Experimental Drugs for Chemotherapy- and Cancer-Related Anemia

Figures & data

Figure 1 Pathogenetic mechanisms of cancer-related anemia and main related targeted approaches. The pathogenesis of cancer-related anemia involves multiple mechanisms induced by chronic inflammation associated to cancer and leading to functional iron deficiency and impaired erythropoiesis. Then, a multitargeted approach including conventional treatment such as ESAs, blood transfusion, iron therapy, as well as drugs targeting the inflammatory pathway, modulators of the iron metabolism, hepcidin antagonists, novel regulators of erythropoiesis and nutritional support should be considered. Figure was created in BioRender.com.

Abbreviations: ESAs, erythropoiesis stimulating agents; Hgb, haemoglobin; HIF, hypoxia inducible factor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, Interleukin; ROS, reactive oxygen species; STAT-3, signal transducer and activator of transcription 3.

Figure 2 Pathogenesis of chemotherapy-induced anemia and therapeutic strategies. Chemotherapy-induced anemia is related to the toxic effect of anticancer treatments on bone marrow or to a nephrotoxic effect, which negatively influence EPO production. Additionally, anticancer treatments can induce gastro-enteric side effects, such as anorexia, nausea, and vomiting, and diarrhoea, which lead to iron and vitamins deficiency. Thus, treatment includes ESAs, iron therapy (oral or intravenous iron) and nutritional support. Figure was created in BioRender.com.

Abbreviations: Fe, iron; ESAs, erythropoiesis stimulating agents.

Table 1 Management of Chemotherapy- and Cancer- Related Anemia

	ESAs^a,b,c	Iron Supplementation	Other Supportive Agents	Novel Agents	References
Absolute iron deficiency (ID): Ferritin < 30 ng/mL and TSAT < 20% CRP normal value	ESAs could be used after iron deficiency correction^Citation26	Oral iron supplementation or IV iron formulations (the choice depends on the severity of anemia and gastrointestinal absorption)^Citation26,Citation62,Citation63,Citation96	Nutritional support (folate, vitamins B,C,D, polyphenols, L-carnitine, aminoacids)^Citation156	Oral iron liposomal formulation^Citation161 Third generation IV iron formulations (ie, ferric carboxymaltose)^Citation97,Citation162,Citation163	[^Citation26,Citation62,Citation63,Citation96,Citation97,Citation156,Citation161^–^Citation163]
Possible functional iron deficiency (FID): Ferritin 30–500 ng/mL and TSAT <50% High CRP	ESAs^Citation26,Citation62,Citation63,Citation96	IV iron supplementation; oral iron is not indicated for gastrointestinal malasorbption^Citation26,Citation62,Citation63,Citation96	Anti-inflammatory agents Nutritional support (folate, vitamins B,C,D, polyphenols, L-carnitine, aminoacids)^Citation156	Third generation IV iron formulations (ie, ferric carboxymaltose)^Citation97,Citation162,Citation163	[^Citation26,Citation62,Citation63,Citation96,Citation97,Citation156,Citation162,Citation163]
Functional iron deficiency (FID): Ferritin >500–800 ng/mL and TSAT <50% High CRP	ESAs^Citation26,Citation62,Citation63,Citation96	Supplementation with iron mobilizing agents such as lactoferrin should be preferred to IV iron^Citation101,Citation110	Anti-inflammatory agents Nutritional support (folate, vitamins B,C,D, polyphenols, L-carnitine, aminoacids)^Citation156	Hepcidin antagonists^Citation114	[^Citation26,Citation62,Citation63,Citation96,Citation101,Citation110,Citation114,Citation156]
Iron overload: Ferritin > 800 ng/mL and TSAT >50% High CRP	ESAs^Citation26,Citation62,Citation63,Citation96	Supplementation with iron mobilizing agents^Citation101,Citation110 Oral or IV Iron supplementation is not indicated^Citation26	Anti-inflammatory agents Nutritional support (folate, vitamins B,C,D, polyphenols, L-carnitine, aminoacids)^Citation156	Hepcidin antagonist^Citation114	[^Citation26,Citation62,Citation63,Citation96,Citation101,Citation110,Citation114,Citation156]

Notes: ^aESAs are indicated only patients undergoing myelosuppressive treatment with palliative intent when Hb<10 g/dl.^26,62,63,96 bESAs could be used in presence of chronic kidney disease (moderate to severe) independently from concomitant chemotherapy according to specific guidelines.²⁶ cIn every category red blood cell transfusion may be indicated when Hb levels are <7–8 g/dl; it may be an option even at higher Hb levels (Hb <10 g/dl) depending on anemia-related symptoms and performance status, the severity of anemia and rate of Hb decline, and individual risk factors such as comorbidities (ie, bleeding, surgery, cardiovascular and ischemic disease).^26,62,63 References are indicated by superscript near to each statement and also in the last column.

Abbreviations: ESAs, erythropoiesis-stimulating agents; ID, iron deficiency; TSAT, transferrin saturation; CRP, C-reactive protein; IV, intravenous; FID, functional iron deficiency.

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