Factors Associated with Peripheral Blood Stem Cell Yield in Volunteer Donors Mobilized with Granulocyte Colony-Stimulating Factors: The Impact of Donor Characteristics and Procedural Settings

Abstract

Peripheral blood stem cells (PBSCs) are increasingly used as the source of hematopoietic stem cells, but there are large variations in harvest outcome between individuals mobilized by granulocyte colony-stimulating factor (G-CSF). We examined the effects of donor characteristics and procedure factors on the day 1 CD34+ cell yield in 373 unrelated healthy donors. G-CSF was administered subcutaneously at a planned dose of 8.3 to 11μg/kg daily for 5 days, followed by harvest started on day 5 of G-CSF treatment. Of the 373 donors, 159 (42.6%) had the radial artery as the inlet access for harvest. Poor day 1 cell yield was defined as < 10 × 106 CD34+ cells/L of processed blood for the first apheresis; 62 donors (16.6%) did not attain this threshold. The male donors had significantly higher yields at harvest compared with the female donors. The female donors had higher CD34+ cell yields if the circulation access was through an artery than if is was through a vein. In a multiple regression analysis, donor age, sex, body mass index (BMI), preharvest white blood cell and circulating immature cell counts, access type, and flow rate correlated with day 1 yield. Female sex, older age, venous access, and a higher flow rate were significantly associated with greater risk for a day 1 poor yield of CD34+ cells (odds ratio = 3.0074, 1.045, 4.3362, and 1.1131, respectively). A higher BMI may decrease the risk (odds ratio = 0.8472). In donors at higher risk for poor CD34+ cell yield, strategies for increasing CD34+ cells must be considered. Peripheral blood stem cells (PBSCs) are increasingly used as the source of hematopoietic stem cells, but there are large variations in harvest outcome between individuals mobilized by granulocyte colony-stimulating factor (G-CSF). We examined the effects of donor characteristics and procedure factors on the day 1 CD34+ cell yield in 373 unrelated healthy donors. G-CSF was administered subcutaneously at a planned dose of 8.3 to 11μg/kg daily for 5 days, followed by harvest started on day 5 of G-CSF treatment. Of the 373 donors, 159 (42.6%) had the radial artery as the inlet access for harvest. Poor day 1 cell yield was defined as < 10 × 106 CD34+ cells/L of processed blood for the first apheresis; 62 donors (16.6%) did not attain this threshold. The male donors had significantly higher yields at harvest compared with the female donors. The female donors had higher CD34+ cell yields if the circulation access was through an artery than if is was through a vein. In a multiple regression analysis, donor age, sex, body mass index (BMI), preharvest white blood cell and circulating immature cell counts, access type, and flow rate correlated with day 1 yield. Female sex, older age, venous access, and a higher flow rate were significantly associated with greater risk for a day 1 poor yield of CD34+ cells (odds ratio = 3.0074, 1.045, 4.3362, and 1.1131, respectively). A higher BMI may decrease the risk (odds ratio = 0.8472). In donors at higher risk for poor CD34+ cell yield, strategies for increasing CD34+ cells must be considered. IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat a wide variety of malignant and nonmalignant hematologic diseases. Peripheral blood stem cells (PBSCs) are increasingly used as the source of stem cells in HSCT because of improved neutrophil and platelet engraftment, avoidance of general anesthesia for collection, and potentially better graft-versus-leukemia effect [1Korbling M. Przepiorka D. Huh Y.O. et al.Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts.Blood. 1995; 85: 1659-1665PubMed Google Scholar, 2Bensinger W.I. Martin P.J. Storer B. et al.Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.N Engl J Med. 2001; 344: 175-181Crossref PubMed Scopus (833) Google Scholar].A high stem cell dose may be associated with improved hematopoietic recovery and survival in patients undergoing HSCT. Large variations exist among individuals mobilized by granulocyte colony-stimulating factor (G-CSF), however. Poor mobilization is currently defined as collection of < 2 × 106 CD34+ cells/kg of recipient body weight (BW), which may be associated with prolonged or incomplete engraftment [3Tricot G. Jagannath S. Vesole D. et al.Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients.Blood. 1995; 85: 588-596PubMed Google Scholar, 4Stockerl-Goldstein K.E. Reddy S.A. Horning S.F. et al.Favorable treatment outcome in non-Hodgkin's lymphoma patients with “poor” mobilization of peripheral blood progenitor cells.Biol Blood Marrow Transplant. 2000; 6: 506-512Abstract Full Text PDF PubMed Scopus (59) Google Scholar]. In some patients, mobilization may be ineffective to allow collection of this threshold dose. Even in healthy individuals used for allogeneic transplants, these poor mobilizers may represent up to 20% of donors [5Takeyama K. Ohto H. PBSC mobilization.Transfus Apher Sci. 2004; 31: 233-243Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. Although some previous reports have focused on the donor features associated with stem cell yields, currently there are no well-accepted criteria for identifying a poor mobilizer. This might be related to variability in study design and conclusions.As the number of stem cell volunteer donors has increased worldwide, the number of patients with several well-matched HLA donors also has increased. A recent study found that 56% of patients will have ≥ 10 HLA-matched adult donors in the current National Marrow Donor Program (NMDP) files [6Confer D.L. Miller J.P. Optimal donor selection: beyond HLA.Biol Blood Marrow Transplant. 2007; 13: 83-86Abstract Full Text Full Text PDF Scopus (14) Google Scholar]. Identifying factors associated with a better quality and greater quantity of stem cells may provide an opportunity to enhance patient recovery while maintaining a safe process for stem cell donation for the donors. In an attempt to gain insight into the donor factors that may affect the quantity of stem cell collection from volunteer donors, we retrospectively analyzed the relationship between the harvest yields of CD34+ cells on first apheresis and the characteristics of volunteer donors from the Tzu-Chi stem cell donor registry. We also studied the impact of the apheresis procedures, which has not been evaluated in depth to date.MethodsDonors and MobilizationBetween January 2003 and March 2008, a total of 375 healthy unrelated volunteers underwent PBSC harvesting in our institution and were eligible for this retrospective analysis. All donors agreed to PBSC donation after being informed about the procedures for both bone marrow harvest and PBSC collection. Before donation, a complete medical history, physical examination, and laboratory analysis, including a blood test, electrocardiogram, and chest X-ray, were performed. Informed consent was obtained from each participant. Two donors (0.5%) were excluded from the analysis because of failure to obtain consent or incomplete data. This retrospective study was approved by the local institutional review board.For stem cell mobilization, G-CSF (filgrastim; Kirin Brewery Co, Tokyo, Japan) was administered s.c. at a dose of 10 μg/kg of donor BW once a day for 5 consecutive days in all donors. Each donor received the G-CSF at local clinics at approximately the same time every day. To avoid calculation errors, the actual dose was determined at the time of the donor health examination and simplified to fit the combination of available dosage forms. The G-CSF dosages ranged from 8.3 to 11 μg/kg, as shown in Table 1.Table 1G-CSF Dose According to Donor BWDonor BW, kg45-5455-6970-8586-9596-100101-115>116G-CSF dose, μg45060075090097510501200 Open table in a new tab PBSC CollectionLeukapheresis was performed with a continuous-flow cell separator (Cobe Spectra; Cobe Laboratories, Denver, CO) at a planned flow rate of 40 to 60 mL/minute. The actual flow rate was calculated by dividing the total processed blood volume (mL) by the processing time (min). The circulation system was accessed from bilateral antecubital veins by means of a 16- to 18-gauge catheter for both the inlet and the return line or by a radial artery 20-gauge catheter as the inlet line and a 16- or 18-gauge catheter in the antecubital vein as the return line. The use of arterial or venous circulation as the inlet was at the discretion of each apheresis physician after evaluating the donor's vascular access and his or her willingness. In brief, venous was the first 2 large venous was on the or by than an arterial access was considered. In donors with a flow rate the physician may to the access to an artery to obtain an flow donors in peripheral venous and arterial access was venous were in the vein. The apheresis procedure was started approximately after of the G-CSF dose. a apheresis was the procedure was performed on the of the blood cell apheresis and PBSC were obtained an cell blood cells circulating immature cells and CD34+ cells were for analysis. were was defined as circulating and by in a peripheral blood were calculated by a of the by each donor's number of CD34+ cells was from the by flow analysis. In brief, of was with of or in The a and the a and cell with the CD34+ cell was performed a flow and and were in each were analyzed to the as S. M. et of hematopoietic progenitor cells by flow of a and the Marrow Transplant. PubMed Scopus Google Scholar]. and were used to and with or high which are not of progenitor The CD34+ cell was defined in the the of cells from previous The number of CD34+ cells in the was determined by dividing the number of CD34+ by the number of and this by the cell yield was defined as the number of CD34+ cells/L of processed To obtain an of the first apheresis were in the analysis of factors harvest A day 1 CD34+ cell of < 10 × was a poor yield in our outcome including and were and age, body mass index (BMI), and apheresis for male and female donors were compared the and the BMI was defined as the body weight in by in The means of including flow processed and day 1 CD34+ cell yield for arterial and venous were compared on all and by regression was used to the among potential including donor and day 1 The risk for poor day 1 CD34+ cell yields was evaluated a regression in which ratio the of the A was the was < All were the 2 of the and yields at stem cell harvest. The donor was with a of The G-CSF dose was was the first stem cell donation and PBSC mobilization for all donors. A total of donors were accessed with a vein as the apheresis donors a venous The day 1 processed volume was of donor weight in The day 1 CD34+ cell cell yield, and recipient cell dose were × 106 cells, × and × of recipient BW, According to our of day 1 poor yield, 62 donors (16.6%) had a yield < 10 × 106 CD34+ cells/L of processed blood after the first of Donor and in as number as number (42.6%) dose, 1 actual flow day 1 processed blood processed blood volume donor BW, platelet 1 total CD34+ cell 1 CD34+ cells donor BW, 1 CD34+ cells recipient BW, 1 CD34+ cell yield, of processed as number Open table in a new tab total of donors the of a CD34+ cell dose of 5 × of recipient BW after the first apheresis Of the donors with a day 1 harvest < 5 × underwent a apheresis on the day. a of 2 the dose. Although all donors a day 1 CD34+ cell of < 2 × underwent a of donors had a recipient cell dose the threshold. The of donors the CD34+ cell dose of ≥ × of recipient BW was after 1 apheresis and after 2 that of CD34+ According to 5 × × 2 × Open table in a new tab 1 PBSC the of sex, the male donors had significantly higher day 1 total CD34+ cell < cell yield < and recipient cell dose < compared with the female donors The male donors had higher total processed and flow rate but platelet counts, processed volume of donor BW, and arterial access G-CSF dose, and and did not between the of G-CSF and for and Female dose, platelet as was calculated by the 1 actual flow day 1 processed 1 processed volume donor BW, 1 total CD34+ cell 1 CD34+ cells donor BW, 1 CD34+ cells recipient BW, 1 CD34+ cell yield, of processed are as was from the for artery as was calculated by the Open table in a new tab the effect of access type, use of a radial artery as the inlet access was associated with a higher flow rate and total processed The stem cell harvest did not significantly on arterial or venous access in a of female donors The day 1 CD34+ cell and cell yield were higher in with arterial access compared with with venous access, the recipient cell dose was not significantly between the 2 = with or as the 1 actual flow day 1 processed 1 processed volume donor BW, day 1 CD34+ cell 1 CD34+ cells donor BW, 1 CD34+ cells recipient BW, 1 CD34+ cell yield, of processed are as and was from a Open table in a new tab In multiple regression analysis, factors significantly correlated with day 1 CD34+ cell yields were donor age, sex, access type, flow and and and flow rate were correlated with cell yield, BMI and and were correlated with cell yield. G-CSF dose and first day total processed blood volume did not affect the number of CD34+ cells/L of processed of Donor and on 1 CD34+ is as as dose, is as as processed platelet is as as is as as Open table in a new tab the of each factor for poor day 1 CD34+ cell yield 10 × of processed blood female = older = venous access = and higher flow rate = were significantly associated with increased risk on regression analysis. A higher BMI was associated with a risk = 0.8472). was a of risk for day 1 poor yield in donors with higher laboratory but the was not The associated with each factor are in Table of for a Poor of 1 CD34+ 2 × of is as as dose, is as as processed platelet is as as is as as Open table in a new tab donors G-CSF 1 donor a dosage to effects of G-CSF dose was to on the and days because of and and bone her daily G-CSF dose was Two donors received a G-CSF dosage than donor had a dosage of μg/kg, on a rapid in BW to after the health the donor had a dosage of μg/kg to a in the calculation of his donor a G-CSF dosage because of a high on the day of donors the apheresis related to as and were the these with and did not the Two donors with radial artery access a local after catheter both had at or related to was donor the his platelet was apheresis and after The was by local was mobilized are used in allogeneic is available about the factors the outcome of stem cell collection from healthy have used for apheresis and the and dosages of used for outcome analysis, and Przepiorka D. et mobilization of CD34+ cells in donors with PubMed Scopus Google Scholar, et of factors associated with peripheral blood progenitor cell collection in PubMed Scopus Google Scholar, et peripheral blood progenitor cell collection from donors for allogeneic Google Scholar, K. et al.Peripheral blood circulating immature cell CD34+ cell yields in mobilization in healthy 2004; PubMed Scopus Google Scholar, K. M. for collection and collection Apher Sci. 2004; 31: Full Text Full Text PDF PubMed Scopus Google Scholar, D. PBSC mobilization and collection in healthy Apher Sci. Full Text Full Text PDF PubMed Scopus Google Scholar, H. et associated with granulocyte colony-stimulating peripheral blood stem cell yield in healthy PubMed Scopus Google Scholar, D. et al.Peripheral blood stem cell yield in donors with granulocyte colony-stimulating factor impact of age, sex, donor weight and of G-CSF J PubMed Scopus Google Scholar, S. S.F. et and laboratory of allogeneic peripheral blood stem cell mobilization in an PubMed Scopus Google cell dose is used as the outcome the impact of donor characteristics on PBSC harvest. harvest at 2 if the first not the cell dose. The may the impact of donor factors on stem cell harvest by of among donors and also may to to in criteria for a apheresis among the number of CD34+ cells as the may be et of factors associated with peripheral blood progenitor cell collection in PubMed Scopus Google Scholar]. In previous have the CD34+ cell dose on donor or recipient BW or on the volume of blood processed to the yields among donors. A high or recipient weight will the donor into outcome in analysis, however. donor BW is not a factor for because is not and be because have effect on stem cell on the we used the number of CD34+ cells/L of processed blood volume the first apheresis to factors and procedures associated with the outcome of harvest after 1 of < 10 × 106 CD34+ cells/L of processed blood volume was defined as a poor yield on a of 2 of a total of of processed blood × 106 CD34+ cells/kg for a recipient with BW of 60 We that this a of donors with harvest outcome compared with the for a poor cells < 2 × of recipient which is by the recipient This threshold for a poor day 1 yield to high and for day 1 CD34+ cells < 2 × of recipient BW in our our donor as age, and laboratory had impact on with previous of these factors with stem cell This also might be the the for these donor factors were not in previous et Przepiorka D. et mobilization of CD34+ cells in donors with PubMed Scopus Google that donor was associated with a greater risk of poor The for in our study be related to the and of our donor age, to age, to of et In to the donor factors that had we that female had a harvest outcome and a higher risk for poor yield in our was to have no effect on stem cell yield in previous et of factors associated with peripheral blood progenitor cell collection in PubMed Scopus Google Scholar, D. PBSC mobilization and collection in healthy Apher Sci. Full Text Full Text PDF PubMed Scopus Google a was by K. et al.Peripheral blood circulating immature cell CD34+ cell yields in mobilization in healthy 2004; PubMed Scopus Google Scholar, M. H. M. et for mobilization of peripheral blood progenitor cells from allogeneic donors and PubMed Google Scholar]. Two recent large found higher total CD34+ cell and cell yield in male donors D. et al.Peripheral blood stem cell yield in donors with granulocyte colony-stimulating factor impact of age, sex, donor weight and of G-CSF J PubMed Scopus Google Scholar, M. et of progenitor cells with G-CSF in male but not female unrelated stem cell J PubMed Scopus Google Scholar]. A between G-CSF and also has been on mobilization in a male donor by G-CSF M. et of progenitor cells with G-CSF in male but not female unrelated stem cell J PubMed Scopus Google Scholar]. This is with a recent by et S. S.F. et and laboratory of allogeneic peripheral blood stem cell mobilization in an PubMed Scopus Google significantly of circulating CD34+ cells in female donors. In poor mobilizers with G-CSF for the peripheral CD34+ cell may a to days compared with donors et of factors for CD34+ cell harvest yields from patients mobilized with and PubMed Scopus Google or higher of G-CSF may be et PBSC mobilization with G-CSF for patients a first of PubMed Scopus Google Scholar]. The for the poor mobilization by G-CSF in female donors to be outcome of stem cell harvest on 2 mobilization and harvest. et S. S.F. et and laboratory of allogeneic peripheral blood stem cell mobilization in an PubMed Scopus Google analyzed the effect of donor characteristics on the circulating CD34+ cell counts, which represent the outcome of previous have examined stem cell harvest yield with donor factors have factors the outcome of PBSC collection. recent have focused on the effect of Although may stem cell yield, as flow rate and circulation access, also may et H. et associated with granulocyte colony-stimulating peripheral blood stem cell yield in healthy PubMed Scopus Google donor and factors associated with PBSC yield but in a = was to in of flow rate to processed volume to and of access arterial also that flow rate was correlated with the outcome of stem cell harvest. of cells, CD34+ cells, and were all higher in the arterial access × × and × the between the arterial and venous did not for that in = Although in our the harvest stem cell also did not significantly between the 2 access the are as a the female donors with venous access did CD34+ cell We also found an between venous access and increased risk for poor stem cell yield on regression analysis. This is to a previous a decrease in circulating hematopoietic progenitor cells after to in the circulation et in circulating hematopoietic progenitor cells by in the 2001; Full Text PDF PubMed Scopus Google Scholar]. of the large and progenitor cells in the is be the of in patients with The that in also may arterial apheresis will have a effect than venous because of the in circulation compared with The affect of access in female donors might be to the impact of circulation access, which be in a of circulating stem of this is to the for the apheresis actual flow rate in our study was compared with previous donors had a flow rate the by the In our flow rate was that used in a previous study H. et associated with granulocyte colony-stimulating peripheral blood stem cell yield in healthy PubMed Scopus Google which also had a high of arterial donors. donors about apheresis with a higher flow our actual flow rate was not to our planned flow This may be to the body and total blood volume in our compared with the and also to the greater in arterial The flow rate was not defined or in previous of factors stem cell harvest flow rate may to be in a because was not high in our retrospective we found that female sex, older age, higher flow and venous access were significantly associated with increased risk for poor day 1 CD34+ cell yield 10 × of processed A higher BMI may decrease the In a donor with multiple characteristics for poor CD34+ cell yield an older female with a strategies for increasing CD34+ cell yield must be The of arterial access be evaluated the preharvest health examination, and a flow rate of apheresis may be in to strategies to circulating stem cells, as a higher or multiple daily dose of G-CSF or a combination of G-CSF and granulocyte colony-stimulating may be M. H. M. et for mobilization of peripheral blood progenitor cells from allogeneic donors and PubMed Google Scholar, et colony-stimulating factor in peripheral blood stem cell mobilization in patients had mobilization with and Marrow Transplant. PubMed Scopus Google Scholar, H. et of once daily granulocyte colony-stimulating factor for stem cell mobilization in healthy donors for allogeneic J 2000; PubMed Scopus Google Scholar]. marrow stem cells may be used as an source in female donors, because our no between and cell in bone marrow harvest The by which these factors affect stem cell harvest IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat a wide variety of malignant and nonmalignant hematologic diseases. Peripheral blood stem cells (PBSCs) are increasingly used as the source of stem cells in HSCT because of improved neutrophil and platelet engraftment, avoidance of general anesthesia for collection, and potentially better graft-versus-leukemia effect [1Korbling M. Przepiorka D. Huh Y.O. et al.Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts.Blood. 1995; 85: 1659-1665PubMed Google Scholar, 2Bensinger W.I. Martin P.J. Storer B. et al.Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.N Engl J Med. 2001; 344: 175-181Crossref PubMed Scopus (833) Google Scholar].A high stem cell dose may be associated with improved hematopoietic recovery and survival in patients undergoing HSCT. Large variations exist among individuals mobilized by granulocyte colony-stimulating factor (G-CSF), however. Poor mobilization is currently defined as collection of < 2 × 106 CD34+ cells/kg of recipient body weight (BW), which may be associated with prolonged or incomplete engraftment [3Tricot G. Jagannath S. Vesole D. et al.Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients.Blood. 1995; 85: 588-596PubMed Google Scholar, 4Stockerl-Goldstein K.E. Reddy S.A. Horning S.F. et al.Favorable treatment outcome in non-Hodgkin's lymphoma patients with “poor” mobilization of peripheral blood progenitor cells.Biol Blood Marrow Transplant. 2000; 6: 506-512Abstract Full Text PDF PubMed Scopus (59) Google Scholar]. In some patients, mobilization may be ineffective to allow collection of this threshold dose. Even in healthy individuals used for allogeneic transplants, these poor mobilizers may represent up to 20% of donors [5Takeyama K. Ohto H. PBSC mobilization.Transfus Apher Sci. 2004; 31: 233-243Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. Although some previous reports have focused on the donor features associated with stem cell yields, currently there are no well-accepted criteria for identifying a poor mobilizer. This might be related to variability in study design and conclusions.As the number of stem cell volunteer donors has increased worldwide, the number of patients with several well-matched HLA donors also has increased. A recent study found that 56% of patients will have ≥ 10 HLA-matched adult donors in the current National Marrow Donor Program (NMDP) files [6Confer D.L. Miller J.P. Optimal donor selection: beyond HLA.Biol Blood Marrow Transplant. 2007; 13: 83-86Abstract Full Text Full Text PDF Scopus (14) Google Scholar]. Identifying factors associated with a better quality and greater quantity of stem cells may provide an opportunity to enhance patient recovery while maintaining a safe process for stem cell donation for the donors. In an attempt to gain insight into the donor factors that may affect the quantity of stem cell collection from volunteer donors, we retrospectively analyzed the relationship between the harvest yields of CD34+ cells on first apheresis and the characteristics of volunteer donors from the Tzu-Chi stem cell donor registry. We also studied the impact of the apheresis procedures, which has not been evaluated in depth to