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

Anemia Definition : Decreased RBC mass and HB concentration Anemia 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 stimulus Hyper- regenerative anemia is due to increased peripheral RBC destruction

Mechanisms of Anemia Production Disorders: w Factor Deficiency (RBC Size) -Iron, Vit. B 12, Folate w Hematopoietic Cell Damage Survival Disorders: w Blood Loss w Red Blood Cell Destruction (Shape) -Hemolytic Anemias

Anemia of Chronic Disease (ACD) Classical definition nAnemia occurring in – chronic infectious, inflammatory or neoplastic disorders nnot due to – marrow replacement by tumor, bleeding, or hemolysis ncharacterized by – hypoferremia in the presence of adequate iron stores Means RT Jun, Krantz SB. Blood 1992; 80(7):

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 *

Anemia of Chronic Disease

Ring sideroblast

carbohydrate protein protein + carbohydrate = glycoproteinERYTHROPOIETIN

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) *

Amino Acid Sequence of Erythropoietin Erslev (1991); Mulcahy (2001) *

Erythropoietin Receptor Cell membrane Extracellular domain Intracellular domain WSXWS motif Box 1 Two pairs of cysteines Mulcahy (2001) Box 2 *

Erythropoietin Receptor Activation ErythropoietinBivalent antibody Disulfide bond Erythropoietin mimetic peptides Mulcahy (2001)

Macrophage +Epo -Epo Epo prevents apoptosis of erythroid progenitors CFU-E

Biological effects of EPO Erythropoiesis Controls RBC production Controls RBC production Promotes survival, proliferation, and differentiation of erythroid progenitors Promotes survival, proliferation, and differentiation of erythroid progenitors Exerts effects on late erythroid progenitors Exerts effects on late erythroid progenitors 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 level (g/dL) Erythropoietin (plasma U) Hillman (1992) Normal Erythropoietin Production and 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 Patients with Cancer 0.5 Probability of having moderate or severe anaemia (Hb ≤10.5 g/dl) 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 erythrocyte survival 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 (B 12, 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 *

Shortened survival Factors involved in the cause and development of anaemia in cancer patients Tumour cells RBCs Activated immune system Macrophages TNF Anaemia IFN- ,  IFN-  IFN-  IL-1IL-1IL-1 TNFTNFTNF  1 -antitrypsin ReducedImpairedSuppressed EPOironBFU-e productionutilisationCFU-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 (B 12, 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 (B 12, 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 (B 12, Folate def.) Anemia of Renal Failure Microangiopathic anemia Autoimmune Hemolytic Anemia Therapy-induced Anemia

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.

Anemia in Cancer Patients Iron Deficiency Anemia Anemia of Chronic Disease Bone Marrow Involvement Pure Red Cell Aplasia Megaloglastic Anemia (B 12, 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 % 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 (B 12, 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 (B 12, 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 (B 12, Folate def.) Anemia of Renal Failure Microangiopathic anemia Autoimmune Hemolytic Anemia Therapy-induced Anemia

Normal peripheral blood smear

Microangiopathic Anemia

Anemia in Cancer Patients Iron Deficiency Anemia Anemia of Chronic Disease Bone Marrow Involvement Pure Red Cell Aplasia Megaloglastic Anemia (B 12, Folate def.) Anemia of Renal Failure Microangiopathic anemia Autoimmune Hemolytic Anemia Therapy-induced Anemia

Autoimmune Hemolytic Anemia

Anemia in Cancer Patients Iron Deficiency Anemia Anemia of Chronic Disease Bone Marrow Involvement Pure Red Cell Aplasia Megaloglastic Anemia (B 12, Folate def.) Anemia of Renal Failure Microangiopathic anemia Autoimmune Hemolytic Anemia Therapy-induced Anemia

Treatment Options for Cancer-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

Österborg. Med Oncol 1998;15(Suppl 1):S47–9 Ludwig et al. N Engl J Med 1990;322:1693–9 Recombinant erythropoietin effect on hemoglobin level Hb (g/dL) Days of treatment 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 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