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

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

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

White Blood Cells

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

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’

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

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

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

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)

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

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.

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.

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 (500-600 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.

Granocyte/Lenograstim GCSF manufacturers Zarzio Biosimilar Sandoz produce via the e-coli method http://www.zarzio.com/ Neulasta Original Amgen produce via the e-coli method http://www.neulasta.com/ Nivestim Biosimilar Hospira produce via the e-coli method http://www.nivestim.eu/ Granocyte/Lenograstim Original Chugai produce by synthesis in Chinese Hamster Ovary (CHO) cells, this process makes it indistinguishable from human GCSF http://www.chugai-pharm.co.uk/products Neupogen/Filgrastim Original Amgen produce by recombinant technology: The human GCSF gene is inserted into an e-coli bacteria which in turn produces GCSF http://www.neupogen.com/ 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

How to administer…

GRANOCYTE Instructions

GRANOCYTE Instructions

GRANOCYTE Instructions

GRANOCYTE Instructions

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?

NEULASTA Instructions

NEULASTA Instructions

NEULASTA Instructions

NEULASTA Instructions

NIVESTIM Instructions

NIVESTIM Instructions

NIVESTIM Instructions

ZARZIO Instructions

ZARZIO Instructions

ZARZIO Instructions

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

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.

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