CLINICAL USE OF STIMULATING

FACTORS
MUHAMMAD HAYUN
 DEFINITION
• Colony-stimulating factors (CSFs) 
glycoproteins that bind to receptor proteins 
hemopoietic stem cells,  activating
intracellular signaling pathways  the cells to
proliferate and differentiate  a specific kind
of blood cell
 SOURCES
• Lymphosit, makrofag and stroma cell
• Eritropoetin  Kidney (90%) n liver
• Thrombopoetin  Liver
 GENERAL CHARACTERISRIC
• Glycoprotein  very low concentrations
• Working in a hierarchy
• Produced by several cell types
• Affects more than one cell line
• Active  stem cells / progenitor cells and the functional
end
• Synergistic or additive interactions with other growth
factors.
• Often working in neoplastic cells is equivalent to a normal
cell
• Multiple work: proliferation, differentiation, maturation,
functional activation, inhibits apoptosis
STIMULATING FACTORS
Role of growth factors in normal
haemopoiesis
ACTION OF CYTOKINE
 Signal Transduction
• Initiated by cytokine binding
• Activates JAK (Janus kinase)
• Phosphorylation of tyrosine
• Binding of STAT(Signal transducers and
activators of transcription)
• Translocation of STAT to cell’s DNA
• Transcription of specific target genes
 Self-sufficiency in
growth signals
Ras Pathway
• Growth factor binds receptor
• Receptor exchanges GTP for
GDP on Ras
– Ras activated
Blocked in
• RasRafMekMap mutant
Kinasetranscription RAS
Gly→Val
factors genes turned on
 Eritropoietin
• Major production sites : Kidney, liver
• Induced by hypoxia
• Selected biologic activities : proliferation, differentiation, and
survival of erythroid precursors
• Receptor  EPO receptor
• Natural antagonist soluble EPO receptor
EPO RECEPTORS
 Clinical indications….
•Anemia of renal failure
Hb ≤ 10 gr/dl , feritin serum ≥ 100 µg/L n transferin saturation ≥20%
; dose 50-150 IU/kg subcutan 2-3/wk for 4 wk.
• Anemia of prematurity
Dose :250-400 U/Kg
• Malignancy
150-300 IU/Kg ; at least 4 wk
• AIDS
150-400 IU/Kg if endogenous EPO level < 500 IU/mL
• MDS
Endogen EPO > 200 IU/Kg no respon
• Aplastic anemia
Endogen EPO < 200 IU/Kg
 Granulocyte-macrophage Colony Stimulating
Factor
• Production sites T and B cells, macrophages, mast cells,
fibroblasts, endothelial cells
• Selected biologic activities
• Stimulates growth of multi-lineage progenitors, BFU-E,
granulocyte, macrophage, and eosinophil colonies
• Induces migration and proliferation of vascular endothelial
cells
• Activates mature phagocytes (neutrophils, macrophages,
eosinophils)
• Receptor Type I receptor with alpha and beta subunits
• Major clinical indications
• Neutropenia due to myelosuppressive chemotherapy or BMT
• Peripheral blood stem cell mobilization
• Graft failure
 Granulocyte colony stimulating factor
• Major production sites Stromal cells, endothelial
cells, fibroblasts, monocytes
• Induced by TNF-α and IL-1
• Selected biologic activities Regulates production and
function of neutrophils
• Receptor G-CSF receptor
• Major clinical indications
• Neutropenia due to chemotherapy or BMT
• Chronic and cyclic neutropenia
• AIDS-related neutropenia
• Autoimmune neutropenia.
• Peripheral blood stem cell mobilization
 Figure 5 The major biologic actions of G-CSF

Eyles JL et al. (2006) Granulocyte colony-stimulating factor and neutrophils—forgotten mediators of

inflammatory disease Nat Clin Pract Rheumatol 2: 500–510 doi:10.1038/ncprheum0291
 Prmiary prophylactic CSF
administration (ASCO)
• Recommendeprevention of FN high risk :
1. Age
2. Medical history
3. Disease characteristics
4. Myelotoxicity of the chemotherapy agent
. Clinical trial data : use of CSF when risk of FN >
20%
 Primary…………………………
• Age > 65 years
• Poor performance status
• Previous FN
• Poor nutritional status
• Open wounds or active infections
• Administration of combined chemoradioterapy
• Cytopenia due to bone marrow involvement by
tumor
• Other serious comorbidities
 Secondary Prophylactic
• Experienced a neutropenic complication from
a prior cycle of chemoterapy
• For which primary prophylacxis was not
received
• In which a reduced dose may compromise
disease-free or overallsurvival or treatment
outcome
 Therapeuetic use of CSF
• Should not be routinely used  afebrile
neutropenia

• Should be FN who at high risk for infection-

associated complications or predictive of poor
clinical
 High risk (therapeutical use ):
• Prolonged > 10 days n profound <1000/µL
• Age 65 years
• Uncontrolled primary disease
• Pneumonia
• Hypotension n multi-organ dysfunction
(sepsis syndrom)
• Invasive fungal infection
 CSF as adjuncts to progenitor cell
transplantation
• Administrion of CSF to mobilize PBPC often in
conjuntion with chemotherapy and their
administration after autologous, but NOT
allogenic,
 CSF in Leukemia n MDS
• AML :
1. CSF use after completion of the initial
induction chemotherapy
2. Can be recommended after the completion of
consolidation chemoterapy
3. For primming effect is not recommended
• MDS :Intermitten administration may be
considered in a subset of patients with severe
neutropenia and recurrent infection
 CSF in ALL n Relapse
• ALL : After the completion initial first few days
of chemotherapy of the initial induction or
first post remission course
• Acute leukemia in relapse : Should be used
judiciously, or not at all,
CSF in Patients receiveng radiotherapy
with/without concurrrent
chemoterapy
• Chemoradiotherapy : CSF should be avoidede
concomittant chem n radio  mediastinum
• Radiotherapy alone : prolonged delays
secondary to neutropenia are expected -
CSF may be considered
 CSF in pediatric population
• Primary prophylaxis likellihood of FN
• Secondary n therapeuetic high risk pediatric
patients
• ALL  caution
 CSF Initiatiation, Dosing, Duration and
Administration
• G-CSF : 5 g/kg/d ; 24-72 h after the
administration of myelotoxic chemotherapy; until
ANC at least 2-3 x 10 9/L. For PBPC , G-CSFstarted
at least 4 d before the first leukapheresis until the
last leukapheresis.
• GM-CSF : 250 g/ m2/d less than 24 h the last
chemotherapy n 12 h radiotherapy. until an ANC
greater than 1.5 x10 9 /L for 3 consecutive days is
obtained. The drug should be discontinued early
or the dose be reduced by 50% if the ANC
increases to greater than 20 109/L
 Macrophage colony stimulating factor
• Major production sites Monocytes/macrophages, Fibroblasts,
Epithelial cells, Vascular endothelium, Osteoblasts
• Selected biologic activities
• Influences monocyte/macrophage development and function
• Stimulates hematopoiesis
• Induces osteoclast production
• Helps maintain pregnancies
• Lowers cholesterol levels
• Affects microglial function
• Receptor Fms
• Major clinical trials
• Enhances hematopoietic recovery after chemotherapy or
transplantation
• Attenuates neutropenia in chronic neutropenia
• Lowers serum cholesterol
 Stem cell factor
• Major sites of production Marrow stroma, Hematopoietic
cells, Gut epithelial cells, Central nervous system Thymus,
Skin keratinocytes
• Selected biologic activities :
• Promotes hematopoiesis at multiple levels
• Influences primordial germ cell and melanocyte migration
during embryonic life
• Affects immunoregulatory cells
• Receptor c-kit
• Natural antagonists Soluble c-kit receptor
• Major clinical trials
• Peripheral blood progenitor mobilization (SCF = G-CSF
better than SCF alone)
• Aplastic anemia (trilineage responses seen)
 Trombopoietin
• Major sites of production Liver, Kidneys, Smooth muscle,
Marrow stroma, Brain
• Selected biologic properties:
• Major regulator of platelet production
• Acts in synergy with EPO to stimulate growth of erythroid
progenitors
• Acts in synergy with IL-3 and SCF to stimulate proliferation and
prolong survival of hematopoietic stem cells
Receptor Mpl
Major clinical trials
• Accelerates platelet recovery after chemotherapy
• Increases platelet yield from normal donors for platelet
transfusions
• Enhances mobilization of peripheral blood progenitor cells by G-CSF
• Nonimpressive effects on platelet recovery after myeloablative
therapy
• Trombopoetin In clinical trial :
1. TPO
2. PEG-rHuMGDF
• Romiplostim; dose 1 µg - 10 µg/kgBW subcutan (
4-9th day) or intravenous (1st-3rd day)
• Eltrombopag; 50 mg/d - 75 mg/d
 Summary
• Colony stimulating factors (CSFs) are secreted
glycoproteins that bind to receptor proteins on the
surfaces of hemopoietic stem cells, thereby activating
intracellular-signaling pathways that can cause the cells
to proliferate and differentiate into a specific kind of
blood cell. Colony stimulating factor produced by
several cell types and work synergistically more than
one cell line and hierarchy. Many of the molecules have
been cloned and have entered clinical trials. Even,
Several growth factors have been used extensively in
the clinic such as erythropoietin, G-CSF, GM-CSF. The
emerging understanding of their role and the
availability of recombinant molecules for clinical
therapeutics suggest that their exploitation is still in the
nascent stages and will ultimately impact most fields of
medicine.
Receptors with enzyme function
Receptors with enzyme domains Ligands

Receptor-Tyrosine kinases
Receptor-Serine/Threonine kinases
Receptor-Tyrosine phosphatases
Receptor-Guanylyl cyclases Cell membrane

Receptors associated with enzymes

(direct or via adaptors)

Tyrosine kinases
Serine/Threonine kinases
Phosphatases Enzym
Enzym-
Enzyme
domäne

Adaptor
MECHANISM
 Clinical Uses of Hematopoietic Growth Factors
Hematopoietic Growth Factor
Erythropoietin, darbepoetin alfa
Granulocyte colony-stimulating factor (G-CSF; Neutropenia
filgrastim)
Granulocyte-macrophage colony-stimulating
factor (GM-CSF; sargramostim)
Interleukin-11 (IL-11, oprelvekin)
Romiplostim
Clinical Condition Being Treated or
Prevented
Anemia
Stem cell transplantation
Mobilization of peripheral blood
progenitor cells (PBPCs)
Thrombocytopenia
Thrombocytopenia
Recipients
Patients with chronic renal failure
HIV-infected patients treated with zidovudine
Cancer patients treated with myelosuppressive cancer
chemotherapy
Patients scheduled to undergo elective, noncardiac,
nonvascular surgery
Cancer patients treated with myelosuppressive cancer
chemotherapy
Patients with severe chronic neutropenia
Patients with nonmyeloid malignancies treated with
stem cell transplantation
Mobilization of peripheral blood progenitor cells
(PBPCs)
Patients with nonmyeloid malignancies
Donors of stem cells for allogeneic or autologous
transplantation
Patients with nonmyeloid malignancies who receive
myelosuppressive cancer chemotherapy
Patients with idiopathic thrombocytopenic purpura
G-CSF receptor