Chemotherapy-associated Anemia Research Articles

Metabolic exhaustion and casein kinase 1α drive deguelin-induced premature red blood cell death

1. Deguelin (DGN), a retinoid isolated from many plants, exhibits a potent anticancer activity against a wide spectrum of tumour cells. There is a dearth of evidence, however, regarding the toxicity of DGN to red blood cells (RBCs). This is relevant given the prevalent chemotherapy-associated anaemia observed in cancer patients. 2. RBCs were exposed to 1-100 μM of DGN for 24 h at 37 °C. Haemolysis and related markers were photometrically measured while flow cytometry was employed to detect phosphatidylserine exposure through Annexin-V-FITC binding and light scatter properties. Additionally, cytosolic Ca2+ and reactive oxygen species were quantified using Fluo4/AM and H2DCFDA, respectively. DGN was also tested against specific signalling inhibitors in addition to vitamin C and ATP. 3. DGN caused a significant increase in Annexin-V-positive cells which was accompanied by cell shrinkage without Ca2+ elevation or oxidative stress. DGN also elicited dose-responsive haemolysis which was ameliorated by preventing KCl efflux and in the presence of sucrose, D4476, and ATP. In whole blood, DGN significantly reduced the reticulocyte count and increased platelet distribution width and large cell count. 4. DGN triggers premature RBC eryptosis and haemolysis through casein kinase 1α and ATP depletion, and exhibits a specific toxicity towards reticulocytes and platelets.

The Effect of Erythropoiesis-Stimulating Agent on the Management of Chemotherapy-Induced Anemia and Tumor Growth in Diffuse Large B-Cell Lymphoma Patients

Bacground : Erythropoiesis stimulating agents (ESA) increase hemoglobin levels, reduce red blood cell (RBC) transfusion requirements and improve the quality of life (QoL) in patients with chemotherapy-associated anemia (CAA). The purpose of this study is to investigate the efficacy and safety of ESA for management of anemia caused by chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL). And this study estimated quality of life as measured by Functional Assessment of Cancer Therapy Scales for anemia (FACT-An) additionally. Until now, several studies suggested that ESA can affect the progression of tumors. This study conducted experiments to confirm whether the results of previous studies were also applied to lymphoma cells.Patients and Methods : This prospective, multicenter, phase II study enrolled 50 Histologically confirmed DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristin, and prednisolone (R-CHOP) chemotherapy. This study enrolled patients who were shown hemoglobin < 10.0 g/dL at least 3 cycles after starting R-CHOP, were planning to receive at least 4 times of darbepoetin, could read Quality of life as measured by FACT-An and agreed with informed consent. However, this study excluded patients who combined iron deficiency anemia, received erythropoietin at least one months before starting darbepoetin, serious pre-existing medical condition, and untreated primary or metastatic CNS(central nervous system) malignancy. This study was registered in clinicaltrial.gov, and more information can be found at NCT02890602. All patients received darbepoietin alfa at fixed dose of 360 mg once every 3 weeks and if the hemoglobin level exceeds 12 g/dL, administration of darbepoietin was stopped temporarily. In addition, DLBCL cell lines or primary DLBCL cells were tested in vitro to investigate if there were any adverse effects of ESAs on the cancer cell growth.Results : Fifty patients were enrolled between Sep 2012 and Oct 2016. The median age was 64.5 years (range: 34-79 years). The baseline clinical features were as follows: female sex, 68.0%; ECOG >1, 75.5%; stage III/IV, 80.0% and International Prognostic Index score (IPI) > 2, 53.3%, and mean serum ferritin level, 648.13±982.52. The baseline mean hemoglobin level was 9.24 g/dL and overall mean change in hemoglobin level was 1.54±1.3 g/dL at 16 weeks. 46% of total enrolled patients achieved an increase in Hb levels of at least 2 g/dL after 16 weeks of darbepoietin administration and median time to response was 8 weeks. The change of OoL was not significant from baseline to finish of ESA. Most adverse events were hematologic complications which were attributed to the primary disease or received chemotherapy. Only one patient had a thrombotic event which was Common Terminology Criteria for Adverse Events (CTCAE) grade I. Transfusion necessity was determined by clinical judgment and the transfusion rates were 18%. In in vitro study using DLBCL cells, erythropoietin or darbepoietin did not alter cancer cell viability nor rituximab-mediated cytotoxicity under the conditions we have tested.Conclusions : Our study has demonstrated that ESA is effective and safe for patients suffering from anemia after RCHOP chemotherapy. The use of ESA in patients with DLBCL did not deteriorate the quality of life of the patients during chemotherapy. Finally, our research have also shown that the use of ESA does not affect the growth of lymphoma cells. (EPOMA ClinicalTrials.gov number, NCT02890602) DisclosuresNo relevant conflicts of interest to declare.

Reprogramming of erythrocyte lifespan by NFκB-TNFα naphthoquinone antagonist β-lapachone is regulated by calcium overload and CK1α.

The pathophysiology of chemotherapy-associated anemia, prevalent in at least 75% of patients, remains difficult to establish. Chemotherapy-related anemia is attributed in part to eryptosis, and it is therefore of considerable interest to interrogate the toxicity of investigative anticancer compounds to red blood cells (RBCs). Beta-lapachone (LAP), an anthraquinone extracted from the bark of Lapacho tree (Tabebuia avellanedae), is effective against a myriad of cancer cells. However, the toxicity of LAP to RBCs remains unexplored. Hemoglobin leakage as a surrogate for hemolysis was photometrically measured, while flow cytometry was employed to capture phosphatidylserine (PS) exposure with Annexin-V-FITC, calcium levels with Fluo4/AM, cell size by forward scatter (FSC), and oxidative stress by H2DCFDA. Our results show that LAP, at antitumor levels (10-30µM), induces dose-dependent hemolysis secondary to calcium influx from the extracellular space. Moreover, LAP stimulates eryptosis, as evident from PS exposure, which is associated with reduced cell volume and intracellular calcium overload. Importantly, it is also revealed that the cytotoxicity of LAP is mediated through casein kinase 1α. Altogether, this report shows, for the first time, that LAP possesses both hemolytic and eryptotic potential against RBCs that necessitates careful application in chemotherapy. PRACTICAL APPLICATIONS: Lapacho is a widely consumed herbal tea with origins in the Tabebuia avellanedae tree endogenous to South America. LAP is one of the active ingredients in lapacho with promising antitumor potential. We show that LAP is cytotoxic to human RBCs by virtue of eryptosis and hemolysis, and we identify associated molecular mechanisms. Given that these two manifestations are known to contribute to chemotherapy-induced anemia, our study provides invaluable insights into the suitability of LAP in cancer management and sheds some light on possible strategies to limit its undesirable side effects.

Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update.

To update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer setting. ASCO and ASH convened an Expert Panel to review the evidence and revise previous recommendations as needed. The primary literature review included 15 meta-analyses of RCTs and two RCTs. A growing body of evidence suggests that adding iron to treatment with an ESA may improve hematopoietic response and reduce the likelihood of RBC transfusion. The biosimilar literature review suggested that biosimilars of epoetin alfa have similar efficacy and safety to reference products, although evidence in cancer remains limited. ESAs (including biosimilars) may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose hemoglobin has declined to < 10 g/dL. RBC transfusion is also an option. With the exception of selected patients with myelodysplastic syndromes, ESAs should not be offered to most patients with nonchemotherapy-associated anemia. During ESA treatment, hemoglobin may be increased to the lowest concentration needed to avoid transfusions. Iron replacement may be used to improve hemoglobin response and reduce RBC transfusions for patients receiving ESA with or without iron deficiency. Additional information is available at www.asco.org/supportive-care-guidelines and www.hematology.org/guidelines .

Anemia and Iron Deficiency in Cancer Patients: Role of Iron Replacement Therapy.

Anemia in cancer patients is quite common, with remarkable negative impacts on quality of life and overall prognosis. The pathogenesis is complex and typically multifactorial, with iron deficiency (ID) often being a major and potentially treatable contributor. In turn, ID in cancer patients can be due to multiple concurring mechanisms, including bleeding (e.g., in gastrointestinal cancers or after surgery), malnutrition, medications, and hepcidin-driven iron sequestration into macrophages with subsequent iron-restricted erythropoiesis. Indeed, either absolute or functional iron deficiency (AID or FID) can occur. While for absolute ID there is a general consensus regarding the laboratory definition (that is ferritin levels <100 ng/mL ± transferrin saturation (TSAT) <20%), a shared definition of functional ID is still lacking. Current therapeutic options in cancer anemia include iron replacement, erythropoietic stimulating agents (ESAs), and blood transfusions. The latter should be kept to a minimum, because of concerns regarding risks, costs, and limited resources. Iron therapy has proved to be a valid approach to enhance efficacy of ESAs and to reduce transfusion need. Available guidelines focus mainly on patients with chemotherapy-associated anemia, and generally suggest intravenous (IV) iron when AID or FID is present. However, in the case of FID, the upper limit of ferritin in association with TSAT <20% at which iron should be prescribed is a matter of controversy, ranging up to 800 ng/mL. An increasingly recognized indication to IV iron in cancer patients is represented by preoperative anemia in elective oncologic surgery. In this setting, the primary goal of treatment is to decrease the need of blood transfusions in the perioperative period, rather than improving anemia-related symptoms as in chemotherapy-associated anemia. Protocols are mainly based on experiences of Patient Blood Management (PBM) in non-oncologic surgery, but no specific guidelines are available for oncologic surgery. Here we discuss some possible approaches to the management of ID in cancer patients in different clinical settings, based on current guidelines and recommendations, emphasizing the need for further research in the field.

Romiplostim for Treatment and Prevention of Chemotherapy-Associated Thrombocytopenia

Introduction Romiplostim is a fusion protein agonist of the thrombopoietin receptor, approved by the US FDA for the treatment of immune thrombocytopenia (ITP) after failure of glucocorticoid therapy. This agent has been examined in other settings, including its use in the management of the thrombocytopenic surgical patient (Marshall et al., Transfusion 2015) and its use for the treatment of refractory aplastic anemia (Gill et al., Br J Haematol 2016). Thrombocytopenia is a complication of chemotherapy in cancer patients that may lead to treatment delays, dose reductions, and discontinuation of therapy (Kuter DJ, Oncology 2015). This study is a retrospective, single-center review of cancer patients who either developed thrombocytopenia as a result of chemotherapy or who had an underlying pre-existing thrombocytopenic disorder (such as ITP or chronic liver disease) who were supported with romiplostim during all or part of their chemotherapy. Methods We performed a retrospective review of patients with solid tumor malignancies who received at least two sequential weekly doses of romiplostim concurrently with chemotherapy. We collected patient demographics, dates and doses of romiplostim administration with corresponding platelet (Plt) counts, and outcomes of therapy, including ability of the treating oncologist to administer chemotherapy before initiating and during use of romiplostim as measured by number of treatment cycles administered, number and duration of delays in therapy, and number and extent of clinically necessary dose reductions. Results Review of pharmaceutical dispensation records from at our institution from January 1, 2010 through April 1, 2016 revealed 19 patients concurrently treated with romiplostim and chemotherapy, with 15 meeting our inclusion criteria (Table 1). At initiation of romiplostim, 40% of patients had a Plt count ≥75 x 109/L and 26.7% of patients had a Plt count ≥100 x 109/L, with a median Plt count of 72 x 109/L (range, 21-145 x 109/L). Patients were treated with weekly injections of romiplostim, with platelet count measured at the time of drug administration; the most common starting dose was 3 mcg/kg. The average duration of romiplostim therapy required to achieve a platelet count ≥75 x 109/L was 13.6 days, and the average time to achieve a platelet count ≥100 x 109/L was 21.1 days. During treatment with romiplostim, 85.3% and 73.2% of all platelet counts measured were ≥75 x 109/L and ≥100 x 109/L, respectively (Figure 1). All patients were able to receive two or more cycles (range, 2-18) of chemotherapy while on romiplostim. Twelve patients (80%) had delays in receiving antineoplastic therapy attributed to thrombocytopenia prior to initiation of romiplostim, with an average per-patient cumulative delay time of 4.7 weeks; 5 patients (33.3%) concurrently treated with romiplostim and chemotherapy had such delays (p=0.010 by Pearson's chi-squared test), with an average per-patient cumulative delay time of 1 week. Eleven patients (73.3%) required at least 1 dose-reduction in chemotherapy attributed to thrombocytopenia prior to initiation of romiplostim; 4 patients (26.7%) required at least 1 such dose-reduction while receiving romiplostim (p=0.011 by Pearson's chi-squared test). Three patients required platelet transfusion and 10 patients required red blood cell (RBC) transfusion while receiving romiplostim, though 8 of the patients received RBC transfusions only for chemotherapy-associated anemia or fatigue. While receiving romiplostim, no patient suffered a thrombotic event, and 3 patients suffered from bleeding (1 patient developed grade 1 mucosal bleeding and 2 patients developed grade 3 gastrointestinal bleeding). Conclusion In patients with solid tumor malignancies with chemotherapy-associated thrombocytopenia or who have co-existing thrombocytopenic disorders (such as ITP or chronic liver disease), this study provides evidence that romiplostim is safe and increases the platelet count sufficiently in a majority of patients to allow subsequent chemotherapy to be given at full dose and on schedule. Table 1 Patient Characteristics. Table 1. Patient Characteristics. Fgure 1 Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Fgure 1. Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Disclosures Kuter: Protalex: Research Funding; ONO: Consultancy; Pfizer: Consultancy; 3SBios: Consultancy; Eisai: Consultancy; GlaxoSmithKline: Consultancy; Bristol-Myers Squibb: Research Funding; Genzyme: Consultancy; Shire: Consultancy; Amgen: Consultancy, Paid expert testimony; Shionogi: Consultancy; Rigel: Consultancy, Research Funding; Syntimmune: Consultancy; MedImmune: Consultancy; CRICO: Other: Paid expert testimony.

Darbepoetin Hits a Double As Epoetin Hits a Home Run in Response to the 2007 FDA Black Box Warning

Background: Darbepoetin and epoetin are erythropoiesis stimulating agents (ESAs) that have been used to treat chemotherapy related anemia in cancer patients since 2002 and 1993. ESAs reduce rates of blood transfusions in both CKD and cancer patients. In the cancer setting, toxicities for ESAs include venous thromboembolism (VTE), tumor progression, and death. In March 2007, these toxicities were described by FDA in a revised "black box" warning. The warning advised clinicians to use the lowest dose possible of ESAs among persons with chemotherapy associated anemia and to administer ESAs to cancer patients who are receiving chemotherapy for palliation versus the curative setting. While several studies report decreased ESA utilization among cancer patients with chemotherapy-induced anemia following the Black Box warning, these studies have not reported on changes in ESA use for darbepoetin versus epoetin nor have they reported on changes in VTE rates. We report on darbepoetin versus epoetin utilization trends in cancer patients with chemotherapy-associated anemia in addition to VTE and transfusion rates during the years 2002 to 2010.Methods: We merged South Carolina Medicaid data with South Carolina Cancer Registry dataset for the years 2002- 2010. Breast, non-small cell lung and colorectal patients 18 years of age and older evaluated. From the chemotherapy population in this cohort based on tumor registry data, ESA users were identified from medical and pharmacy claims. The final sample contained persons with a first ESA claim after chemotherapy administration among Medicaid persons who are not dually enrolled in Medicare and Medicaid.Results: Of 1,315 chemotherapy patients who received an ESA, 940 (71%) were darbepoetin users and 375 (29%) were epoetin users. In 2002, epoetin and darbepoetien users accounted for 37.5% and 13% of the chemotherapy population respectively. Epoetin users decreased to 13% for 2004-2006 and declined further to 3.4% by 2010. Darbepoetin administration increased to 43.5% in 2005 among cancer patients receiving chemotherapy and decreased to 7.1% among chemotherapy patients by 2010. Among chemotherapy patients who received epoetin, VTE rates were 8% in 2002 and 3% in 2010 (p<0.05). In contrast, among darbepoetin-treated cancer patients, VTE rates were 5.5% in 2002 and 5.1% in 2010. For transfusions among epoetin-treated cancer patients, transfusion rates were between 5% and 7% in the years 2002- 2008, and then increased to 13% in 2009 and 2010. In contrast, among cancer patients who received darbepoetin, transfusion rates were 7% in the years 2002- 2009 and 9% in 2009. For VTEs, logistic regression indicated that epoetin users had a 60% reduction in VTE odds after the black box warning was disseminated in 2007 and darbepoetin users' had a 35% reduction (p<.05). For transfusions, epoetin users had a 158% increase in odds of receiving a transfusion after the black box warning was added in 2007 and darbepoetin users had a 74% increase after the Black Box warning (p<.05). There is also a marked change in per-cycle dose administration for darbepoetin, but not for epoetin users. While darbepoetin treated cancer patients received a significantly higher monthly, epoetin patients received a lower monthly dose after the black box was disseminated, dose (table).Conclusion: Among cancer patients with chemotherapy-associated anemia who received ESAs between 2002 and 2010, darbepeotin users exhibited a decrease in utilization, little to no response in VTEs or transfusion risks, and marked increases in per cycle and per month dosing. In contrast, epoetin users showed decreased utilization, decreased per-cycle and per-month dosing, decreased VTE rates, and increased transfusion rates. The Black Box warning appears to have had differential effects on epoetin- versus darbepoetin-treated cancer patients with chemotherapy associated anemia.Table 1EpoetinDarbepoetin200220072010200320072010Utilization38%9%3%33%35%7%Transfusions2%6%12%4%7%6%VTEs8%4%3%6%7%5%Mean Total Monthly Dose110,026 IU95,507 IU99,625 IU328mcg403mcg452mcgDifferences between epoetin and darbeoetin patients from 2002-2010 DisclosuresNo relevant conflicts of interest to declare.

Chemotherapy-associated anemia in patients with lung cancer: an epidemiological, retrospective and multicenter study.

Providing epidemiological data and treatment of anemia in lung cancer patients undergoing first-line chemotherapy. Epidemiological, observational, retrospective and multicenter study carried out at 30 sites throughout Spain. The prevalence of anemia (hemoglobin [Hb] level <12 g/dl) was 18.3% and the incidence 80.7%. Mean Hb levels were 13.4 g/dl (95% Cl: 13.2-13.6) and 11.5 g/dl (95% Cl: 11.3-11.7) at starting and at the end of chemotherapy, respectively. Of the 294 patients with anemia, 174 (59.2%) were treated. Erythropoiesis-stimulating agents were given to 90.2% patients, alone in 31.6% and combined iron in 39.7%, transfusion in 9.2% and iron and transfusion in 9.8%. These results suggest an appropriate and rational use of erythropoiesis-stimulating agents in the treatment of chemotherapy-associated anemia in lung cancer patients. [corrected].

Lessons from the Past: Long-Term Safety and Efficacy Outcomes of a Prematurely Terminated, Randomized Phase III Trial of Precautionary Versus Hemoglobin-Based Erythropoietin Administration for Chemotherapy-Associated Anemia in Patients with Solid Tumors

ABSTRACT Aim: Prophylactic erythropoiesis-stimulating agent (ESA) administration for chemotherapy-induced anemia (CIA) is not supported by current guidelines. Long-term follow-up of patients that had been treated with EPO for CIA in the past may provide useful information. Methods: In 2002 we undertook a prospective, randomized phase III trial of prophylactic versus hemoglobin (Hgb)-based (threshold: 12 mg/dl) ESA administration in patients with solid tumors and CIA, which was permanently suspended in 2005 in the view of published data at that time, while patient surveillance continued. Herein we present safety and efficacy outcomes after more than a decade of follow-up. Results: Among 630 evaluable patients, 40.1% were male, 50.9% had advanced cancer at diagnosis, 39.2% had Hgb levels Conclusions: Prophylactic administration of ESA for CIA in patients with solid tumors was associated with increased incidence of a composite of thrombosis-related adverse events, especially in patients receiving adjuvant treatment, but did not have a detrimental impact on relapse/progression and survival rates. Disclosure: All authors have declared no conflicts of interest.

Treatment with erythropoiesis-stimulating agents in chronic kidney disease patients with cancer

Treatment of anemia remains an important component in the care of patients with nondialysis chronic kidney disease (CKD) and end-stage renal disease (ESRD). Erythropoietin-stimulating agents (ESAs) remains a key anemia treatment strategy in this patient population. However, anemia management in this group can become more complicated by prior or current history of malignancy. There has been a great deal of work both scientifically and in clinical trials in oncology that have revealed certain concerns and risks of ESA use in patients with cancer. In this review, we will bring together knowledge from nephrology and oncology literature to help nephrologists understand the implications for ESA treatment when CKD/ESRD is complicated by cancer. We also suggest an approach to the management of anemia in this patient group with active or previous malignancy.

Iron Parameters and Relation To Prognosis In Elderly Patients With Aggressive Lymphoma Receiving First Line Immunochemotherapy: An Analysis Of The Lysa LNH 03-6B Study

IntroductionAnemia is a common feature at diagnosis of patients with lymphoid malignancies and has been previously described as an important prognostic factor (Moullet et al. Ann Oncol 1998). Recent guidelines recommend evaluating iron parameters as part of the initial assessment of cancer associated anemia in order to propose iron therapy for patients with functional or absolute iron deficiency. However, incidence of iron parameters abnormalities and impact on prognosis is largely unknown. MethodsThe phase III randomized LNH 03-6B protocol included elderly patients from 60 to 80-year with untreated diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index (aaIPI) of 1 or more. Patients were randomized between 8 cycles of R-CHOP given every 2 or 3 weeks (Delarue et al. Lancet Oncol 2013) and between a prophylactic treatment with Darbepoetin alfa in order to maintain hemoglobin level between 13 and 14 g/dL versus an usual management of chemotherapy-induced anemia including ESAs and transfusions. Iron parameters including serum iron, transferrin and ferritin levels and transferrin saturation (TSAT) were measured at screening and at the end of study treatment. Iron deficiency was defined by TSAT below 20% and was considered either as true or functional if ferritin level was below or above normal or value, respectively. ResultsAt diagnosis, median serum iron level was 9 µmol/L (n=358 patients, range: 0.14-62.6), median transferrin level was 2.1 g/L (n=262 patients, range: 0.3-29), median ferritin level was 325 ng/mL (n=321 patients, range: 6-6071) and median TSAT was 17% (n=258 patients, range: 2-57). Among patients with available TSAT data, 163/258 (63%) presented a coefficient lower than 20%. When comparing with the whole study population, patients with TSAT ≤ 20% had similar baseline characteristics including aaIPI. In univariate analysis, there is no difference of PFS (HR: 1.078, 95%CI: 0.734-1.584, p=0.7006) and OS (HR: 0.963, 95%CI: 0.622-1.491, p=0.8664) according to TSAT. By contrast, in univariate and multivariate analysis, patients with ferritin level lower than normal and patients with ferritin level higher than normal presented, compared with patients with normal ferritin level, worse PFS (respectively, HR: 4,973, 95%CI: 1.673-14.780, p=0.039; HR: 1,654, 95%CI: 1.094-2.499, p =0,017) and OS (respectively HR: 6.204, 95%CI: 1.713-22.475, p=0.0055; HR: 1.8, 95%CI: 1.108-2.923, p =0.0175). ConclusionElderly patients with untreated aggressive lymphoma and iron deficiency as measured by TSAT showed similar characteristics compared to the whole population. TSAT level did not impact prognosis in contrast to ferritin level, whose variations could be independent of iron metabolism. The high frequency of iron deficiency at diagnosis raise the question of the use of IV iron as a frontline treatment of chemotherapy-associated anemia. A prospective, placebo-controlled, phase III trial is planned within our group, whose primary objective will be to demonstrate efficacy of ferric carboxymaltose alone compared to placebo as measured by the diminution of percentage of patients requiring red blood cell transfusion and/or ESA administration. Disclosures:No relevant conflicts of interest to declare.

Clinical experience with ferric carboxymaltose in the treatment of cancer- and chemotherapy-associated anaemia

BackgroundIntravenous (i.v.) iron can improve anaemia of chronic disease and response to erythropoiesis-stimulating agents (ESAs), but data on its use in practice and without ESAs are limited. This study evaluated effectiveness and tolerability of ferric carboxymaltose (FCM) in routine treatment of anaemic cancer patients.Patients and methodsOf 639 patients enrolled in 68 haematology/oncology practices in Germany, 619 received FCM at the oncologist's discretion, 420 had eligible baseline haemoglobin (Hb) measurements, and 364 at least one follow-up Hb measurement. Data of transfused patients were censored from analysis before transfusion.ResultsThe median total iron dose was 1000 mg per patient (interquartile range 600–1500 mg). The median Hb increase was comparable in patients receiving FCM alone (1.4 g/dl [0.2–2.3 g/dl; N = 233]) or FCM + ESA (1.6 g/dl [0.7–2.4 g/dl; N = 46]). Patients with baseline Hb up to 11.0 g/dl and serum ferritin up to 500 ng/ml benefited from FCM treatment (stable Hb ≥11.0 g/dl). Also patients with ferritin >500 ng/ml but low transferrin saturation benefited from FCM treatment. FCM was well tolerated, 2.3% of patients reported putative drug-related adverse events.ConclusionsThe substantial Hb increase and stabilisation at 11–12 g/dl in FCM-treated patients suggest a role for i.v. iron alone in anaemia correction in cancer patients.

A Review of Safety, Efficacy, and Utilization of Erythropoietin, Darbepoetin, and Peginesatide for Patients with Cancer or Chronic Kidney Disease: A Report from the Southern Network on Adverse Reactions (SONAR)

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk-benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States.

1561P - Predictive Diagnostics for Response to Therapy of Chemotherapy Associated Anemia with Darbepoetin Alfa +/- Intravenous Iron in Cancer Patients: PFAD-3 a Multicentre Cohort Study in Outpatients

ABSTRACT Introduction Seven randomized studies have demonstrated a benefit of combining erythropoiesis stimulating agents (ESA) with intravenous iron (iv Fe) in the treatment of chemotherapy-associated anemia in cancer patients (pts). Because, so far there is no proven recommendation for the best pretherapeutic diagnostics to select optimal therapy (ESA, iron or both), we conducted a multicenter cohort study. Methods Cancer pts were included and eligible for response if they had a symptomatic anemia (hemoglobin (Hb) Results Between 03/07 - 08/10 in 9 outpatient clinics 331 pts received DA on day 0. Mean age was 66.3 years, 58% were women. 202 pts (61%) received at least one dose iv Fe additionally to DA on day 0. Baseline Hb was 9.53g/dl (SD 0.78) and increased in average 1.23g/dl (SD 1.34) and 1.53 g/dl (SD 1.49) til weeks 6 and 9, respectively. Transfusion rate in weeks 3-9 was 15.1%. Associations of relevant criteria with response are shown in the table. Table: 1561P . Predictive factor for response* to DA to DA with additional iv-iron to DA without iv-iron OR (95% CI) (N)*** OR (95% CI) (N)*** OR (95% CI) (N)*** Ferritin (F) 1.80 (0.85-3.81) (200) 4.60 (1.62-13.09) (135) 0.13 (0.02-1.07) (65) TSAT 1.28 (0.72-2.27) (200) 1.10 (0.80-3.59) (136) 0.65 (0.24-1.76) (64) sTFR ≥ 1.76 mg/dl 1.51 (0.87-2.60) (216) 1.70 (0.87-3.30) (146) 1.13 (0.43-2.99) (70) FI, sTFR/logF ≤ 3.2** 3.92 (0.43-35.70) (197) 7.29 (0.38-140.76) (134) 0.57 (0.02-17.60) (63) eEPO 1.96 (0.80-4.80) (200) 2.26 (0.65-7.89) (142) 1.29 (0.34-4.90)(58) Δ sTFR d14-1 ≥25% 1.75 (0.78-3.91) (153) 1.85 (0.73-4.68) (103) 1.98 (0.35-11.35) (50) Δ Hb d21-1 ≥0,6 g/dl 6.09 (3.23-11.49) (189) 8.20 (3.71-18.10) (130) 3.11 (1.05-9.23) (59) * Hb d42 ≥ 11 g/dl or Δ Hb d42-d1 ≥ 1.5 g/dl,no transfusion d21-d42 ** If CRP > 5 mg/l : FI ≤ 2 *** Odds ratio, confidence intervall,and number of pts with … … DA therapy conform with protocol,treatment response and predictivefactors evaluable Conclusion The results confirm the increase of Hb within the first 3 weeks as strong predictor for response to DA in week 6. Pts with Hb-increase ≥ 0.6 g/dl have a 6-fold higher chance of being responders than those without. Ferritin is a stronger predictor for response to iv Fe than TSAT. Supported by Amgen, Munich, Germany. Disclosure H..T. Steinmetz: Member of advisory boards for Amgen, Janssen, Medice, Novartis, Roche, Vifor. Investigator in studies for Amgen, Janssen, Novartis, Roche, Vifor., M. Neise: Investigator in studies with Amgen, J. Mittermuller: Investigator in studies with Amgen, H.W. Tessen: Investigator in studies with Amgen, M. Reiser: Investigator in studies with Amgen, K. Severin: Ivestigator in studies with Amgen, Roche, Vifor, S. Schmitz: Investigator in studies with Amgen, Novartis, Roche, Vifor. All other authors have declared no conflicts of interest.

PD07-06: Adjuvant Chemotherapy with or without Darbepoetin alpha in Node-Positive Breast Cancer: Survival and Quality of Life Analysis from the Prospective Randomized WSG ARA Plus Trial.

Abstract Background: Darbepoetin alpha (ARA) is currently used to reduce chemotherapy-associated anemia (CAA) rates in various solid tumors. A possible negative impact of ARA on patient survival has been suggested in some clinical trials. The objective of the prospective randomized phase III ARA Plus trial is to compare the survival effect of darbepoetin alpha use (ARA+/ARA-) in combination with modern standard adjuvant chemotherapy targeting guideline-recommended Hb-levels in high-risk breast cancer (BC). Methods: ARA Plus compared 6 cycles T75A50C500 q3w or 6 cycles F500E100C500 q3w (at discretion of each center) in patients with node positive BC (aged 18–65 years). Patients were randomized to darbepoetin (ARA+) 500 μg q3w until completion of radiotherapy or to standard supportive care (ARA-). ARA was started at Hb-levels ≤13 g/dL (amendment 01/2008: Hb ≤12 g/dL) and stopped at &amp;gt;14 g/dL (&amp;gt;12 g/dL). Primary endpoint is event-free survival (EFS: relapses, death without disease evidence, second malignancy). Overall survival (OS), toxicity, Hb-levels and quality of life are secondary endpoints. Survival analysis was planned after 7 years of study duration. EFS was tested using χ2-test (α=0.05) with a statistical power of β=80% and log-rank test. Quality of life was measured using FACT questionnaires at beginning of therapy, mid, end of therapy, and at 1 year afterwards. Results: 1234 pts (616 ARA+/618 ARA-) from 70 centres in Germany were randomized between 01/04 and 06/08. 1198 intent to treat patients (ITT) were analysed (1096 TAC; 102 CEF). Baseline characteristics were well balanced in ARA+ and ARA- arms: median age 53/53 years; tumor size 2.4/2.4cm; number of + LN 3/3; HR+ 80%/ 83.5%, G3 40.7%/36.7%. Toxicity data have been reported earlier (SABCS 2008). At median follow up of 40 months, 168 events (81 ARA+, 83 ARA-) and 134 relapses (65 ARA+, 69 ARA-) were reported. There was no significant difference in 3-year EFS between ARA+ and ARA- arms (89.2% vs. 87.6%, p=0.97, χ2-test). 37 deaths were reported in the ARA- and 36 in the ARA+ arm. 3-year OS was 95.4% and 95.1% for ARA+ and ARA-, respectively (p=0.85). Only nodal involvement (≥4 vs. 1–3), negative HR, tumor size &amp;gt;2 cm and G3 were significant survival predictors by multivariate analysis. Unplanned retrospective analysis revealed better EFS for ARA+ vs. ARA- in HR- (p=0.05), and no difference in HR+ group (p=0.6). In ARA+ patients, Hb-levels were stable over the whole treatment period with rare overstimulation. In ARA- patients, Hb-levels decreased during therapy (median of all cycles ARA+/ARA-: 12.5/11.6 g/dL). There was no correlation between mean Hb-levels and survival in either study arm. There were no significant differences in mean FACT scores changes (general, anemia, cognitive) from begin to end of therapy in either study arm. More detailed analyses are ongoing. Conclusions: To date, the WSG ARA plus trial is the only prospectively randomized trial in early high-risk BC exclusively focusing on the impact of adjuvant ARA on patient outcome. Supportive administration of ARA appears to be safe and to have no significant survival effect when used in combination with TAC or CEF according to current guidelines. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-06.

Wachstumsfaktoren - Erythropoetine

Since the 90's, human erythropoietin is produced recombinantly and used clinically. There are various products from different suppliers, which differ primarily in their production but not in their half-life or effectiveness. 2001 genetically modified darbepoetin alpha was launched, which is characterized by an approximately three times longer half-life. A further extension of the half-life to 130 hours is achieved with the current continuous erythropoietin receptor activator (CERA), which therefore must be applied only once or twice a month. The indication for epoetin therapy is primarily for the symptomatic renal anemia and chemotherapy-associated anemia. Corrections of low hemoglobin levels in asymptomatic patients are not allowed. The generally recommended hemoglobin target range is 10-12 g/dl. Hb values > 13 g/dl should be avoided because they are associated with significant adverse effects and do not improve patient survival.

3000 POSTER DISCUSSION Effectiveness and Tolerability of Ferric Carboxymaltose in the Correction of Cancer – and Chemotherapy-associated Anaemia – a Multicenter Observational Study

3000 POSTER DISCUSSION Effectiveness and Tolerability of Ferric Carboxymaltose in the Correction of Cancer – and Chemotherapy-associated Anaemia – a Multicenter Observational Study

The relationship between serum hepcidin levels and clinical outcomes in patients with chemotherapy-associated anemia treated in a controlled trial.

9031 Background: The Mayo Clinic Cancer Research Consortium recently published results from a phase III, randomized study (MC04CC) of darbepoetin alfa (DA) combined with intravenous (IV) ferric gluconate 187.5 mg q3wks x 5 doses, oral ferrous sulfate, or no iron supplementation for patients (pts) with chemotherapy-associated anemia (CAA) (Steensma et al, J Clin Oncol 2011;29:97-105). There was no benefit from IV iron in the MC04CC trial, possibly due to iron parameters of enrolled pts. The peptide hepcidin is a major regulator of systemic iron homeostasis, but the relationship between hepcidin and response to erythropoiesis-stimulating agents (ESAs) or IV iron therapy has not been systematically studied in pts with CAA. Methods: Serum hepcidin concentration was measured in pre-treatment samples from 405/489 eligible pts enrolled in the MC04CC study, using a sensitive quantitative mass spectrometry-based method. Hemoglobin and transfusion endpoints were analyzed, stratified by hepcidin tertiles and treatment group. Results: See table. Conclusions: Pts with serum hepcidin levels in the lower two tertiles appeared to have a better clinical response to DA plus higher doses of IV iron than either pts with higher hepcidin levels, or pts with lower hepcidin levels who did not receive higher dose IV iron. Hepcidin measurements may help predict response to ESAs and supplemental iron. DA + placebo DA + oral iron DA + IV iron (pts receiving <4 doses IV iron) DA + IV iron (pts receiving 4 or 5 doses IV iron) Hemoglobin response Total 106/163 (65%) 109/163 (67%) 40/71 (56%) 74/92 (80%) Hepcidin 1st tertile (≤20.2 ng/mL) 30/47 (64%) 26/41 (63%) 12/20 (60%) 24/26 (92%) Hepcidin 2nd tertile (>20.2-64.3 ng/mL) 36/53 (68%) 32/53 (60%) 6/11 (55%) 20/21 (95%) Hepcidin 3rd tertile (>64.3 ng/mL) 23/36 (64%) 29/37 (78%) 14/24 (58%) 25/36 (69%) Hepcidin missing 17/27 (63%) 22/32 (69%) 8/16 (50%) 5/9 (56%) RBC transfusion Total 22/163 (13%) 21/163 (13%) 12/71 (17%) 8/92 (9%) Hepcidin 1st tertile 6/47 (13%) 4/41 (10%) 2/20 (10%) 0/26 (0%) Hepcidin 2nd tertile 8/53 (15%) 9/53 (17%) 2/11 (18%) 0/21 (0%) Hepcidin 3rd tertile 6/36 (17%) 5/37 (14%) 4/24 (17%) 6/35 (17%) Hepcidin missing 2/27 (7%) 3/32 (9%) 4/16 (25%) 2/9 (22%)

Predictors and patterns of red blood cell transfusion use among newly diagnosed cancer patients with chemotherapy-associated anemia in Western Denmark (1998&amp;ndash;2003)

Objective:Cancer patients receiving chemotherapy are at increased risk of anemia. We conducted a population-based historical cohort study in newly diagnosed cancer patients with chemotherapy-associated anemia in order to characterize red blood cell transfusion (RBCT) use.Design:This study evaluated cancer patients diagnosed between January 1, 1998 and December 31, 2003 using Danish National Patient Registry data. Patients were receiving chemotherapy and had a hemoglobin level ≤10.9 g/dL during the 4 months following cancer diagnosis. We characterized patterns of RBCT use and inpatient and outpatient hospitalization for transfusion. Adjusted Poisson regression models were used to evaluate the likelihood of RBCT, estimated by relative risk (RR), based on demographic and clinical factors.Results:Women constituted 58% of 1782 patients studied; the median age was 58 years. Two-thirds (67%) had solid tumors; 67% had stage III or IV disease at diagnosis. Overall, 713 (40%) patients received an RBCT within 120 days of cancer diagnosis, of which 94% were administered in the inpatient setting; 84% of these patients required subsequent transfusions. The median (Q1, Q3) pretransfusion hemoglobin level was 9.0 (8.4, 9.8) g/dL. Patients aged <20 years were more likely to receive an RBCT than older patients (RR 1.89; 95% confidence interval [CI] 1.44–2.49). Compared with stage IV disease, those with stage II or III disease had a lower likelihood of RBCT (stage II: RR 0.52, 95% CI: 0.37–0.72; stage III: RR 0.68, 95% CI: 0.55–0.83). Patients diagnosed with breast cancer were less likely to receive an RBCT than patients with hematologic cancers (RR 0.34, 95% CI: 0.21–0.55).Conclusion:In this study, 40% of cancer patients with chemotherapy-associated anemia in Western Denmark received an RBCT, usually in the inpatient setting; of these, most required subsequent transfusions. Younger age increased the likelihood of receiving an RBCT, and earlier stage or breast cancer decreased RBCT likelihood.

Serious Adverse Drug Reactions (sADRS) Associated with Hematopoietic Growth Factors: A Systematic Review From the Southern Network on Adverse Reactions (SONAR) Program

AbstractAbstract 2555Erythrpoiesis stimulating agents (ESAs) and the granulocyte hematopoietic growth factors granulocyte colony stimulating factor (G-CSF) and pegylated G-CSF revolutionized supportive care approaches to anemia and neutropenia, respectively. Thrombopoietin-receptor agonists improve antibody-mediated thrombocytopenia management. For these drugs, as with all agents, a comprehensive understanding of sADRs is important, however, often difficult to do. We reviewed sADRS described in meta-analyses and web-site materials maintained by regulatory agencies and manufacturers reports (1989 to July 2010; n=2,094). Overall, 28 systematic reviews, six package inserts, three medication guides, four FDA Risk Evaluation and Mitigation Systems (REMS) materials, 16 Summaries of Product Characteristics/Product Assessment Reports were included. For ESAs, common sADRs associated with increased relative risks (RRs) included: mortality among cancer patients with chemotherapy-associated anemia or cancer patients not receiving active treatment (RRs: 1.1–1.2); cerebrovascular and cardiovascular events among chronic kidney disease patients ((RRs: 1.3, 1.9), and venous thromboembolism in the cancer setting (RRs;16-1.7). For G-CSF/pegylated-GCSF, rare instances of myelodysplasia/acute myeloid leukemia (MDS/AML) associated with statistically increased RRs were reported among breast cancer patients receiving chemotherapy in trials reported from one NCI-sponsored clinical trials group, one meta-analysis, and one review of Medicare/SEER databases (RR: 1.9–2.1), although the absolute risks were very small (< 2 per 100,000 treated patients). Other rarely reported sADRs (total N < 20) included splenic rupture following G-CSF stimulation of healthy peripheral blood stem donors. Bone marrow fibrosis and collagen deposition were reported with thrombopoietin receptor agonists, although the implications of this finding is uncertain. Also, instances of VTEs were reported among persons who developed high platelet counts following administration of these thrombopoeitin receptor agonists. SADRs are commonly associated with ESA administration in a range of settings, are uncommon occurrences with G-CSF/pegylated G-CSF, and are not well characterized for thrombopoieitin receptor agonists. Formal pharmacovigilance initiatives are ongoing, including FDA mandated REMS with restricted distribution requirement for ESAs in the cancer setting (APPRISE) and the NEXUS and the PROMACTA CARES programs for thrombopoeitin receptor agonists.ESAs (Cancer)ESAs (CKD)G-CSF/Pegylated G-CSFVTEMortalityCerebrovascular and CVDAML/MDSRR1.57 and 1.671.10 to 1.171.34 and 1.922.14 and 1.9295% CI1.31–1.87 and 1.35–2.061.02–1.20 and 1.06–1.301.03–1.74 and 1.38–2.261.12–4.08 and 1.19–3.07Baseline RiskAbsolute RiskCommonCommonCommonRare (2/100,000) Disclosures:Bennett:Pfizer: Consultancy.