Conflict of Interests
• Advisory board: Janssen Pharmaceutical Compagnies; Vifor
Pharma; Takeda Pharmaceuticals
• Speaker board: Janssen Pharmaceutical Compagnies
Anemia in Cancer
Definition
• Anemia
= Condition in which the number of red blood cells or their oxygen-carrying
capacity is insufficient to meet physiologic needs (WHO)
• Varies by age, sex, altitude, smoking, pregnancy status
http://www.who.int/topics/anaemia/en/; http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
Hb: hemoglobin; LLN: lower level of normal
Anemia in Cancer
Definition
• Anemia
= Condition in which the number of red blood cells or their oxygen-carrying
capacity is insufficient to meet physiologic needs (WHO)
• Varies by age, sex, altitude, smoking, pregnancy status
• = Disorder characterized by a reduction in the amount of hemoglobin in 100
ml of blood (NCI-CTCAE)
http://www.who.int/topics/anaemia/en/; http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
Grade
1 2 3 4 5
Anemia Hb < LLN-10.0
g/dL
Hb < 10-8.0
g/dL
Hb< 8.0 g/dL
+ transfusion
needed
Life-threatening
consequences; urgent
intervention indicated
Death
Hb: hemoglobin; LLN: lower level of normal
Anemia in Cancer
Production of Red Blood Cells
Koury et al.Hematology Am Soc Hematol Educ Program 2012
HSC: hematopoietic stem cells; CMPs: common myeloid progenitors; BFU-Es: burst-forming unit-erythroid; CFU-E: Colony-forming
units-erythroid; Pro-EB: proerythroblast; Ortho-EB: orthochromatic erythroblast; Baso-EB: basophilic erythroblast; Poly-EB:
polychromatophilic erythroblast
Anemia in Cancer
Production of Red Blood Cells
• Regulated by
– Erythropoietin
– Hepcidin
Koury et al.Hematology Am Soc Hematol Educ Program 2012; Naka et al. Int J Hematol. 2011
Anemia in Cancer
Production of Red Blood Cells
• Regulated by
– Erythropoietin
– Hepcidin
• Dependent on
– Vitamin B12 supply
– Folic acid supply
– Iron supply
– DNA repair
• Reactive oxygen species
• DNA damage responses
Koury et al.Hematology Am Soc Hematol Educ Program 2012; Naka et al. Int J Hematol. 2011
Anemia in Cancer
Production of Red Blood Cells
• Erythropoietin (EPO)
– = Glycoprotein hormone
– Stimulates Colony Forming Units-erythroid to divide 3-5 times generating 8–64
erythroblasts within 7-8 days after activation by EPO
Jelkmann. Transfus Med Hemother 2013; Koury et al.Hematology Am Soc Hematol Educ Program 2012; Koulnis et al. PLoS One 2011;
http://en.wikipedia.org/wiki/File:TruncatedEpoReceptors.png
F’ =Fas expressing
Anemia in Cancer
Production of Red Blood Cells
• Erythropoietin (EPO)
– = Glycoprotein hormone
– Stimulates Colony Forming Units-erythroid to divide 3-5 times generating 8–64
erythroblasts within 7-8 days after activation by EPO
– Inhibits Fas-mediated apoptosis of erythroblasts
• Down-modulation of Fas and Fas Ligand
Jelkmann. Transfus Med Hemother 2013; Koury et al.Hematology Am Soc Hematol Educ Program 2012; Koulnis et al. PLoS One 2011;
http://en.wikipedia.org/wiki/File:TruncatedEpoReceptors.png
F’ =Fas expressing
Anemia in Cancer
Production of Red Blood Cells
• Erythropoietin (EPO)
– Produced by
• Kidney
• Hepatocytes
Haase. Blood Rev 2013
Anemia in Cancer
Production of Red Blood Cells
• Erythropoietin (EPO)
– Produced by
• Kidney
• Hepatocytes
– Regulated by Hypoxia Inducible Factor (HIF-2)
Haase. Blood Rev 2013
Anemia in Cancer
Production of Red Blood Cells
• Hepcidin
– = Peptide hormone
– = Regulator of iron homeostasis
• Inhibitor of ferroportin
– Protein present in enterocytes and macrophages
– Transports iron out of cells and into storage pools
http://medical-dictionary.thefreedictionary.com/Hepcidin: Haase. Blood Rev 2013
Anemia in Cancer
Production of Red Blood Cells
• Hepcidin
– Produced by hepatocytes
– Regulated by
Fleming et al. N Eng J Med 2012
GDF-15: growth differentiation factor 15; TWSG1: twisted gastrulation protein homolog 1; BMP-6: bone morphogenetic protein
6; HFE: hemochromatosis protein; BMPR: bone morphogenetic protein receptor; HAMP: hepcidin gene; JAK-STAT Janus-
associated kinase–signal transducers and activators of transcription
Anemia in Cancer
Causes: Increased Loss of Erythrocytes
• Primary tumor-related loss
– Lesions leading to bleeding (e.g. epithelial lesions in gastro-
intestinal (3% IDA at diagnosis), genitourinary, respiratory
tract)
• Diagnosis-related loss
– Excessive phlebotomy
– Bleeding complications of diagnostic punctures
• Treatment-related loss
– Surgery
– Treatment-induced mucositis
– Treatment-induced pancytopenia with bleeding complications
– Immune deficiency with infectious complications
Anemia in Cancer
Causes: Increased Loss of Erythrocytes
• Hemolysis
– Glucose-6-phosphate dehydrogenase deficiency
• Increased oxidative stress from drugs (chemotherapy), infections or toxins
– Autoimmune hemolytic anemia
• Warm antibody-mediated disease
• Cold agglutinin disease
– Infections
– Micro-angiopathic disorders
• Thrombotic thrombocytopenic purpura
• Hemolytic uremic syndrome
– Chemotherapy-induced erythrocyte destruction (Positive Anti-C3)
• Fluorouracil, melphalan
http://www.fpnotebook.com/legacy/HemeOnc/Pharm/DrgIndcdHmlytcAnm.htm
Anemia in Cancer
Causes: Decreased Production of Erythrocytes
• Nutritional deficiencies
– Folic acid, vitamin B12, iron
• Depressed bone marrow function
– Insufficient stimulation (e.g. (relative) lack of erythropoietin)
– Invasion by cancer cells
– Treatment-related decrease in bone marrow function
• Chemotherapy
• Radiotherapy
• Anemia of chronic disease
• Anemia of chronic disease: interference with erythropoiesis
Anemia in Cancer
Causes: Decreased Production of Erythrocytes
BFU-E: burst-forming unit-erythroid; CFU-E:Colony-forming units-erythroid; EB: erythroblasts; Ret: reticulocytes; EPO: erythropoietin;
IL-1: interleukin-1; TNF-α: tumor necrosis factor; INF: interferon
Tumor cell CFU-EBFU-E
EB Ret
Macrophage
Aapro et al. Ann Oncol 2012
• Anemia of chronic disease: interference with erythropoiesis
Anemia in Cancer
Causes: Decreased Production of Erythrocytes
BFU-E: burst-forming unit-erythroid; CFU-E:Colony-forming units-erythroid; EB: erythroblasts; Ret: reticulocytes; EPO: erythropoietin;
IL-1: interleukin-1; TNF-α: tumor necrosis factor; INF: interferon
Tumor cell
IL-1
Decreased production EPO
CFU-EBFU-E
EB Ret
Macrophage
Kidney
Decreased maturation
Aapro et al. Ann Oncol 2012
• Anemia of chronic disease: interference with erythropoiesis
Anemia in Cancer
Causes: Decreased Production of Erythrocytes
BFU-E: burst-forming unit-erythroid; CFU-E:Colony-forming units-erythroid; EB: erythroblasts; Ret: reticulocytes; EPO: erythropoietin;
IL-1: interleukin-1; TNF-α: tumor necrosis factor; INF: interferon
Tumor cell
IL-1
Decreased production EPO
CFU-EBFU-E
EB Ret
Macrophage
Kidney
Decreased maturation
INF
Aapro et al. Ann Oncol 2012
• Anemia of chronic disease: interference with erythropoiesis
Anemia in Cancer
Causes: Decreased Production of Erythrocytes
BFU-E: burst-forming unit-erythroid; CFU-E:Colony-forming units-erythroid; EB: erythroblasts; Ret: reticulocytes; EPO: erythropoietin;
IL-1: interleukin-1; TNF-α: tumor necrosis factor; INF: interferon
Tumor cell
TNF-α
Increased apoptosis
IL-1
Decreased production EPO
CFU-EBFU-E
EB Ret
Macrophage
Kidney
Decreased maturation
INF
Aapro et al. Ann Oncol 2012
• Anemia of chronic disease: interference with iron metabolism
Anemia in Cancer
Causes: Decreased Production of Erythrocytes
Tumor cell CFU-EBFU-E
EB Ret
Macrophage
Liver
IL-6
Bowel
Hepcidin
Decreased iron
absorption
BFU-E: burst-forming unit-erythroid; CFU-E:Colony-forming units-erythroid; EB: erythroblasts; Ret: reticulocytes; EPO: erythropoietin;
IL-6: interleukin-6
Aapro et al. Ann Oncol 2012
• Anemia of chronic disease: interference with iron metabolism
Anemia in Cancer
Causes: Decreased Production of Erythrocytes
Tumor cell CFU-EBFU-E
EB Ret
Macrophage
Liver
IL-6
Bowel
Hepcidin
Decreased iron
absorption
Decreased
iron release
BFU-E: burst-forming unit-erythroid; CFU-E:Colony-forming units-erythroid; EB: erythroblasts; Ret: reticulocytes; EPO: erythropoietin;
IL-6: interleukin-6
Reticulo-endothelial
system
Aapro et al. Ann Oncol 2012
Anemia in Cancer
Epidemiology
• Prevalence
Ludwig et al. Eur J Cancer 2004
European Cancer Anemia
Survey (ECAS)
(01.2001- 02.2002)
N = 14.912
1,3%8,7%
29,3%
61.7%
> 12 g/dL 10.0 - 11.9 g/dL
8.0 - 9.9 g/dL < 8.0 g/dL
Anemia in Cancer
Epidemiology
• Prevalence according to tumor type
Groopman et al. J Natl Cancer Inst 1999
37.539.5
43.9
40.041.1
25.9
39.5
16.3
8.4
14.1 14.0
4.9
8.3
12.4
0
5
10
15
20
25
30
35
40
45
50
Lung Metastatic breast Advanced
ovarian
Lymphomas Advanced
colorectal
Advanced head
and neckTotal
Anemia Grade 1 or 2
Anemia Grade 3 or 4
Pa
tie
nts
(%
)
Anemia in Cancer
Epidemiology
• Prevalence according to time point in disease history
Hamilton et al. Fam Pract 2004; de Castro et al. Clin Transl Oncol, 2014; Dicato et al. Ann Oncol 2010; Ghosh et al. Natl Med J India. 2013; Nelson et al. Cancer Res 1963; Lim et al. World J Gastroenterol 2012
Cancer Time pointAnemia
(%)Type (%)
Colorectal Diagnosis 11–57 IDA
All types Diagnosis 38.6 IDA (31.8), FID (27.2 )
Lymphoma Diagnosis 42.4IDA (39.1), FID (71.7), Vit B12 + folate
deficiency (21.7); AHA (10.9)*
Gastric Gastrectomy 40 Vit B12 deficiency
Gastric Gastrectomy 37.1 IDA
All types During chemotherapy 20-100 CIA
*: Indian population; IDA: iron deficiency anemia; FID: functional iron deficiency; vit: vitamin; AHA:autoimmune hemolytic
anemia: CIA: chemotherapy-induced anemia
Anemia in Cancer
Epidemiology• Treatment-related anemia
Dicato et al. Ann Oncol 2010
Cancer Agent/regimen Grade1-2 (%) Grade3-4(%)
Breast Paclitaxel 93 7
Breast Vinorelbine 67–71 5–14
Breast Paclitaxel + daunorubicin 78–84 8–11
Head and neck Cisplatin – 11
Head and neck 5-FU – 11
Head and neck 5-FU + carboplatin 42 14
Non-Hodgkin lymphoma CHOP 49 17
Non-small cell lung cancer Docetaxel 73–85 2–10
Non-small cell lung cancer Paclitaxel + carboplatin 10–59 5–34
Ovarian Cisplatin + cyclophosphamide 43 9
Small cell lung cancer Topotecan – 32
Small cell lung cancer Cisplatin + etoposide 59 16–55
Small cell lung cancer VIP – 52