1. John Murray Nurse Clinician EBMT
e-learning GCSF
John Murray
Nurse Clinician EBMT

2. Contents 1 What is GCSF 2 Biology 3 How was GCSF discovered 4 History
6 GCSF manufacturers
7 How does it work
8 Approved uses
9 Types of GCSF available
10 Instructions on use

3. What is GCSF? GCSF stands for ‘Granulocyte Colony Stimulating Factor’
GCSF and Granulocytes are produced by endothelium, macrophages and other immune cells. There are 3 types of granulocyte
GCSF has 2 structural forms; with 174 & 180 amino acids
GCSF was first discovered while testing Heamopoetic Stem Cells (HSCs) for colony stimulating substances.
Neutrophil
Eosinophil
Basophil

4. White Blood Cells

5. History
1983 Australia Walter and Eliza Hall Institute purified mouse GCSF
Groups in Japan Germany & USA followed in 1986 with human clone version
Amgen - neupogen (filgrastim) 1989
Chugai –
granocyte (lenograstim) 1991
1983
1986
1989
1991

6. How was GCSF discovered?
Haemopoietic stem cells were cultured on a semi solid matrix (SSM)
When a single cell (10) starts proliferating, all of the cells derived from it (20) will remain clustered
Hence the substance discovered to stimulate granulocytes was called ‘Granulocyte Colony Stimulating Factor’ or ‘GCSF’
The name ‘colony-stimulating factor’ or ‘CSF’ comes from the discovery method
It was then possible to test substances on the colonies and examine which colonies were stimulated 20 20 20 10 10
1. The name ‘colony-stimulating factor’ or ‘CSF’ comes from the discovery method
2. Haemopoietic stem cells were cultured on a semi solid matrix (SSM)
3. When a single cell (10) starts proliferating, all of the cells derived from it (20) will remain clustered
4. It was then possible to test substances on the colonies and examine which colonies were stimulated
5. Hence the substance discovered to stimulate granulocytes was called ‘Granulocyte Colony Stimulating Factor’ or ‘GCSF’

7. Biology
In order to interact with the cell, there must be GCSF receptors present
The GCSF receptor is present on precursor cells in Bone Marrow
In response to GCSF, cell signalling mechanisms instruct the cell to proliferate and differentiate into mature granulocytes
Main use is for
HSC mobilisation
Decreasing incidence of neutropenia

8. How does it work?
GCSF binds to surface receptors of neutrophil precursors and mature neutrophils stimulating
Proliferation
Differentiation
Commitment, and
End cell function

9. Approved uses
Most UK centres base their practice on guidelines published by
British Committee for Standards in Haematology (BCSH), 2003
American Society of Clinical Oncology (ASCO), 2006
National Comprehensive Cancer Network clinical guidelines
Local policy and procedure must be adhered to, please refer to
Trust SOP agreed criteria
JACIE agreed criteria

10. Primary prophylaxis Primary prophylaxis
Not routinely recommended in previously untreated patients undergoing induction chemotherapy
Primary GCSF treatment may be warranted in high-risk patient populations where the incidence of febrile neutropenia (FN) is at least 40%
In patients with diffuse aggressive lymphoma aged > 65 years
Pre-existing neutropenia
Extensive prior chemotherapy
Previous irradiation to the pelvis or other areas containing large amounts of bone marrow
A history of recurrent febrile neutropenia while receiving earlier chemotherapy of similar or lesser dose
Conditions that potentially enhance the risk of serious infection (Poor performance status, active infection, decreased immune function)

11. Secondary prophylaxis
Adjunctive use
The evidence suggests that GCSF’s should not be used routinely as adjunctive therapy to antibiotics in patients with uncomplicated febrile neutropenia (FN) of duration <10 days or afebrile neutropenia.
However, the ASCO guidelines suggest that the use of GCSF’s should be considered in patients at high risk of infection associated complications and adverse prognostic factors, such as those with Adjuvant chemotherapy
Profound neutropenia (ANC < 0.1x10e9/L)
Pneumonia
Hypotension
Multi organ dysfunction (sepsis syndrome)
Invasive fungal infection
Elderly patients >65 years or those with post-treatment lymphopenia
Expected prolonged duration of neutropenia >10 days
Secondary prophylaxis
This was proposed as a treatment for patients who have had an episode of febrile neutropenia with a previous course of chemotherapy. The patient would be able to continue with the equivalent chemotherapy dose or not have significant treatment delays if used.
Possible clinical contexts for secondary prevention might include
Adjuvant chemotherapy
Chemotherapy for germ cell tumours
Elderly patients with high grade NHL
Dose escalated or intensive schedules for Hodgkin’s and Non-Hodgkin’s lymphoma
AML following consolidation treatment
AML following induction treatment if appropriate to reduce hospital stay and antibiotic use
ALL following intensive phases of therapy
In patients who have previously experienced episodes of complicated neutropenia
Adjunctive use
The evidence suggests that GCSF’s should not be used routinely as adjunctive therapy to antibiotics in patients with uncomplicated febrile neutropenia (FN) of duration <10 days or afebrile neutropenia.
However, the ASCO guidelines suggest that the use of GCSF’s should be considered in patients at high risk of infection associated complications and adverse prognostic factors, such as those with Adjuvant chemotherapy
Profound neutropenia (ANC < 0.1x10e9/L)
Pneumonia
Hypotension
Multi organ dysfunction (sepsis syndrome)
Invasive fungal infection
Elderly patients >65 years or those with post-treatment lymphopenia
Expected prolonged duration of neutropenia >10 days

12. With chemotherapy Acute Myeloid Leukemia (AML)
The routine use of CSF is recommended after consolidation chemotherapy (level Ib, Grade A). CSF is recommended after induction if it is appropriate to reduce hospital stay or antibiotic usage.
Acute Lymphoblastic Leukemia (ALL)
GCSF is indicated to reduce the severity of neutropenia following intensive phases of therapy (level Ib, grade A).
Myelodysplastic Syndrome (MDS)
CSF’s are indicted to reduce the severity of neutropenia in patients receiving intensive chemotherapy (level Ib, grade A). CSF’s are also recommended on an intermittent basis for patients with neutropenia and infection (level IV, grade C), but continuous prophylactic use is not routinely justified.

13. Bone marrow failure syndromes
With chemotherapy
Aplastic anaemia
There is insufficient evidence to make any general recommendations and hence patients should be given CSF’s only on an individual therapeutic trial basis (level IV, grade C).
Bone marrow failure syndromes
GCSF is recommended when improvement of neutrophil count is appropriate (level III, grade B).
Malignant lymphomas
There is evidence to support the routine use of CSF’s to reduce the incidence of infection, chemotherapy delay and hospitalization especially when the risk of febrile neutropenia exceeds 40% (level Ia, grade A). There is also emerging evidence of improved survival with GCSF-supported dose intensification in elderly patients with high-grade NHL (level Ib, grade A). At present, this evidence is insufficient to justify a change in policy in all patients with lymphoma, but elderly patients may benefit from G-CSF support.

14. Mobilisation
G-CSF’s are recommended by the BSCH for the mobilisation of peripheral blood progenitor cells (PBPC)
Dose is calculated by weight; reference tables are available in Mount Vernon Guidelines 2010.
GCSF can be used alone or in conjunction with chemotherapy.
Biosimilars not recommended by EBMT 2011
The recent and pending patent expirations for a number of biopharmaceuticals have prompted the study and development of alternative versions of biological products referred to as biosimilars. Unlike generics of small molecules that are considered identical to the reference product, biosimilars are drugs similar but not identical to the innovative drug, characteristics of which are closely related to the manufacturing process. Guidelines for approval of biosimilars have been issued by the EMEA and vary according to the product. In general, the approval of biosimilars is based on the demonstration of equivalent efficacy and safety to the innovator product in comparative studies. In the case of G-CSF, equivalence has to be demonstrated in the prophylaxis of severe cytotoxic chemotherapy-induced neutropenia and extrapolation of efficacy to the other indications of the reference product (e.g. mobilisation of stem cells) is then allowed. Because there is a limited clinical database on approval of a biosimilar ( patients app.), pharmacovigilance is becoming essential, particularly as only six-month follow up is needed for safety in registration studies.
Considering the limited experience with G-CSF biosimilar’s and the extrapolation process for approval in less common indications, we feel that the use of biosimilar’s for stem cell mobilisation and collection in healthy donors presents an ethical dilemma. Since healthy donors receive no therapeutic benefit from the receipt of G-CSF’s for stem cell mobilisation, ethical concerns dictate that drug safety is of paramount concern for these individuals. Considering the detrimental effect that unexpected toxicity might have in normal individuals, sufficient experience with the biosimilar product and adequate follow up should be required. Therefore the EBMT recommends evaluation of efficacy and safety data for stem cell mobilisation before using biosimilar G-CSF in healthy donors. This can only be obtained by performing clinical trials with an adequate number of stem cell mobilisation procedures with adequate follow up in autologous conditions. Until studies have been performed to provide the required efficacy and safety data, the EBMT does not recommend the use of biosimilar G-CSF’s for mobilisation of stem cells in healthy donors for stem cell transplantation.

15. Granocyte/Lenograstim
GCSF manufacturers
Zarzio
Biosimilar
Sandoz produce via the e-coli method
Neulasta
Original
Amgen produce via the e-coli method
Nivestim
Biosimilar
Hospira produce via the e-coli method
Granocyte/Lenograstim
Original
Chugai produce by synthesis in Chinese Hamster Ovary (CHO) cells, this process makes it indistinguishable from human GCSF
Neupogen/Filgrastim
Original
Amgen produce by recombinant technology: The human GCSF gene is inserted into an e-coli bacteria which in turn produces GCSF
Although pharmacologically equivalent, there is a slight difference between e-coli and CHO cell derived GCSF pharmacokinetically
Lenograstim
Original
Chugai produce by synthesis in Chinese Hamster Ovary (CHO) cells, this process makes it indistinguishable from human GCSF
Filgrastim
Amgen produce by recombinant technology: The human GCSF gene is inserted into an e-coli bacteria which in turn produces GCSF
Neulasta
Amgen produce via the e-coli method
Nivestim
Biosimilar
Hospira produce via the e-coli method
Zarzio
Sandoz produce via the e-coli method
Although pharmacologically equivalent, there is a slight difference between e-coli and CHO cell derived GCSF pharmacokinetically

16. How to administer…

17. GRANOCYTE
Instructions

18. GRANOCYTE
Instructions

19. GRANOCYTE
Instructions

20. GRANOCYTE
Instructions

21. NEUPOGEN Instructions How do I prepare my Neupogen injection?
Before you inject Neupogen you must do the following:
2 Do not touch the needle or push the plunger.
You may notice a small air bubble in the pre-filled syringe.
You do not have to remove the air bubble before injecting. Injecting the solution with the air bubble is harmless.
3 You can now use the pre-filled syringe.
1 To avoid bending the needle, gently pull the cover from the needle without twisting as shown in pictures 1 and 2.
The best places to inject are the top of your thighs and the abdomen. If someone else is injecting you, they can also use the back of your arms.
You may change the injection site if you notice the area is red or sore.
How do I prepare my Neupogen injection?

22. NEULASTA
Instructions

23. NEULASTA
Instructions

24. NEULASTA
Instructions

25. NEULASTA
Instructions

26. NIVESTIM
Instructions

27. NIVESTIM
Instructions

28. NIVESTIM
Instructions

29. ZARZIO
Instructions

30. ZARZIO
Instructions

31. ZARZIO
Instructions

32. GCSF Common Side Effects
Bone pain
Red itchy skin
Fever and chills
Fluid retention

33. Plerixafor Originally for HIV and manufactured by Genzyme
Works as a HSC mobiliser
Licensed for lymphoma and myeloma poor mobilisers in conjunction with GCSF
Dose
Plerixafor (Mozibil™) ADULT over 18 years, 240 micrograms/kg daily 6-11 hours before initiation of apheresis; usual duration 2-4 days (max. 7 days) by subcutaneous injection. Mozobil injection supplied as 1.2mL-vial
Indications
Peripheral Blood Stem Cell Mobilisation, with GCSF in patients with Lymphoma or Myeloma
Instructions for injecting Plerixafor
You will most likely receive your Plerixafor injections at your transplant center or hospital, depending on hours of operation.
Plerixafor will be given to you as an injection under your skin (this is called a subcutaneous injection).
A member of your healthcare team will inject the medication into a fleshy part of your body (such as your hip or leg).
Plerixafor is given in combination with GCSF. Your doses of GCSF should be given each day starting 4 days before your first evening dose of Plerixafor and every morning you are scheduled for a session of apheresis.

34. Thank you