Prospective studies have shown rapid engraftment using granulocyte–colony-stimulating factor–mobilized peripheral blood stem cells (G-PBSCs) for allogeneic transplantation, though the risks for graft-versus-host disease (GVHD) may be increased. It was hypothesized that the use of G-CSF to prime bone marrow (G-BM) would allow rapid engraftment without increased risk for GVHD compared with G-PBSC. Patients were randomized to receive G-BM or G-PBSCs for allogeneic stem cell transplantation. The study was designed (β < .8) to detect a difference in the incidence of chronic GVHD of 33% (α < .05). The plan was to recruit 100 patients and to conduct an interim analysis when the 6-month follow-up point was reached for the first 50 patients. Fifty-seven consecutive patients were recruited (G-BM, n = 28; G-PBSC, n = 29). Patients in the G-PBSC group received 3-fold more CD34+ and 9-fold more CD3+ cells. Median times to neutrophil (G-BM, 16 days; G-PBSC, 14 days; P < .1) and platelet engraftment (G-BM, 14 days; G-PBSC, 12 days; P < .1) were similar. The use of G-PBSC was associated with steroid refractory acute GVHD (G-BM, 0%; G-PBSC, 32%; P < .001), chronic GVHD (G-BM, 22%; G-PBSC, 80%; P < .02), and prolonged requirement for immunosuppressive therapy (G-BM, 173 days; G-PBSC, 680 days;P < .009). Survival was similar for the 2 groups. Compared with G-PBSC, the use of G-BM resulted in comparable engraftment, reduced severity of acute GVHD, and less subsequent chronic GVHD.

The use of granulocyte–colony-stimulating factor (G-CSF) mobilized peripheral blood cells (G-PBSCs) as a source of stem cells for autologous transplantation has resulted in increased yield of CD34+ cells and accelerated engraftment compared to harvested bone marrow (BM).1 Prospective studies have also suggested accelerated engraftment when G-PBSCs are used in allogeneic transplantation.2-10 

The major complication of allogeneic stem cell transplantation is graft-versus-host disease (GVHD). The incidence of grades II-IV acute GVHD after HLA-identical sibling donor BM transplantation varied with patient age, sex matching, donor parity, and cyclosporin and methotrexate dose intensities, but it ranges from 30% to 50% in most published series.11-14 T-cell depletion of the graft prevents this complication but results in an increase in the incidence of graft rejection, infection, and disease recurrence.15-18 

Approximately 30% of patients surviving beyond day 100 after HLA-identical sibling donor BM transplantation acquire clinical extensive chronic GVHD (cGVHD).19 Risk factors for the development of cGVHD include prior acute GVHD, increasing patient age, and use of a parous female donor for a male recipient.20-22 Prolonged cyclosporin prophylaxis may decrease the occurrence of cGVHD.23 The addition of buffy coat to the marrow inoculum, used successfully to reduce the incidence of graft failure in transfused patients with aplastic anemia, resulted in a significant increase in the incidence of cGVHD.22Chronic GVHD is associated with significant morbidity and mortality and with adverse risk factors at the onset including thrombocytopenia, progressive onset, and elevated bilirubin level.19 24 

The dose of T cells infused, therefore, may influence the development and severity of chronic GVHD. G-PBSC results in a 4- to 10-fold increase in the number of T cells compared with BM. Retrospective comparisons of G-PBSC and BM as stem cell sources have suggested an increase in the incidence of extensive chronic GVHD.25 

Several reports demonstrate increased progenitor cell yield and accelerated neutrophil and platelet recovery after the harvest of G-CSF–stimulated bone marrow (G-BM) for autologous and allogeneic transplantation.26-31 We hypothesized that the use G-BM may result in rapid engraftment without altering the incidence of acute GVHD but with a reduced risk for cGVHD when compared with G-PBSC.

Patient accrual and characteristics

Between January 1997 and July 1999, all patients undergoing allogeneic stem cell transplantation from an HLA-identical sibling were asked to participate in a randomized trial of G-PBSC or G-BM as the source of stem cells. All patients and donors signed consent forms approved by the Ethics Committee of the Royal Brisbane Hospital.

Stem cell collections

All donors received G-CSF (Amgen, Thousand Oaks, CA) 10 μg/kg per day as a single evening injection. Randomization to G-BM or G-PBSC was performed before transplantation in permuted blocks of 4 donors, stratified according to the risk for patient disease recurrence (high risk was defined as acute myeloid leukemia [AML] beyond CR1, chronic myeloid leukemia [CML] beyond chronic phase, myelodysplasia, and high-grade or transformed non-Hodgkin lymphoma). Donors randomized to G-BM received G-CSF for 5 days; G-BM harvest was performed on the sixth day (volume, 15-20 mL/kg patient adjusted ideal weight). Donors randomized to G-PBSC received G-GSF for 5 days, with collections performed on the fifth (stored overnight at 4°C) and sixth days, to obtain a minimum CD34 cell count of 2 × 106/kg recipient ideal body weight. A provision was made to perform a third collection if this yield was not achieved. Collections were made with a continuous flow blood cell separator (Cobe Laboratories, Lakewood, CA; volume, 200 mL; collection rate, 1 mL/min; flow rate, 40-70 mL/min). Cells were then pooled and infused on transplantation day 0.

Supportive care

All patients received cyclosporin by 2-hour intravenous infusion at a dose of 5 mg/kg day −1 to day +1, then 3 mg/kg adjusted to trough levels of 100 to 300 μg/mL. Methotrexate was administered on day +1 at a dose of 15 mg/m2 and subsequently on days +3 and +6 at a dose of 10 mg/m2. Each dose was followed 24 hours later by a single dose of 15 mg folinic acid (days +2, +4, +7). In the absence of disease recurrence or active GVHD, cyclosporin was tapered between day +100 and day +180. Use of growth factors after transplantation was limited to those patients with delayed neutrophil recovery at day +21. All patients received 200 mg fluconazole daily from day +1 and 500 mg/m2 acyclovir 3 times daily intravenously while they had cytopenia; subsequently, they received 1 g twice daily valacyclovir once they could tolerate oral therapy. Cytomegalovirus (CMV) surveillance included weekly polymerase chain reaction and pp65 antigenemia testing (until day +100). Treatment for CMV reactivation included 5 mg/kg ganciclovir twice daily for 1 week and then once daily Monday through Friday for 3 weeks. Bactrim was given before transplantation and was restarted after day +21. Fluconazole, Bactrim, and valacyclovir administration were continued until 1 month after the cessation of all immunosuppressive therapy. Acute GVHD grades II-IV was treated with 2 mg/kg prednisone and was tapered at a rate of 0.25 mg/kg per week. Patients with refractory acute GVHD were treated with antithymocyte globulin (75 mg/kg over 5 days), high-dose prednisone (10 mg/kg), and tacrolimus. Chronic GVHD was treated with cyclosporin–tacrolimus with prednisone as the first-line therapy for at least 6 months. Second-line therapy was added at 2 months for treatment failure and included mycophenolate, clofazimine, and thalidomide administered in a sequential manner based on treatment response.

Evaluations and definitions

Stem cell products were analyzed for CD34+ subsets and T-cell subsets by flow cytometry using previously published methods.32 Neutrophil engraftment was defined as having occurred after the first of 3 days with an absolute neutrophil count (ANC) greater than 500/μL after the posttransplant nadir. Platelet engraftment was defined as having occurred on the first of 7 consecutive days with a platelet count greater than 20 000/μL without platelet transfusions. Acute and chronic GVHD were graded by Seattle criteria. Response of acute GVHD to prednisone was defined as sensitive (no flare on prednisone taper), dependent (flare before day +100 on prednisone taper), and refractory (no response or progression after 5 days at 2 mg/kg). Patients who died while in relapse after transplantation were categorized as having died of relapse. Patients who died without disease recurrence were categorized as experiencing nonrelapse mortality.

Statistics

The hypothesis in this study was that the use of G-PBSCs would result in an increase in the incidence of clinical extensive chronic GVHD 6 months after transplantation. A sample of 80 patients would be required to detect a difference of 33% with a power of 80% and a 1-sided α of 0.05. Assuming 80% of patients would survive longer than 100 days, we aimed to enroll 100 patients. The study design included an interim analysis when the first 50 patients survived more than 180 days after transplantation. Study closure rules at this time point included an excess cumulative incidence of severe (grades III-IV) acute GVHD or clinical extensive chronic GVHD, defined byP < .02. Time to engraftment, cumulative incidence of acute and chronic GHVD, duration of immunosuppression therapy, and survival were compared using the log rank test. Death or relapse before day 100 was treated as a competing risk for determination of the cumulative incidence of acute GVHD. Patients alive in remission at day +100 were considered at risk for the development of chronic GVHD. Subsequent death or disease recurrence was treated as a competing risk. Potential risk factors for the development of GVHD (age, CMV serostatus, sex match, donor parity, disease risk, conditioning regime, log CD3, CD34, total nucleated cell dose per kilogram patient weight, and cell source) were included in multivariate models (logistic regression for acute GVHD, Cox regression for cGVHD), where univariate analysis determinedP < .1.

Study population

Patient characteristics are shown in Table1. There was a predominance of patients with AML in CR1 in the G-BM group and with CML in chronic phase in the G-PBSC group. Median follow-up time of surviving patients was 645 days.

Table 1.

Patient demographics

G-BM (n = 28)G-PBSC (n = 29)P
Age (y) 44  (16-60) 46  (24-58) .2  
High risk (%) 9  (32) 11  (38) .6 
Diagnosis    
 AA 1/0 0/0  
 AL 8/1 1/4  
 CML 2/1 8/1  
 MDS 0/5 0/4  
 MM 4/0 4/0  
 MF 0/0 1/0  
 NHL/CLL 4/2 4/2  
CMV   .7 
D−R− (%) 5  (18) 3  (10)  
D−R+ (%) 7  (25) 5  (17)  
D+R− (%) 3  (11) 4  (14)  
D+R+ (%) 13  (46) 17  (59)  
Sex match   .4  
 M to M (%) 5  (18) 5  (17)  
 M to F (%) 10  (36) 6  (21)  
 F to M (%) 8  (29) 8  (28)  
 F to F (%) 5  (19) 10  (35)  
 PF to M (%) 5  (18) 4  (14)  
Conditioning   .3 
 CYTBI (%) 5  (18) 5  (17)  
 BUCY (%) 19  (68) 21  (72)  
 Other (%) 4  (14) 3  (10)  
G-BM (n = 28)G-PBSC (n = 29)P
Age (y) 44  (16-60) 46  (24-58) .2  
High risk (%) 9  (32) 11  (38) .6 
Diagnosis    
 AA 1/0 0/0  
 AL 8/1 1/4  
 CML 2/1 8/1  
 MDS 0/5 0/4  
 MM 4/0 4/0  
 MF 0/0 1/0  
 NHL/CLL 4/2 4/2  
CMV   .7 
D−R− (%) 5  (18) 3  (10)  
D−R+ (%) 7  (25) 5  (17)  
D+R− (%) 3  (11) 4  (14)  
D+R+ (%) 13  (46) 17  (59)  
Sex match   .4  
 M to M (%) 5  (18) 5  (17)  
 M to F (%) 10  (36) 6  (21)  
 F to M (%) 8  (29) 8  (28)  
 F to F (%) 5  (19) 10  (35)  
 PF to M (%) 5  (18) 4  (14)  
Conditioning   .3 
 CYTBI (%) 5  (18) 5  (17)  
 BUCY (%) 19  (68) 21  (72)  
 Other (%) 4  (14) 3  (10)  

AA indicates aplastic anemia; AL, acute leukemia; MDS, myelodysplasia; MM, multiple myeloma; MF, myelofibrosis; NHL, non-Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; D, donor; R, recipient; M, male; F, female; PF, parous female; CYTBI, 120 mg/kg cyclophosphamide + total body irradiation (12 Gy, 6 fractions); BUCY, 16 mg/kg busulfan + 120 mg/kg cyclophosphamide.

Stem cell products

Uncorrected yields of nucleated cells and of CD34+ and CD3+ cells are shown in Table2. There was little difference in the number of nucleated cells infused, whereas the numbers of CD34+ and CD3+ cells were, respectively, 3-fold and 9-fold greater for the G-PBSC product.

Table 2.

Median numbers of CD34+ progenitors and T cells infused

G-BMG-PBSCP
TNC/kg (× 1088.6  (3.7-12.8) 10.4  (5.0-18.1)   .006 
CD34/kg (× 1062.6  (0.8-6.3) 7.2  (1.9-19.9) < .0001  
CD3/kg (× 10645  (16-77) 403  (43-714) < .0001 
G-BMG-PBSCP
TNC/kg (× 1088.6  (3.7-12.8) 10.4  (5.0-18.1)   .006 
CD34/kg (× 1062.6  (0.8-6.3) 7.2  (1.9-19.9) < .0001  
CD3/kg (× 10645  (16-77) 403  (43-714) < .0001 

Ranges are indicated in parentheses (actual patient weights).

Engraftment

There was a suggestion of more rapid engraftment in the G-PBSC group than in the G-BM group, though the results did not reach significance. Median time to neutrophil recovery was 16 days (range, 12-23 days) using G-BM compared with 14 days (range, 10-23 days) for G-PBSC recipients (P < .1). This analysis excluded 2 patients who died before day 28 without achieving neutrophil recovery (1 from each group). Median time to platelet recovery was 14 days (range, 9-22 days) after G-BM and 12 days (range, 8-25 days) after G-PBSC transplantation (P < .1). Three patients (2 in the G-BM group; 1 in the G-PBSC group) who died before day 28 without reaching platelet recovery were excluded from the analysis. Median numbers of transfused packed cells (3 G-BM, range, 0-15; 3 G-PBSC, range, 0-32; P < .3) and platelet transfusion episodes (5 G-BM, range, 2-22; 3 G-PBSC, range, 1-47; P < .3) between day 0 and day +30 after transplantation were similar for the 2 groups.

Acute graft-versus-host disease

The cumulative incidence of grades II-IV acute GVHD was 52% in the G-BM compared to 54% in the G-PBSC group (P < .6). Five patients (2 in the G-BM group; 3 in the G-PBSC group) died before day 100 without acquiring acute GVHD. The incidence of grades III-IV acute GVHD was 22% in the G-BM group compared with 43% after G-PBSC transplantation (P < .09; Figure1). The proportion of patients with steroid-dependent or refractory acute GHVD (47% G-PBSC; 18% G-BM;P < .02) was significantly increased after G-PBSC transplantation (Figure 2). No other factors were found to be associated with the development of severe or steroid dependent or resistant acute GVHD. The risk for grades III-IV acute GVHD after G-PBSC transplantation was increased when the T-cell dose exceeded 403 × 106/kg (P < .06).

Fig. 1.

Cumulative incidence of severe grades III-IV acute GVHD.

G-PBSC, 43%; G-BM, 22%; P < .09.

Fig. 1.

Cumulative incidence of severe grades III-IV acute GVHD.

G-PBSC, 43%; G-BM, 22%; P < .09.

Close modal
Fig. 2.

Cumulative incidence of prednisone dependent or refractory acute GHVD.

G-PBSC, 47%; G-BM, 18%; P < .02.

Fig. 2.

Cumulative incidence of prednisone dependent or refractory acute GHVD.

G-PBSC, 47%; G-BM, 18%; P < .02.

Close modal

Chronic graft-versus-host disease

Forty-two patients were alive and in remission at day +100 after transplantation and thus were considered at risk for the development of chronic GVHD. Overall incidence of clinical chronic GVHD (limited and extensive) was significantly higher after G-PBSC transplantation (G-PBSC, 90%; G-BM, 47%; P < .02). The use of G-PBSC was a major risk factor for the development of clinical extensive chronic GVHD (G-PBSC, 80%; G-BM, 22%; P < .002; Figure3). According to multivariate analysis, age greater than 45 years (relative risk [RR], 3.6; confidence interval [CI], 1.2-9.2; P < .02) and use of G-PBSC (RR, 5.1; CI, 1.7-15; P < .004) remained independently predictive for the development of clinical extensive cGVHD.

Fig. 3.

Cumulative incidence of clinical extensive chronic GVHD.

G-PBSC, 80%; G-BM, 22%; P < .003.

Fig. 3.

Cumulative incidence of clinical extensive chronic GVHD.

G-PBSC, 80%; G-BM, 22%; P < .003.

Close modal

There were no differences in the pattern of onset, incidence of thrombocytopenia, or hyperbilirubinemia at the time of development of cGVHD. Duration of immunosuppression therapy (Figure4) was significantly prolonged after G-PBSC transplantation (median, 680 days; range, 173-890+ days) than in the G-BM group (median, 173 days; range, 111-913+ days) (P < .009).

Fig. 4.

Kaplan-Meier estimates of the percentage of patients remaining on immunosuppression therapy.

Median duration: G-PBSC, 680 days; G-BM, 173 days;P < .009.

Fig. 4.

Kaplan-Meier estimates of the percentage of patients remaining on immunosuppression therapy.

Median duration: G-PBSC, 680 days; G-BM, 173 days;P < .009.

Close modal

Relapse and survival

Eight patients had relapses—5 after G-BM (2 with high-risk disease) and 3 after G-PBSC (2 with high-risk disease) transplantation. Sustained remission has followed the withdrawal of immunosuppression therapy (chemorefractory myeloma, G-BM, n = 1) and donor lymphocyte infusion and interferon (AML in CR2, G-BM, n = 1). Overall survival rate at 18 months was 66% ± 6% (standard risk, 75% ± 7%; high risk, 50% ± 11%) and was not affected by stem cell source (G-BM, 67% ± 9%; G-PBSC, 64% ± 9%; P < .9) (Figure 5).

Fig. 5.

Kaplan-Meier estimates of the percentage of patients surviving at 18 months.

G-PBSC, 64%; G-BM, 67%; P < .9.

Fig. 5.

Kaplan-Meier estimates of the percentage of patients surviving at 18 months.

G-PBSC, 64%; G-BM, 67%; P < .9.

Close modal

G-PBSCs have replaced BM as the stem cell source of choice for autologous transplantation. This has been based on the ease of collection and the rapidity of engraftment. Interest has now extended to the use of G-PBSC for allogeneic transplantation. Concerns regarding the severity of GVHD because of the increased T-cell load have been expressed; however, retrospective comparisons2,3,5,6,9,25,33 and prospective randomized studies4,7,8,10 have yielded conflicting results. G-BM for allogeneic transplantation has been evaluated in a small series of patients with acceleration of neutrophil and platelet engraftment and has been compared with those of historical controls.30This study shows that the use of G-BM results in rapid, sustained engraftment with a reduced risk for severe acute and subsequent clinical extensive chronic GVHD in comparison with G-PBSC.

There is scant information on the use of G-BM for stem cell transplantation. Studies in mice have suggested a 50% reduction in the number of spleen colony-forming units and granulocyte macrophage–colony-forming units in femoral bone marrow after 4 days of G-CSF at 500 μ/kg, with a return to baseline levels 24 hours after the cessation of therapy. The administration of G-CSF and stem cell factor to splenectomized mice decreased the number of pluripotent hematopoietic stem cells in the bone marrow 4-fold. However, by 14 days after complete injection, the marrow had expanded 10-fold in repopulating ability.34 Studies in humans found an increase in bone marrow cellularity and lineage-restricted myeloid progenitors after mobilization with 5 days of G-CSF. There was no difference in yields of CD34+ cell CFU-GM, and engraftment times were similar to those for historical controls.35 By contrast, Slowman et al36 found an increased yield of CD34+ cells without accelerating time to neutrophil engraftment. Damiani et al26 randomized 55 patients undergoing autologous stem cell transplantation to receive G-BM or G-PBSC, with collections performed after 3 days of G-CSF at 16 μg/kg. There was no difference in the times to neutrophil (G-BM, 12 days; G-PBSC, 11 days) or platelet (G-BM, 13 days; G-PBSC, 11 days) recovery.26 Weisdorf27 randomized patients to receive G-CSF or GM-CSF for 6 days before either BM or PBSC harvests. PBSCs were harvested when the BM was either hypocellular or involved by disease. The source of stem cells did not impact the time to count recovery. Isola et al30 administered G-CSF to healthy donors at a dose of 10 μg/kg for 2 days before harvest. Compared with historical controls of unstimulated bone marrow, G-BM contained similar numbers of nucleated cells, CD34+ cells, and CD3+ cells but an increase in granulocyte macrophage colony-forming units. Engraftment was accelerated compared with unstimulated bone marrow (ANC greater than 1000/μL, 17 vs 26 days; PLT greater than 20 000/L, 20 vs 26 days). A long-term follow-up study confirmed stable donor engraftment.31 Couban et al29 administered G-CSF (median dose, 12 μg/kg) for 4 days before G-BM harvest. Neutrophil (18 days) and platelet (22 days) engraftment were accelerated to control groups receiving G-BM. Serody et al28 compared sequential cohorts receiving G-BM or G-PBSC (G-CSF 10 μg/kg for 4 days) for allogeneic transplantation. GVHD prophylaxis used abbreviated methotrexate, as in our study, though leucovorin was not used. Platelet recovery (G-BM, 16 days; G-PBSC, 13 days), but not neutrophil recovery (G-BM, 16 days; G-PBSC, 17 days), was faster after G-PBSC. The incidence of grades II-IV acute GVHD (G-BM, 27%; G-PBSC, 60%; P < .07) and chronic GVHD (G-BM, 37%; G-PBSC, 68%; P < .05) were increased in the G-PBSC group.

Based on our results, it appears that engraftment times after autologous or allogeneic stem cell transplantation are comparable using G-BM or G-PBSCs as stem cell sources. The optimal dosage and scheduling of G-CSF administration before harvest remain to be determined. It is possible that delayed collection of G-BM34 may further optimize engraftment kinetics. Contaminating peripheral blood contributes significantly to the yield of CD34+ cells; however, in this study preharvest peripheral blood CD34+cell counts were not performed. We also found G-BM harvest times to be greatly reduced compared with standard BM collection, paralleling the observation of others.29 This was particularly useful with overweight donors or those who presented anatomic challenges.

In line with other studies, we found that the incidence of grades II-IV acute GVHD was similar after G-PBSC and G-BM allografting. However, in contrast to these studies, we found that patients who acquired acute GVHD after G-PBSC transplantation were more likely to have severe organ involvement and to respond poorly to prednisone therapy. One suggested mechanism for the increased incidence of severe acute GVHD in the current study is the abbreviated methotrexate schedule used in this study. It has been shown that the risk for grades II-IV acute GVHD for patients undergoing HLA-identical sibling marrow is increased (28% vs 39%; P < .03) with the omission of day 11 methotrexate. The risk for grades III-IV acute GVHD, however, was not affected by day 6 or day 11 methotrexate administration.14In our study, the incidence of grades III-IV acute GVHD in the G-PBSC group was highest when the T-cell dose exceeded 4 × 108/kg. It is possible that the omission of day 11 methotrexate is particularly relevant to the development of grades III-IV acute GVHD in patients receiving high T-cell doses. This observation contrasts with the findings of a study of 160 patients in which CD34 rather than CD3 cell dose was found to correlate with the development of grades II-IV acute GVHD (no variables were found to correlate with the development of grades III-IV acute GVHD).6 Various GVHD prophylaxis regimes were used in this study, though the lowest incidence of grades III-IV GVHD was observed with tacrolimus and mini-methotrexate (5 mg/m2 days 1, 3, 6).

The primary end-point in this study was the development of clinical extensive cGVHD. The study was closed after the initial interim analysis because of the highly significant difference in the incidence of this complication. Retrospective analyses comparing unstimulated BM and G-PBSCs as stem cell sources have suggested an increase in the incidence of cGVHD,25,33 and they parallel Storb's22 original observation of increased cGVHD after the addition of donor buffy coat to promote engraftment in transfused patients with aplastic anemia undergoing allogeneic BM transplantation. Randomized studies have reached differing conclusions, though the French multigroup study, which also used abbreviated methotrexate prophylaxis, found a significantly higher incidence of extensive cGVHD in the G-PBSC group.8 

This study was not designed to detect a difference in survival between the 2 study groups, but their survival curves are similar. The development of cGVHD is known to be protective against disease recurrence for patients with acute leukemia and CML.37-40 Prospective randomized studies and a retrospective comparison have suggested improved leukemia-free survival after G-PBSC, restricted to patients with advanced disease4,7 (defined by acute leukemia beyond CR1 and CML beyond chronic phase). This difference was variably attributed to reduced disease recurrence4 and reduced treatment-related mortality.33 Given that a high response rate to donor lymphocyte infusions has been demonstrated for relapsing chronic-phase CML, it seems unlikely that the use of G-PBSC would result in a survival advantage for this group of patients.41-43 The response rate to donor lymphocyte infusions is low for relapsing AML and ALL, and it is likely that the use of G-PBSC would be of advantage for these patients.

In conclusion, we have demonstrated that the use of G-BM results in rapid and sustained engraftment. Compared with G-PBSC, median neutrophil and platelet recovery was delayed by 2 days. Optimal timing of bone marrow harvest after G-CSF administration remains to be determined. Although the incidence of grades II-IV acute GVHD was similar for the 2 groups, patients undergoing G-PBSC transplantation were more likely to acquire severe acute GVHD refractory to prednisone and cGVHD with a prolonged requirement for immunosuppression therapy to control symptoms. We recommend the use of G-BM rather than G-PBSCs, especially for patients in whom disease recurrence can be effectively treated with donor lymphocyte infusions.

This work is a component of a Masters thesis through the Department of Epidemiology, University of Newcastle, NSW, Australia.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

1
Smith
TJ
Hillner
BE
Schmitz
N
et al
Economic analysis of a randomized clinical trial to compare filgrastim-mobilized peripheral blood progenitor-cell transplantation and autologous bone marrow transplantation in patients with Hodgkin's and non-Hodgkin's lymphoma.
J Clin Oncol.
15
1997
5
10
2
Bacigalupo
A
Van Lint
MT
Valbonesi
M
et al
Thiotepa cyclophosphamide followed by granulocyte colony-stimulating factor mobilized allogeneic peripheral blood cells in adults with advanced leukemia.
Blood.
88
1996
353
357
3
Bensinger
WI
Clift
R
Martin
P
et al
Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation.
Blood.
88
1996
2794
2800
4
Bensinger
WI
Martin
PJ
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.
344
2001
175
181
5
Przepiorka
D
Anderlini
P
Ippoliti
C
et al
Allogeneic blood stem cell transplantation in advanced hematologic cancers.
Bone Marrow Transplant.
19
1997
455
460
6
Przepiorka
D
Ippoliti
C
Khouri
I
et al
Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus.
Transplantation.
62
1996
1806
1810
7
Powles
R
Mehta
J
Kulkarni
S
et al
Allogeneic blood and bone marrow stem cell transplantation in haematological malignant diseases: a randomised trial [see comments].
Lancet.
355
2000
1231
1237
8
Blaise
D
Kuentz
M
Fortanier
C
et al
Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Societe Francaise de Greffe de Moelle.
J Clin Oncol.
18
2000
537
546
9
Pavletic
ZS
Bishop
MR
Tarantolo
SR
et al
Hematopoietic recovery after allogeneic blood stem cell transplantation compared with bone marrow transplantation in patients with hematologic malignancies.
J Clin Oncol.
15
1997
1608
1616
10
Heldal
D
Tjonnfjord
G
Brinch
L
et al
A randomised study of allogeneic transplantation with stem cells from blood or bone marrow.
Bone Marrow Transplant.
25
2000
1129
1136
11
Bross
DS
Tutschka
PJ
Farmer
ER
et al
Predictive factors for acute graft-versus-host disease in patients transplanted with HLA-identical bone marrow.
Blood.
63
1984
1265
1270
12
Flowers
ME
Pepe
MS
Longton
G
et al
Previous donor pregnancy as a risk factor for acute graft-versus-host disease in patients with aplastic anaemia treated by allogeneic marrow transplantation.
Br J Haematol.
74
1990
492
496
13
Gale
RP
Bortin
MM
van Bekkum
DW
et al
Risk factors for acute graft-versus-host disease.
Br J Haematol.
67
1987
397
406
14
Nash
RA
Pepe
MS
Storb
R
et al
Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate.
Blood.
80
1992
1838
1845
15
Goldman
JM
Gale
RP
Horowitz
MM
et al
Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: increased risk for relapse associated with T-cell depletion.
Ann Intern Med.
108
1988
806
814
16
Marmont
AM
Horowitz
MM
Gale
RP
et al
T-cell depletion of HLA-identical transplants in leukemia.
Blood.
78
1991
2120
2130
17
Martin
PJ
Hansen
JA
Buckner
CD
et al
Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts.
Blood.
66
1985
664
672
18
Mitsuyasu
RT
Champlin
RE
Gale
RP
et al
Treatment of donor bone marrow with monoclonal anti–T-cell antibody and complement for the prevention of graft-versus-host disease: a prospective, randomized, double-blind trial.
Ann Intern Med.
105
1986
20
26
19
Sullivan
KM
Agura
E
Anasetti
C
et al
Chronic graft-versus-host disease and other late complications of bone marrow transplantation.
Semin Hematol.
28
1991
250
259
20
Niederwieser
D
Pepe
M
Storb
R
et al
Factors predicting chronic graft-versus-host disease and survival after marrow transplantation for aplastic anemia.
Bone Marrow Transplant.
4
1989
151
156
21
Atkinson
K
Horowitz
MM
Gale
RP
et al
Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation.
Blood.
75
1990
2459
2464
22
Storb
R
Prentice
RL
Sullivan
KM
et al
Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings.
Ann Intern Med.
98
1983
461
466
23
Lonnqvist
B
Aschan
J
Ljungman
P
et al
Long-term cyclosporin therapy may decrease the risk of chronic graft-versus-host disease [letter; comment].
Br J Haematol.
74
1990
547
548
24
Wingard
JR
Piantadosi
S
Vogelsang
GB
et al
Predictors of death from chronic graft-versus-host disease after bone marrow transplantation.
Blood.
74
1989
1428
1435
25
Storek
J
Gooley
T
Siadak
M
et al
Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease [see comments].
Blood.
90
1997
4705
4709
26
Damiani
D
Fanin
R
Silvestri
F
et al
Randomized trial of autologous filgrastim-primed bone marrow transplantation versus filgrastim-mobilized peripheral blood stem cell transplantation in lymphoma patients [see comments].
Blood.
90
1997
36
42
27
Weisdorf
D
Miller
J
Verfaillie
C
et al
Cytokine-primed bone marrow stem cells vs. peripheral blood stem cells for autologous transplantation: a randomized comparison of GM-CSF vs.
G-CSF. Biol Blood Marrow Transplant.
3
1997
217
223
28
Serody
JS
Sparks
SD
Lin
Y
et al
Comparison of granulocyte colony-stimulating factor (G-CSF)–mobilized peripheral blood progenitor cells and G-CSF–stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation.
Biol Blood Marrow Transplant.
6
2000
434
440
29
Couban
S
Messner
HA
Andreou
P
et al
Bone marrow mobilized with granulocyte colony-stimulating factor in related allogeneic transplant recipients: a study of 29 patients.
Biol Blood Marrow Transplant.
6
2000
422
427
30
Isola
LM
Scigliano
E
Skerrett
D
et al
A pilot study of allogeneic bone marrow transplantation using related donors stimulated with G-CSF.
Bone Marrow Transplant.
20
1997
1033
1037
31
Isola
L
Scigliano
E
Fruchtman
S
Long-term follow-up after allogeneic granulocyte colony-stimulating factor–primed bone marrow transplantation.
Biol Blood Marrow Transplant.
6
2000
428
433
32
Sutherland
DR
Anderson
L
Keeney
M
et al
The ISHAGE guidelines for CD34+ cell determination by flow cytometry: International Society of Hematotherapy and Graft Engineering.
J Hematother.
5
1996
213
226
33
Champlin
RE
Schmitz
N
Horowitz
MM
et al
Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT).
Blood.
95
2000
3702
3709
34
Bodine
DM
Seidel
NE
Orlic
D
Bone marrow collected 14 days after in vivo administration of granulocyte colony-stimulating factor and stem cell factor to mice has 10-fold more repopulating ability than untreated bone marrow.
Blood.
88
1996
89
97
35
Johnsen
HE
Hansen
PB
Plesner
T
et al
Increased yield of myeloid progenitor cells in bone marrow harvested for autologous transplantation by pretreatment with recombinant human granulocyte-colony stimulating factor [see comments].
Bone Marrow Transplant.
10
1992
229
234
36
Slowman
S
Danielson
C
Graves
V
et al
Administration of GM-/G-CSF before bone marrow harvest increases collection of CD34+ cells.
Prog Clin Biol Res.
389
1994
363
369
37
Weiden
PL
Sullivan
KM
Flournoy
N
et al
Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.
N Engl J Med.
304
1981
1529
1533
38
Sullivan
KM
Storb
R
Buckner
CD
et al
Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms.
N Engl J Med.
320
1989
828
834
39
Sullivan
KM
Weiden
PL
Storb
R
et al
Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia [published erratum appears in Blood. 1989;74:1180].
Blood.
73
1989
1720
1728
40
Horowitz
MM
Gale
RP
Sondel
PM
et al
Graft-versus-leukemia reactions after bone marrow transplantation.
Blood.
75
1990
555
562
41
Collins
RH
Jr
Shpilberg
O
Drobyski
WR
et al
Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation [see comments].
J Clin Oncol.
15
1997
433
444
42
Kolb
HJ
Schattenberg
A
Goldman
JM
et al
Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients: European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia [see comments].
Blood.
86
1995
2041
2050
43
Mackinnon
S
Papadopoulos
EB
Carabasi
MH
et al
Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease.
Blood.
86
1995
1261
1268

Author notes

James Morton, Bone Marrow Transplant Unit, Royal Brisbane Hospital, Herston Rd, Herston, Q4029, Australia; e-mail:[email protected].

Sign in via your Institution