Page 1712 - Hematology_ Basic Principles and Practice ( PDFDrive )

1522 Part IX Cell-Based Therapies

profile. Recombinant methionyl human G-CSF (filgrastim) and
Mobilization and Collection of Peripheral Blood Stem Cells for
Autologous PBSC Transplantation recombinant human G-CSF (lenograstim) were the two forms of this
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cytokine initially available for clinical use. There are slight differ-
Five important considerations when prescribing a mobilization regimen ences between these two similar cytokines in their ability to mobilize
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for collection of peripheral blood stem cells (PBSCs) for autologous PBSCs. Watts and colleagues studied 20 healthy volunteers and
transplantation are as follows: (1) A regimen of chemotherapy followed found that peak levels of colony-forming unit–granulocyte-macro-
by granulocyte colony-stimulating factor (G-CSF) results in higher phages (CFU-GMs) in the peripheral blood were 28% higher after
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numbers of circulating CD34 cells than will be found with G-CSF treatment with the glycosylated molecule (lenograstim), attributed to
alone. (2) The choice of chemotherapy (or cytokine alone mobiliza- the higher specific activity of this form. De Arriba and colleagues
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tion) should be appropriate to the disease and stage of disease for treated 30 women with breast cancer in a randomized study of these
the patient. (3) Each cycle of prior chemotherapy and any previous two drugs, using dosages containing bioequivalent units of activity
treatment with radiotherapy will decrease the response to mobilization +
therapy. (4) Tumor infiltration of the marrow will increase the prob- and found no difference in mobilization of CD34 cells. The two
ability of circulating tumor cells and will decrease the response to forms have otherwise similar biologic activity and are not further
mobilization therapy. (5) Some patients will benefit from tandem cycles distinguished in this discussion.
of dose-intense therapy, and the prescription should target adequate Regulatory agencies including the United States Food and Drug
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quantities of CD34 cells for these patients. With these considerations Administration (US FDA), the European Medicines Agency, and
in mind, elective collection of PBSCs either before extensive treatment others established regulatory pathways leading to approval of biologic
or after a limited number of cycles of debulking chemotherapy should medicines that are highly similar to an already-approved biologic
be considered. Additional cycles of chemotherapy can be given after product (“biosimilar”). 65,66 In the US, The Biologics Price Competi-
PBSC collection is completed, for those patients who require further tion and Innovation Act of 2009 created an abbreviated licensure
tumor reduction before proceeding to transplantation. The timing of
apheresis after chemotherapy and G-CSF mobilization is best guided pathway for biological products shown to be “biosimilar” to or
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by measurement of the level of peripheral blood CD34 cells. Daily or “interchangeable” with an FDA-licensed biologic product, known as
every-other-day quantification of these cells can be initiated after the the “reference product.” This abbreviated licensure pathway permits
white blood cell count reaches 1000/µL. Patients with poor mobiliza- reliance on existing scientific knowledge about the safety and effec-
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tion of CD34 cells should be considered for large-volume apheresis tiveness of the reference product, and enables a biosimilar biologic
or addition of a chemokine such as plerixafor to reduce the costs product to be licensed based on less than a full complement of
associated with daily doses of G-CSF, laboratory testing, apheresis product-specific preclinical and clinical data usually required before
procedures, and cryopreservation. Patients who fail to mobilize may marketing of a new drug. The biosimilar must show it has no clini-
have successful collections if given a short drug “holiday” before cally meaningful differences in terms of safety and effectiveness from
undergoing mobilization with high-dose G-CSF with plerixafor.
the reference product. Only minor differences in clinically inactive
components are allowable. Filgrastim-sndz is the first biosimilar drug
approved by the US FDA, and is marketed with the same indication
lineage, macrophages, and mesenchymal stem cells that are respon- for use as filgrastim. Tbo-filgrastim, however, was licensed under a
sible for controlling the balance between HSC quiescence, self- different mechanism, and does not have US FDA approval for use in
renewal, and differentiation. A number of pathways with mutually PBPC collection. The use of a biosimilar G-CSF in mobilization of
recognized cellular adhesion molecules and their respective ligands PBPCs must be extrapolated from laboratory data such as mobiliza-
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responsible for the spontaneous migration of HSCs from the stem tion of CD34 cells, and it is conceivable, although considered very
cell niche, as well as the multistep process of homing back into the unlikely, that differences in the mobilization of stem and other cells,
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niche, have been identified. The mechanisms by which granulocyte as well as in toxicity to the donor, may occur. 67,68 Clinical experience
colony-stimulating factor (G-CSF) and other cytokines promote describing similar mobilization results are now being reported for
mobilization of HSCs are being elucidated and appear to be an these drugs. 69
indirect effect (HSCs do not express receptors for G-CSF) on the
CXC-chemokine receptor 4 (CXCR4)/stromal cell-derived factor-1
(SDF-1) axis mediated by monocytes and the sympathetic nervous Mobilization of Hematopoietic Stem Cells Using
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system. The mechanisms of mobilization by chemotherapy and Granulocyte Colony-Stimulating Factor
CXCR4 antagonists such as plerixafor are also being determined, and
the elucidation of the mechanisms of mobilization and homing may G-CSF is the most potent cytokine currently available for mobiliza-
result in more effective harvesting and transplantation techniques. 59 tion of HSCs. In a randomized study of healthy volunteers comparing
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G-CSF, GM-CSF, and the combination of both, Lane and colleagues
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reported an average 0.99% CD34 cells in the peripheral blood of
Cytokine Mobilization healthy donors treated with 10 µg/kg per day of G-CSF compared
with 0.25% for donors treated with the same dose of GM-CSF. The
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The ability of recombinant hematopoietic cytokines to increase the quantity of CD34 cells in the peripheral blood before treatment
level of myeloid progenitor cells in the blood, as well as mature blood averaged 1.6/µL. After GM-CSF treatment, the level increased to
cells, was reported in 1988 by different groups for both G-CSF and 3/µL, but with G-CSF, the level increased to 61/µL. Each group
granulocyte-macrophage colony-stimulating factor (GM-CSF). 60,61 underwent one leukapheresis on the 5th day of treatment, and the
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Subsequently, a number of different investigators reported the collec- collections from donors treated with G-CSF averaged 119 × 10
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tion of PBSCs from patients using a variety of mobilization regimens, CD34 cells compared with 12.6 × 10 for the donors treated with
including cytokines alone, cytokine combinations, and combinations GM-CSF.
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of chemotherapy with cytokines. Various other recombinant human The appearance of CD34 cells during administration of G-CSF
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hematopoietic cytokines, including erythropoietin and fusion mol- follows a distinct time course, with the maximal level of CD34 cells
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ecules, increase the quantity of CD34 cells in the peripheral blood occurring on day 5 after daily G-CSF administration. Smaller
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but have not been developed for clinical transplantation. numbers of CD34 are present on days 4 and 6, and the level falls
rapidly on subsequent days despite a continual rise in white blood
Granulocyte Colony-Stimulating Factors cell (WBC) count. +
The number of CD34 cells collected after G-CSF treatment is
Including Biosimilars proportional to the number of these cells in the peripheral blood
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before initiation of the cytokine. Although doses as low as 5 mcg/
G-CSF is the cytokine most commonly used because of its efficacy kg/day have been used, there is a dose response to G-CSF, with higher
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compared with other cytokines and its relatively benign toxicity average levels of CD34 cells achieved with 10 mcg/kg/day compared