pathophysiology and incidence of anaemia in cancer...

Pathophysiology and Epidemiology

of Anemia in Cancer Patients

D. Schrijvers

MD, PhD

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

http://www.who.int/topics/anaemia/en/

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

http://www.who.int/topics/anaemia/en/

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

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• Regulated by

– Erythropoietin

– Hepcidin

Koury et al.Hematology Am Soc Hematol Educ Program 2012; Naka et al. Int J Hematol. 2011

Anemia in Cancer


• 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


• 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



– = 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



– Produced by

• Kidney

• Hepatocytes

Haase. Blood Rev 2013

Anemia in Cancer



– Produced by

• Kidney

• Hepatocytes

– Regulated by Hypoxia Inducible Factor (HIF-2)

Haase. Blood Rev 2013

Anemia in Cancer


• 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


• 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


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 in Cancer




Tumor cell

IL-1

Decreased production EPO

CFU-EBFU-E

EB Ret

Macrophage

Kidney

Decreased maturation



Anemia in Cancer




Tumor cell

IL-1


CFU-EBFU-E

EB Ret

Macrophage

Kidney


INF



Anemia in Cancer




Tumor cell

TNF-α

Increased apoptosis

IL-1


CFU-EBFU-E

EB Ret

Macrophage

Kidney


INF


• Anemia of chronic disease: interference with iron metabolism

Anemia in Cancer



EB Ret

Macrophage

Liver

IL-6

Bowel

Hepcidin

Decreased iron

absorption


IL-6: interleukin-6


• Anemia of chronic disease: interference with iron metabolism

Anemia in Cancer



EB Ret

Macrophage

Liver

IL-6

Bowel

Hepcidin

Decreased iron

absorption

Decreased

iron release


IL-6: interleukin-6

Reticulo-endothelial

system


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

Anemia in Cancer

Conclusions

• Different causes and mechanisms are contributing to the

development of anemia in cancer

• Erythropoietin and hepcidin play a major role in anemia of chronic

disease

• Anemia is prevalent in patients with cancer

pathophysiology and incidence of anaemia in cancer...

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