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Granulocyte Colony Stimulating Factors -

Use / Indications

-Dr. Abish Adhikari13.05.2013

BPKMCH, Nepalabishadh@gmail.com

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Blood Cell Maturation

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Granulocyte Colony Stimulating Factor

• Endogenous G-CSF is produced in Marrow stromal cells, Neutrophils, Monocytes, T cells, Endothelial cells etc.

• It regulates the production, maturation, and function of the neutrophil lineage.

• G-CSF in blood ranges from 20 to 100 pg/mL in healthy individuals and rises inversely with neutrophil concentration.

• Patients who are bacteremic and neutropenic can have serum levels of G-CSF exceeding 2,000 pg/mL

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rHu-G-CSF

• Recombinant Human Granulocyte Colony-stimulating Factor.

• "Filgrastim, a recombinant protein produced in Escherichia coli, has an amino acid sequence identical to endogenous G-CSF, with a little alteration*."

• Other forms available are, 'Pegfilgastrim', 'lenograstim'& 'nartograstim'.

*the exception of the addition of an N-terminal methionine and absence of glycosylation

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Filgastrim• A single, non-glycosylated, polypeptide

chain that contains 175 amino acids and has a molecular mass of 18.8 KD.

• Half-life ~ 3.5 hrs (IV or SC)• Clearance increases as blood neutrophil

concentration increases. (negative feedback mechanism)

Pegfilgrastim is a polyethylene glycol-conjugated version of filgrastim designed for longer half-life, thereby necessitating fewer injections. ~33 hours

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Effects of Filgastrim• Accelerates production through reduction

of transit time from stem cell to mature neutrophil.

• Inhibition of neutrophil apoptosis.• Stimulates the entry of quiescent stem and

progenitor cells into cell cycle.

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Side Effects of Filgastrim

• Most common is mild to moderate bone pain.

• Splenomegaly is reported in chronic use.• Transient Dyspnea, pulmonary infiltrates.• Transient neutropenia in iv administration.

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Guidelines for Use

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• Highlights:– Primary Prophylaxis– Secondary Prophylaxis– To enable delivery of dose dense chemotherapy– Adjunct to stem cell Transplant– Delayed engraftment graft failure– AML / ALL– Myelodysplastic Syndromes

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Primary Prophylaxis

• Administered in first cycle of treatment.– Regimen with more than 20% incidence of FN– A decrease in dose intensity compromising

survival/cure– Patient at risk of serious complications from

FN (age, low PS, Infection, prior large RT field)• Primary prophylaxis results in relative risk

reduction of FN by 50 - 90%

FN, febrile neutropenia

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Secondary Prophylaxis• "Secondary prophylaxis with CSFs is

recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative."

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Secondary Prophylaxis• "Secondary prophylaxis with CSFs is

recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative."

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Secondary Prophylaxis

• "No definitive conclusions can be drawn regarding the benefits of secondary prophylaxis on survival, quality of life, or cost. Randomized trials to properly test the hypothesis are required."

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Therapy for febrile Neutropenia• CSFs should not be routinely used as

adjunctive treatment with antibiotic therapy.• Should be only considered in:

– Expected prolonged (> 10 days) and profound (<100/cmm) neutropenia,

– Age greater than 65 years, – Uncontrolled primary disease, – Pneumonia, hypotension and multiorgan

dysfunction, sepsis, invasive fungal infection,– Being hospitalized at the time of the

development of fever.

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To Increase Chemotherapy Dose-Density

• Survival benefit shown in a few specific settings (eg, node-positive breast cancer)

• 2,005 patients randomly assigned to receive one of the following: (I) sequential A × 4 → T × 4 → C × 4,doses 3 wkly, (II) sequential A × 4 → T × 4 → C × 4 doses 2 wkly with filgrastim, (III) concurrent AC × 4 → T × 4 every 3 weeks,(IV) concurrent AC × 4 → T × 4 every 2 weeks with filgrastim.

Four-year DFS was 82% for the dose-dense regimens and 75% for the others

Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741

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Not Recommened in

• Treatment of established neutropenia in afebrile patients.

• Use of CSF to increase dose intensity.• Concurrent administration of CSFs with

chemotherapy and radiation therapy should be avoided.

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Initiation, Duration, Dosing, and Administration

• Should be given 24 to 72 hours after the administration of myelotoxic chemotherapy.

• CSF should be continued ANC reachesat least 2,000/mmc.

• In adults, the recommended : 5μg/kg/d

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• Recommendations:– Patient with increased risk of FN.– Regimen with increased risk of FN.– To support intensive chemotherapy regimens.– In patients with existing FN. (marginally

improves the time spent in hospital and time to recover from neutropenia)#

# J Clin Oncol. 2005 Jun 20;23(18):4198-214.Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials.Clark OA, Lyman GH, Castro AA, Clark LG, Djulbegovic B.Hospital Celso Pierro/PUC-Campinas, Sao Paulo, Brazil.

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20*NCCN

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Summary

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Summary

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Thank you