MYELOID GROWTH FACTORS

HEMATOPOIETIC SYSTEM

MYELOID TISSUESBone marrow and the cells derived from it (e.g., red cells, platelets, granulocytes and monocytes)

LYMPHOID TISSUESThymus, Lymph nodes and spleen.

Origin of definitive hematopoietic stem cells- 3rd week of fetal embryonic development

mesoderm of intraembryonic aorta/gonad/mesonephros region.

3rd month HSC’s migrate to liver chief site for blood cell

formation.

4th month migration to bone marrow.

At birth, marrow of entire skeleton is hematopoietically active.

Hepatic hematopoiesis inactive.

By puberty, hematopoiesis marrow of axial skeleton.

PLEURIPOTENT HSC

2 MULTIPOTENT PROGENITORS

COMMON LYMPHOID PROGENITOR CELLS

COMMON MYELOID PROGENITOR CELLS

COMMITTED PROGENITORS(COLONY FORMING UNITS)

PRECURSORS- MYELOBLASTS, PROERYTHROBLASTS, MEGAKARYOBLASTS.

MATURE GRANULOCYTES, RED CELLS AND PLATELETS.

The marrow response to short term physiologic needs is

regulated by haematopoietic growth factors through effects

on the committed progenitors.

As these progenitors differentiate, they also begin to express

receptors for lineage specific growth factors which stimulate

their short term growth and survival.

Some of the growth factors are: stem cell factor(c-KIT

ligand), FLT-3 ligand, erythropoietin, Granulocyte

Macrophage- Colony Stimulating Factor, Granulocyte

Colony Stimulating Factor, thrombopoietin.

Feedback loops are mediated through growth factors to tune the

marrow output allowing the numbers of the formed blood

elements (RBC, WBC and platelets) to be maintained within

appropriate ranges.

Many diseases alter the production of the blood cells.

Conversely, other disorders are associated with defects in

haematopoiesis that leads to one or more types of deficiency of

blood cell.

Primary tumours of the hematopoietic cells are the most

important diseases that interfere marrow function.

Specific genetic diseases, infections, toxins, nutritional deficiencies

and chronic inflammation of any cause can also decrease the

production of blood cells by the marrow.

MYELOID GROWTH FACTORS

Glycoproteins.

Stimulate proliferation and differentiation of one or more myeloid

cell lines.

Enhance the function of mature granulocytes and monocytes.

Recombinant forms are:

• Granulocyte Colony Stimulating Factor (G-CSF)

• Granulocyte Macrophage Colony Stimulating Factor (GM-CSF)

• Stem Cell Factor (SCF)

Produced naturally by number of different cells fibroblasts,

endothelial cells, macrophages and T cells.

Act via membrane receptors, cytokine superfamily.

Activates JAK/STAT signal transduction pathway.

Enhances the migration, phagocytosis, superoxide production

and antibody dependent cell mediated toxicity of neutrophils,

monocytes and eosinophils.

Ability to mobilize HSC’s increased concentration in

peripheral blood use of PBSC’s rather than bone marrow

stem cells for autologous or allogenic hematopoietic stem

cell transplantation.

GM-CSF : broader biologic action than G-CSF.

Stimulates proliferation and differentiation of erythroid and megakaryocyte progenitors as well.

Acts together with interleukin-2stimulate T-cell proliferation active factor site of inflammation.

Also mobilises PBSC’s but less efficacious and more toxic compared to G-CSF.

Recombinant human G-CSF- Filgrastim

Produced in a bacterial expression.

Non glycosylated peptide of 175 amino acids.

Molecular weight 18kDa.

Pegfilgrastim-

Covalent conjugation product of filgrastim and a form of

polyethylene glycol.

Lenograstim-

Glycosylated form of recombinant G-CSF.

Recombinant human GM-CSF- Sargramostim

Produced in a yeast expression.

Partially glycosylated peptide of 127 amino acids.

3 molecular species with molecular weights of 15,500; 15,800;

19,500.

These preparations have serum half-lives of 2-7 hours.

May be administered Intravenously or subcutaneously.

CLINICAL PHARMACOLOGYA. Cancer Chemotherapy- Induced Neutropenia: Neutropenia???

G-CSF:

Rx of chemotherapy-induced neutropenia.

Accelarates rate of neutrophil recovery after dose intensive

myelosuppressive chemotherapy.

Reduces the duration of neutropenia

Raises the nadir count following a cycle of chemotherapy.

Clinical guidelines for the use of G-CSF after cytotoxic chemotherapy recommend reserving G-CSF for :

Patients at high risk for febrile neutropenia based on age, medical history, and disease characteristics.

Patients receiving dose-intensive chemotherapy regimens that carry a greater than 40% risk of causing febrile neutropenia.

Patients with a prior episode of febrile neutropenia after cytotoxic chemotherapy.

Patients at high risk for febrile neutropenia.

Patients who are unlikely to survive an episode of febrile neutropenia.

Pegfilgrastim, administered once per chemotherapy cycle as an alternative to G-CSF.

Doses:G-CSF: 5mcg/kg/d

GM-CSF: 250mcg/m2/d

Started within 24-72 hours after completing chemotherapy.

Completed until absolute neutrophil count is greater than 10,000cells/µl

Pegfilgrastim is given as a single dose of 6mg.

Other applications:

Congenital neutropenia

Cyclical neutropenia

Myelodysplasia

Aplastic anaemia.

Do not stimulate the formation of erythrocytes and platelets- combined with other growth factors- treatment of pancytopenia.

Play an important role in autologous stem cell transplantation for patients undergoing high dose chemotherapy.

High dose regimens myelosuppression counteracted by reinfusion of patients own HSC’s.

Administration of G-CSF or GM-CSF early after autologous stem cell

transplantation, reduce the time to engraftment and recovery from

neutropenia in patients receiving stem cells obtained either from bone

marrow or from peripheral blood.

These effects used in treatment of lymphoma or solid tumours.

Also used to support patients who have received allogeneic bone marrow transplantation for treatment of hematologic malignancies or bone marrow failure states.

Mobilisation of PBSC’s: G-CSF is the cytokine most commonly used; because of its increased efficacy and reduced toxicity compared with GM-CSF.

To mobilize stem cells, patients or donors are given 5-10 mcg/kg/d subcutaneously for 4 days. On the fifth day, they undergo leukapheresis.

The success of PBSC transplantation depends on transfusion of adequate numbers of stem cells.

CD34, an antigen present on early progenitor cells and absent from later, committed, cells, is used as a marker for the requisite stem cells.

The goal is to infuse at least 5 × 10 6 CD34 cells/kg.

This number of CD34 cells usually results in prompt and durable engraftment of all cell lineages.

Plerixafor- bicyclam molecule originally developed as an anti-HIV

drug because of its ability to inhibit the CXC chemokine receptor 4

(CXCR4), a co-receptor for HIV entry into CD4+ T lymphocytes.

The novel hematopoietic stem cell mobiliser added with G-CSF for patients with multiple myeloma and non-Hodgkin’s lymphoma.

Early clinical trials ability to increase CD34 cells in peripheral blood.

Plerixafor-

Administered subcutaneously

Four days after G-CSF treatment

11 hours prior to leukapheresis

can be used with G-CSF for up to four continuous days.

TOXICITY

G-CSF and pegfilgrastim are used more frequently than GM-CSF

G-CSF and pegfilgrastim can cause bone pain

GM-CSF: fever, malaise, arthralgias, myalgias, capillary leak syndrome (peripheral edema, pericardial/pleural effusions)

Allergic reactions (infrequent)

Splenic rupture- rare, but a serious complication

Plerixafor-

Injection site reactions, GI disturbances, dizziness, fatigue, and

headache.

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