Hepcidin and multiple myeloma related anemia

Cucuianu, Andrei; Patiu, Mariana; Rusu, Anca

doi:10.1016/j.mehy.2005.08.041

Cited by 12 publications

(7 citation statements)

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“…It has been reported that increased IL6 upregulates hepcidin production, which binds and downregulates its cellular receptor, ferroportin, causing iron sequestration leading to anemia (24). Associations between hepcidin, ferritin, and soluble transferrin receptors have been observed in patients with chronic kidney disease (25).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease

Casper

Chaturvedi

Munshi

et al. 2015

Clinical Cancer Research

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Purpose: Siltuximab (IL6 antibody) is approved for the treatment of multicentric Castleman disease (MCD). Effects of IL6 inhibition on the inflammatory milieu accompanying MCD have not been characterized.Experimental Design: Trends in inflammatory-and anemiaassociated markers, measured over the course of a placebo-controlled study of siltuximab (11 mg/kg q3w) in patients with MCD (n ¼ 79), were characterized.Results: Baseline IL6 and C-reactive protein (CRP) levels were significantly correlated (r ¼ 0.708; P < 0.0001). CRP levels decreased (median, 92%) by cycle 1 day 8 (C1D8), remaining suppressed during siltuximab treatment while remaining stable in the placebo group. There were no associations between baseline CRP or IL6 and MCD symptom burden, histologic subtype, ethnicity, maximum CRP decrease, and response parameters. A hemoglobin response (change ! 15 g/L at week 13) was observed with siltuximab (61%; P ¼ 0.0002). Median hepcidin decrease from baseline at C1D8 with siltuximab was 47% versus median 11% increase with placebo. Maximum post-baseline changes in hepcidin levels among siltuximab recipients were correlated with maximum changes for hemoglobin (r ¼ À0.395; P ¼ 0.00607), total ironbinding capacity (TIBC; r ¼ À0.354; P ¼ 0.01694), and ferritin (r ¼ 0.599; P ¼ 0.0001). Greater median changes from baseline in ferritin, hemoglobin, and TIBC were observed in anemic siltuximab-treated patients.Conclusions: IL6 neutralization with siltuximab resulted in sustained CRP suppression and improvement of anemia, in part, by hepcidin pathway inhibition.

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Section: Introductionmentioning

confidence: 99%

Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease

Casper

Chaturvedi

Munshi

et al. 2015

Clinical Cancer Research

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“…The anemia is usually normocytic/normochromic, 4 serum-iron levels are normal to low, serum ferritin is high, and hemosiderin is prominent in bone marrow macrophages. 5 This suggests than iron release from reticuloendothelial macrophages is impaired, consistent with anemia of inflammation. 6 The main mediator of anemia of inflammation is the ironregulatory hormone, hepcidin.…”

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confidence: 95%

In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2

Maes

Nemeth

Roodman

et al. 2010

Blood

122

110

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Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MMrelated anemia. Searching for hepcidininducing cytokines in MM, we quantified the stimulation of hepcidin promoterluciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti-IL-6 blocked it with a minority of sera, whereas anti-BMP-4, -6, or -9 antibodies had no effect. BMP-2-immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera. (Blood. 2010;116(18):3635-3644) IntroductionMultiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematologic cancers. 1 The disease is characterized by monoclonal proliferation of plasma cells together with overproduction of a monoclonal antibody, 2 often accompanied by anemia, hypercalcemia, renal insufficiency, or bone lesions. 3 Approximately 97% of MM patients develop anemia during the course of their illness, and 70% are anemic at diagnosis. The anemia is usually normocytic/normochromic, 4 serum-iron levels are normal to low, serum ferritin is high, and hemosiderin is prominent in bone marrow macrophages. 5 This suggests than iron release from reticuloendothelial macrophages is impaired, consistent with anemia of inflammation. 6 The main mediator of anemia of inflammation is the ironregulatory hormone, hepcidin. Hepcidin is produced by hepatocytes and acts on the iron exporter, ferroportin. Binding of hepcidin to ferroportin induces the internalization and degradation of ferroportin, thereby preventing cellular iron efflux and causing retention of iron, mainly inside enterocytes, macrophages, and hepatocytes. 7 Pathologic induction of hepcidin by inflammation causes hypoferremia, restricting the iron supply for erythropoiesis and, eventually, causing anemia. The interleukin-6 (IL-6)-hepcidin axis was shown to be important for inflammation-related hypoferremia. 8 However, in chronic inflammation, IL-6-independent pathways may also induce hepcidin mRNA. 9 Recently, 2 studies described the involvement of hepcidin in anemia of MM in humans. We reported that patients with stage III MM (n ϭ 44) at diagnosis had higher urinar...

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“…This is particularly important since IL-6 levels are no longer reliable per commercial assay after siltuximab has been initiated [38]. IL-6 is known to induce hepcidin, which is an iron regulatory peptide hormone produced by the liver that contributes to hemoglobin homeostasis and may cause anemia of inflammation [47][48][49]. Neutralization of IL-6 with siltuximab has been found to decrease hepcidin and improve anemia, which is believed to occur because sequestered iron is released [19].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Siltuximab: A Targeted Therapy for Idiopathic Multicentric Castleman Disease

Fajgenbaum

Kurzrock²

2015

Immunotherapy

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Human herpes virus-8 (HHV-8)-negative or idiopathic multicentric Castleman disease (iMCD) is a rare and deadly disorder that sits at the nexus of hematology/oncology, virology and immunology. Management of iMCD has been challenging due to limited understanding of etiology and pathogenesis and few treatment options. The recent approvals in North America, Europe and Brazil of siltuximab, a monoclonal antibody against IL-6, for iMCD now provide a safe and effective therapy that targets a key aspect of pathogenesis. In the first ever randomized, placebo-controlled trial in iMCD, siltuximab significantly reduced disease burden and symptoms in a large portion (34%) of patients. The optimal dose is 11 mg/kg intravenously every 3 weeks. At this time, duration of treatment is often life-long or until treatment failure. Additional research is needed to identify biomarkers that may assist with predicting treatment effectiveness in iMCD and to investigate the role of siltuximab in HHV-8-positive MCD and pediatric iMCD patients.

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Hepcidin and multiple myeloma related anemia

Cited by 12 publications

References 11 publications

Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease

Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double-Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease

In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2

Siltuximab: A Targeted Therapy for Idiopathic Multicentric Castleman Disease

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