Laura M.

Aguirre-Aguinaldo,MD,DPPS

1. To briefly review the process of hematopoiesis. 2. To discuss the PK/PD properties of the different hematopoietic agents available. 3. To describe their indications for use. 4. To discuss the adverse effects which are related to the use of these substances. 4. To know specific precautions which should be employed when administering/using these medications if any.

H E M A T O P O I E S I S

ERYTHROPOETIN

Hematopoietic Growth Factors

Together with cytokines, are involved in the regulation and differentiation of the blood cells. They include the following:
Factors regulating specific cell lineage Factors regulating multiple cell lineage Factors indirectly regulating hematopoiesis by inducing gene expression of growth factors and cytokines

Hematopoietic Growth Factors

ERYTHROPOIETIN (EPO) Stimulates proliferation and maturation of committed erythroid progenitors to increase red cell production

STEM CELL FACTOR (SCF, c-kit ligand, Steel factor) and FLT-3 LIGAND (FL) Act synergistically with a wide range of other colony-stimulating factors and interleukins to stimulate pluripotent and committed stem cells FL also stimulates both dendritic and NK cells (anti-tumor response) SCF also stimulates mast cells and melanocytes

Hematopoietic Growth Factors

INTERLEUKINS IL-1, IL-3, IL-5, IL-6, IL-9, and IL-11 Act synergistically with each other and SCF, GM-CSF, G-CSF, and EPO to stimulate BFU-E, CFU-GEMM, CFU-GM, CFU-E, and CFU-Meg growth

Numerous immunologic roles, including stimulation of B cell and T cell growth

IL-5 Controls eosinophil survival and differentiation IL-6 IL-6 stimulates human myeloma cells to proliferate IL-6 and IL-11 stimulate BFU-Meg to increase platelet production

Hematopoietic Growth Factors

INTERLEUKINS IL-1, IL-2, IL-4, IL-7, and IL-12 Stimulate growth and function of T cells, B cells, NK cells, and monocytes Co-stimulate B, T, and LAK cells IL-8 and IL-10 Numerous immunological activities involving B and T cell functions IL-8 acts as a chemotactic factor for basophils and neutrophils

Hematopoietic Growth Factors

GRANULOCYTE-MACROPHAGE COLONY STIMULATING FACTOR (GM-CSF) Acts synergistically with SCF, IL-1, IL-3, and IL-6 to stimulate CFU-GM, and CFUMeg to increase neutrophil and monocyte production With EPO may promote BFU-E formation Enhances migration, phagocytosis, superoxide production, and antibodydependent cell-mediated toxicity of neutrophils, monocytes, and eosinophils Prevents alveolar proteinosis GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) Stimulates CFU-G to increase neutrophil production Enhances phagocytic and cytotoxic activities of neutrophils

Hematopoietic Growth Factors

MONOCYTE/MACROPHAGE COLONY STIMULATING FACTOR (M-CSF, CSF-1) Stimulates CFU-M to increase monocyte precursors Activates and enhances function of monocyte/macrophages MACROPHAGE COLONY STIMULATING FACTOR (M-CSF) Stimulates CFU-M to increase monocyte/macrophage precursors Acts in concert with tissues and other growth factors to determine the proliferation, differentiation, and survival of a range of cells of the mononuclear phagocyte system THROMBOPOIETIN (TPO, Mpl ligand) Stimulates the self-renewal and expansion of hematopoietic stem cells Stimulates stem cell differentiation into megakaryocyte progenitors Selectively stimulates megakaryocytopoiesis to increase platelet production Acts synergistically with other growth factors, especially IL-6 and IL-11

TERMS
Anemia below normal concentration of circulatory hemoglobin or Hct concentration less than 40% in men and 37% in women. Symptoms are due to the reduced Hgb carrying capacity of the RBCs. * pallor, shortness of breath, fatigue, decreased mental alertness, apathy, headaches

TERMS
Two categories of Anemia: Hypoproliferative: bone marrow production of RBC is inadequate; low Rct count Hyperproliferative: high Rct count, increased destruction of RBC despite increased production of the bone marrow

Causes of Anemia
Hypoproliferative
Microcytic anemia: iron deficiency, anemia of chronic dse,sideroblastic anemia Normocytic: anemia of chronic dse, endocrine anemia, bone marrow failure Macrocytic: Vit. B12 deficiency, folic acid deficiency,myelodysplastic syndrome

Hyperproliferative
Hemolytic: Hemoglobinopathies, autoimmune, membrane disorder, drug-induced, metabolic abnormalities, G6PD deficiency, infections

Erythropoiesis Stimulating Agents (ESA)

ESA connotes substances used for stimulation of erythrocyte production Erythropoietin The most important regulator of committed erythrocyte progenitors (CFU-E) Severe anemia is a consequence of its absence ( seen in patients with CRD)

Erythropoiesis Stimulating Agents (ESA)

Erythropoietin and renal disease Recombinant human erythropoietin (epoetin alfa) and blood doping Available preparations of epoetin alfa include EPOGEN, PROCRIT, and EPREX, supplied in single-use vials containing 2000-40,000 units/mL for IV or SC administration.

Erythropoiesis Stimulating Agents (ESA)

When injected IV, epoetin alfa is cleared from plasma with a t1/2 of 4-8 hours. Once-weekly dosing can be sufficient to achieve an adequate response since the effect on marrow progenitors lasts much longer. Although allergic reactions have been reported, no consistent pattern of significant allergic reactions has emerged

Erythropoiesis Stimulating Agents (ESA)

Darbepoetin alfa (ARANESP) recently approved, a novel erythropoiesis-stimulating protein Approved for clinical use in patients with indications similar to those for epoetin alfa

Therapeutic uses, monitoring and adverse effects

There is a clear dose-response relationship between erythropoietin and rise of hematocrit values Indications: Treatment of anemias due to surgery, AIDS, cancer chemotherapy and chronic inflammatory conditions

Therapeutic uses, monitoring and adverse effects

Possible complications:
development of functional iron deficiency ( normal ferritin levels, low transferrin saturation) Monitor hemoglobin (hgb) and hematocrit (hct) levels. Decrease dose if there is > 4 point increase in hct or increase in hgb by > 1g/dL in two weeks

Therapeutic uses, monitoring and adverse effects

Possible complications:
Development of thromboembolic events during hemodialysis. Targeting ideal hemoglobin/hematocrit levels may contribute to risk Increased risk of cancer recurrence and decreased survival Hypertension Resistance to treatment Pure red cell aplasia Headache, nausea, vomiting, flu-like symptoms, diarrhea, edema, tachycardia, shortness of breath, stinging at injection site,

Specific Indications
Anemia of chronic renal failure
SC route preferred 2-4 months of treatment until target hgb/hct is reached Starting dose 80-120 u/kg 3x/week, average 75 u/kg 3x/week Children usually require higher doses

Specific Indications
Cancer related Anemias:
150 u/kg 3x/week or 450-600 u/kg 1x a week can reduce transfusion requirements Recommended once hgb levels 10 g/dL May have a cytoprotectant effect May stimulate growth of tumor cells

Anemia in AIDS
In patients on zidovudine therapy Doses given at 100-300 u/kg 3x/week SC

Granulocyte-Macrophage ColonyStimulating Factor

Recombinant human GM-CSF (sargramostim) is a 127 amino acid glycoprotein produced in yeast Its primary therapeutic effect is to stimulate myelopoiesis Initially given to patients undergoing autologous bone marrow transplantation. The shortened duration of neutropenia significantly reduced transplant morbidity without a change in long-term survival or risk of inducing an early relapse of the malignant process

Granulocyte-Macrophage ColonyStimulating Factor

Sargramostim (LEUKINE) is administered by SC injection or slow IV infusion at doses of 125-500 g/m2 per day. Plasma levels of GM-CSF rise rapidly after SC injection and then decline with a t1/2 of 2-3 hours. When given IV, infusions should be maintained over 3-6 hours. A transient decrease in the absolute leukocyte count secondary to margination and sequestration in the lungs is noted during initial treatment followed by a dose-dependent, biphasic increase in leukocyte counts over the next 7-10 days

Granulocyte-Macrophage Colony-Stimulating Factor

The dose may be increased if the patient fails to respond after 7-14 days of therapy. However, higher doses are associated with more pronounced side effects, including bone pain, malaise, flu-like symptoms, fever, diarrhea, dyspnea, and rash. Capillary leak syndrome may develop in some patients with prolonged use with peripheral edema and pleural and pericardial effusions. Other serious side effects: transient supraventricular arrhythmia, elevation of serum creatinine, bilirubin, and hepatic enzymes and dyspnea.

Granulocyte Colony-Stimulating Factor

Recombinant human G-CSF filgrastim (NEUPOGEN) is a 175 amino acid glycoprotein produced in Escherichia coli Acts mainly to stimulate CFU-G to increase neutrophil production. It also enhances the phagocytic and cytotoxic functions of neutrophils.

Granulocyte Colony-Stimulating Factor

Indications: used in the treatment of severe neutropenia after autologous hematopoietic stem cell transplantation and highdose cancer chemotherapy. Filgrastim shortens the period of severe neutropenia and reduces morbidity secondary to bacterial and fungal infections. also is effective in the treatment of severe congenital neutropenias. In patients with cyclic neutropenia, G-CSF therapy will increase the level of neutrophils and shorten the length of the cycle sufficiently to prevent recurrent bacterial infections. can improve neutrophil counts in some patients with myelodysplasia or marrow damage (moderately severe aplastic anemia or tumor infiltration of the marrow).

Granulocyte Colony-Stimulating Factor

The neutropenia of AIDS patients receiving zidovudine also can be partially or completely reversed. Routinely used in patients undergoing peripheral blood stem cell (PBSC) collection for stem cell transplantation. G-CSF induced mobilization of stem cells into the circulation has been promoted as a way to enhance repair of other damaged organs in which PBSC might play a role.

Granulocyte Colony-Stimulating Factor

Filgrastim is administered by SC injection or IV infusion over at least 30 minutes at doses of 120 g/kg per day. The usual starting dose in a patient receiving myelosuppressive chemotherapy is 5 g/kg per day. The distribution and clearance rate from plasma (t1/2 of 3.5 hours) are similar for both routes of administration

Granulocyte Colony-Stimulating Factor

Adverse reactions to filgrastim include: mild to moderate bone pain in patients receiving high doses over a protracted period Local skin reactions following SC injection, and rare cutaneous necrotizing vasculitis. Patients with a history of hypersensitivity to proteins produced by E. coli should not receive the drug. Marked granulocytosis, with counts >100,000/L, can occur in patients receiving filgrastim over a prolonged period of time. Mild to moderate splenomegaly has been observed in patients on long-term therapy.

Thrombopoietic Growth Factors

Oprelvekin (interleukin-11): the first growth factor approved by the US FDA for the treatment of secondary thrombocytopenia in cancer patients receiving chemotherapy Recombinant human IL-11 oprelvekin (NEUMEGA) is a bacterially derived 19,000-Da polypeptide of 177 amino acids Stimulates the production of megakaryocytes and thrombocytes by activation IL-11 receptors on the progenitor cells of platelets

Thrombopoietic Growth Factors

t1/2: 7-hour after SC injection. In normal subjects, daily administration of Oprelvekin leads to a thrombopoietic response in 5-9 days. The drug is available in single-use vials containing 5 mg and is administered to patients at 25-50 g/kg per day SC.

Thrombopoietic Growth Factors

Approved for use in patients undergoing chemotherapy for nonmyeloid malignancies that displayed severe thrombocytopenia (platelet count <20,000/L) on a prior cycle of the same chemotherapy, and it is administered until the platelet count returns to >100,000/L.

Thrombopoietic Growth Factors

Major complications: fluid retention and associated cardiac symptoms . Fluid retention reverses upon drug discontinuation, but volume status should be carefully monitored in elderly patients, those with a history of heart failure, or those with preexisting fluid collections in the pleura, pericardium, or peritoneal cavity. Other effects: blurred vision, paresthesias and rash or erythema at injection site

Thrombopoietic Growth Factors

Others: Recombinant thrombopoietin
recombinant human megakaryocyte growth and development factor (rHuMGDF); produced in bacteria recombinant human thrombopoietin (rHuTPO), produced in mammalian cells

Romiplostim (NPLATE) Eltrombopag ( PROMACTA)

IRON
The average adult body contains 3-5g of iron
70% in ferrous (Fe+2) state in Hgb & myoglobn 25% as ferric (Fe+3 ) in the form of ferritin and stored as hemosiderin 5% found attached to transferrin or in heme and flavin enzymes

IRON
Dietary iron is mainly absorbed in the ferrous form ( duodenum and upper jejenum) Plasma iron is bound to transferrin in the ferric state
Transferrin is a protein carrier that transports either dietary or storage iron entering the plasma for redistribution and utilization

IRON
Majority of the iron is transported to the reticuloendothelial system and hepatocytes
Stored w/in the protein ferritin

Elimination is primarily thru exfoliation of GI mucosal cells

1mg/day in adult males 2mg/ day (menstrual loss) in females

Treatment of Iron Deficiency:

Clinically, the effectiveness of iron therapy is best evaluated by tracking the reticulocyte response and the rise in the hemoglobin or the hematocrit. Hematocrit is observed for at least 4-7 days after beginning therapy. A measurable increase in the hemoglobin level takes even longer. A decision as to the effectiveness of treatment should not be made for 3-4 weeks after the start of treatment. An increase of 20 g/L in the concentration of hemoglobin by that time should be considered a positive response, assuming that no other change in the patient's clinical status can account for the improvement and that the patient has not been transfused

Treatment of Iron Deficiency:

Oral administration of ferrous sulfate is the best standard therapy for iron deficiency. Best absorbed taken on an empty stomach with ascorbic acid ( >200mg) which binds to it and facilitates transport to intestinal cells Absorption is impaired by antacids and other medications that reduce stomach acid production.

Treatment of Iron Deficiency:

Dose: 150-300 mg of elemental iron per day, average 200mg ( 2-3mg/kg) divided into 3-4 doses Children can tolerate higher doses: 5mg/kg Duration of treatment: months, variable Common adverse effects: upper GI discomfort, constipation, heartburn, nausea,diarrhea, transient staining of teeth Food sources: organ meats, brewer s yeast, wheatgerm, egg yolks, oysters, certain dried beans and fruit

Commonly used oral preparations

Ferrous sulfate, hydrated Ferrous sulfate, dessicated Ferrous gluconate Ferrous fumarate 325 20% 65 3-4

Preparation

Tablet size (mg)

Elemental iron per tablet (%)

Elemental iron Dosage per tablet (tablets/day) (mg)

200

30%

60- 65

3-4

325

12%

36 -39

3-4

100

33

6-8

325

33%

106 -107

2-3

IRON
To compute for elemental iron: Elemental Fe=
No of tabs x (mg of FeSO4/tab) (% elemental iron) weight of the patient (kg)

Parenteral Iron
Common indications are iron malabsorption (e.g., sprue, short bowel syndrome), severe oral iron intolerance, as a routine supplement to total parenteral nutrition, and in patients who are receiving erythropoietin Parenteral iron also has been given to irondeficient patients and pregnant women to create iron stores, something that would take months to achieve by the oral route.

Parenteral Iron
Parenteral iron therapy should be used only when clearly indicated because acute hypersensitivity, including anaphylactic and anaphylactoid reactions, can occur in 0.2-3% of patients. Other reactions to intravenous iron include headache, malaise, fever, generalized lymphadenopathy, arthralgias, urticaria and exacerbation of rheumatoid arthritis. Four iron formulations are available in the U.S. These are iron dextran (DEXFERRUM or INFED), sodium ferric gluconate (FERRLECIT), ferumoxytol (FERAHEME), and iron sucrose (VENOFER).

IRON POISONING
Free iron is toxic to many cellular processes Children may be more at risk Defense mechanisms to prevent toxicity:
Once absorbed, either stored w/in ferritin or prepared for release to transferrin; Constant sloughing of intestinal cells

IRON POISONING
The body is poorly equipped to handle excessive amounts of iron In excessive doses, absorption continues towards a concentration gradient Intestinal mucosal injury promotes further absorption Normal protective mechanisms (transport and storage proteins) become saturated

IRON
Iron Overdose High levels of free circulating iron

Cellular Toxicity

VITAMIN B12
Cyanocobalamin/ Hydroxocobalamin MOA: a co factor required for essential enzymatic reactions that form tetrahydrofolate, convert homocysteine to methionine and metabolize L-methylmalonylCoA Effects: essential for amino and fatty acid metabolism and in DNA synthesis

VITAMIN B12
Indication: Treatment of vitamin B12 deficiency which manifests as megaloblastic anemia and is the basis of pernicious anemia Vitamin B12 deficiency can irreversibly damage the nervous system. Progressive swelling of myelinated neurons, demyelination, and neuronal cell death are seen in the spinal column and cerebral cortex

Vitamin B12 Deficiency

Cobalamin, source is dietary animal proteins. Humans depend on exogenous sources of vitamin B12. In nature, the primary sources are certain microorganisms that grow in soil, sewage, water, or the intestinal lumen of animals that synthesize the vitamin. Vegetable products are free of vitamin B12 unless they are contaminated with such microorganisms Deficiency states are rare except in vegetarians and infants of vegetarian mothers.

Vitamin B12 Deficiency

Disease states:
Achlorhydria secondary to gastric atrophy or gastric surgery Pancreatic disorders Bacterial overgrowth Intestinal parasites Sprue Localized damage to ileal mucosal cells Children with methylmalonic aciduria and homocystinuria

Vitamin B12 Deficiency

Causes a wide range of neurological signs and symptoms, including paresthesias of the hands and feet, decreased vibration and position senses with resultant unsteadiness, decreased deep tendon reflexes, and in the later stages, confusion, moodiness, loss of memory, and even a loss of central vision. The patient may exhibit delusions, hallucinations, or even overt psychosis. Vitamin B12 deficiency must be considered in elderly patients with dementia or psychiatric disorders, even if they are not anemic.

Vitamin B12 Deficiency

Diagnosis is based on low serum levels of Vit. B12 or increase serum and urine concentrations of methylmalonic acid Treatment: Initially parenteral administration of Vit. B12 (cyanocobalamin or hydroxocobalamin) IM or SC never IV Dose: Cyanocobalamin at 0.1-1.0 mg IM daily for 1-2 weeks.
For pernicious anemia, lifelong monthly injections with cyanocobalamin 1 mg.

Vitamin B12 Deficiency

Hydroxocobalamin given in doses of 100 g intramuscularly has been reported to have a more sustained effect than cyanocobalamin, with a single dose maintaining plasma vitamin B12 concentrations in the normal range for up to 3 months. However, some patients show reductions of the concentration of vitamin B12 in plasma within 30 days, similar to that seen after cyanocobalamin. Furthermore, the administration of hydroxocobalamin has resulted in the formation of antibodies to the transcobalamin II vitamin B12 complex.

FOLIC ACID
Folacin (pteroylglutamic acid) MOA: a precursor of an essential donor of methyl groups used for synthesis of amino acids, purines and deoxynucleotide Effects: adequate supplies are required for essential biochemical reactions involving amino acid metabolism, and purine and DNA synthesis

FOLIC ACID
Indication: treatment of megaloblastic anemia and prevention of congenital neural tube defects. Mainly absorbed in the proximal portion of the jejenum Well absorbed orally Not toxic in overdose Use with caution in patients who might also be deficient in Vit. B12

FOLIC ACID
Many food sources are rich in folates, especially fresh green vegetables, liver, yeast, and some fruits. However, lengthy cooking can destroy up to 90% of the folate content Normal daily requirement is 100 g It is especially recommended for pregnant women to take folate supplements since deficiency is linked to development of congenital neural tube defects.

Folic Acid Deficiency

May result because of disease states, use of drugs such as methotrexate, trimethoprim , oral contraceptives and some anticonvulsants Treatment: Initially give 1-5 mg IM then per orem 1-2mg daily for two weeks. Severe Vit. C deficiency may be a barrier to effective treatment

Deficiency of Other Nutrients

Copper deficiency:
Extremely rare; copper supplied in the diet is usually sufficient May interfere with iron absorption and release from reticuloendothelial cells May affect mitochondrial production of heme Microcytic anemia

Deficiency of Other Nutrients

Pyridoxine deficiency:
may have a role in the treatment of acquired or hereditary sideroblastic anemia Anti-TB drugs isoniazid and pyrazinamide and the anti-Parkinson s drug levodopa can cause sideroblastic anemia Not beneficial if the defect is due to chloramphenicol or lead

Deficiency of Other Nutrients

Riboflavin deficiency:
Associated with infection and protein deficiency Gross, generalized malnutrition Hypoproliferative anemia or pure red-cell aplasia