The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents

Mhaskar, Rahul; Wao, Hesborn; Miladinovic, Branko; Kumar, Ambuj; Djulbegovic, Benjamin

doi:10.1002/14651858.cd009624.pub2

Cited by 35 publications

References 69 publications

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“…The primary literature review included 15 meta-analyses of RCTs 1,2,13-25 and two RCTs. 6,26 Three meta-analyses 15,20,22 addressed the addition of iron to an ESA. The remaining 12 meta-analyses 1,2,13,14,[16][17][18][19]21,[23][24][25] addressed ESA versus control (placebo or best standard therapy).…”

Section: Resultsmentioning

confidence: 99%

“…The use of supplemental iron with an ESA was evaluated in three metaanalyses. 15,20,22 Compared with an ESA alone, a 2016 Cochrane review by Mhaskar et al 20 reported that the combination of an ESA and iron increased the likelihood of hematopoietic response (RR, 1.17; 95% CI, 1.09 to 1.26) and reduced the likelihood of RBC transfusion (RR, 0.74; 95% CI, 0.60 to 0.92) without significantly affecting risk of thromboembolism (RR, 0.95; 95% CI, 0.54 to 1.65) or quality of life (standardized mean difference, 0.01; 95% CI, 20.10 to 0.12). Intravenous (IV) iron provided a greater benefit than oral iron with respect to mean change in HgB level (IV iron mean difference, 0.84; 95% CI, 0.21 to 1.46; P = .009; oral iron mean difference, 0.07; 95% CI, 20.19 to 0.34; P = .59; P = .03 for interaction).…”

Section: Recommendation 10mentioning

confidence: 99%

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

Bohlius

Bohlke

Castelli

et al. 2019

JCO

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PURPOSE 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. METHODS 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. RESULTS 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. RECOMMENDATIONS 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 .

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Section: Resultsmentioning

confidence: 99%

Section: Recommendation 10mentioning

confidence: 99%

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

Bohlius

Bohlke

Castelli

et al. 2019

JCO

Self Cite

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“…Moreover, inhibition of eryptosis may counteract anemia, a common clinical disorder of malignancy and its treatment [111][112][113][114][115][116][117][118][119]. Anemia in malignancy is at least in part due to eryptosis, which is triggered by both, the disease and by cytostatic treatment [13, 15, 44, 47, 50, 53-55, 62, 65, 74, 76, 88, 111, 120-128].…”

Section: Discussionmentioning

confidence: 99%

“…Anemia in malignancy is at least in part due to eryptosis, which is triggered by both, the disease and by cytostatic treatment [13, 15, 44, 47, 50, 53-55, 62, 65, 74, 76, 88, 111, 120-128]. Anemia correlates with unfavourable outcome [112,113,[129][130][131][132] and drugs are thus needed which counteract tumor growth and by the same token inhibit eryptosis. Despite its inhibitory effect on eryptosis, sonidegib causes,…”

Section: Discussionmentioning

confidence: 99%

Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death

Bhuyan¹,

Sahu²,

Cao³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The Hedgehog pathway disrupting drug sonidegib is used in the treatment of basal cell carcinoma. Side effects of sonidegib include anemia, which could result either from impaired erythropoiesis or from loss of erythrocytes e.g. due to suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling with phosphatidylserine translocation to the cell surface and by cell shrinkage. Eryptosis is stimulated by cell stress, including energy depletion, hyperosmotic shock, oxidative stress and excessive increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i). The present study explored, whether sonidegib exerts an effect on eryptosis. Methods: Human erythrocytes have been treated with energy depletion (glucose withdrawal for 48 hours), hyperosmotic shock (addition of 550 mM sucrose for 6 hours), oxidative stress (addition of 0.3 mM tert-butylhydroperoxide [tBOOH] for 50 min) or Ca²⁺ ionophore ionomycin (1 µM for 60 min) in absence and presence of sonidegib (2-6 µg/ ml). After treatment flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, and cell volume from forward scatter. Hemolysis was estimated from the hemoglobin concentration in the supernatant. Results: In the absence of cell stress exposure to sonidegib did not significantly modify annexin-V-binding or forward scatter, but triggered hemolysis. Energy depletion, hyperosmotic shock, oxidative stress and ionomycin, all markedly and significantly increased the percentage of annexin-V-binding erythrocytes, and decreased the forward scatter. Sonidegib significantly blunted the effect of energy depletion, hyperosmotic shock, and oxidative stress, but not of ionomycin on annexin-V-binding. Sonidegib further significantly blunted the effect of energy depletion, but not of hyperosmotic shock, oxidative stress, and ionomycin on forward scatter. Conclusions: Sonidegib is a novel inhibitor of erythrocyte cell membrane scrambling following energy depletion, hyperosmotic shock and oxidative stress.

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“…[77][78][79][80][81][82][83][84][85] The anemia is compounded by chemotherapy. 78,79,[86][87][88][89] Attempts to treat the anemia of malignancy by erythropoiesis-stimulating agents were associated with reduced patient survival time presumably because of stimulation of tumour growth and thrombosis. 79,[84][85][86] The present brief review discusses the compelling evidence that anemia of malignancy and chemotherapy results from stimulation of eryptosis, and may be avoided by xenobiotics counteracting eryptosis.…”

Section: Introductionmentioning

confidence: 99%

Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor-associated anemia

et al. 2017

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In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis characterized by cell shrinkage and cell membrane scrambling. Eryptotic erythrocytes are rapidly cleared from circulating blood and may adhere to the vascular wall. Stimulation of eryptosis thus impairs microcirculation and leads to anemia as soon as the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis. Signaling stimulating eryptosis includes increase of cytosolic Ca -activity, ceramide, caspases, calpain, p38-kinase, protein-kinase C, Janus-activated kinase 3, casein-kinase 1α, and cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein-kinase, mitogen- and stress-activated kinase, and sorafenib- and sunitinib-sensitive tyrosine-kinases. Eryptosis is triggered by complement, hyperosmotic shock, energy-depletion, oxidative stress, multiple xenobiotics including diverse cytostatic drugs, diabetes, hepatic failure, iron-deficiency, chronic kidney disease, hemolytic-uremic-syndrome, fever, systemic lupus erythematosus, infections, sepsis, sickle cell anemia, thalassemia, glucose-6-phosphate-dehydrogenase deficiency, and Wilson´s disease. Compelling evidence points to a decisive role of eryptosis in anemia of malignancy. As shown for lung cancer, eryptosis inducing plasma components accumulate in cancer patients and trigger oxidative stress and ceramide. The tumor-induced eryptosis leads to anemia despite increased erythropoiesis. The stimulation of eryptosis in malignancy is compounded by cytostatic treatment, as a large number of cytostatic agents trigger eryptosis. Inhibiting eryptosis may be a useful strategy in reducing tumor-induced anemia and impaired microcirculation. Inhibitors of eryptosis may, however, be harmful, if they similarly interfere with death of tumor cells. Clearly, additional experimental effort is required to achieve killing of tumor cells with simultaneous avoidance of stimulated eryptosis.

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The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents

Cited by 35 publications

References 69 publications

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

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

Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death

Suicidal death of erythrocytes in cancer and its chemotherapy: A potential target in the treatment of tumor-associated anemia

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