≥350,000 cells/μL than those receiving oral iron or no iron (IRR 0.7, P=0.013). Furthermore, IV iron treatment was also associated with a 40% reduction in the rate of thromboembolic events (IRR 0.6, P=0.2), which was not independent of changes in platelet status. These findings suggest one possible mechanism for the increase in VTE associated with ESA use: that iron-restricted erythropoiesis induced by ESA therapy can lead to elevation in platelet count, providing an additional risk factor for VTE for patients who are already predisposed. We encourage a retrospective review of other ESA clinical trials and prospective trials to test this hypothesis, and whether or not intravenous iron, in addition to improving responsiveness to ESA by preventing iron-restricted erythropoiesis, can also decrease the incidence of VTE in such patients in order to enhance the safety of ESA therapy. Table 1 Thromboembolic Adverse Event* No Iron (N=63) Oral Iron (N=61) IV Iron (N=63) Pts Events Pts Events Pts Events *COSTART term Cerebrovascular Accident 0 0 1 1 2 2 Pulmonary Embolism 1 1 2 3 1 1 Ischemia, cerebral 0 0 1 1 0 0 Thrombophlebitis 1 1 2 2 1 1 Thrombophlebitis, deep 6 9 2 4 3 3 Overall 6 11 7 11 6 7

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly administered as supportive care for anemia in patients receiving chemotherapy. While comparative analyses of these agents using claims data are available, electronic medical records offer a new data source for such analyses, one which may provide greater clinical detail. This retrospective, observational study using electronic medical record data was conducted to gain a better understanding of real-world treatment patterns and clinical outcomes in patients with cancer receiving chemotherapy and ESA therapy. METHODS: Electronic medical record data from a large oncology/hematology practice in the southeastern United States was collected from January 1, 2005 to September 30, 2006. Inclusion criteria consisted of patients receiving ≥ 2 doses of either epoetin alfa (EPO) or darbepoetin alfa (DARB) with concurrent chemotherapy and a cancer diagnosis 30 days prior to or during the ESA treatment episode. An ESA treatment episode was defined as continuous treatment with EPO or DARB and without EPO or DARB administration 35 days prior to the first or after the last administration. Patients were excluded if they had a diagnosis of myelodysplastic syndrome or switched ESA medications during an episode. Baseline characteristics, cancer type, chemotherapy utilization, ESA dosing, and response to ESA therapy were measured during the most recent complete ESA treatment episode. Response to therapy was defined as attainment of Hb ≥11.0 g/dL at any point during the treatment episode from an initial Hb of RESULTS: A total of 1,211 patients were included in the EPO group; 62.5% women, mean age 62.0 ± 13.1, and mean starting Hb level 10.8 ± 1.0 g/dL. In the DARB group, there were 419 patients; 68.5% women, mean age 60.0 ± 13.5, and mean starting Hb 10.9 ± 1.0 g/dL. The proportion of patients with lung cancer was significantly higher in the EPO cohort (EPO 24.4% vs DARB 15.8%, p=0.0003) while the proportion of patients with breast cancer was significantly higher in the DARB cohort (EPO 31.5% vs DARB 39.6%, p=0.0023). All other cancer types were similar between the groups. A greater proportion of EPO patients received platinum-based chemotherapy compared to those receiving DARB (EPO 37.3% vs DARB 26.5%, p DISCUSSION: These results indicate that EMR data can provide detailed information on usage patterns within a practice. In this clinic, differences were seen in the type of patient receiving either EPO or DARB, while more than half of patients with chemotherapy-induced anemia received their ESA treatment every 2 weeks, regardless of agent. Additionally, more patients with an initial Hb of

Background: Avoiding unnecessary medical visits related to erythropoiesis-stimulating agent (ESA) treatment represents an important consideration for managed-care organizations. Observational data have reported varying visit patterns for cancer chemotherapy patients receiving epoetin alfa (EPO) and darbepoetin alfa (DARB). Few studies have characterized visit patterns in this population during ESA treatment. Objective and Purpose: The objective of this analysis was to describe visit patterns and identify the proportion of medical visits made exclusively for ESA treatment in cancer chemotherapy patients. Methods: Analysis of medical claims between 1/2004–12/2005 using the Integrated Health Care Information Systems national database, representing >35 health plans, was conducted. Patients were ≥18 years old, had a cancer diagnosis, received >1 ESA administration, and concurrent chemotherapy (during or within 14 days of ESA initiation). Medical visits during the ESA treatment duration (time from first to last ESA administration) were categorized into mutually exclusive groups based on procedure codes recorded on the visit day: ESA administration, chemotherapy/radiotherapy administration, physician visit, blood count, WBC growth factor administration and other (hydration, antiemetics/antibiotics, etc). Results: 3,462 EPO and 2,839 DARB patients were identified representing 107,149 unique visits (EPO 62,785, DARB 44,364). Mean ESA treatment duration was similar between groups (Days: EPO 59.3; DARB 57.6, p=0.212). The proportion of visits were categorized into mutually exclusive service groups, presented below. Conclusion: Cancer chemotherapy patients receiving ESAs incurred visits for many reasons, but primarily for receiving chemotherapy. Less than 5% of all visits were solely related to ESA administration, regardless of ESA received. | Service Group | EPO | DARB | |:----------------------- | ----- | ----- | | Chemotherapy | 10.3% | 12.2% | | Chemotherapy + ESA | 24.9% | 27.3% | | Physician visit | 11.9% | 12.5% | | Physician visit + ESA | 13.0% | 9.9% | | Blood count | 1.1% | 2.1% | | Blood count + ESA | 10.1% | 8.4% | | WBC growth factor | 0.3% | 0.5% | | WBC growth factor + ESA | 5.9% | 6.8% | | Other | 15.9% | 14.8% | | Other and ESA | 2.6% | 2.6% | | ESA only | 4.1% | 2.9% | | Total | 100% | 100% | Table

A recently completed randomized open-label multicenter clinical trial in cancer pts with CT-induced anemia showed that an extended dose regimen of EPO 120,000 U administered subcutaneously Q3W effectively maintained hemoglobin (Hb) levels within the range of 11–13 g/dL whether initiated early (Hb of ≥11 and ≤12 g/dL) or at a standard threshold (Hb13 g/dL and dose reduced for Hb>12 g/dL or increase >1.5 g/dL in any 3-wk period (current labeling recommends Hb not to exceed 12 g/dL). If, at any dosing visit after the 1st EPO dose, Hb decreased to ≥65 Yrs

Background: Prevalent in the vast majority of patients at diagnosis, anemia associated with myelodysplastic syndromes (MDS) has historically been treated through red blood cell (RBC) transfusions. More recently, the erythropoiesis-stimulating agents (ESAs), epoetin alfa (EPO) and darbepoetin alfa (DARB), have also been employed for the treatment of MDS-associated anemia. To characterize real-world utilization of ESAs in adult patients with MDS, this retrospective analysis of medical claims examined EPO and DARB dosing patterns, ESA treatment costs, and RBC transfusion use. Methods: An analysis of de-identified medical claims from January 2004–March 2006 using the Integrated Health Care Information Services (IHCIS) national database, which encompasses over 35 health plans, was conducted. Patients included were ≥18 years old, had ≥1 claim for MDS (ICD-9 code: 238.7) prior to ESA therapy, were newly initiated on either EPO or DARB, and received ≥2 doses during the treatment period. Patients with cancer (ICD-9 codes: 140–209) within 180 days prior to ESA treatment initiation were excluded. The study period terminated with either the last ESA treatment dose, end of data availability, initial AML diagnosis, or initial stem cell transplant, whichever occurred first. Dosing frequency was classified into mutually exclusive categories: once weekly (QW; ≤9 days), once every two weeks (Q2W; 9.1 to 18 days), and once every three weeks or longer (≥Q3W; >18 days), based on the average dosing interval during treatment. Mean cumulative ESA dose was used to calculate drug cost (based on July 2007 WAC: $12.005/1,000 Units for EPO and $4.576/mcg for DARB) and dose ratio (Units EPO: mcg DARB). RBC transfusions were identified from medical procedure codes, and the proportion of patients transfused during treatment was compared between the two groups. Results: A total of 193 patients, 146 receiving EPO and 47 receiving DARB, formed the study population. Patients receiving EPO were older (69.9 vs. 66.2 years for DARB, p=0.018) with a similar proportion of women (56.2% vs. 51.1%, p=0.541). Extended dosing frequency (defined as every two weeks or greater, ≥Q2W) during treatment was observed in the majority of patients in both groups (EPO: QW 43%, Q2W 35%, ≥Q3W 22%; DARB: QW 15%, Q2W 60%, ≥Q3W 25%). Mean treatment duration was similar for both groups (EPO: 88.3 days; DARB: 87.1 days; p=0.944). The mean cumulative ESA dose administered was 406,685 Units for the EPO group and 1,509 mcg for the DARB group, corresponding to a dose ratio of 270:1 (Units EPO: mcg DARB). Use of concurrent white blood cell growth factors (G-CSF or GM-CSF) was similar (EPO 8.2%, DARB 6.4%, p =0.683). RBC transfusion was administered to 8.9% of EPO patients compared to 8.5% of DARB patients (p=0.934) Cumulative drug cost was lower in the EPO group by $2,022 (EPO $4,882; DARB $6,904; p=0.101) compared to DARB. Conclusion: Based on these data from actual clinical practice, the majority of MDS patients received extended dosing regimens (≥Q2W) of either EPO or DARB. A dose ratio of 270:1 (Units EPO: mcg DARB) between the two agents and 29% lower drug cost in the EPO group was observed. These findings are similar to those previously reported from published real-world ESA drug utilization studies in other therapeutic areas.

A set of commonly accepted hematologic endpoints is used to assess ESAs by regulatory bodies like the FDA, clinical guideline committees like NCCN, and independent health care assessment bodies like AHRQ. These include percentage of pts who received transfusions (TFNs) from week (wk) 1 to end of treatment period (EOTP), reached target Hb ≥11g/dL, and achieved a ≥3-point change in FACT-F score from baseline (BL). Other exploratory, unvalidated endpoints have been suggested (1 g/dL rise in Hb in 4 wks or change in area-under-the-Hb-concentration curve [ΔHbAUC]), but the AHRQ report (2006) characterized these as being insensitive to discriminate between ESAs. We examined the commonly accepted and the exploratory hematologic endpoints described above using pooled data from 10,328 pts with CIA enrolled in 20 clinical trials: 8079 darbepoetin alfa (DA) pts, 1677 epoetin alfa (EA) pts, and 572 placebo (PBO) pts. DA dosing frequencies were every 1 (QW), 2 (Q2W), or 3 (Q3W) wks; EA dosing frequencies (3 times a week and QW) were pooled. A mixed logit model was used to analyze the percentage of pts with TFNs and who achieved the target Hb, a ≥3-point change in FACT-F score, and a 1-g/dL Hb rise in 4 wks; a linear mixed model was used to analyze ΔHbAUC. Values were adjusted for BL Hb ( DA Q3W [n=2205] DA Q2W [n=4649] DA QW [n=1992] EA [n=1694] PBO [n=572] Sample size varies by endpoint. Adjusted mean = least squares mean; 1-in-4 = 1 g/dL rise in 4 wks. TFN Wk 1 to EOTP, Adjusted % (95%CI) 27.6 (24.1–31.4) 26.8 (23.4–30.5) 33.4 (29.2–37.8) 27.1 (23.2–31.3) 53.5 (47.5–59.5) Pts Achieving Target Hb, Adjusted % (95%CI) 72.2 (68.8–75.4) 74.2 (71.0–77.2) 69.4 (65.3–73.1) 73.6 (69.6–77.2) 35.2 (30.1–40.6) Pts with ≥3-point Change in FACT-F, Adjusted % (95%CI) 45.3 (47.8–48.2) 50.9 (47.8–54.0) 42.6 (39.3–46.0) 39.3 (35.6–43.1) 35.0 (30.2–40.1) Adjusted Mean ΔHbAUC (95%CL) 13.22 (9.43–17.01) 10.07 (6.65–13.49) 15.44 (10.35–17.70) 15.16 (12.76–17.56) 0.92 (0.14–0.22) Mean % Pts with 1-in-4 (95%CL) 51 (43–60) 33 (26–41) 48 (43–53) 43 (39–49) 25 (19–31)

Background: Anemia is common in patients with acute lymphocytic leukemia (ALL), lymphoblastic lymphoma (LL), and Burkitt’s lymphoma (BL) treated with chemotherapy and is associated with poor cancer control. Studies have shown that even mild correction of anemia has been associated with a significant improvement in quality of life. Although there are studies that show a survival benefit in patients receiving epoetin alfa (EPO), there are at least two randomized trials which reported negative outcomes with respect to progression-free survival in patients with solid tumors treated with EPO. The current standard of care for treatment of anemia in ALL, LL, and BL is packed red blood cell transfusions (PRBC). However, transfusions are time consuming and carry risks of infection and transfusion reaction. Objectives: To evaluate if EPO 1) decreases number and frequency of transfusions, and 2) adversely influences the complete remission (CR) rate to chemotherapy. Methods: Patients with newly diagnosed ALL, LL, or BL receiving hyper-CVAD were randomized to EPO vs standard of care within 14 days of starting chemotherapy. EPO dose was 40,000 units SQ weekly and escalated to 60,000 units after four weeks if indicated. Both arms received blood transfusions as per uniform guidelines. Patients were considered evaluable if they had been on the study for at least five weeks. Results: Forty-six of 70 patients were evaluable and included in this first interim analysis; 23 were treated with EPO. There were 16 ALL, 4 BL, and 3 LL on EPO and 20 ALL, 1 BL, and 2 LL in the standard of care arm. The two groups were comparable in baseline hemoglobin and number of courses of chemotherapy completed. Median age was lower in the EPO arm (32, range 20–71) when compared to the standard of care arm (42, range 16–68; p=0.37). There were more male patients in the EPO arm than standard of care arm (14 vs. 9; p= 0.144). Median baseline erythropoietin level was 299 (range 12–10532) in the EPO arm vs. 104 (range 7–491; p=0.02) in the standard of care arm. The median total number of PRBC units in the EPO group was 12 (range 4–23) compared with 16 (range 9–31) in the standard of care group (p= 0.01). The median number of transfusion events (frequency) was 7 (range 2–13) in the EPO arm compared with 9 (range 4–18) in the standard of care arm (p= 0.03). Time to neutrophil and platelet recovery was comparable in both arms. All patients with ALL had a CR in both arms. On the EPO arm, 1 patient with BL and 1 patient with LL had a partial remission. One patient with LL on the EPO arm had no response to chemotherapy. All patients with BL and LL on the standard of care arm had a CR (p=0.073). Conclusions: In patients with ALL, LL, and BL on hyper-CVAD, EPO decreased the frequency and number of packed red blood cell transfusions. EPO does not affect recovery of other cell lines. Use of EPO in this patient population does not appear to have an adverse impact on CR rates in patients with ALL. The numbers of BL and LL are too small to draw conclusions regarding effect of EPO on response rates.