Techniques for Stem Cell Mobilization

Large increases in the number of circulating stem and progenitor cells occur during recovery from myelosuppressive chemotherapy, typically when the absolute neutrophil count (ANC) has reached 1000/pl and rapidly rising. The exact point of maximal stem cell mobilization is difficult to predict and highly patient dependent (see Commonly, cyclophosphamide (a total dose of 4 g/m2 over 2 days) has been used. Multiple-drug regimens as part of the primary treatment can also be used to induce a nadir after which PBSC collection is possible. Because of the concern that the DNA damage may occur in hematopoietic stem cells, and hence increased risk of secondary (treatment-related) leukemia, topoiso-

merase inhibitors (e.g., etoposide) are often not used to induce the nadir. In one study, use of PBSC collected after etoposide resulted in a 7- to 12-fold relative risk of secondary leukemia (Krishnan et al. 2000), with other studies also demonstrating an increased risk attributable more to the prior chemotherapy than to the preparative regimen used for the stem cell transplant (Kollmannsberger et al. 1998). This effect, together with the observation that multiple cycles of chemotherapy reduce yields of PBSC collection (Jerjis et al. 2000), argue that PBSC should be collected as early in treatment as possible, but after sufficient therapy (usually two to three cycles of chemotherapy) to clear circulating tumor (Faulkner et al. 2000; Moss et al. 1990).

The use of chemotherapy to mobilize PBSC may not be possible or desirable in every patient, has a risk of toxicity during the nadir, and is clearly not appropriate for normal allogeneic donors in whom the chemotherapy has no potential benefit. An alternative approach of using hematopoietic growth factors (HGF) is in widespread use. Donors are placed on a daily regimen of HGF injections, followed by initiation of PBSC collection on day 4-5 of treatment. The HGF treatment continues until the apheresis is complete. There are several choices of HGF doses and regimens (Table 11.6.3). Filgrastim (rhuG-CSF) is the most common HGF used for this purpose. Doses given vary widely. There is a modest dose-response effect between 2 and 16 mg/kg of G-CSF. Although doses as high as 24 mg/kgday-1 have been used for mobilization, there is little evidence that these very high doses are more efficacious and they have the disadvantage of greater cost and higher incidence of side effects, especially bone pain.

Sargramostim (rhuGM-CSF) is an alternative. Comparisons of G-CSF and GM-CSF as single agents reveal either no significant advantage of one HGF over the other in terms of PBSC collection efficiency or extent of progenitor cell mobilization (Gazitt 2002), or a modest advantage for G-CSF (Weaver et al. 2001). Laboratory studies have suggested that PBSC collected after G-CSF mobilization may have a polarization in T-cell response toward the more suppres-sive T-helper lymphocyte type 2 (Th2) response (Sloand et al. 2000). This may have a theoretical

Table 11.6.3 Regimens for PBSC mobilization advantage for (a) recovery of cellular immunity after SCT, and (b) the risk of graft-vs-host disease after allogeneic SCT. The combination of G-CSF and GM-CSF may be superior to either alone, although one pediatric study failed to show an advantage for the combination.

The one setting in which the combination of G-CSF plus GM-CSF may be superior is when a patient has had inadequate numbers of stem cells collected over several aphereses. In these so-called poor mobi-lizers, combination HGF regimens may improve the likelihood that adequate PBSC can be collected (Stiff 1999). Other HGF have been tested as PBSC mobiliz-ers, including stem cell factor and thrombopoietin, but there is no evidence to suggest superiority in terms of clinical outcome during transplant over the standard use of G-CSF, even when higher numbers of CD34+ cells are collected. On the other hand, collection of higher numbers of CD34+ cells has the potential to reduce the number of LVL a donor must undergo, which is a benefit in terms of cost, convenience, and potential donor exposure, especially in children. Balanced against this is the high cost of HGF, and the fact that adding a second HGF doubles this cost. In patients who are receiving myelosup-pressive chemotherapy, HGF such as filgrastim are often used to improve recovery. The concurrent use of chemotherapy and an HGF improve PBSC mobilization as well (Knudsen et al. 1996; Levine and Boxer 2002), although a randomized trial did not show this improved mobilization to have an impact on survival or engraftment (Narayanasami et al. 2001). Thus, any patient receiving chemotherapy after which PBSC collection is planned should be placed on an HGF, even if similar courses during the treatment are not supported by an HGF.

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