anemia of chronic disease and erythropoietin hanna rosenbaum hematology and bone marrow...
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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
*
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
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)
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
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
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
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
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
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.
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Pure Red Cell Aplasia
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.
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced Anemia
Anemia in Cancer Patients Iron Deficiency Anemia
Anemia of Chronic Disease
Bone Marrow Involvement
Pure Red Cell Aplasia
Megaloglastic Anemia (B12, Folate def.)
Anemia of Renal Failure
Microangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy-induced 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