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Journal of Clinical Oncology, Vol 18, Issue 9 (May), 2000: 1824-1830
© 2000 American Society for Clinical Oncology

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

By Omer N. Koç, Stanton L. Gerson, Brenda W. Cooper, Mary Laughlin, Howard Meyerson, Leila Kutteh, Robert M. Fox, Emese M. Szekely, Nancy Tainer, Hillard M. Lazarus

From the Departments of Medicine and Pathology, Case Western Reserve University; Ireland Cancer Center; and University Hospitals of Cleveland, Cleveland, OH.

Address reprint requests to Omer N. Koç, MD, Case Western Reserve University, BRB-3 Hematology/Oncology, 10900 Euclid Ave, Cleveland, OH 44106; email onk2{at}po.cwru.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Patient response to hematopoietic progenitor-cell mobilizing regimens seems to vary considerably, making comparison between regimens difficult. To eliminate this inter-patient variability, we designed a cross-over trial and prospectively compared the number of progenitors mobilized into blood after granulocyte-macrophage colony-stimulating factor (GM-CSF) days 1 to 12 plus granulocyte colony-stimulating factor (G-CSF) days 7 to 12 (regimen G) with the number of progenitors after cyclophosphamide plus G-CSF days 3 to 14 (regimen C) in the same patient.

PATIENTS AND METHODS: Twenty-nine patients were randomized to receive either regimen G or C first (G1 and C1, respectively) and underwent two leukaphereses. After a washout period, patients were then crossed over to the alternate regimen (C2 and G2, respectively) and underwent two additional leukaphereses. The hematopoietic progenitor-cell content of each collection was determined. In addition, toxicity and charges were tracked.

RESULTS: Regimen C (n = 50) resulted in mobilization of more CD34+ cells (2.7-fold/kg/apheresis), erythroid burst-forming units (1.8-fold/kg/apheresis), and colony-forming units–granulocyte-macrophage (2.2-fold/kg/apheresis) compared with regimen G given to the same patients (n = 46; paired t test, P < .01 for all comparisons). Compared with regimen G, regimen C resulted in better mobilization, whether it was given first (P = .025) or second (P = .02). The ability to achieve a target collection of >= 2 x 106 CD34+ cells/kg using two leukaphereses was 50% after G1 and 90% after C1. Three of the seven patients in whom mobilization was poor after G1 had >= 2 x 106 CD34+ cells/kg with two leukaphereses after C2. In contrast, when regimen G was given second (G2), seven out of 10 patients failed to achieve the target CD34+ cell dose despite adequate collections after C1. Thirty percent of the patients (nine of 29) given regimen C were admitted to the hospital because of neutropenic fever for a median duration of 4 days (range, 2 to 10 days). The higher cost of regimen C was balanced by higher CD34+ cell yield, resulting in equivalent charges based on cost per CD34+ cell collected.

CONCLUSION: We report the first clinical trial that used a cross-over design showing that high-dose cyclophosphamide plus G-CSF results in mobilization of more progenitors then GM-CSF plus G-CSF when tested in the same patient regardless of sequence of administration, although the regimen is associated with greater morbidity. Patients who fail to achieve adequate mobilization after regimen G can be treated with regimen C as an effective salvage regimen, whereas patients who fail regimen C are unlikely to benefit from subsequent treatment with regimen G. The cross-over design allowed detection of significant differences between regimens in a small cohort of patients and should be considered in design of future comparisons of mobilization regimens.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE RELATIVE EFFECTIVENESS of different peripheral-blood progenitor-cell (PBPC) mobilization regimens has been difficult to determine because of considerable heterogeneity in patient characteristics and responses to a given mobilizing regimen.1-4 Even randomized trials evaluating two different mobilization treatments are confounded by known and unknown patient variables that influence progenitor mobilization independent of the assigned treatment. To eliminate this inter-patient variability, we prospectively compared the number of hematopoietic progenitors mobilized into blood after two different regimens in the same patient in a randomized cross-over clinical trial.

Optimal strategy to mobilize hematopoietic progenitors into blood remains controversial. There are insufficient data directly comparing hematopoietic cytokines with chemotherapy and cytokine mobilization of PBPC in respect to potency, toxicity, and cost. To this end, we compared two such regimens in patients scheduled to undergo high-dose chemotherapy and autologous PBPC transplantation. The first regimen consisted of a combination of granulocyte-macrophage colony-stimulating factor ([GM-CSF] Sargramostatin; Immunex, Seattle, WA) on days 1 to 12 plus granulocyte colony-stimulating factor ([G-CSF] Filgrastim; Amgen, Thousand Oaks, CA) on days 7 to 12 designated as regimen G, which allows rapid collection of PBPCs without the toxicity of chemotherapeutic agents.5 The second strategy, designated as regimen C, consisted of high-dose cyclophosphamide 4 g/m2 plus G-CSF on days 3 to 14. This approach had been shown to mobilize high numbers of PBPCs but frequently was associated with the development of neutropenic fever requiring hospitalization.6-8 The cross-over study design allowed us to directly compare the efficacy of each mobilization in the same patient, eliminated the inter-patient variability, and reduced the sample size requirement. Our results indicate that high-dose cyclophosphamide plus G-CSF results in mobilization of twice the number of CD34+ cells per kilogram of patient weight per leukapheresis but was associated with febrile neutropenia in 30% of the patients, increasing the potential morbidity and cost of this therapy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
This randomized cross-over phase III study was open to adult patients (18 to 65 years old) who were referred to our center for consideration of high-dose chemotherapy with autologous PBPC transplantation. The study protocol was approved by the Institutional Review Board for Human Investigations at the University Hospitals of Cleveland, and patients gave written informed consent. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate visceral organ function, including left ventricular ejection fraction of at least 50%, forced expiratory volume in 1 second and diffusion capacity of carbon monoxide more than 50% of predicted level, serum direct bilirubin <= 2.0 mg/dL, and an actual or calculated creatinine clearance >= 60 mL/min. At the start of therapy, a blood neutrophil count >= 1.2 x 109/L and a platelet count >= 100 x 109/L were required. Patients were excluded if they previously had received cumulative doxorubicin exposure in excess of 500 mg/m2 or had major CNS dysfunction, active infection, or a history of autoimmune disease. Patients were not excluded for evidence of tumor on routine histologic staining of bilateral paraffin-embedded posterior iliac crest bone marrow biopsy specimens.

Mobilization and Collection of PBPCs
Mobilization regimen C consisted of cyclophosphamide 4.0 g/m2 intravenous (IV) infusion over 6 hours on day 1, along with mesna 3.0 g/m2 IV, then 500 mg every 3 hours orally/IV for 8 doses and prednisone 2.0 mg/kg orally on days 1 to 4. At 36 to 48 hours after completion of the cyclophosphamide, patients began subcutaneous injections of recombinant human G-CSF 10 µg/kg/d. On recovery of the leukocyte count above 1 x 109/L (usually 12 to 15 days after cyclophosphamide treatment), patients underwent two leukapheresis procedures. Mobilization regimen G consisted of GM-CSF 250 µg/m2/d subcutaneously days 1 to 12 plus G-CSF 10 µg/kg/d subcutaneously days 7 to 12. Patients underwent two leukapheresis procedures on days 11 and 12. On enrollment patients were randomized to receive either regimen C (C1) or regimen G (G1) as the first planned treatment followed by two daily leukapheresis procedures. After an obligatory wash-out period of a minimum 2 weeks from the completion of the second leukapheresis procedure, patients then were crossed-over to the alternative mobilization regimen, G (G2) or C (C2), followed by two additional leukapheresis procedures (Fig 1). Leukaphereses were performed using Cobe Spectra (COBE, Lakewood, CO) pheresis equipment. Mean volume 20 L (four times total blood volume) pheresis was performed daily for 2 days after each mobilization therapy. If the total number of CD34+ cells collected did not reach >= 2.0 x 106/kg after scheduled collections, additional collections were performed, but only the first two collections after each regimen were used for analysis. Cells were cryopreserved using a controlled-rate liquid nitrogen freezer using previously published methods.9



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  		Fig 1. Protocol design and analysis: statistical analyses were either paired (between same patient’s apheresis products) or unpaired (between apheresis products of randomized cohorts). C1: cohort randomized to receive chemotherapy plus G-CSF as first mobilization regimen. G2: same cohort of patients crossed over to receive GM-CSF and G-CSF as a second-line mobilization regimen. G1 and C2: cohort randomized to receive mobilization regimens in a reverse order. Two aphereses products (arrows) after each regimen were analyzed for stem-cell content.

 
Clonogenic Assay for Committed Hematopoietic Progenitors
Peripheral-blood mononuclear cells (1 x 105/mL) were grown in methylcellulose (Stem Cell Technologies, Vancouver, British Colombia, Canada) containing (final concentration) 100 U/mL of human interleukin-3 (Sandoz Research Institute, Nutley, NJ), 4 U/mL of erythropoietin (Amgen, Thousand Oaks, CA), 100 U/mL of GM-CSF (Immunex, Seattle, WA), and 0.1 mmol/L of hemin (Sigma, St Louis MO). Cells were plated in duplicate and grown at 37°C, 5% CO2. Twelve to 14 days later, colonies greater than 50 cells were enumerated. Colony-forming units–granulocyte-macrophage (CFU-GM) and erythroid burst-forming units (BFU-E) were identified based on morphologic assessment, as previously reported.9 Yields of CFU-GM, BFU-E, and total CFU (CFU-GM + BFU-E) per collection were determined by multiplication of their concentration (colonies per 1 x 105 cells) with the total number of mononuclear cells collected.

CD34+ Cell Enumeration
Peripheral-blood mononuclear cells (1 x 106 cells in 100 µL phosphate-buffered saline with 1% bovine serum albumin and 0.1% NaAzide [sodium azide; Sigma, St Louis, MO]) were stained with phycoerythrin (PE)-conjugated anti-CD34 monoclonal antibody HPCA-2 and fluorescein isothiocyanate–conjugated anti-CD45 monoclonal antibody (Becton Dickinson, Mountain View, CA) for 30 minutes at 4°C. Flow cytometric analyses were performed with a FACScan analyzer (Becton Dickinson, San Jose, CA) equipped with a filter set for fluorescein isothiocyanate–PE dual-color fluorescence. For each sample, 250,000 events were acquired as list mode data using CellQuest software (Becton Dickinson, San Jose, CA). The percentage of CD34+ cells was determined by analyzing the entire CD45+ (dim and bright) population on a CD34-PE FL2-height (x-axis) versus SSC-height (y-axis) dot plot. Background fluorescent activity was determined by isotype antibody and subtracted from each measurement. The total of CD34+ cells was calculated by multiplying the percentage of CD34+ cells by the total number of nucleated cells in the pheresis product, which was the product of the WBC count from Sysmex-100 (TOA Medical Electronics, Kobe, Japan) hematology analyzer and the volume of the pheresis product.

High-Dose Chemotherapy and Stem-Cell Support
After PBPC procurement, patients were given high-dose chemotherapy based on their diagnosis. Patients with lymphoma were given carmustine 600 mg/m2, etoposide 2,400 mg/m2, and cisplatin 200 mg/m2, as previously described.10 Patients with breast cancer were given cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 as continuous IV infusion over 96 hours through a central venous catheter from days T-7 through T-3.11 Patients with multiple myeloma were treated with melphalan 140 mg/m2 and total-body irradiation (12 Gy). On the day of transplant (T-0), patients were infused with all collected leukapheresis products (combined regimen G and C collections). All patients received either recombinant human G-CSF 10 µg/kg subcutaneously or GM-CSF 500 µg/m2 daily starting 4 to 24 hours after the PBPC infusion until neutrophil engraftment (absolute neutrophil count > 0.5 x 109/L).

Supportive Care
All patients had multilumen, indwelling central venous pheresis catheters and were cared for in single hospital rooms. Antibiotics were given empirically for fever and neutropenia, and all patients were supported with irradiated blood components. Irradiated, packed RBC transfusions were given in an attempt to keep the hematocrit more than 25%, and irradiated platelet transfusions were given for platelet counts less than 10 x 109/L or bleeding complications. Cytomegalovirus-negative blood products were given to cytomegalovirus seronegative patients. Toxicity grading was accomplished using the National Cancer Institute common toxicity criteria.

Statistics
The statistical significance of the data obtained was analyzed by the Student’s t test (paired and unpaired, StatView; Abacus Concepts, Berkeley, CA). A P value less than .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics and Hematopoietic Engraftment
Thirty-one patients were registered between July 1996 and February 1999. Two patients were not assessable; one withdrew to undergo autologous bone marrow harvesting, and the other patient had disease progression before PBPC collections. Out of 29 assessable patients, 25 completed both of the scheduled mobilization treatments, whereas three received only regimen C, and one received only regimen G. Clinical characteristics of the study patients are listed in Table 1. Median age was 47 years; 12 patients had lymphoma, eight had multiple myeloma, and nine had solid tumors and received a mean of two previous chemotherapy regimens (range, one to three regimens). Bone marrow involvement was more frequent among patients randomized to regimen G first (G1) as opposed to C1, but this difference was not statistically significant. Twenty-three of 29 patients proceeded with high-dose chemotherapy. Reasons for not receiving high-dose chemotherapy were progressive disease in four subjects and failure to obtain a minimum total of 2 x 106 CD34+ cells/kg in the combined collections in two patients. Two other patients had to have a third apheresis collection after the second mobilization to reach target CD34+ cell dose. Patients who received high-dose chemotherapy were supported with a mean of 10.6 x 106 autologous CD34+ cells/kg (range, 2.15 to 42.4 x 106). Median days to neutrophil recovery (absolute neutrophil count > 500/µL) was 10 days (range, 8 to 18 days), and median days to platelet recovery (platelet count > 20,000/µL, unsupported) was 13.5 days (range, 8 to 42 days).


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  		Table 1. Patient Characteristics
 
Progenitor Mobilization
Progenitor-cell content of each leukapheresis product was determined by enumeration of CD34+ cells by flow cytometry and clonogenic progenitors using methylcellulose culture assay and corrected for patient body weight. Leukapheresis products obtained after mobilization regimen C (C1 and C2, n = 50) were compared with those obtained after regimen G (G1 and G2, n = 46) in a paired analysis (Table 2). Leukapheresis products after regimen C contained 2.5-fold more CD34+ cells (mean ± SD; 3.36 ± 4.41 x 106/kg v 1.36 ± 1.97 x 106/kg; P = .0075), 1.7-fold more BFU-E (118 x 104/kg v 69 x 104/kg; P < .0001), and 2.2-fold more CFU-GM (55 x 104/kg v 25 x 104/kg; P < .002). The sequence of administration of these two regimens did not alter this observation. Median time between administration of regimens was 26 days (mean, 28.7 days; range, 21 to 80 days). Compared with regimen G, regimen C resulted in collection of higher numbers of CD34+ cells whether it was given first (C1 v G2, P = .013) or second (C2 v G1, P = .04) (Tables 2 and 3). As listed in Table 3, all paired analyses were statistically significant (white boxes) as opposed to unpaired analyses (gray boxes), indicating the importance of the cross-over trial design permitting us to use paired statistics. In our patient cohorts initially assigned to regimen C1 or regimen G1, differences in progenitor-cell numbers did not reach significance because of high variability within each cohort (Table 3). The superiority of regimen C was established by the paired analysis described above, which overcame the intracohort variability. In addition, when regimen G was given after C (G2), collections obtained had significantly lower CD34+ cell, BFU-E, and CFU-GM content when compared with C1 and C2 and lower BFU-E content when compared with G1.


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  		Table 2. Comparison of the Progenitor Collections Based on Mobilization Regimen and Sequence
 

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  		Table 3. Statistical Comparison of the Progenitor Collections Based on Mobilization Regimen and Sequence
 
Ability to achieve a target collection of >= 2 x 106 CD34+ cells/kg after two leukapheresis was 50% (seven of 14 patients) after G1, 90% (nine of 10 patients) after C1 (C1 v G1: P = .08), 69% (nine of 13 patients) after C2, and 30% (three of 10 patients) after G2 (Fig 2). When all collections from C (C1 and C2) were compared with collections from G (G1 and G2), a significantly higher proportion of patients achieved the target collection after C (78% v 42%, respectively; P = .017). Three of the seven patients who exhibited poor mobilization after G1 (< 2 x 106 CD34+ cell/kg) had >= 2 x 106 CD34+ cell/kg with two leukapheresis after C2. In contrast, when regimen G was given second (G2), seven (70%) out of 10 patients failed to achieve the target CD34+ cell dose with two collections.



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  		Fig 2. Total number of CD34+ cells collected per kg of patient weight (x 106) after two apheresis procedures based on the type of mobilization regimen given. Left panel: patients randomized to receive regimen C first (C1) followed by G2. Right panel: patients randomized to receive regimen G first (G1) followed by C2. Dotted line shows the threshold of 2 x 106 CD34+ cell/kg.

 
To determine whether the mobilization regimen affected the relationship between the CD34+ cells and clonogenic progenitors in a given collection, we calculated the ratio of CD34+ cells to total CFU in each leukapheresis unit. There was no difference in this ratio between collections obtained after regimen G (162 ± 135) and regimen C (188 ± 155, P = .5).

Toxicity and Cost
After regimen C, 30% of the patients (nine out of 29) were admitted to the hospital for a median of 4 days (range, 2 to 10 days) because of neutropenic fever. There was no treatment-related mortality, and all patients were discharged from the hospital. Transfusion support data were available for 23 patients. Nine patients (39%) required transfusion of a mean (± SD) of 3.1 ± 1.9 units of packed RBCs, and seven patients (30%) required transfusion of a mean (± SD) of 5 ± 4 pooled or apheresis platelets during the 4 weeks after cyclophosphamide therapy. In contrast, only one patient had to be given a single unit of pheresis platelets during the 2 weeks after initiation of growth factor–only mobilization. At the University Hospitals of Cleveland, mean (± SD) charges for the administration of high-dose cyclophosphamide for our patients were $5,356 ± $945, and addition of G-CSF raised the charges to approximately $8,726 per patient. Mean (± SD) charges for neutropenic fever hospitalization for the nine patients were $8,295 ± $4,070. We further adjusted the total charges for high-dose cyclophosphamide and G-CSF by adding 30% of the neutropenic fever charges (30% risk for this expense), 39% of the mean PRBC transfusion charges ($215), and 30% of the mean platelet transfusion charges ($804) to $8,726, bringing total charges for this regimen to approximately $12,233. This value is in sharp contrast to the charges for 12 days of GM-CSF and 6 days of G-CSF administration, which is approximately $4,711. We did not include charges common to both regimens, such as outpatient nursing, apheresis procedures, and stem-cell measurements. Therefore, the cost estimates are relative and not absolute. Based on these figures, the relative cost of collecting one CD34+ cell per kg of patient weight was 0.36¢ for regimen C ($12,233/3.36 x 106) and 0.35¢ for regimen G ($4,711/1.36 x 106).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We report the first direct comparison of two different mobilization strategies in a cross-over clinical trial, showing that high-dose cyclophosphamide and G-CSF results in mobilization of significantly more progenitors than the combination of GM-CSF and G-CSF when tested in the same patient. This difference in regimens persisted regardless of the sequence of their administration. The cross-over design allowed paired analysis of apheresis products from the same patient, circumvented the problem of high inter-individual variance, and produced statistically significant results using a relatively small number of patients. Our results demonstrate a dramatic and statistically significant difference in numbers of progenitors mobilized with regimen C compared with the alternate regimen G when directly compared in the same patient. In contrast, this difference was not apparent when apheresis collections were compared between randomized cohorts of patients given regimen C1 or G1 as the first regimen because of large variability within cohorts and small sample size, demonstrating the value of the cross-over design. In addition, our results indicate that if the initial use of regimen G fails to generate a target number of progenitors, subsequent use of regimen C may allow collection of the target number of progenitors. In contrast, patients given regimen G second (G2) had poor collections compared with their initial regimen C (C1) collections. Furthermore, these collections (G2) contained significantly lower numbers of BFU-E when compared with those obtained if regimen G was given first (G1, P = .04, unpaired comparison). This observation suggests that recent administration of high-dose cyclophosphamide may alter progenitor-cell response to hematopoietic cytokines or alter the pool of cytokine responsive progenitors.

As new techniques emerge to improve the efficiency of PBPC mobilization, it is important to consider randomized cross-over study design, given the high degree of variability in patient characteristics and response to mobilization therapy. Shpall12 et al recently reported that the combination of stem-cell factor and G-CSF is superior to G-CSF alone in PBPC mobilization in a randomized trial involving 203 breast cancer patients. Although a higher percentage of patients achieved a target CD34+ cell yield with fewer apheresis procedures (63% v 47% of patients, with four v >= six procedures, respectively), it is not known whether patients who fail to have adequate mobilization with G-CSF can be mobilized with G-CSF plus stem-cell factor. There are also data indicating that combination chemotherapy may be superior to single-agent cyclophosphamide for PBPC mobilization. In a nonrandomized study, Demirer13 et al found that paclitaxel plus cyclophosphamide mobilizes a higher number of CD34+ cells per day, particularly on the first day of apheresis. Again, it is not possible to determine whether this difference is partly because of variability in the patient population studied and whether patients who fail to have adequate mobilization after cyclophosphamide can have good yields after combination chemotherapy. These questions can be answered in a cross-over trial with relatively few patients.

The number of CD34+ cells/kg infused and prior exposure to alkylator therapy are known to correlate with the time for neutrophil and platelet count recovery.2,14 The threshold CD34+ cell dose for hematopoietic engraftment is in dispute but is generally considered to be >= 2 x 106/kg for patients with <= 24 months of prior chemotherapy exposure and >= 5 x 106/kg for patients with longer exposure.4 Recently, Schulman et al15 reported that infusion of higher numbers of CD34+ cells is associated with a reduction in the cost of autologous PBPC transplantation. When compared with patients receiving >= 5 x 106 CD34+ cells/kg, patients who received less CD34+ cells required more transfusion support, longer hospital stay, and increased antibiotic/antifungal use, increasing the transplant cost by approximately $10,000 ($41,516 v $32,382, respectively). Therefore, attempts to obtain the highest number of CD34+ cells at minimum cost is desirable. We found that the relative cost of a single CD34+ cell/kg was comparable whether obtained after regimen G or C. The inexpensive regimen G yielded a low number of CD34+ cells compared with the more expensive regimen C, which yielded a high number of CD34+ cells. On the other hand, a higher proportion of patients failed to achieve the threshold level CD34+ cell collection after regimen G, which would substantially increase the cost if another mobilization is attempted or render that patient ineligible for PBPC support. Meisenberg et al16 compared mobilization with G-CSF alone with low-dose cyclophosphamide plus sequential administration of GM-CSF and G-CSF in patients with breast cancer. The mean number of leukapheresis procedures required to achieve a target dose of CD34+ cells (4 x 106/kg) was 1.3 for the combination regimen and 2.7 for G-CSF alone. Interestingly, the charges for the entire procedure were $7,381 for G-CSF alone and $5,508 for cyclophosphamide plus growth factors because of the lower number of leukapheresis procedures required in the latter group. Recently, Desikan et al8 reported results for 44 myeloma patients who were randomized to receive either G-CSF or cyclophosphamide (6g/m2) plus G-CSF for progenitor-cell mobilization. Patients who received cyclophosphamide plus G-CSF required a longer time interval for completion of progenitor-cell collections, and the incidence of neutropenic fever was 32%, which was similar to our results. The median number of CD34+ cells collected after cyclophosphamide plus G-CSF was significantly higher than G-CSF alone (33.4 x 106/kg v 5.8 x 106/kg, respectively). Although it seems that cyclophosphamide plus G-CSF resulted in collection of 5.8-fold more CD34+ cells compared with G-CSF, the magnitude of difference may be misleading because data were derived from two randomized cohorts of patients. There were no differences in posttransplant hematopoietic recovery of these myeloma patients between groups because all patients were infused with a minimum of 2 x 106 CD34+ cells/kg.

Although we have not analyzed subsets of CD34+ cells mobilized, we found no significant difference in total CFU/CD34+ cell ratios between collections obtained after regimens G and C, indicating preservation of phenotype/function (clonogenicity) relationships in both cohorts. There are data indicating that hematopoietic growth factors may preferentially mobilize more immature progenitors, ie, CD34+CD38-, as opposed to chemotherapy.17 Whether these more subtle changes in phenotype of mobilized progenitors are as important as the total number of CD34+ cells mobilized needs to be further investigated.

In summary, our results indicate that a randomized cross-over study design performs well when comparing PBPC mobilization strategies by circumventing variability in patient characteristics that alter PBPC mobilization kinetics. We show that high-dose cyclophosphamide plus G-CSF results in superior PBPC mobilization and that its higher cost is balanced by a higher CD34+ cell yield. In addition, high-dose cyclophosphamide plus G-CSF may allow adequate CD34+ cell collections in patients who previously failed hematopoietic growth factor mobilization.


   ACKNOWLEDGMENTS
 
Supported in part by Public Health Service grant nos. P30CA43703, MO1RR00080–35, and ACS PRTA-35 from the American Cancer Society and by Immunex Corporation, Seattle, WA.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Bensinger WI, Longin K, Appelbaum F, et al: Peripheral blood stem cells (PBSCs) collected after recombinant granulocyte colony-stimulating factor (rhG-CSF): An analysis of factors correlating with the tempo of engraftment after transplantation. Haematol 87:825-831, 1994

2. Tricot 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 85:588-596, 1995[Abstract/Free Full Text]

3. Weaver C, Hazelton B, Birch R, et al: An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood 86:3961-3969, 1995[Abstract/Free Full Text]

4. Bensinger W, Appelbaum F, Rowley S, et al: Factors that influence collection and engraftment of autologous peripheral blood stem cells. J Clin Oncol 13:2547-2555, 1995[Abstract]

5. Winter J, Lazarus H, Rademaker A: Phase I/II study of combined granulocyte colony stimulating factor and granulocyte-macrophage colony-stimulating factor administration for the mobilization of hematopoietic progenitor cells. J Clin Oncol 14:277-286, 1996[Abstract]

6. Gianni A, Siena S, Bregni M: Granulocyte-macrophage colony-stimulating factor to harvest circulating hematopoietic stem cells for autotransplantation. Lancet:580-585, 1989

7. To L, Shepperd M, Haylock D: Single high doses of cyclophosphamide enable the collection of high numbers of hematopoietic stem cells from the peripheral blood. Exp Hematol 18:442-447, 1990[Medline]

8. Desikan R, Barlogie B, Jagannath S, et al: Comparable engraftment kinetics following peripheral blood stem cell infusion mobilized with granulocyte colony-stimulating factor with or without cyclophosphamide in multiple myeloma. J Clin Oncol 16:1547-1553, 1998[Abstract/Free Full Text]

9. Lazarus H, Andersen J, Chen M, et al: Recombinant GM-CSF after autologous bone marrow transplantation for relapsed non-Hodgkin’s lymphoma: Blood and bone marrow progenitor growth studies—A phase II Eastern Cooperative Oncology Group trial. Blood 78:830-837, 1991[Abstract/Free Full Text]

10. Lazarus H, Crilley P, Ciobanu N, et al: High-dose carmustine, etoposide, cisplatin (BEP) and autologous bone marrow transplantation for relapsed and refractory lymphoma. J Clin Oncol 10:1682-1689, 1992[Abstract/Free Full Text]

11. Antman K, Ayash L, Elias A, et al: A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol 10:102-110, 1992[Abstract]

12. Shpall EJ, Wheeler CA, Turner SA, et al: A randomized phase III study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients. Blood 98:2491-2501, 1999

13. Demirer T, Buckne D, Storer B, et al: Effect of different chemotherapy regimens on peripheral blood stem cell collections in patients with breast cancer receiving granulocyte colony-stimulating factor. J Clin Oncol 15:648-690, 1997

14. Weaver CH, Birch R, Greco FA, et al: Mobilization and harvesting of peripheral blood stem cells: Randomized evaluations of different doses of filgrastim. Haematol 100:338-347, 1998

15. Schulman K, Birch R, Zhen B, et al: Effect of CD34+ cell dose on resource utilization in patients after high-dose chemotherapy with peripheral-blood stem-cell support. J Clin Oncol 17:1227-1233, 1999[Abstract/Free Full Text]

16. Meisenberg B, Brehm T, Schmeckel A, et al: A combination of low dose cyclophosphamide and colony-stimulating factors is more cost effective than granulocyte colony stimulating factors alone in mobilizing peripheral blood stem and progenitor cells. Transfusion 38:209-215, 1998[Medline]

17. Lagarias D, Richman C: CD34+CD38- primitive progenitor cells constitute a lower proportion of CD34+ cells in patients receiving chemotherapy with G-CSF mobilization than patients and normal donors receiving G-CSF. Blood 92:723a, 1998 (suppl 10, abstr)

Submitted May 20, 1999; accepted January 5, 2000.




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C. A. Gregory, E. Reyes, M. J. Whitney, and J. L. Spees
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M. Condomines, P. Quittet, Z.-Y. Lu, L. Nadal, P. Latry, E. Lopez, M. Baudard, G. Requirand, C. Duperray, J.-F. Schved, et al.
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C. Carlo-Stella, M. Di Nicola, R. Milani, A. Guidetti, M. Magni, M. Milanesi, P. Longoni, P. Matteucci, F. Formelli, F. Ravagnani, et al.
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U. Narayanasami, R. Kanteti, J. Morelli, A. Klekar, A. Al-Olama, C. Keating, C. O'Connor, E. Berkman, J. K. Erban, K. A. Sprague, et al.
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L. Akard and O. N. Koc
Optimum Methods to Mobilize Stem Cells
J. Clin. Oncol., August 16, 2000; 18(16): 3063 - 3063.
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