Page 1713 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 95 Practical Aspects of Hematologic Stem Cell Harvesting and Mobilization 1523

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with 5 mcg/kg/day. With appropriate dosing of allogeneic donors, blood at this highest dose level again was only 8.4-fold. In a random-
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adequate numbers of CD34 cells can be collected in one procedure ized study comparing GM-CSF with G-CSF, or both drugs used in
for transplantation of most patients. A similar dose response is sequence after chemotherapy administration, patients had faster
observed in autologous patients and may extend to doses as high as recovery of counts, required less supportive care including transfu-
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40 mcg/kg/day. An advantage to twice-daily dosing of G-CSF has sions, and achieved greater collections of CD34+ cells if given one
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been suggested but not confirmed. Anderlini and colleagues com- of the G-CSF–containing regimens. 79
pared administration of 6 mcg/kg given twice daily with 12 mcg/kg Administration of GM-CSF results in somatic complaints and
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given once daily and found no differences in CD34 cells per liter of hepatic function abnormalities similar to those reported after G-CSF
blood processed during the apheresis procedure or the total yield of administration. In addition, 44% to 80% of patients experience fever,
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CD34 cells per kilogram collected. In contrast, a second trial enroll- sometimes after each dose, as well as generalized or local skin reac-
ing primarily pediatric patients noted better results with the twice- tions. Doses greater than 20 mcg/kg/day are poorly tolerated because
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daily schedule. Patients, especially those previously treated with of fluid retention, pleural and pericardial inflammation, and venous
chemotherapy or radiotherapy, will generally have lower quantities of thrombosis. A “first-dose reaction”, characterized by hypoxia
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CD34 cells mobilized. 59 and hypotension occurring within 3 hours of administration, has
been described for some recipients, especially after intravenous
Toxicity and Complications of Granulocyte administration.
Colony-Stimulating Factor
Other Hematopoietic Cytokines
The toxicity of G-CSF has been most clearly defined in studies of
allogeneic donors. 30,75,76 The autologous patient will experience a Recognition of the mobilization potential of G-CSF led many
similar toxicity profile, but with the added complications of the investigators to study other hematopoietic cytokines, including
underlying malignancy and its treatment. erythropoietin, monocyte–colony-stimulating factor, interleukin
Almost all recipients of G-CSF will develop somatic complaints, (IL)-3, PIXY 321 (a fusion molecule), and stem cell factor (SCF) for
of which skeletal pain is most prominent (see Fig. 95.1), but also their capacity to mobilize HSCS into the peripheral blood. Used as
including fatigue, insomnia, and nausea. 30,37,38,41,75–77 The somatic single agents, these cytokines resulted in only an approximately 5- to
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complaints are generally tolerable, and few donors will require reduc- 10-fold increase in circulating CFU-GM or CD34 cells.
tion in dose or discontinuation of the medicine. At present, there
appear to be minimal, if any, long-term health risks for the donor.
Few serious complications of the mobilization regimen and donation Chemotherapy Plus Cytokine Mobilization
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process have been reported. G-CSF increases spleen size, with a rare
patient or donor experiencing splenic rupture. G-CSF may induce a The number of HSCs in the peripheral blood is moderately increased
hypercoagulable state, which is of concern for donors (and patients) during the early hematologic recovery phase after marrow hypoplasia-
requiring central venous catheter placement or for those who may producing chemotherapy. Chemotherapy plus cytokine generally
have other risk factors for the development of deep venous thrombosis mobilizes greater numbers of PBSCs than either agent alone. This
(such as air travel immediately after the collection procedures). finding was confirmed in a randomized study comparing cyclophos-
Patients with autoimmune disorders may experience a flare-up of phamide followed by G-CSF versus G-CSF alone, in which higher
their disease during administration of G-CSF, and a variety of case numbers of CD34 cells were found for the patients treated with the
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reports of ophthalmologic and other adverse events have been chemotherapy-based regimen. However, no differences in the degree
reported for healthy donors or patients treated with G-CSF. of tumor cell contamination of PBSC components, speed of hema-
Of concern is the possibility that cytokine administration will tological recovery after transplantation, or survival probability were
increase the risk for marrow dysplasia or malignancy. Although this found. A wide variety of different chemotherapy regimens has been
is a theoretical concern in that these cytokines are known to stimulate used successfully for mobilization of HSCs into the blood, with
growth of leukemia cells, no clinical evidence from large registry cyclophosphamide- or ifosfamide-based regimens being most com-
reviews of healthy donor experiences indicates that these agents will monly used. The primary consideration is that the choice of chemo-
induce abnormalities in the hematopoietic stem cell. 77,78 therapy used for mobilization must also meet the treatment needs of
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G-CSF administration results in a number of changes in blood the patient. Demirer and colleagues studied the effect of different
counts and chemistries in addition to the coagulation factor changes. chemotherapy regimens for mobilization of HSCs for patients with
Alanine aminotransferase, lactate dehydrogenase, and alkaline phos- breast cancer. Four regimens were used, all involving cyclophospha-
phatase levels increase, and the levels of blood urea nitrogen and bili- mide (CY), but including etoposide with or without cisplatin, or
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rubin may decrease. The elevation in alkaline phosphatase level is paclitaxel. All patients also received G-CSF. The median quantity of
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primarily of bone origin; γ-glutamyl transferase levels remain normal. CD34 cells collected on the first day of apheresis after cyclophos-
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These abnormalities of serum chemistries resolve within 2 weeks after phamide mobilization was 0.9 × 10 per kilogram of patient weight.
discontinuation of the medication. G-CSF administration also will The addition of etoposide and then of etoposide and cisplatin
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result in a decrease in platelet count, especially if the cytokine is increased the first-day yield to 8.1 × 10 and 3.5 × 10 CD34 cells/
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administered over 5 to 10 days. WBC counts fall rapidly after kg, respectively, in separate cohorts of patients. The median number
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discontinuation of G-CSF. In approximately 10% of donors, the of CD34 cells harvested on the first day of apheresis after cyclophos-
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WBC count may fall to abnormal levels (but generally still remain phamide plus paclitaxel was 11.1 × 10 /kg, and more than 50% of
above 1000/µL), reaching a nadir 10 to 14 days after discontinuation the women mobilized with this last regimen achieved the target dose
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of the cytokine before stabilizing at normal levels. of CD34 cells in one apheresis procedure. Of the 100 women
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studied, 94 achieved the target dose of greater than 5 × 10 CD34
cells/kg. Only four patients failed to reach a lower but acceptable dose
Granulocyte-Macrophage Colony-Stimulating Factor of 2.5 × 10 CD34 cells/kg.
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Much of the early experience with the use of hematopoietic cytokines
for mobilization of HSCs involved GM-CSF and chemotherapy. 61,79 Chemokines
GM-CSF is not as potent as G-CSF, 70,79 although as with G-CSF,
there is a dose response in mobilization of PBSCs with GM-CSF over Chemokines (chemoattractant cytokines) are a family of approxi-
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a range from 0.3 to 30 mcg/kg/day, without a plateau. In this mately 40 related small proteins that influence leukocyte (and
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dose-ranging study, however, the average increase in CFU-GM in the malignant cell) migration and function. Chemokines with varying