Hematopoietic Growth Hematopoietic Growth Factors Factors Colony Stimulating Factors.Colony Stimulating Factors.

Erythropoietin (Epoetin alfa).Erythropoietin (Epoetin alfa). Granulocyte colony-stimulating Granulocyte colony-stimulating

factor(G-CSF).factor(G-CSF). Granulocyte-macrophage colony-Granulocyte-macrophage colony-

stimulating factor (G-CSF).stimulating factor (G-CSF). Interleukin-11 (IL-11).Interleukin-11 (IL-11). Thrombopoietin.Thrombopoietin.

Hematopoietic Growth Hematopoietic Growth FactorsFactors Regulate the proliferation and Regulate the proliferation and

differentiation of hematopoietic differentiation of hematopoietic progenitor cells in the bone progenitor cells in the bone marrow.marrow.

Useful in hematologic as well as Useful in hematologic as well as nonhematologic conditions, nonhematologic conditions, potential anticancer and potential anticancer and antiinflammatory drugs.antiinflammatory drugs.

ErythropoietinErythropoietin 34-39 kDa glycoprotein.34-39 kDa glycoprotein. Was the first isolated growth factor.Was the first isolated growth factor. Originally purified from urine of Originally purified from urine of

patients with severe anemia.patients with severe anemia. Recombinant human erythropoietin Recombinant human erythropoietin

(rHuEPO, or Epoietin alfa) is produced (rHuEPO, or Epoietin alfa) is produced in a mammalian cell expression in a mammalian cell expression system.system.

Half-life after iv administration is 4-13 Half-life after iv administration is 4-13 hours.hours.

It is not cleared by dialysis.It is not cleared by dialysis. Darbepoetin alfa has longer half life.Darbepoetin alfa has longer half life.

ErythropoietinErythropoietin Produced in the kidney in response Produced in the kidney in response

to hypoxia through increased rate of to hypoxia through increased rate of transcription of the gene .transcription of the gene .

Needs active bone marrow (no Needs active bone marrow (no deficiency, no primary bone marrow deficiency, no primary bone marrow disease and no suppression by drugs disease and no suppression by drugs or chronic diseases).or chronic diseases).

Normal serum level 20 IU/L.Normal serum level 20 IU/L. Elevated in most of anemias (up to Elevated in most of anemias (up to

thousands) but lowered in anemia of thousands) but lowered in anemia of chronic renal failure.chronic renal failure.

ErythropoietinErythropoietin Stimulates erythroid proliferation Stimulates erythroid proliferation

and differentiation by interacting and differentiation by interacting with specific receptors( JAK/STAT with specific receptors( JAK/STAT cytokine receptor) on red cell cytokine receptor) on red cell progenitor.progenitor.

Releases reticulocytes from the bone Releases reticulocytes from the bone marrow.marrow.

ErythropoietinErythropoietinIndications:Indications: 1.1. Anemia of chronic renal failure:Anemia of chronic renal failure:

– These are the patients most likely to These are the patients most likely to benefit from treatment.benefit from treatment.

– 50-150 IU/kg IV or SC three times a 50-150 IU/kg IV or SC three times a week.week.

– Failure to respond is usually due to iron Failure to respond is usually due to iron or folic acid deficiency.or folic acid deficiency.

ErythropoietinErythropoietinIndications:Indications: 2.2. Primary bone marrow disorders and Primary bone marrow disorders and

secondary anemias:secondary anemias: aplastic anemia, aplastic anemia, myeloproliferative and myelodysplastic myeloproliferative and myelodysplastic disorders, multiple myeloma and bone disorders, multiple myeloma and bone marrow malignancies. Also anemia of marrow malignancies. Also anemia of chronic inflammation, AIDS and cancer.chronic inflammation, AIDS and cancer.

– Response is better with low baseline Response is better with low baseline erythropoietin levels.erythropoietin levels.

– Patients require higher doses(100-500 IU/kg).Patients require higher doses(100-500 IU/kg).

– Response is generally incomplete.Response is generally incomplete.

ErythropoietinErythropoietinIndications:Indications: 3.3. Anemia of zidovudine treatment.Anemia of zidovudine treatment. 44 Anemia of prematurity.Anemia of prematurity. 5.5. After phlebotomies for After phlebotomies for

autologous transfusion for elective autologous transfusion for elective surgery.surgery.

6.6. Iron overload.Iron overload. 7.7. Unethically, used by athletes.Unethically, used by athletes.

ErythropoietinErythropoietin

Toxicity:Toxicity: Due to rapid increases in Due to rapid increases in

hematocrit and hemoglobin: hematocrit and hemoglobin: hypertension and thrombotic hypertension and thrombotic complications.complications.

Allergic reactions are infrequent Allergic reactions are infrequent and mild.and mild.

Myeloid Growth FactorsMyeloid Growth Factors Originally purified from cultured Originally purified from cultured

human cells.human cells. rHuG-CSF “Filgrastim” 1991:rHuG-CSF “Filgrastim” 1991:

– Produced in a bacterial cell expression Produced in a bacterial cell expression system.system.

– 175 amino acids, 18 kD mol. wt.175 amino acids, 18 kD mol. wt.– Has a half life of 2-7 hours.Has a half life of 2-7 hours.– PegfilgrastimPegfilgrastim= Filgrastim covalently = Filgrastim covalently

conjugated with polyethylene glycol. conjugated with polyethylene glycol. Injected once per chemotherapy cycle.Injected once per chemotherapy cycle.

Myeloid Growth FactorsMyeloid Growth FactorsrHuGM-CSF “Sargramostim”:rHuGM-CSF “Sargramostim”:

– Produced in a yeast cell expression Produced in a yeast cell expression system.system.

– 127 amino acids, 15-19 kD mol. wt.127 amino acids, 15-19 kD mol. wt.– Has a half life of 2-7 hours.Has a half life of 2-7 hours.

Myeloid Growth FactorsMyeloid Growth FactorsG-CSF:G-CSF: Works on( JAK/STAT receptors.Works on( JAK/STAT receptors. Stimulates proliferation and Stimulates proliferation and

differentiation of progenitors differentiation of progenitors committed to the neutrophil lineage.committed to the neutrophil lineage.

Activates the phagocytic activity of Activates the phagocytic activity of mature neutrophils and prolongs mature neutrophils and prolongs their survival in the circulation.their survival in the circulation.

Mobilizes hemopoietic stem cells Mobilizes hemopoietic stem cells into the peripheral circulation. into the peripheral circulation.

Myeloid Growth FactorsMyeloid Growth FactorsGM-CSF:GM-CSF: Has broader actions. Also works on Has broader actions. Also works on

JAK/STAT receptors.JAK/STAT receptors. Stimulates proliferation and Stimulates proliferation and

differentiation of early and late differentiation of early and late granulocytic progenitor cells as well as granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors.erythroid and megakaryocyte progenitors.

With interleukin-2, also stimulates T-cell With interleukin-2, also stimulates T-cell proliferation.proliferation.

Locally, it is an active factor of Locally, it is an active factor of inflammation.inflammation.

Mobilizes peripheral blood stem cells, but Mobilizes peripheral blood stem cells, but less than G-CSF.less than G-CSF.

Clinical Applications of Myeloid Growth Clinical Applications of Myeloid Growth FactorsFactors

Cancer Chemotherapy-Induced Cancer Chemotherapy-Induced Neutropenia:Neutropenia:

Granulocyte transfusion is not practical.Granulocyte transfusion is not practical. G-CSF accelerates neutrophil recovery, G-CSF accelerates neutrophil recovery,

leading to reduced episodes of febrile leading to reduced episodes of febrile neutropenia, need for antibiotics and days neutropenia, need for antibiotics and days of hospitalization , but do not improve of hospitalization , but do not improve survival.survival.

G-CSF is reserved for risky patients.G-CSF is reserved for risky patients. GM-CSF can produce fever on its own.GM-CSF can produce fever on its own. They are safe even in the They are safe even in the

postchemotherapy supportive care of postchemotherapy supportive care of patients with AML.patients with AML.

Clinical Applications of Myeloid Growth Clinical Applications of Myeloid Growth FactorsFactors

Congenital neutropenia.Congenital neutropenia. Cyclic neutropenia.Cyclic neutropenia. Myelodysplasia.Myelodysplasia. Aplastic anemia.Aplastic anemia.

Clinical Applications of Myeloid Growth Clinical Applications of Myeloid Growth FactorsFactors

Autologous Stem Cell Transplantation:Autologous Stem Cell Transplantation:– High dose chemotherapy regimens produce High dose chemotherapy regimens produce

extreme myelosuppression, which is extreme myelosuppression, which is counteracted by reinfusion of the patient’s counteracted by reinfusion of the patient’s own hematopoietic stem cells which are own hematopoietic stem cells which are collected before the chemotherapy.collected before the chemotherapy.

Allogenic Bone Marrow Transplantation.Allogenic Bone Marrow Transplantation. Mobilization of peripheral blood stem Mobilization of peripheral blood stem

cells (PBSCs).cells (PBSCs).– Patients or donors are given GM-CSF (5-10 Patients or donors are given GM-CSF (5-10

mcg/kg/day) for 4 days, then leukapheresis, mcg/kg/day) for 4 days, then leukapheresis, CD34 is used as a marker for the stem cells. CD34 is used as a marker for the stem cells. At least 5x10At least 5x106 6 CD34 cells/kg should be CD34 cells/kg should be reinfusedreinfused toto ensure effective engraftment.ensure effective engraftment.

Toxicity of Myeloid Growth Toxicity of Myeloid Growth FactorsFactors

Bone pain.Bone pain. Fever, malaise, arthralgia, myalgia.Fever, malaise, arthralgia, myalgia. Capillary Leak Syndrome: peripheral Capillary Leak Syndrome: peripheral

edema, pleural or pericardial edema, pleural or pericardial effusions.effusions.

Allergic reactions.Allergic reactions. Splenic rupture.Splenic rupture.

Megakaryocyte Growth Megakaryocyte Growth FactorsFactors

Interleukin-11 (IL-11):Interleukin-11 (IL-11):– 65-85 kDa protein.65-85 kDa protein.– Produced by fibroblasts and stromal Produced by fibroblasts and stromal

cells in the bone marrow.cells in the bone marrow.– Half life is 7-8 hours after sc injection.Half life is 7-8 hours after sc injection.

Oprelvekin:Oprelvekin:– Is the recombinant form.Is the recombinant form.– Produced by expression in Produced by expression in E.coli.E.coli.

Megakaryocyte Growth Megakaryocyte Growth FactorsFactors

Interleukin-11 (IL-11):Interleukin-11 (IL-11):– Acts through a specific receptor.Acts through a specific receptor.– Stimulates the growth of multiple Stimulates the growth of multiple

lymphoid and myeloid cells.lymphoid and myeloid cells.– Stimulates the growth of primitive Stimulates the growth of primitive

megakaryocytic progenitors.megakaryocytic progenitors.– Increases the number of peripheral Increases the number of peripheral

platelets and neutrophils. platelets and neutrophils.

Megakaryocyte Growth Megakaryocyte Growth FactorsFactors

Clinical Applications of IL-11:Clinical Applications of IL-11: ThrombocytopeniaThrombocytopenia

Platelets transfusion is an Platelets transfusion is an alternative.alternative. Approved for the secondary prevention Approved for the secondary prevention

of thrombocytopenia in patients of thrombocytopenia in patients receiving cytotoxic chemotherapy for receiving cytotoxic chemotherapy for treatment of nonmyeloid cancers.treatment of nonmyeloid cancers.

Megakaryocyte Growth Megakaryocyte Growth FactorsFactors

Clinical Applications of IL-11 :Clinical Applications of IL-11 : Does not appear to have an effect on Does not appear to have an effect on

leukopenia caused by leukopenia caused by myelosuppressive chemotherapy.myelosuppressive chemotherapy.

Given by SC injection, 50mcg/kg/day Given by SC injection, 50mcg/kg/day for 2-3 weeks after chemotherapy. for 2-3 weeks after chemotherapy. Or, until platelet count rises to Or, until platelet count rises to <<50,000 cells/50,000 cells/µµl.l.

Megakaryocyte Growth Megakaryocyte Growth FactorsFactors

Thrombopoietin:Thrombopoietin:

- It is still an investigational agent.- It is still an investigational agent.

- 65-85 kDa glycoprotein.- 65-85 kDa glycoprotein.- Recombinant form is produced by - Recombinant form is produced by

expression in human cells. expression in human cells. - Independently stimulates the - Independently stimulates the

growth growth of primitive of primitive megakaryocytic megakaryocytic progenitors. progenitors.

- Also stimulates mature - Also stimulates mature megakaryotes.megakaryotes.

- Activates mature platelets to - Activates mature platelets to respond respond to aggregation-inducing stimuli.to aggregation-inducing stimuli.

Megakaryocyte Growth Megakaryocyte Growth FactorsFactors

Toxicity:Toxicity: Fatigue, headache, dizziness, Fatigue, headache, dizziness,

anemia, dyspnea, transient atrial anemia, dyspnea, transient atrial arrhythmias and hypokalemia.arrhythmias and hypokalemia.