Anemia of chronic disease and Erythropoietin Hanna Rosenbaum Hematology and Bone marrow transplantation department

Anemia of chronic disease and Erythropoietin

Hanna Rosenbaum

Hematology and Bone marrow transplantation department

Anemia

Definition : Decreased RBC mass and HB concentrationAnemia is a result of imbalance between between RBC production and destruction Hypo-regenerative anemia is due to decreased RBC production secondary to impaired marrow function or lack of erythropoietin stimulusHyper- regenerative anemia is due to increased peripheral RBC destruction

Mechanisms of Anemia

Production Disorders: Factor Deficiency (RBC Size) -Iron, Vit. B12, Folate Hematopoietic Cell DamageSurvival Disorders: Blood Loss Red Blood Cell Destruction (Shape) -Hemolytic Anemias

Anemia of Chronic Disease (ACD)Anemia of Chronic Disease (ACD)

Classical definitionClassical definition Anemia occurring in –Anemia occurring in –

chronic infectious, inflammatory or chronic infectious, inflammatory or neoplastic disordersneoplastic disorders

not due to –not due to –

marrow replacement by tumor, bleeding, marrow replacement by tumor, bleeding, or hemolysisor hemolysis

characterized by –characterized by –

hypoferremia in the presence of hypoferremia in the presence of adequate iron storesadequate iron stores

Means RT Jun, Krantz SB. Blood 1992; 80(7): 1639-1647

Anemia of Chronic Disease

Inflammation, neoplasia

Blunted erythropoietin response

Impaired iron utilization

Bone marrow stores adequate

Low serum iron

Ludwig (1998)

*

Anemia of chronic disease

• Excessive production of cytokines

• Ineffective erythropoiesis

• Interfere with:

– Effect of EPO on bone marrow

– Release of stored iron in

Reticuloendothelial system

Cancer-Related Anemia

• Chemotherapy/radiation therapy

• Anemia of chronic disease

• Blood loss

• Bone marrow infiltration

• Nutritional deficiency

• Hemolysis

*


Ring sideroblast

Erythropoietin Erythropoietin dependencedependence

Hematopoietic stem cellHematopoietic stem cell

††BFUBFU--EE

‡‡CFUCFU--EE

ErythroblastsErythroblasts

ReticulocytesReticulocytes

Major steps of Major steps of erythropoiesiserythropoiesis and and erythropoietin dependenceerythropoietin dependence

† BFU† BFU--E = burstE = burst--forming unitforming unit––erythroid; ‡ CFUerythroid; ‡ CFU--E = colonyE = colony--forming unitforming unit––erythroiderythroidBron, Seville 2000

carbohydrate

protein

protein + carbohydrate = glycoprotein

ERYTHROPOIETINERYTHROPOIETIN

Erythropoietin

• Glycoprotein of 34 kDa

• Produced in kidney and liver; trace amounts in brain

• Stimulates survival and differentiation of erythroid progenitors

Lacombe (1998, 1999); Krantz (1991); Bernaudin (2000)

*

10 201

16040

30

50

60

70

80

90

100

110

120

130

140150

N-linked (3)glycosylation

O-linked (1)glycosylation

Amino acid

SS S

S

Amino Acid Sequenceof Erythropoietin

Erslev (1991); Mulcahy (2001)

*

Erythropoietin Receptor

Cell membrane

Extracellular domain

Intracellular domain

WSXWS motif

Box 1

Two pairs ofcysteines

Mulcahy (2001)

Box 2

*

Erythropoietin Receptor Activation

Erythropoietin Bivalent antibody

Disulfide bond

Erythropoietin mimetic peptides

Mulcahy (2001)

Macrophage

+Epo

-Epo

Epo prevents apoptosis of erythroid progenitors

CFU-E

BiologicalBiological effects of EPOeffects of EPO

ErythropoiesisErythropoiesis

• Controls RBC productionControls RBC production

• Promotes survival, proliferation, Promotes survival, proliferation, and differentiation of erythroid and differentiation of erythroid progenitorsprogenitors

• Exerts effects on late erythroid Exerts effects on late erythroid progenitorsprogenitors

Mulcahy, Seville 2000

Regulation of Erythropoietin

Hypoxia Inflammatory (HIF-1) cytokines

-+Erythropoietin

Ludwig (1998); Lacombe (1999)HIF-1 = hypoxia-induced factor-1

The physiological role of erythropoietin in the healthy adult

Decreased oxygen delivery to the kidneys

Peritubular interstitial cells detect low oxygen levels in the blood

Pro-erythroblasts in red bone marrow mature more quickly into reticulocytes

More reticulocytes enter circulating blood

Larger number of red blood cells (RBC)in circulation

Increased oxygen delivery to tissues

Return to homeostasis when response brings oxygen delivery to kidneys back to normal

EPO

Peritubular interstitial cells secrete erythropoietin (EPO) into the blood

Hb

lev

el (

g/d

L)

Erythropoietin (plasma U)

104103102101

3

12

15

18

6

9

Hillman (1992)

Normal Erythropoietin Productionand Hb Levels

Anemia of Renal Failure

In advanced disease

Toxicity from therapy

Therapy: Erythropoietin

Physiology of Erythropoietin

Recombinant

Erythropoietin

Recombinant Human Erythropoietin – Epoietin (EPO)

A purified glycoprotein that stimulates endogenous erythropoietin.

Gene for human erythropoietin was cloned in 1983 – A LANDMARK DISCOVERY

Produced from mammalian cells into which the gene coding for human EPO has been inserted.

Indistinguishable from human urinary erythropoietin in its biologic activity and immunologic reactivity.

Anemia is Highly Prevalent in Patientswith Cancer

0.5

Pro

bab

ilit

y o

f h

avin

g m

od

erat

e o

r se

vere

an

aem

ia (

Hb

≤10

.5 g

/dl)

00

0.1

0.2

0.3

0.4

122 4 6 8 10

Months after start of chemotherapy

Coiffier et al. Eur J Cancer 2001

Pathogenesis of anemia in cancer

ANAEMIA

(Bone marrow involvement)

Iron distribution defect

Shortened erythrocytesurvival time

Depression of erythropoiesis or EPO production (cytokine-mediated)

Cytotoxic chemotherapy

Haemolysis (NHL)

Renal failure (multiple myeloma)

Pure red cell aplasia(T cell NHL)

Anaemia of Chronic Disease

Anemia in Cancer Patients Iron Deficiency Anemia


Bone Marrow Involvement

Pure Red Cell Aplasia

Megaloglastic Anemia (B12, Folate def.)


Microangiopathic anemia

Autoimmune Hemolytic Anemia

Therapy-induced Anemia

Impact of Anemia in Patients With Cancer

• Fatigue

• Shortness of breath

• Lack of energy to perform daily functions; QOL

• Complicates coexisting disease

• Associated with poor prognosis and increased mortality

• May compromise efficacy and tolerability of treatment

*

Shortenedsurvival

Factors involved in the cause and development of anaemia in cancer patients

Tumour cells

RBCs

Activatedimmune system

MacrophagesTNF

Anaemia

IFN-,IFN-IFN-IL-1 IL-1 IL-1TNF TNF TNF

1-antitrypsin

Reduced Impaired SuppressedEPO iron BFU-e

production utilisation CFU-e

Nowrousian MR. Med Oncol 1998;15(Suppl. 1):S19–28

Erythrophagocytosis

Dyserythropoiesis

TNF = tumour necrosis factor; IFN = interferon; IL-1 = interleukin-1;BFU-e = erythroid burst-forming unit; CFU-e = erythroid colony-forming unit




























BONE MARROW BIOPSY

BONE MARROW ASPIRATE

Bone marrow involvement

Follicular lymphoma

Neuroblastoma

Metastatic Adenocarcinoma

Anemia Due to Marrow Infiltration

Except in hematological malignancies, usually associated with advanced disease.

Breast and prostate Ca are an exception – marrow involvement often with only mild anemia or normal Hb.











In lymphoma, NSCLC, breast and gastric cancer.

Humoral and cellular events suppression of erythropoiesis.

Therapy of underlying cancer response in 30-50%

For others, may need immunosuppressive / cytotoxic therapy.




























Normal peripheral blood smear

Microangiopathic Anemia




















Treatment Options forCancer-Related Anemia

Transfusion

• Used in cases of acute anemia

• Many associated risks

• RECOMBINANT ERYTHROPOIETIN

Harrison (2000)

Types of Transfusion Reactions

Immediate

Hemolytic

Febrile

Non-cardiogenic pulmonary edema

Other allergic

Delayed

Delayed hemolytic

Post-transfusion purpura

Infections

Graft vs host disease

Chronic immunosuppression

0 30 60 90 120 150 180 210

Österborg. Med Oncol 1998;15(Suppl 1):S47–9Ludwig et al. N Engl J Med 1990;322:1693–9

Recombinant erythropoietin effect on hemoglobin level

Hb (g/dL)

Days of treatment

8

12

14

10

4

6

Epoetin

Transfusions

Guideline Recommendations for Anaemia Management in Patients with Cancer

ASCO/ASH Initiate epoetin in patients with Hb ≤10 g/dl (or

Hb >10 to <12 g/dl depending on clinical circumstances)

SC 30 000 IU (150 IU/kg) once weekly; double dose in absence of response (Hb increase <1–2 g/dl) after 4 weeks

Raise Hb to 12 g/dl and maintain; insufficient evidence to support ‘normalisation’ of Hb >12 g/dl

Rizzo et al. J Clin Oncol 2002; 20: 4083–107

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Anemia of chronic disease and Erythropoietin Hanna Rosenbaum Hematology and Bone marrow transplantation department