Stimulation Of Erythropoiesis Research Articles

SCT in Jehovah's Witnesses: the bloodless transplant

Auto-SCT and Allo-SCT are procedures conventionally associated with intensive transfusion support. This dependence has historically prevented SCT in individuals with religious or personal objections to transfusion. More recently, a growing body of literature supports the feasibility of 'bloodless transplants': SCT without the transfusion of RBCs, plts or plasma. It is possible to perform 'bloodless' autologous or reduced-intensity allogeneic transplants in properly selected patients. The success of these procedures depends on the transplantation technique and on meticulous attention to blood conservation and supportive care. In this study, the literature supporting bloodless transplantation will be reviewed. Supportive measures such as the optimal stimulation of erythropoiesis and thrombopoiesis in the transplant patient will be discussed, as will the prevention and management of bleeding during extreme thrombocytopenia. Many of these techniques, learned and refined in Jehovah's Witnesses, may help reduce bleeding and transfusion requirements in the general transplant population.

Effective erythropoiesis and HbF reactivation induced by kit ligand in β-thalassemia

In human beta-thalassemia, the imbalance between alpha- and non-alpha-globin chains causes ineffective erythropoiesis, hemolysis, and anemia: this condition is effectively treated by an enhanced level of fetal hemoglobin (HbF). In spite of extensive studies on pharmacologic induction of HbF synthesis, clinical trials based on HbF reactivation in beta-thalassemia produced inconsistent results. Here, we investigated the in vitro response of beta-thalassemic erythroid progenitors to kit ligand (KL) in terms of HbF reactivation, stimulation of effective erythropoiesis, and inhibition of apoptosis. In unilineage erythroid cultures of 20 patients with intermedia or major beta-thalassemia, addition of KL, alone or combined with dexamethasone (Dex), remarkably stimulated cell proliferation (3-4 logs more than control cultures), while decreasing the percentage of apoptotic and dyserythropoietic cells (<5%). More important, in both thalassemic groups, addition of KL or KL plus Dex induced a marked increase of gamma-globin synthesis, thus reaching HbF levels 3-fold higher than in con-trol cultures (eg, from 27% to 75% or 81%, respectively, in beta-thalassemia major). These studies indicate that in beta-thalassemia, KL, alone or combined with Dex, induces an expansion of effective erythropoiesis and the reactivation of gamma-globin genes up to fetal levels and may hence be considered as a potential therapeutic agent for this disease.

Cost Analytic Model to Determine the Least Costly Inpatient Erythropoiesis Stimulating Therapy Regimen

Unlike in outpatient settings, the comparative costs of epoetin alpha (EPO) and darbepoetin alpha (DARB) have not been evaluated broadly from the inpatient hospital perspective. To develop a cost analytic model comparing hospital inpatient costs for erythropoiesis stimulating therapies within the nephrology and oncology settings. A cost analytic model incorporating erythropoietic drug, pharmacy, and nursing costs was developed from the inpatient hospital perspective to evaluate comparative costs of EPO and DARB. Erythropoietic drug costs were calculated using unit wholesale acquisition cost multiplied by the number of units or micrograms while comparing the following dosing regimens: EPO 3 times weekly, EPO once weekly, and DARB once weekly. Pharmacy costs included dispensing and delivery costs, while nursing costs incorporated administration time costs; all were calculated by estimated fractional hours per activity multiplied by hourly wages. The total frequency of erythropoiesis stimulating therapy administrations was determined based on the average hospital length of stay. The first erythropoiesis stimulating therapy dose was assumed to occur on day 3 of hospitalization. For total inpatient costs, a weighted average was calculated across disease states. One-way sensitivity analyses were conducted by varying length of stay, day of initial erythropoiesis stimulating therapy dose, pharmacy and nursing costs, and once-weekly DARB dose. EPO 3 times weekly was the least costly regimen across all disease states evaluated. Threshold analysis indicated that the cost of once-weekly DARB regimens would have to be reduced by 37% to equal the cost of EPO 3 times weekly for an average length of stay. Sensitivity analyses did not considerably affect the results. EPO 3 times weekly was found to be the least costly erythropoiesis stimulating therapy regimen for nephrology and oncology inpatients for the average length of stay as well as most other lengths of stay considered. Once-weekly EPO was the least costly erythropoiesis stimulating therapy regimen for several other lengths of stay, while once-weekly DARB was never found to be the least costly regimen.

CNTO 530: Molecular pharmacology in human UT-7 EPO cells and pharmacokinetics and pharmacodynamics in mice

CNTO 530 is a 58 kD antibody Fc domain fusion protein, created using Centocor's MIMETIBODY™ platform, that contains two EMP1 sequences as a pharmacophore. CNTO 530 has no sequence homology with EPO but acts as a novel erythropoietin receptor agonist. In UT-7 EPO cells, CNTO 530 caused protein phosporylation of the erythropoietin receptor associated signaling pathway (Jak2, STAT5, AKT and ERK1/2). CNTO 530 also rescued these cells from apoptosis and mediated proliferation. In mice, pharmacokinetic analysis showed that CNTO 530 was slowly cleared from circulation with a t½ ≈ 40 h. Pharmacodynamic analysis in mice showed that a single sc dose of CNTO 530 caused a long-lived stimulation of erythropoiesis that translated into increases in red blood cell counts and hemoglobin values that were maintained for at least 28 d. In conclusion, CNTO 530 is a long-lived EPO-R agonist that stimulates erythropoiesis in a manner similar to epoetin-α. These data suggest that CNTO 530 may be an effective treatment of anemia in humans.

Discrimination of Recombinant and Endogenous Urinary Erythropoietin by Calculating Relative Mobility Values from SDS Gels

Erythropoietin (EPO) promotes the production of red blood cells, the key factor in the regulation of the oxygen transport, and has been abused by athletes for performance enhancement in endurance sports. Current methods to detect EPO misuse are based on isoelectric focussing (IEF), double blotting, and chemiluminescence detection. A new approach utilizing SDS-PAGE mobilities of target analytes is presented. Employing two internal standards (novel erythropoiesis stimulating protein and recombinant rat EPO), the assay provides a tool which allows the calculation of relative mobility values for endogenous urinary EPO and recombinant epoetins (e.g., Dynepo) and, thus, the distinction of these analytes in doping control samples. A reference group of 53 healthy volunteers and samples originating from a Dynepo (epoetin delta) excretion study conducted with a single person were analyzed and led to a significant discrimination of endogenous urinary and recombinant EPO. A clear differentiation was accomplished over a period of four days post-administration of a single injection of 50 IU/kg body weight. Hence, the method may be useful as a screening procedure in doping control or as complementary confirmation tool to the established IEF assay.

Complement Cascade (CC) Cleavage Fragments - C3a and C5a Anaphylatoxins - As New Unexpected Hypoxia-Related Stimulators of Erythropoiesis.

Hypoxia leads to both secondary polycythemia and activation of complement cascade (CC) in bone marrow (BM) (Leukemia 2007, 21:973–982) by classical pathway (Blood 2006, 107:835–840) and important CC proteins (e.g., C3 and C5) are produced by BM macrophages in erythropoietic islands. These observations prompted us to study the potential role of CC cleavage fragments in erythropoiesis. We noticed that human and murine cells from the erythroid lineage express functional G-protein coupled C3aR and C5aR and that C3 and C5 cleavage fragments - anaphylatoxins C3a, desArgC3a, C5a and desArgC5a enhance SDF-1-mediated chemotaxis of erythroid progenitors and induce in normal erythroblastsi.adhesion to fibronectin,ii.calcium flux andiii.phosphorylation of MAPKp42/44 and AKT.To further explore the potential role of the C3a–C3aR and C5a–C5aR axes in erythropoiesis, we focused on C3aR−/− and C5−/− mice. We noticed that C3aR−/− animals compared to wild type (wt) littermates havei.lower hematocrits andii.display delayed recovery of hematocrit values after sublethal irradiation.More importantly, we noticed that the number of clonogeneic BFU-E progenitors in BM of C3aR−/− mice, but not CFU-GM and CFU-Meg, is reduced by ∼65%. Similarly, however, less pronounced changes were observed in C5−/− mice. Thus, in order to learn more about the role of the C3a–C3aR and C5a–C5aR axes in erythropoiesis we moved to an in vitro model and co-stimulated normal human CD34+ or murine SKL cells with CC anaphylatoxins in the presence of suboptimal doses of EpO and KL, but no effect on BFU-E colony formation was observed. We found, however, that CC anaphylatoxins increase in early erythroid cells expression of mRNA for VEGF and MMP-2 (C3a >desArgC3a > C5a >desArgC5a) - which are important for maturation/enucleation and egress of erythrocytes from the BM into peripheral blood. These data were subsequently confirmed by ELISA (VEGF) and zymography (MMP-2). Furthermore, we noticed that at the morphological level C3aR−/− and C5−/− mice as compared to wt littermates had a significantly reduced number of erytropoietic islands in BM. This suggests that in the absence of the CC anaphylatoxins, maturing erythroblasts do not traffic properly in the BM microenvironment and do not associate with C3 and C5 producing central macrophages in erythropoietic islands. In conclusion, the C3a–C3aR and C5a–C5aR axes modulate the interaction of erythroid progenitors with the hematopoietic environment and play an important and underappreciated role in developmental trafficking of erythroid cells in BM. Thus, CC anaplylatoxins may enhance erythropoietic effects of erythropoietin in polycythemias related to hypoxia. Furthermore, since hypoxia activates CC, we postulate that CC anaphylatoxins could be involved in the pathogenesis of hypoxia-related polycythemias and C3aR or C5aR antagonists could find a potential supportive role in controlling erythropoiesis.

Oral Treatment with PBI-1402 Increases Hemoglobin Level and Red Blood Cell Count: A Novel Approach to Treating Chemotherapy-Induced Anemia.

Background: PBI-1402 is a novel orally active low molecular weight synthetic compound with erythropoiesis stimulating activity. Furthermore, a clinical phase I study showed that PBI-1402 induced a significant increase (100%, p < 0.0001, compared to placebo) of relative and absolute reticulocyte count in healthy volunteers after 21 days of oral treatment and was devoid of significant side effects.Outcomes: The objectives of this clinical phase Ib/II trial were to study the safety and tolerability of PBI-1402 and to assess its biological efficacy on hemoglobin (Hb) level and red blood cell (RBC) count in patients with Chemotherapy-Induced Anemia (CIA).Methods: An open label phase Ib/II trial, monitored by a US CRO (Pharm-Olam International), was conducted in patients developing anemia after chemotherapy treatment. Three cohorts of 6 CIA patients received 8 weeks of treatment with PBI-1402 once a day, at different doses, and were monitored every two weeks for safety, tolerability, Hb level, RBC count and blood chemistry. Patients remained on their chemotherapy during PBI-1402 treatment.Results: To date, 12 CIA patients have completed their PBI-1402 treatment. 83% of patients demonstrated a significant increase in RBC (p = 0.015) and 66% in Hb (p = 0.038). Among the responders, the mean Hb increase was 1.1 g/dL (p = 0.0007) from a baseline Hb value of 9.8 g/dL. No patient required a blood transfusion and only one patient had an Hb content below 9 g/dL (8.9 g/dL). PBI-1402 was well tolerated and no significant side effects were observed.Conclusion: PBI-1402, via a mechanism of action distinct from erythropoietin, induced sufficient erythropoiesis to raise the RBC level and Hb in CIA patients. In addition, PBI-1402 is safe and well tolerated. PBI-1402 offers the potential for a novel therapy of the anemia of CIA.

Darbepoetin 500 mcg Q3W, Alone or in Combination with Peg-Filgrastim, in Low/Int1 IPSS Risk Myelodysplastic Syndromes Unresponsive to Recombinant Erythropoietin.

Darbepoetin (DPO), a long acting erythropoiesis stimulating protein, is effective in inducing erythroid responses in 40–71% of anemic patients with myelodysplastic syndromes (MDS) when given at fixed doses of 150–300 mcg once-a-week. Of interest, some of these responses have been reported in MDS patients previously treated with (and occasionally unresponsive to) recombinant erythropoietin (r-EPO). We aimed to explore, on a compassionate basis, the effects of a higher DPO dose, administered with longer intervals, specifically in this last setting of patients. A single s.c. injection of DPO at the dose of 500 mcg s.c. was given every 3 weeks (Q3W) in fifteen anemic MDS patients, who had a history of an unsuccessful prior treatment with alpha or beta r-EPO (total weekly doses of r-EPO received: 30.000–80.000 U, for at least 8 weeks), both primary resistant or with loss of efficacy after an initial response. Informed consent was obtained in all cases. Nine patients were male, six female; mean age was 71 years (range 62–82). According to WHO classification, there were 5 RA, 3 RARS, 6 RCMD and 1 RCMD-RS. IPSS score was low in 6 patients and intermediate-1 in the remaining 9 subjects. Baseline Hb levels ranged from 6.2 to 9.1 g/dl, twelve patients being transfusion-dependent. All patients were treated with at least 3 DPO doses (nine weeks of therapy) and were evaluable for short term response and safety. No relevant adverse effect attributable to DPO was recorded. According to recently revised IWG criteria, three patients (20%) achieved an erythroid response. Transfusion-independence was obtained in one of two transfusion-dependent responders. All responses occurred after 2 doses of DPO in patients with baseline endogenous EPO below 200 miu/ml, two of whom previously treated with r-EPO 10.000 U s.c. t.i.w, while one had received 40.000 U s.c. b.i.w. Erythroid responses were maintained prolonging intervals between two DPO administrations up to 6 weeks. Based on the previously described possible synergism between r-EPO and myeloid growth-factors in MDS and to the concomitant presence of symptomatic neutropenia, five patients non-responding to DPO alone received Peg-filgrastim, a novel, pegylated form of granulocyte-colony stimulating factor (G-CSF) with prolonged terminal half-life, at the dose of 6 mg s.c. every 3 weeks, in combination with DPO, for an additional period of 9 weeks. The treatment was well tolerated, but no improvement in Hb levels or reduction in transfusional support was observed. A significant increase in peripheral blood WBC count occurred in all patients treated with Peg-filgrastim. In this preliminary experience, DPO given at the fixed dose of 500 mcg Q3W was effective in some anemic MDS patients considered unresponsive to r-EPO. However, it should be taken into account the fact that at least two of responders had probably previously received r-EPO at sub-optimal doses (less than 40.000 U per week). The adjunct of Peg-filgrastim in this setting of patients resulted in an improvement of neutropenia, without effects on Hb levels.

Enzyme substrate recognition in oxygen sensing: how the HIF trap snaps

The transcriptional activator HIF (hypoxia-inducible factor) is a focal point of biomedical research because many situations in physiology and in pathology coincide with hypoxia. The effects of HIF activation may be a facet of normal growth, as in embryonic development, they may counterbalance a disease, as seen in the stimulation of erythropoiesis in anaemia, and they may be part of the pathological processes, as exemplified by tumour angiogenesis. The oxygen-sensitive alpha-subunits of HIF are primarily regulated by the enzymatic hydroxylation that induces rapid proteasomal degradation. The HIFalpha hydroxylases belong to a superfamily of dioxygenases that require the co-substrates oxygen and 2-oxoglutarate as well as the cofactors Fe2+ and ascorbate. The regulation of enzyme turnover by the concentration of the cosubstrate oxygen constitutes the interface between tissue oxygen level and the activity of HIF. The HIFalpha prolyl hydroxylases, termed PHDs/EGLNs (prolyl hydroxylase domain proteins/EGL nine homologues), bind to a conserved Leu-Xaa-Xaa-Leu-Ala-Pro motif present in all substrates identified so far. This recognition motif is present twice in HIF1alpha, which gives rise to a NODD [N-terminal ODD (oxygen-dependent degradation domain)] containing Pro402 of HIF1alpha and a CODD (C-terminal ODD) where Pro564 is hydroxylated. PHD1/EGLN2 and PHD2/EGLN1 hydroxylate both ODDs with higher activity towards CODD, whereas PHD3/EGLN3 is specific for CODD. The reason for this behaviour has been unclear. In this issue of the Biochemical Journal, Villar and colleagues demonstrate that distinct PHD/EGLN domains, that are remote from the catalytic site, function in substrate discrimination. This elegant study improves our understanding of the interaction of the oxygen-sensing PHDs/EGLNs with their substrates, which include, but are not limited to, the HIFalpha proteins.

Epoetin-induced pure red cell aplasia: diagnosis and treatment

Antibody-mediated pure red cell aplasia is now recognized as a rare complication of erythropoiesis-stimulating agent therapy. The incidence of this adverse effect peaked in 2002, but new cases still appear sporadically. The aim of this review is to discuss the latest opinions regarding the detection and management of this condition. The diagnosis of classical erythropoiesis-stimulating agent induced pure red cell aplasia is made by a constellation of clinical features, including severe transfusion-dependent anaemia, reticulocytopenia, low or absent erythroblasts in the bone marrow, and the presence of circulating antierythropoietin antibodies. Recently, some cases have been reported in which the bone marrow findings show red cell hypoplasia rather than aplasia; this may represent earlier presentations of the same condition. Management of pure red cell aplasia as a complication of erythropoiesis-stimulating agent therapy consists of stopping the drug and implementing an immunosuppressive regimen to reduce or abolish erythropoietin antibody production. A recent animal study suggested that a possible alternative strategy may be to administer a novel peptide-based erythropoietin receptor agonist called Hematide that does not cross react with antierythropoietin antibodies, and will allow ongoing stimulation of erythropoiesis; this is the subject of a current clinical trial.

Comparative Erythropoietin Receptor Binding Kinetics of C.E.R.A. and Epoetin-β Determined by Surface Plasmon Resonance and Competition Binding Assay

C.E.R.A., a continuous erythropoietin (EPO) receptor activator, has been developed to provide stable maintenance of hemoglobin levels at once-monthly dosing intervals and smooth and steady anemia correction. The comparative EPO receptor binding properties of C.E.R.A. and epoetin-β were assessed by surface plasmon resonance using soluble recombinant EPO receptors and by competition binding on cultured UT-7 cells. Calculated equilibrium dissociation constants (surface plasmon resonance assay) for C.E.R.A. and epoetin-β were 140 and 2.9 nmol/l, respectively. Respective IC₅₀ values (competition binding assay) were 200 and 1.5 nmol/l. Compared with epoetin-β, C.E.R.A. has ∼50- to 100-fold lower affinity for EPO receptor binding sites. Analysis of the equilibrium binding curves indicates that the difference in affinity is mainly due to slower association. The different receptor binding properties of C.E.R.A. may enable continuous stimulation of erythropoiesis and, combined with a long half-life and slow systemic clearance, permit administration at extended intervals.

Expression of erythropoietin and its receptor in neuroblastomas

Children with high-risk neuroblastomas (NB) potentially may benefit from treatment with recombinant human erythropoietin (Epo). Epo is a stimulator of erythropoiesis, acting through its receptor (EpoR). The objective of the current study was to evaluate expression levels of Epo and EpoR in NB and in normal tissues and their effects on the proliferation of tumor cells. A tissue microarray study was performed with 101 primary tumors, 39 paired metastases, 56 paired control tissues, and 6 human NB cell lines. Immunohistochemical staining was performed using antibodies against Epo and EpoR. Immunostaining intensity was evaluated by using a semiquantitative score based on the percentage of positive cells. An in vitro analysis of cell proliferation and cell cycle in the presence of recombinant Epo was performed in the 6 cell lines. The expression of EpoR was found to be significantly higher in tumors than in paired control tissues (P < .0001) compared with the expression of Epo (P = .06), and the expression of EpoR was significantly higher in lymph node metastases than in paired primary tumors (P = .02) compared with Epo (P = .99). Survival analysis demonstrated that the patients who had tumors with the highest expression of EpoR had a significantly better overall survival (P = .03). In the in vitro study, recombinant Epo did not modify proliferation and cell cycle in the cell lines regardless of the EpoR expression level. Epo and EpoR were expressed in NB but did not modify tumor cell proliferation. The results of the current study suggested that Epo may be used safely for supportive care in children with NB.

Darbepoetin alfa protects podocytes from apoptosis in vitro and in vivo

Detachment or apoptosis of podocytes leads to proteinuria and glomerulosclerosis. There are no current interventions for diabetic or non-diabetic glomerular diseases specifically preventing podocyte apoptosis. Binding of erythropoiesis stimulating proteins (ESPs) to receptors on non-hematopoietic cells has been shown to have anti-apoptotic effects in vitro, in vivo, and in preliminary human studies. Recently, erythropoietin receptors were identified on podocytes; therefore, we tested effects of darbepoetin alfa in preventing podocyte apoptosis. Cultured immortalized mouse podocytes were treated with low-dose ultraviolet-C (uv-C) irradiation to induce apoptosis in the absence or presence of darbepoetin alfa. Apoptosis was quantified by Hoechst staining and by caspase 3 cleavage assessed by Western blots. Pretreatment with darbepoetin alfa significantly reduced podocyte apoptosis with this effect involving intact Janus family protein kinase-2 (JAK2) and AKT signaling pathways. Additionally, darbepoetin alfa was found protective against transforming growth factor-beta1 but not puromycin aminonucleoside induced apoptosis. Mice with anti-glomerular antibody induced glomerulonephritis had significantly less proteinuria, glomerulosclerosis, and podocyte apoptosis when treated with darbepoetin alfa. Our studies show that treatment of progressive renal diseases characterized by podocyte apoptosis with ESPs may be beneficial in slowing progression of chronic kidney disease.

Towards a reliable molecular mass determination of intact glycoproteins by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry

Different matrices and sample-matrix preparation procedures have been tested in order to study their influence on the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectra of intact glycoproteins, which present different degrees of glycosylation (human transferrin; bovine fetuin; bovine alpha(1)-acid-glycoprotein; recombinant human erythropoietin; and the novel erythropoiesis stimulating protein). Using sinapinic acid (SA) and the fast evaporation method, the studied glycoproteins became susceptible to fragmentation at any laser intensity, suggesting that this 'hot' matrix is unsuitable for a reliable molecular mass determination of glycosylated compounds. In contrast, 2,5-dihydroxybenzoic acid (DHB) and 6-aza-2-thiothymine (ATT), with an adequate sample-matrix preparation, provided improved results. Samples containing DHB after crystallization by vacuum drying demonstrated the best performance because the labile functional groups from the glycoforms were apparently fragmented to a lower extent. The average molecular masses obtained using this methodology were in all cases a better estimation than those values reported in the literature. The results were reproducible, and sensitivity was similar to that obtained with SA and the fast evaporation method. These excellent results suggest that this MALDI-TOF-MS methodology could be useful for an improved determination of the average molecular mass values of microheterogeneous compounds such as glycoproteins, glycosylated compounds or, in general, molecular mass values of molecules with similar labile functional groups.

Angiogenic factors in preeclampsia: so complex, so simple?

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Hydroxylation of Hypoxia-Inducible Transcription Factors and Chemical Compounds Targeting the HIF-α Hydroxylases

The hypoxia-inducible transcription factors (HIFs) are central components in the cellular responses to a lack of O(2), i.e. hypoxia. Homologs of the HIF system (HIF-1, -2 and -3) are detectable in all nucleated cells of multicellular organisms. Active HIFs are heterodimers (HIF-alpha/ beta). In hypoxia the O(2)-labile alpha-subunit is translocated to the nucleus where it binds HIF-beta. Over 100 HIF target genes have already been identified. The translational products of these genes increase O(2) delivery to hypoxic tissues, such as erythropoietin which stimulates the production of red blood cells, and they adapt cellular metabolism to hypoxia, such as glycolytic enzymes. HIFs are inactive in normoxia because of O(2)-dependent enzymatic hydroxylation and subsequent degradation of their alpha-subunit. Three HIF-alpha prolyl hydroxylases (PHD1, 2 and 3) initiate proteasomal degradation while an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1) inhibits the function of the C-terminal transactivation domain of HIF-alpha. In addition to O(2) and 2-oxoglutarate, the HIF-alpha hydroxylases require Fe(2+) and ascorbate as co-factors. Products of glycolysis can act as endogenous inhibitors of HIF hydroxylases which may lead to sustained activation of HIFs in cancer cells. The cofactor requirements define the routes to inhibition of the enzymes when HIF activation is desirable. In particular, 2-oxoglutarate analogues have emerged as promising tools for stimulation of erythropoiesis and angiogenesis ("HIF-stabilizers"). However, as the HIF system promotes the transcription of many genes, and other 2-oxoglutarate dependent dioxygenases are likely to be inhibited by the same analogues, careful evaluation of the inhibitors seems mandatory prior to their clinical use.

Does quality of life improvement precede anemia correction in patients with chemotherapy-induced anemia treated with intravenous iron?

9082 Background: Combining intravenous (IV) iron with erythropoiesis-stimulating (ESA) therapy has been shown to increase Hgb response in treating anemia of cancer and chemotherapy. As part of a trial in anemic cancer patients on chemotherapy being treated with an ESA, we compared the effects of IV iron, oral iron, and no iron, on changes in patient-reported HRQOL. Methods: Prospective, randomized, controlled, multicenter trial. Major inclusions: pt starting chemotherapy cycle, Hb &lt;11g/dL, ferritin &gt;100 ng/mL or transferrin saturation &gt;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, PO FeSO4 325 mg tid, or IV ferric gluconate 125 mg IV weekly, for 8 weeks. Change in HRQOL was measured 4 weeks after start and at end of study (week 10, or last observation carried forward) using Functional Assessment of Cancer Therapy (FACT)-Anemia. Results: There were no significant between-group differences at baseline in mean Hb (10.2g/dL), TSAT (31.3%), or serum ferritin (421ng/mL) for the 129 evaluable patients, (mean age 65.3, 69% female). See Table . Hgb responses were significantly greater by end of study in evaluable pts receiving IV FG than oral iron or no iron. Only pts receiving FG reported a significant improvement in FACT-Fatigue subscale (FACT-F). This difference began at 4 weeks, while Hgb response was still similar between groups. No significant improvement in fatigue was reported by either the no iron (ESA alone) nor oral iron group. Conclusions: Combining IV iron with ESA therapy lead to an early and sustained clinically significant (=3) improvement in fatigue score, which preceded the improvement in Hgb response. [Table: see text] [Table: see text]

Second interims analysis of the ARA Plus study: Breast Cancer (BC) adjuvant chemotherapy (CT) with and without darbepoetin- alpha, analysis of serious adverse events

564 Background: TAC is one of the most effective regimens. It‘s associated with higher frequency of anemia and chemotherapy-induced neutropenia (CIN). The erythropoiesis stimulating factor (ESF) support of chemotherapy, its complications and survival effect remain unclear. Erythropoetins do prevent chemotherapy-associated anemia (CAA) and subsequent fatigue syndrome but their potential influence on survival is still unclear. One aim of this analysis is to investigate the correlation between CT, growth factor support and toxicity (SAE‘s). Methods: This ARA Plus phase III trial compare chemotherapy ±ARA in breast cancer patients &gt;18 years old, with positive lymph nodes and with M0 disease. Pts get six cycles of of 5-fluoro-uracile 500mg/m2, epirubicine 100mg/m2 and cyclophosphamide 500mg/m2, (FEC, Bonneterre), 3-weekly or six cycles of docetaxcel 75mg/m2, adriamycin 50mg/m2 and cyclophosphamide 500mg/m2, (TAC, BCIRG) and are randomized to ARA 500μg q3w if Hb&lt;13 g/dl or standard support care. Here arte the results. of SAE‘S. Results: A total of 756 pts (373 + ARA/383 -ARA) from 53 sites were enrolled since January 2004, there are 1234 pts. planned up to January 2008. 185 serious adverse events (SAE) are reported. Of these 185 SAE’s 100 (54%) had an ARA-therapy. Most frequent SAE’s were: leucopenia, febrile neutropenia, thrombosis and infections. In 9 (31%) out of the 29 febrile neuropenia SAE’s, ARA was given. 30 thromboses were reported (23+ARA/7-ARA s.) but only 10 at the verty time ARA was given. In 31 severe infections 16 (51,6%; n.s.) were reported in patients receiving ARA Therapy. From 43 patients with intestinal SAE‘s like Diarrhea/Mucositis/Nausea to 30 pts. (69,8 %) ARA eas given. Conclusions: The combination of CT and ARA is safe concerning febrile neutropenia and furthermore appears to be protective factor of this SAE when combined with TAC. There seem to be more SAE‘s concerning thrombosis and intestinal difficulties.These results allow to hypothesize that ARA therapy is associated with higher toxicity concerning thrombosis which could make the use of heparin necessary but on the other side it shows significant reduced neutropenia. No significant financial relationships to disclose.

Weighing the Hazards of Erythropoiesis Stimulation in Patients with Cancer

On May 10, the FDA convened a meeting to discuss concerns about risks associated with the erythropoiesis-stimulating agents used to treat anemia caused by chemotherapy. Dr. Fadlo Khuri discusses the long-standing debate about whether erythropoietins pose risks in patients with cancer. James Doroshow discusses the use of erythropoiesis-stimulating agents (ESAs) to treat anemia associated with cancer chemotherapy and the new studies suggesting an association between ESAs and an increased risk of tumor growth. Dr. Doroshow is a medical oncologist and the director of the Division of Cancer Treatment and Diagnosis at the National Cancer Institute, Bethesda, Maryland.

Novel Erythropoietic Agents: A Threat to Sportsmanship

Jelkmann W. Novel erythropoietic agents: a threat to sportsmanship. Med Sport 2007; 11(2): 32-42. The mass of hemoglobin (Hb) is an important determinant of aerobic power. Red blood cell production is stimulated by the glycoprotein erythropoietin (EPO). Recombinant human EPO (rHuEPO) engineered in Chinese hamster ovary (CHO) cell cultures (Epoetin alfa and Epoetin beta) and its hyperglycosylated analogue Darbepoetin alfa are known to be misused by athletes. The drugs can be detected in urine by isoelectric focusing, because the pattern of their glycans differs from that of endogenous EPO. However, doping control is becoming much more difficult, as various novel erythropoiesis stimulating agents (ESAs) are - or are to come - on the market. Gene-activated EPO (Epoetin delta) from human fibrosarcoma cells (HT-1080) has been approved in the European Union. rHuEPO (Epoetin omega) produced in transformed baby hamster kidney (BHK) cells is also available. ESAs to come include Biosimilars of the established Epoetins, long-acting pegylated Epoetin beta (CERA), EPO fusion proteins, synthetic erythropoiesis stimulating protein (SEP) and peptidic (Hematide) as well as non-peptidic EPO mimetics. Furthermore, small orally active drugs that are capable of stimulating endogenous EPO production are in preclinical or clinical trials. These include stabilizers of the hypoxia-inducible transcription factors (HIF) that bind to the EPO gene enhancer and GATA inhibitors which prevent GATA from suppressing the EPO gene promoter. It is crucial to inform the athletes and their supporting staff on the potential health risks.