MGF

1. MYELOID GROWTH FACTORS

2. HEMATOPOIETIC SYSTEM
MYELOID TISSUES
Bone marrow and the cells
derived from it (e.g., red cells,
platelets, granulocytes and
monocytes)
LYMPHOID TISSUES
Thymus, Lymph nodes and
spleen.

3.  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.

4.  At birth, marrow of entire skeleton is hematopoietically active.
 Hepatic hematopoiesis inactive.
 By puberty, hematopoiesis marrow of axial skeleton.

5. PLEURIPOTENT HSC
2 MULTIPOTENT PROGENITORS
COMMON LYMPHOID
PROGENITOR CELLS
COMMON MYELOID
PROGENITOR CELLS

6. COMMITTED PROGENITORS
(COLONY FORMING UNITS)
PRECURSORS- MYELOBLASTS,
PROERYTHROBLASTS,
MEGAKARYOBLASTS.
MATURE GRANULOCYTES,
RED CELLS AND PLATELETS.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. MYELOID GROWTH FACTORS

14.  Glycoproteins.
 Stimulate proliferation and differentiation of one or more myeloid
cell lines.
 Enhance the function of mature granulocytes and monocytes.

15.  Recombinant forms are:
• Granulocyte Colony Stimulating Factor (G-CSF)
• Granulocyte Macrophage Colony Stimulating Factor (GM-CSF)
• Stem Cell Factor (SCF)

16. Produced naturally by number of different cells fibroblasts,
endothelial cells, macrophages and T cells.

17. 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.

18.  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.

19. GM-CSF : broader biologic action than G-CSF.
Stimulates proliferation and differentiation of erythroid and
megakaryocyte progenitors as well.
Acts together with interleukin-2stimulate T-cell
proliferation active factor site of inflammation.
Also mobilises PBSC’s but less efficacious and more toxic
compared to G-CSF.

20.  Recombinant human G-CSF- Filgrastim
Produced in a bacterial expression.
Non glycosylated peptide of 175 amino acids.
 Molecular weight 18kDa.

21. Pegfilgrastim-
Covalent conjugation product of filgrastim and a form of
polyethylene glycol.
Lenograstim-
Glycosylated form of recombinant G-CSF.

22. 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.

23. CLINICAL PHARMACOLOGY
A. 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.

25. 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.

26. 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.

27. 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.

28.  Other applications:
 Congenital neutropenia
 Cyclical neutropenia
 Myelodysplasia
 Aplastic anaemia.

29.  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.

30. 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.

31. 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.

35. 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.

36. 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.

37. 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.

38. 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

39. Plerixafor-
 Injection site reactions, GI disturbances, dizziness, fatigue, and
headache.

40. THANK YOU