Page 1714 - Hematology_ Basic Principles and Practice ( PDFDrive )

1524 Part IX Cell-Based Therapies

effects on different WBC populations have been identified, as have a have inadequate collections because only small numbers of HSCs are
number of chemokine receptors. The roles of chemokines and che- present in the peripheral blood despite the administration of hema-
mokine receptors in the trafficking of HSCs into and from the bone topoietic cytokines. Of note, the number of days of apheresis also
marrow compartment are under active investigation. 84 predicts the kinetics of neutrophil engraftment independent of the
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In a preclinical study, administration to both mice and rhesus CD34 cell dose infused, indicating an undefined measurement of
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monkeys of a modified CXC chemokine growth-related oncogene-β graft quality, probably a reflection of the various quantities of CD34
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after 4 days of G-CSF resulted in a fivefold increase in the number cell subsets and CD34 stem cells, as well as the characteristics of the
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of circulating stem and progenitor cells compared with G-CSF alone, stem cell niche. Patient-specific factors predictive of poor mobiliza-
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with also a much shorter time course of release, measured in hours. tion include older age, marrow disease, prior radiotherapy, and prior
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Furthermore, more rapid recovery of hematopoietic function was chemotherapy. Approximately 50% of patients who fail to achieve
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observed for animals given similar quantities of cells collected after the targeted dose of CD34 cells will achieve this goal on a second
administration of the chemokine and cytokine combination. IL-8, a attempt. High-dose (15 mg/kg twice daily) G-CSF after a 2- to
related ligand for the CXCR2, mobilizes stem cells within 15 to 30 4-week drug holiday to allow marrow recovery is one strategy. Com-
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minutes of injection into mice, which appears to involve increased bination cytokine therapy is also of potential value in this situation,
matrix metalloproteinase-9 activity detectable immediately before the and the combination of SCF with G-CSF may be effective for
appearance of HSCs in the peripheral circulation. Murine studies patients who reside in countries where SCF is available. The addition
demonstrate a mobilizing effect of the chemokine SDF-1 and its of GM-CSF to G-CSF is not of proven value. The addition of
receptor CXCR4 that can be blocked by neutralizing antibodies to plerixafor will often be effective when used in combination with
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either. The bicyclam molecule plerixafor disrupts SDF-1/CXCR4 G-CSF for collection of PBSCs from patients who failed a prior
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binding and has been shown to result in mobilization of HSC in mobilization attempt. Treatment with the use of cyclophospha-
murine, canine, and nonhuman transplant models. mide- or ifosfamide-based mobilizing chemotherapy plus a cytokine
Similar signaling pathways are used for mobilization and homing regimen also will be effective, but will be associated with increased
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of normal and malignant hematopoietic cells. Although PBSC toxicity. Bone marrow collection is very unlikely to achieve an
products collected after G-CSF mobilization generally contain fewer acceptable product in that the poor mobilization of PBSCs predicts
detectable tumor cells than does bone marrow harvested from the for a poor marrow harvest. Patients who fail initial collection attempts
same patient, the effects of chemokine treatment on the degree of will frequently fail subsequent attempts, and transplantation of these
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PBSC contamination and on disease relapse after autologous trans- patients with a lower dose of CD34 cells (as low as 1 × 10 CD34
plantation remain to be elucidated. For example, acute myelogenous cells/kg) may be an option.
leukemia cells express CXCR4 in varying levels and homing of It is, therefore, strongly preferable to avoid collection failure.
primary human acute myeloid leukemia cells into nonobese diabetic/ Consideration should be given to the prophylactic collection of
severe combined immunodeficiency mice is CXCR4 dependent, PBSCs early in the course of treatment for patients who later may be
similar to normal human stem cells. Similar studies of chemokine candidates for autologous HSC transplantation but who are advised
control on tumor cell growth, migration, and metastasis are being to receive multiple courses of therapy or therapy involving alkylating
reported from a number of laboratories. There are now reports of a agents or radiation therapy. HSCs can be collected and cryopreserved
possibly increased risk of posttransplant myelodysplasia or acute before extensive therapy while the patient has good marrow function
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leukemia after transplantation using plerixafor-mobilized cells, and stored for years without obvious progressive loss of engraftment
although others have reported that poor mobilizers (who are more potential.
likely to receive this chemokine) have a higher risk of posttransplant
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myelodysplasia, complicating determination of causation of this
complication of transplantation. Timing of Apheresis
A major problem with chemotherapy-based mobilization regimens
Plerixafor is the difficulty in determining the optimal time to commence HSC
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collection. Apheresis devices can collect only those CD34 cells actu-
Plerixafor (AMD3100) is a small-molecule inhibitor of CXCR4. ally being released into and circulating in the peripheral blood. It is
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Clinical studies of HSC mobilization using plerixafor with or without possible to estimate the quantity of CD34 cells that will be collected
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G-CSF priming are being reported in both healthy donors and during apheresis by multiplying the quantity of CD34 cells in the
patients undergoing autologous or allogeneic HSC transplantation. blood by the total volume of blood processed during the apheresis
In a study involving normal volunteers, a single dose of plerixafor procedure and by the efficiency of the apheresis device in collecting
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was equal in mobilization of CD34 cells to administration of a these cells. If the device has an efficiency of 50% and the patient
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standard 5-day course of G-CSF. However, a single dose of plerixafor undergoes a 10-L exchange, approximately 5 × 10 CD34 cells will
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given on day 5 of a daily course of G-CSF administration resulted in be collected for a peripheral blood level of 10 CD34 cells/µL and
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a further 3.8-fold increase in circulating CD34 cells (as well as B 5 × 10 CD34 cells for a blood level of CD34 cells that is 10-fold
and T cells, which may be important in allogeneic transplantation). higher. Although many protocols call for initiation of apheresis after
Randomized phase III studies conducted in patients undergoing chemotherapy mobilization when the WBC count has recovered to
autologous PBSC transplantation in the treatment of multiple greater than 1000/µL, there is a poor, if any, correlation between the
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myeloma or non-Hodgkin lymphoma demonstrated a clear increase peripheral blood white cell or mononuclear cell counts and the CD34
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in CD34 cells collected by the addition of plerixafor to filgrastim. 91,92 cells in the peripheral blood. Characteristics that suggest a higher
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Plerixafor was also effective in remobilization attempts for patients CD34 cell level are a rapidly rising WBC count, shift in differential
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who failed initial collection goals. Plerixafor clearance is propor- to immature myeloid cells, circulating nucleated red cells, and platelet
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tional to the degree of renal function in patients with renal failure. transfusion independence. However, it is much more cost effective to
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Minor gastrointestinal symptoms appear to be the most common obtain an actual measurement of CD34 cells in the blood and to
toxicities of this medication. time the apheresis collection when these cells are present in adequate
numbers. Fig. 95.3 shows such a relationship for patients with lower
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concentrations of CD34 cells in the peripheral blood and illustrates
Strategies for the Patient Who Is Difficult to Mobilize the very poor collections obtained when the peripheral blood CD34
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count is less than 10/µL. Although there is considerable error in the
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Most patients achieve the targeted dose of CD34 cells after process- enumeration of CD34 cells at levels less than 5/µL, this error is not
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ing 20 to 30 L of blood in one to three apheresis procedures. However, clinically relevant because even a doubling of the CD34 cells in this
approximately 5% to as many as 30% of patients in various series low range still results in a very poor apheresis yield.