Chemotherapy Plus Growth Factors For Stem Cell Mobilization

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Although chemotherapy alone can produce increases in progenitors in PB, multiple phase II studies have shown that the addition of growth factors such as G-CSF and GM-CSF to myelosuppressive chemotherapy enhances mobilization and allows for more progenitors to be collected with fewer apheresis procedures while reducing myelotoxicity. Siena et al.37 reported that after highdose CY, an approximately 30-fold expansion of CFU-GM numbers was observed. This increase was further magnified, to over 100 times control values, when GM-CSF was given to accelerate post-CY hematopoietic recovery. These precursors were both increased in number and enriched in the more immature forms. In addition, there was an increase of the most immature CD34+ /CD33- progenitors to multipotent and unipotent colony-forming cells (CD34+ /CD33+) in PB. In a randomized cross-over trial reported by Koc et al.,38 high-dose CY plus G-CSF results in mobilization of more progenitors than GM-CSF plus G-CSF when tested in the same patient regardless of whether CY+GCSF was given as the first or second mobilizing strategy.

The magnitude of the increase in circulating stem cells is related to the intensity of myelosuppressive chemotherapy used. Cyclophosphamide at doses of 1.5, 4, or 7 g/m2 and G-CSF or GM-CSF are effective in mobilizing PBSC; however higher stem-cell yields were obtained with higher doses of CY (7 g/m2).39 When G-CSF was administered from the day after CY, white blood cell (WBC) decreased reaching a nadir around day 7 or 8 followed by an abrupt increase in WBC and PB CD34+ cell counts. Peak circulating CD34+ cells and progenitors were seen on approximately day 9 or 10. PBSC collection usually begins on day 10 or when WBC > 1 X 109/L.

While high-dose CY followed by GM-CSF or G-CSF is the most frequently chemotherapy/growth factor mobilization regimen, it has several limitations, including potential cardiotoxicity, hemorrhagic cystitis, nausea, and vomiting. Several investigators have reported the effectiveness of high-dose etoposide (2 g/m2) with GM-CSF or G-CSF as a mobilizing strategy.40 It is associated with minimal nonhematologic toxicity and has antitumor activity. Several other combination chemotherapy regimens are also effective for stem cell mobilization. Studies suggest that the combination of CY + etoposide, or CY + Taxol or CY+ etoposide + cisplatin are more effective than CY alone.

The dose and type of growth factor utilized with chemotherapy may also be important. Although GM-CSF was the first cytokine to enhance PBSC mobilization by chemotherapy, it is now less commonly used than G-CSF, probably because of side effects such as fever and hypoxemia. The dose of G-CSF used with chemotherapy is lower than when used alone for stem cell mobilization (10-24 ^g/kg per day). A higher dose of G-CSF 16 ^g/kg per day rather than a lower dose of 8 ^g/kg per day was more effective in patients with a variety of malignancies. In a randomized trial reported by Weaver et al.,41 G-CSF or GM-CSF followed by G-CSF after mobilizing chemotherapy was more effective in patients with solid tumors and hematologic malignancies than GM-CSF. In contrast, for patients with NHL, GM-CSF followed by G-CSF permitted more efficient collection of a target number of CD34+ cells than did GM-CSF, while G-CSF was the least efficient of the three cytokine strategies.

It is difficult to conclude which combination of chemotherapy and growth factor is the optimal regimen given the heterogeneity of patient population, the different mobilizing chemotherapy regimens, and the different cytokines used. Moreover, there is no difference in time to recovery of neutrophils and platelets among patients transplanted with PBSC mobilized by different techniques as long as a minimum number of CD34+ cells/kg is given. In general, chemotherapeutic agents that are effective for underlying malignancies should be used for pretransplant cytoreduction as well as PBSC mobilization.42 Agents that are known to damage stem cells such as melpha-lan should be avoided.

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