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Optimum Methods to Mobilize Stem Cells

Indiana Blood and Marrow Transplantation Indianapolis, IN

To the Editor:The comparison by Koç et al¹ of two methods of peripheral-blood progenitor-cell mobilization, cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) versus the combination of granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF, demonstrated a 2.5-fold increase in the number of CD34⁺ cells mobilized by the chemotherapy-containing arm (and a similar increase in the number of colony-forming units–granulocyte-macrophage) in a randomized, matched-pair analysis. The data support that the combination of cyclophosphamide and G-CSF is superior to the combination of GM-CSF and G-CSF, but the difference is probably less than that reported using this data. In the study design, patients were randomized to receive one of the two combinations initially and then the other combination during a second progenitor-harvesting procedure after a 2-week washout period. It is possible that the method of initial progenitor mobilization might influence the second collection. Indeed, a published observation using the combination of cyclophosphamide and etoposide plus G-CSF convincingly showed that an initial program of treatment can influence the outcome of second harvesting procedures, possibly owing to stem-cell exhaustion by aggressive chemotherapy programs.² The data of Koç et al also support this concept. Only one of the 10 patients who first received chemotherapy (Fig 2A) had similar or improved collections using cytokines alone during the second harvest, whereas five of 13 patients had similar or improved numbers of progenitors when cytokines were used during the first harvest and chemotherapy plus G-CSF was used in the second harvest (Fig 2B). The mean number of progenitors also was lower (CD34⁺ cells 0.7 x 10⁶/kg v 1.73 x 10⁶/kg) if cytokine mobilization followed rather than preceded the collection mobilized by cyclophosphamide and G-CSF, although the number of patients seems too small to be statistically significant. Hence, if the data were limited to just the patients mobilized by GM-CSF plus G-CSF during the first harvest and cyclophosphamide and G-CSF during the second, then the relative improvement by the chemotherapy combination becomes less (2.2-fold v 4.2-fold for CD34⁺ cells). Similar results have been published using matched-pair analysis of double harvests in a more homogeneous population in which all patients were mobilized with G-CSF first and then chemotherapy plus G-CSF in the second harvest.³ Nonetheless, there is a significant increase.

Decisions made on the basis of the degree of enhancement of stem-cell mobilization are not clinically trivial, because patients will either be exposed to increased treatment-related toxicity with chemotherapy-containing mobilizing regimens or to increased numbers of apheresis procedures with cytokine-only programs. Most centers are now using a different goal for progenitor collection, 5 x 10⁶ CD34⁺ cells/kg, rather than the value of 2 x 10⁶ reported in the Koç et al¹ article, so the relevant question continues to involve whether the additional cost/benefit associated with chemotherapy-containing programs is worth the expense and risk. This article suggests that the cost per CD34⁺ cell harvested is the same regardless of mobilization strategy. Cost analysis in a similar matched-pair study of sequential progenitor harvests reached the conclusion that despite the fact that a chemotherapy-containing program improved stem-cell mobilization, the overall expense and toxicity were not cost effective.³ Clearly, new, less toxic, more cost-effective progenitor-cell mobilization strategies than GM-CSF plus G-CSF or cyclophosphamide plus G-CSF that can reach a target goal of 5 x 10⁶ progenitors in the fewest number of collections are needed. Koç et al¹ support the important observation that enhanced progenitor-cell mobilization can occur using chemotherapy-based treatments, and now the goal is to find an even better treatment strategy that avoids chemotherapy-related side effects.

REFERENCES

1. Koç ON, Gerson SL, Cooper BW, et al: Randomized cross-over trial of progenitor-cell mobilization: High-dose cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor plus G-CSF. J Clin Oncol 18:1824–1830, 2000[Abstract/Free Full Text]

2. Akard LP, Wiemann M, Thompson J, et al: Impaired stem cell collection by consecutive courses of high-dose mobilizing chemotherapy using cyclophosphamide, etoposide and G-CSF. J Hematother 5:271–277, 1996[Medline]

3. Akard LP, Thompson JM, Dugan MJ, et al: Matched-pair analysis of hematopoietic progenitor cell mobilization using G-CSF vs. cyclophosphamide, etoposide, and G-CSF: Enhanced CD 34+ cell collections are not necessarily cost-effective. Biol Blood Marrow Transplant 5:379–385, 1999[Medline]

Response

Case Western Reserve University Cleveland, OH

In Reply:We appreciate Dr Akard’s comments regarding three important observations made in our article¹ and his prior work.^2,3 These include (1) clear demonstration of a higher number of CD34⁺ cells mobilized using chemotherapy plus cytokines compared with cytokines alone in the same patient, (2) the effect of the first mobilization regimen on the subsequent one, and (3) the increased cost of chemotherapy and cytokines owing to treatment-related complications and chemotherapy administration. We would like to stress the importance of a randomized cross-over study design, which permits statistically significant comparisons with relatively small numbers of patients between various mobilization regimens by eliminating interpatient variability. This approach should be used to test new, less toxic, and potentially more effective stem-cell mobilization strategies.

REFERENCES

1. Koç ON, Gerson SL, Cooper BW, et al: Randomized cross-over trial of progenitor-cell mobilization: High-dose cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor plus G-CSF. J Clin Oncol 18:1824–1830, 2000

2. Akard LP, Wiemann M, Thompson J, et al: Impaired stem cell collection by consecutive courses of high-dose mobilizing chemotherapy using cyclophosphamide, etoposide and G-CSF. J Hematother 5:271–277, 1996

3. Akard LP, Thompson JM, Dugan MJ, et al: Matched-pair analysis of hematopoietic progenitor cell mobilization using G-CSF vs. cyclophosphamide, etoposide, and G-CSF: Enhanced CD 34+ cell collections are not necessarily cost-effective. Biol Blood Marrow Transplant 5:379–385, 1999

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