Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

Bohlius, Julia; Schmidlin, Kurt; Brillant, Corinne; Schwarzer, Guido; Trelle, Sven; Seidenfeld, Jerome; Zwahlen, Marcel; Clarke, Michael; Weingart, Olaf; Kluge, Sabine; Piper, Margaret; Rades, Dirk; Steensma, David P.; Djulbegoviĉ, Benjamin; Fey, Martin F.; Ray‐Coquard, Isabelle; Machtay, Mitchell; Moebus, Volker; Thomas, Gillian; Untch, Michael; Schumacher, Martin; Egger, Matthias; Engert, Andreas

doi:10.1016/s0140-6736(09)60502-x

Cited by 543 publications

(377 citation statements)

References 66 publications

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“…Nevertheless, this treatment addresses only the symptoms, not the cause of the anemia. Furthermore, EPO can provoke cardiovascular and thrombo-embolic side effects, as well as possible tumor progression [21][22][23][24]. Indeed, cancer cells in many tumor types express the Erythropoietin receptor (EPOR) [25], and the interaction between Erythropoietin and the EPOR can activate the expression of genes implicated in angiogenesis -5 -hematopoietic cells independently from Erythropoietin deficiency.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Grigorakaki

Morceau

Chateauvieux

et al. 2011

Biochemical Pharmacology

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Many physiological perturbations can cause anemia. In cancer patients, activation of the immune system leads to the production of proinflammatory cytokines including tumor necrosis factor alpha (TNF), that have been shown to inhibit red-cell production via poorly understood mechanisms. Treatment of anemia by human recombinant erythropoietin (EPO) is strongly suspected to induce tumor growth.This study focuses on the mechanisms involved in TNF-mediated inhibition of erythropoiesis. CD34 + hematopoietic stem/progenitor cells (HSPC) were isolated from human cord blood. Erythropoiesis was achieved in vitro by stimulating cells with EPO. We show that TNF clearly affected erythroid development, as assessed by May-Grünwald/Giemsa staining, flow cytometry analysis and fluorescent microscopy. The amount of hemoglobinproducing cells as well as the expression of GATA-1 target erythro-specific genes (EPO receptor, glycophorin A and globins) was found decreased after TNF treatment of HSPC. In correlation, TNF induced the expression of the transcription factors GATA-2 and PU.1, described as inhibitors of erythropoiesis. In this regard, TNF promoted the formation of the GATA-1/PU.1 complex that has been reported to block the transcriptional activity of GATA-1. Our results clearly demonstrate that TNF prevents EPO-mediated erythropoiesis of HSPC as an early event, by directly affecting erythroid cell development.Keywords: anemia; inflammation; TNF; GATA-1; GATA-2; PU.1Page 3 of 38 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 -3 - IntroductionThe majority of tumors are largely infiltrated by inflammatory cells, such as myelomonocytes and macrophages [1]. In response to the inflammatory environment, these cells produce inflammatory mediators including chemokines and cytokines. These mediators are tightly associated with cancer progression in combination with genetic alterations [2]. One of them, the Tumor Necrosis Factor alpha (TNF), is widely found in the inflammationassociated cancer microenvironment [3][4][5][6]. Interestingly, because TNF is commonly present in cancer and inflammatory diseases, it has been implicated in cancer-and inflammationrelated anemia. Indeed, patients suffering from cancer and chronic inflammation are often anemic [7]. Moreover, in vitro and in vivo studies have led to the conclusion that TNF inhibits hematopoietic progenitors from undergoing erythroid differentiation [8][9][10][11][12][13][14][15]. Anti-TNF treatment is effectively used for the treatment of chronic inflammatory diseases, but leads to increased risk of infection [16,17]. Despite the beneficial effects of anti-TNF, this treatment may promote different types of cancers [18,19].Several events may trigger anemia, including iron deficiency, hemolysis and hemorrhage. In non-hematopo...

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Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Grigorakaki

Morceau

Chateauvieux

et al. 2011

Biochemical Pharmacology

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“…However, it may be difficult to conduct additional studies of optimal EA dosing and schedule, given evolution of concerns about ESA safety in CAA and other oncology treatment indications in the last 10 years [28][29][30][31][32] The study was originally designed to aid in the development of a larger registration trial of extended ESA dosing, but due to changes in the ESA landscape during the course of the study, the study was discontinued and the follow-up study will not be pursued. In view of these results, the FDA-approved schedules testedweekly EA 40,000 Units, and every 3 week DA 500 mcg-are reasonable standards for CAA therapy.…”

Section: Discussionmentioning

confidence: 99%

A randomized comparison of once weekly epoetin alfa to extended schedule epoetin or darbepoetin in chemotherapy‐associated anemia

et al. 2015

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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 with cancer chemotherapy‐associated anemia (CAA). Extended‐interval ESA dosing (administration less than once weekly) is common with DA, but previous studies suggested that EA might also be administered less often than weekly. In this multicenter prospective trial, 239 CAA patients with Hb <10.5 g/dL were randomized to receive EA 40,000 U subcutaneously once weekly (“40K” arm), EA 80,000 U every 3 weeks (“80K”), EA 120,000 U every 3 weeks (“120K” arm), or DA 500 mcg every 3 weeks (“DA”), for 15 weeks. The primary endpoint was the proportion of patients achieving Hb ≥ 11.5 g/dL or increment of Hb > 2.0 g/dL from baseline without transfusion. Secondary endpoints included transfusion requirements, adverse events (AEs), and patient‐reported outcomes (PROs). There were no significant differences between treatment arms in the proportion of patients achieving Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; P > 0.41 for all comparisons) or requiring RBC transfusion, but the median Hb increment from baseline was higher in the 40K and DA arms compared to the two extended dosing EA arms, and Hb response was achieved soonest in the weekly EA arm. There were no differences in PROs or AEs. The FDA‐approved schedules tested—weekly EA 40,000 U, and every 3 week DA 500 mcg—are reasonable standards for CAA therapy. Am. J. Hematol. 90:877–881, 2015. © 2015 Wiley Periodicals, Inc.

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“…A recent Cochrane meta-analysis has shown an increase of venous thrombotic event (VTE) and mortality [1]. This study, however, including outside-of-the-label studies and 20% of the weight of the negative result is due to one single study in which ESA was given with the intent to reach a supernormal Hb level.…”

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confidence: 94%

“…The main unfavourable side effects were venous thrombo-embolic events and an increase in mortality [1].…”

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confidence: 99%

Erythropoiesis-stimulating agents: the present situation

Dicato

2011

Clin Transl Oncol

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Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

Cited by 543 publications

References 66 publications

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

A randomized comparison of once weekly epoetin alfa to extended schedule epoetin or darbepoetin in chemotherapy‐associated anemia

Erythropoiesis-stimulating agents: the present situation

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