Flow cytometry comparison of CD34+ subsets in bone marrow and peripheral blood after priming with glycosylated or non-glycosylated rhG-CSF.
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Antigens, CD34↗
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A randomized trial of granulocyte colony-stimulating factor (Neupogen) starting day 1 vs day 7 post-autologous stem cell transplantation.
The purpose of the study was to evaluate the effect of delayed granulocyte colony-stimulating factor (G-CSF) use on hematopoietic recovery post-autologous peripheral blood progenitor cell (PBPC) transplantation. Patients were randomized to begin G-CSF on day +1 or day +7 post transplantation. Thirty-seven patients with lymphoma or myeloma undergoing high-dose therapy and autologous PBPC rescue were randomized to daily subcutaneous G-CSF beginning on day +1 or day +7 post-transplant. Patients < or =70 kg received 300 microg/day and >70 kg 480 microg/day. All patients were reinfused with PBPCs with a CD34+ cell count >2.0 x 10(6)/kg. Baseline characteristics of age, sex and CD34+ cell count were similar between the two arms, the median CD34+ cell count being 5.87 x 10(6)/kg in the day +1 group and 7.70 x 10(6)/kg in the day +7 group (P=0.7). The median time to reach a neutrophil count of >0.5 x 10(9)/l was 9 days in the day +1 arm and 10 days in the day +7 arm, a difference which was not statistically significant (P=0.68). Similarly, there was no difference in median days to platelet recovery >20000 x 10(9)/l, which was 10 days in the day +1 arm and 11 days in the day +7 arm (P=0.83). There was also no significant difference in the median duration of febrile neutropenia (4 vs 6 days; P=0.7), intravenous antibiotic use (7 vs 8 days; P=0.54) or median number of red blood cell transfusions (4 vs 7 units; P=0.82) between the two arms. Median length of hospital stay was 11 days post-PBPC reinfusion in both groups. The median number of G-CSF injections used was 8 in the day +1 group and 3 in the day +7 group (P < 0.0001). There is no significant difference in time to neutrophil or platelet recovery when G-CSF is initiated on day +7 compared to day +1 post-autologous PBPC transplantation. There is also no difference in number of febrile neutropenic or antibiotic days, number of red blood cell transfusions or length of hospital stay. The number of doses of G-CSF used per transplant is significantly reduced with delayed initiation, resulting in a significant reduction in drug costs. For patients with an adequately mobilized PBPC graft, the initiation of G-CSF can be delayed until day +7 post-PBPC reinfusion.
Adult↗
G-CSF dosage and scheduling following autologous PBSC transplantation.
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Drug Administration Schedule↗
Analysis of rhG-CSF-effects on platelets by in vitro bleeding test and transcranial Doppler ultrasound examination.
Experimental evidence suggests a stimulatory effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on both platelets and coagulation. RhG-CSF is increasingly used to stimulate healthy volunteer donors for blood stem cell mobilization. We therefore assessed 25 healthy donors receiving rhG-CSF for changes in in vitro bleeding test (IVBT), coagulation parameters and cerebral microembolism by transcranial Doppler (TCD) ultrasound. A significant shortening of IVBT was found on day 4 of rhG-CSF administration together with increased levels of fibrinogen and factor VIII and reduced activities of protein C and protein S. Although these changes are quite small it is possible that they may lead to a hypercoagulable state especially in donors with other risk factors for thromboembolism. However, TCD examination failed to detect any signs of microembolism. We therefore conclude that rhG-CSF leads to significant changes in coagulation parameters, but has no effect on TCD detectable microembolism as a stroke risk factor. However donors receiving rhG-CSF should be examined carefully to detect pre-existing changes in the coagulation system and we would like to suggest a routine thrombophilia screen.
Adolescent↗
A single apheresis to achieve a high number of peripheral blood CD34+ cells in a lithium-treated patient with acute myeloid leukaemia.
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Adult↗
A prospective study of G-CSF effects on hemostasis in allogeneic blood stem cell donors.
Granulocyte colony-stimulating factor (G-CSF) is used in healthy donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. However, some data have recently suggested that G-CSF may induce a hypercoagulable state, prompting us to study prospectively 22 PBSC donors before and after G-CSF 5 microg/kg twice daily. We sought evidence for changes in the following parameters: platelet count, von Willebrand factor antigen (vWF:Ag) and activity (vWF activity), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4), platelet activation markers (GMP-140 and PAC-1), activated partial thromboplastin time (aPTT), prothrombin time (PT), coagulant factor VIII (FVIII:C), thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), thrombomodulin (TM) and tissue plasminogen activator antigen (tPA:Ag) prior to G-CSF and immediately before leukapheresis. ADP-induced platelet aggregation studies were also performed. G-CSF administration produced only mild discomfort. We found a significant increase in vWF:Ag (from 0.99 +/- 0.32 U/ml to 1.83 +/- 0.69 U/ml; P < 0.001), in vWF activity (from 1.04 +/- 0.34 U/ml to 1.78 +/- 0.50 U/ml; P < 0.001) and in FVIII:C (from 1.12 +/- 0.37 U/ml to 1.73 +/- 0.57 U/ml; P < 0.001) after G-CSF. Of note, four donors with low baseline vWF had a two- to three-fold increase after receiving G-CSF. G-CSF had no impact on the platelet count, beta-TG, PF-4, GMP-140 or PAC-1. The final% of platelet aggregation decreased from 73 +/- 22% to 37 +/- 26% after G-CSF (P < 0.001). We found a significant decrease in aPTT after G-CSF (29.9 +/- 3.1 s to 28.3 +/- 3.3 s; P = 0.004), but the PT was unaffected. In addition, we also observed a significant increase in TAT, F1+2 and TM, but not in tPA:Ag. Our data suggest that G-CSF may possibly induce a hypercoagulable state by increasing levels of FVIII:C and thrombin generation. In contrast to this information, we found reduced platelet aggregation after G-CSF administration. The clinical implications of these findings remain unclear and larger studies are definitely required.
Adult↗
Autologous stem cell transplantation in multiple myeloma after VAD and EDAP courses: a high incidence of oligoclonal serum Igs post transplantation.
Thirty-seven patients with multiple myeloma (stage II and III, 65% increased beta2-microglobulin level) were prospectively treated with a median of 3.7 VAD courses (range 2-8) followed by cyclophosphamide (6 g/m2) in conjunction with G-CSF (5 microg/kg filgrastrim (n = 14), or 3.5 microg/kg lenograstrim (n = 22)), and peripheral stem cell (PSC) isolation. After regeneration this was followed by one EDAP course and high-dose melphalan (HDM, 200 mg/m2) in combination with re-infusion of PSC. Adequate stem cell mobilization was obtained with both G-CSF regimens. A median of 41x10(6) CD34+ cells/kg (range 4.5-161) was collected in a median of 1.6 leukapheresis procedures following filgrastrim (n = 14) and 24x10(6) CD34+ cells/kg (range 2. 3-80) in a median of 1.7 leukapheresis procedures following lenograstrim (n = 22) which indicated no significant difference (P = 0.24) between both G-CSF regimens. A rapid hematological recovery was obtained after HDM with reinfusion of a median of 9.3x10(6) CD34+ cells/kg. After the total courses the overall response was 84% with a complete remission rate of 30%. Currently the median overall survival is 44.0 months (95% CI 38.9-49.1) with a median follow-up of 33 months (range 3-51) and a median event-free survival of 29.0 months (95% CI 25.3-32.7) (n = 33). Post transplantation a high incidence of oligloclonal serum immunoglobulins (Igs) was observed. In 73% of the patients new oligoclonal or monoclonal serum bands were noticed 3 months post transplantation. IgG-lambda and IgG-kappa bands predominated. In 48% of the cases the oligoclonal Igs disappeared after a median follow-up of 22 months (range 8-36), whereas in 52% of the cases the oligoclonal Igs persisted with a median follow-up of 31 months (range 21-45), which did not correlate with a significant difference in overall, and event-free survival between both subgroups.
Adjuvants, Immunologic↗
Enumeration of HPC in mobilized peripheral blood with the Sysmex SE9500 predicts final CD34+ cell yield in the apheresis collection.
Enumeration of CD34+ cells in the peripheral blood before apheresis predicts the quantity of those cells collected, although the cytometric techniques used are complex and expensive. We found that a subpopulation of lysis-resistant cells in the peripheral blood, identified by the Sysmex SE9500 and designated as HPC, can serve as a surrogate marker predictive of the yield of CD34+ cells. Spearman's rank statistics were used to examine the correlation between WBC, MNC, HPC and CD34+ cells in the peripheral blood and final CD34+ cell yield for 112 samples of peripheral blood and matching apheresis collections from 66 patients and donors. The results indicate that WBC and MNC in the peripheral blood were poor predictors of CD34 content, while HPC gave a correlation coefficient of 0.62. The positive predictive values of different cutoff levels of HPC in the peripheral blood ranging from 5 to 50 x 106/l increased from 0.80 to 0.93 when the target collection was 1 x 106cells/kg. However, for patients with HPC levels below various cutoff levels, the proportion of the collections not reaching that target goal ranged between 0.36 and 0.43, indicating that most collections will still exceed the target goal of CD34+ cells. When the target collection was 2.5 x 106 CD34+ cells/kg, the positive predictive value was lower and negative predictive value was higher.
Adolescent↗
A phase II trial of docetaxel for peripheral blood stem cell mobilization for patients with breast cancer and ovarian cancer.
As docetaxel is known to have significant antineoplastic activity against breast and ovarian cancer, we explored its application as a peripheral blood stem cell mobilizing agent in 33 women with stage lll-IV ovarian carcinoma (n = 10) or stage ll-lV breast cancer (n = 23) who were in preparation for high-dose chemotherapy. Eleven patients had bone and/or bone marrow involvement with their disease. The median number of prior regimens received before mobilization was two (range 1-3). The three dose levels administered were 100 mg/m(2), 110 mg/m(2) and 120 mg/m(2). Patients received one dose of docetaxel in the outpatient setting followed by G-CSF (10 microg/kg/day) starting 4 days after docetaxel administration. Leukapheresis commenced when WBC >1.0 x 10(9)/l or when the WBC began to rise after reaching a nadir. Ninety-seven percent of patients began leukapheresis within 7-9 days after receiving docetaxel (range 7-10 days). The collection goal was >/=2 x 10(6) CD34(+) cells/kg. Twenty-seven (82%) patients reached this goal in a median of 2 leukapheresis days (range 1-3). No grade 2-4 nonhematologic toxicities were noted. Thirteen patients (55%) showed a WBC nadir >1.0 x 10(9)/l. None of the patients experienced neutropenic fever or required blood or platelet transfusion support. In conclusion, docetaxel + G-CSF is an effective, well-tolerated regimen for PBPC mobilization which can be safely administered in the outpatient setting with minimal toxicity.
Adult↗
Storage of unprocessed G-CSF-mobilized whole blood in a modified Leibovitz's L15 medium preserves clonogenic capacity for at least 7 days.
Autologous stem cell transplantation using unprocessed, G-CSF-mobilized whole blood (WB) is a simple, cost-reducing procedure and supports high-dose chemotherapy regimens not exceeding 72 h. Thereafter, clonogenic capacity rapidly decreases if routine anticoagulants are used for storage. In order to increase clinical applicability, we investigated the requirements for optimal preservation of unprocessed WB for 7 days. During storage at 22 degrees C in CPDA-1, a decrease in pH was noted, which was at least partially responsible for the low recovery of clonogenic cells. Subsequently, WB cells were stored in various cell culture media (RPMI 1640, alpha-MEM, X-VIVO15, CellGro SCGM and Leibovitz's L15 medium) containing either serum, serum-free substitutes or no additives. Leibovitz's L15 showed significantly better CFU-GM recoveries than the other media. Using a calcium-free modification of L15 medium (added 3:10 to WB), 94 +/- 24% of CD34(+) cells, 41 +/- 14% of BFU-E, 56 +/- 17% CFU-GM and 90 +/- 14% of LTC-IC were preserved during storage for 7 days at 22 degrees C. Storage at 4 degrees C was also feasible, but showed less optimal recoveries of 52 +/- 29% (CD34), 32 +/- 10% (BFU-E), 13 +/- 7% (CFU-GM) and 58 +/- 9% (LTC-IC). The expression of CD38, Thy-1, c-kit, AC133, L-selectin and CXCR4 on CD34-positive cells remained unchanged. In conclusion, a modified Leibovitz's L15 medium better meets the metabolic requirements of a high-density cell culture and allows safe storage of G-CSF mobilized WB for at least 7 days. The results encourage further exploration of WB transplants stored for 7 days for clinical use.
Adenine↗
Leukaemogenic potency of WEHI-3B cells grown in vitro or in leukaemic mice.
In order to quantify contaminating leukaemia inducing cells in blood or bone marrow from WEHI-3B bearing BALB/c mice (injected with 10(5) WEHI-3B suspension culture cells), in vitro colony forming leukaemia cells (CFU-L) and survival rate and/or survival time of mice transplanted with cells from WEHI bearing mice or suspension culture were correlated. ED(50) (inoculum inducing leukaemia in 50% of the animals) was 109 CFU-L (33-361) from suspension culture cells. Three weeks after initiation of leukaemia 2 x 10(5) BM or 0.5-2.0 x 10(6) blood cells induced 100% mortality of recipients. After mobilisation with CY or CY and G-CSF, the same amount of blood or BM cells did not induce leukaemia in recipients. A significant negative correlation was found between the survival time of leukaemic mice and the log number of CFU-L inoculated from in vivo sources. In terms of CFU-L cells, leukaemia induction to BM or WBC obtained 3 weeks after leukaemia induction were more potent; those from BM or WBC also obtained at 3 weeks but after mobilisation were less potent inducers than those from suspension culture. These data suggest that CFU-L and leukaemogenic cells are associated, but not identical.
Animals↗
Trafficking of CD34+ cells into the peripheral circulation during collection of peripheral blood stem cells by apheresis.
The number of CD34+ cells collected during apheresis is related to the volume of blood processed. In large-volume apheresis (LVL) procedure, more cells can be collected than were originally present in the peripheral blood at the start of the collection procedure. We prospectively studied the levels of CD34+ cells in the blood and apheresis product during LVL procedures for 21 patients with acute myelogenous leukemia or multiple myeloma. These patients experienced a slow decline in blood CD34+ cell concentrations during the apheresis procedure. No patient demonstrated a sustained rise in CD34+ cell counts as a result of the procedure. The number of CD34+ cells collected exceeded the number calculated to be in the peripheral blood at the start of the procedure by an average of 3.0-fold. The efficiency of collection for CD34+ cells averaged 92.6% and did not vary with speed of blood processing, diagnosis, or mobilization regimen. The calculated release of CD34+ cells from other reservoirs into the peripheral blood averaged 3.71 x 10(6)/min (range, 0.36-13.7 x 10(6)/min), and correlated (r = 0.82) with the concentration of these cells in the peripheral blood at the start of the procedure. These data show that the apheresis procedure used in this study does not affect the release of CD34+ cells in a cytokine-treated patient. LVL will result in collection of larger quantities of CD34+ cells than procedures involving processing of smaller volumes of blood, but the number of cells collected is limited by the rate of release of these cells into the peripheral circulation where they are accessible for collection.
Acute Disease↗
GM-CSF-based mobilization effect in normal healthy donors for allogeneic peripheral blood stem cell transplantation.
It is important to optimize methods to mobilize hematopoietic stem cells into peripheral blood (PB) for successful allogeneic peripheral blood stem cell (PBSC) transplantation. Our primary intent was to investigate the role of GM-CSF for mobilization in normal healthy donors and to compare its efficacy in mobilizing stem cells alone, in concurrent combination and in sequential combination with G-CSF in this study. We analyzed the results of the PBSC harvest through large volume leukapheresis from 48 normal healthy donors mobilized by three different regimens including GM-CSF. Donors were assigned sequentially to one of the following regimens for mobilization: GM-CSF 10 microg/kg/day alone (group 1, n = 9); concurrent combination (group 2, n = 20) of G-CSF 5 microg/kg/day and GM-CSF 5 microg/kg/day; sequential combination (group 3, n = 19) of GM-CSF alone 10 microg/kg/day for 3 days followed by G-CSF alone 10 microg/kg/day for 2-3 days. The harvested CD34(+) cell count (P < 0.05) was statistically higher in group 3 than in group 1 or 2. Pre-collection WBC count in donors (P < 0.05), harvested MNC (P < 0.05) and CD3(+) cell count (P < 0.05) of group 2 or 3 were significantly higher than those of group 1. Recipients who received stem cells mobilized with combination regimens showed an earlier recovery of WBC and platelets count than those with GM-CSF alone. The incidence of acute graft-versus-host disease was not statistically different among three recipient groups. GM-CSF-based mobilization was well tolerated in normal healthy donors. The sequential combination regimen appears to be an excellent mobilization strategy and might be preferred as the optimal method in some clinical situations that need a higher number of stem cells.
Adult↗
Safety and efficacy of high-dose G-CSF (24 microg/kg) alone for PBSC moblization in children.
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Adolescent↗
Intensive sequential dose dense chemotherapy with stem cell support as first-line treatment in advanced ovarian carcinoma: a phase II study.
From August 1995 to December 1997, 15 patients with stage III-IV ovarian cancer were treated with outpatient intensive chemotherapy with G-CSF and stem cell support. The first cycle consisted of cyclophophamide IV 6 g/m(2); second, third, fourth and fifth paclitaxel 250 mg/m(2) and the sixth and seventh carboplatin AUC 18. CD34(+) cells were collected after the first cycle and reinfused after completion of cycles 6 and 7. Fourteen patients had stage IIIc and one patient had stage IV disease with liver metastases. All patients underwent laparotomy to maximize tumor debulking. This was optimal in eight patients and suboptimal in seven patients. Second-look surgery was performed in 14 patients. All patients had macroscopic complete responses and 10 patients had complete histologic response. Median follow-up was 48 months (range, 20 to 62). Twelve patients had further progression at a median of 27 months (range, 9 to 42) and nine are alive, three without evidence of disease progression. This pilot study shows that dose-dense chemotherapy with paclitaxel and carboplatin is associated with low toxicity and may improve the outcome of patients with poor prognosis ovarian cancer.
Adult↗
Patients with acute lymphoblastic leukaemia allografted with a matched unrelated donor may have a lower survival with a peripheral blood stem cell graft compared to bone marrow.
We analysed data for 213 patients with ALL and AML who received either peripheral blood stem cells (PBSC) (n=74) or bone marrow (BM) (n=139) from an HLA-matched unrelated donor (EBMT acute leukaemia registry; January 1994 to January 1999). The two groups of patients (by cell source) were comparable with respect to age, sex, disease status, year at transplant and graft T cell depletion. Engraftment was achieved in about 90% regardless of stem cell source or leukaemia type. Kinetics of neutrophil and platelet recovery, similar for both sources in ALL patients, were faster for PBSC in AML patients. The incidence of acute graft-versus-host disease was similar for both sources in AML patients, but higher for PBSC in ALL patients (74 vs 54%, P=0.05). The 1-year probability of chronic graft-versus-host disease was 40 and 45% (P=0.66) in ALL patients compared to 49 and 35% (P=0.13) in AML patients (PBSC vs BM). In AML patients, none of the following differed significantly with cell source: transplant-related mortality, relapse incidence, leukaemia-free survival and overall survival. In ALL patients, the transplant-related mortality for PBSC vs BM was 61 vs 47% (P=0.13), the relapse incidence was 47 vs 39% (P=0.17), the leukaemia-free survival was 21 vs 32% (P=0.04) and the overall survival was 24 vs 34% (P=0.04). These data suggest that the short-term outcome of allogeneic PBSC is not significantly different from that of BM in AML patients who underwent a transplant from a matched unrelated donor but, conversely, that survival with PBSC may be decreased in ALL patients. In conclusion, the source of transplant cells needs to be evaluated by disease, especially when dealing with unrelated donors.
Adolescent↗
Cytotoxic chemotherapy preceding apheresis of peripheral blood progenitor cells can affect the early reconstitution phase of naive T cells after autologous transplantation.
Transient T cell immunodeficiency is a common complication following hematopoietic stem cell transplantation. In breast cancer patients transplanted with autologous peripheral blood progenitor cells (PBPC) harvested after cytotoxic treatment with either cyclophosphamide or epirubicin plus paclitaxel, we evaluated T cells infused in grafts and in peripheral blood during the early reconstitution phase. We found that PBPC grafts harvested after treatment with epirubicin plus paclitaxel contained substantially larger numbers of T cells with less altered composition than after cyclophosphamide. Three months after high-dose cytotoxic chemotherapy, the numbers and the kinetics of circulating naive T cells, but not of memory and CD28- T cells, correlated positively with the number of naive T cells infused PBPC grafts. Finally, retrospective analysis of two cohorts of patients transplanted in different clinical settings with PBPC grafts harvested following cyclophosphamide or epirubicin plus paclitaxel showed apparently different susceptibilities to develop endogenous varicella zoster virus reactivation in the first year after high-dose cytotoxic chemotherapy. On the whole, these data indicate that number and composition of T cells in PBPC grafts vary according to the former cytotoxic therapy, and suggest that autologous transfer of T cells may accelerate the early T cell reconstitution phase and possibly ameliorate immune competence in patients rendered lymphopenic by high-dose chemotherapy.
Antigens, CD↗
Large-scale isolation of CD133+ progenitor cells from G-CSF mobilized peripheral blood stem cells.
We have evaluated the feasibility of large-scale isolation of CD133+ progenitors from healthy mobilized adult donors for potential clinical use in autologous and allogeneic transplantation. A total of 11 healthy volunteer adult donors were mobilized with G-CSF. CD133+ stem cells were isolated from a single leukapheresis using the Clinimacs method. The median percentage of CD133 before positive selection was 0.75% (range 0.39-2.03%). After selection, the median purity and recovery was 94% (range 85.2-98.0%) and 69% (range 44-100%), respectively. The median log10 T-cell depletion obtained by CD133+ positive selection was 4.2 (range 3.8-4.7). The CD133+ progenitors were highly enriched in colony-forming units (CFU) and transplantation into NOD/SCID mice resulted in a high engraftment rate. Transplantation of sorted CD133+/CD34+ cells into NOD/SCID mice showed a higher engraftment compared to CD133-/CD34+ cells. Mobilized peripheral CD133+ stem cells can be purified in large scale for potential clinical use. The biological function of the cells is not impaired. The majority of the NOD/SCID repopulating cells are within the CD133+/CD34+ subpopulation. Therefore, clinical studies using purified CD133+ stem cells can be envisoned to further clarify the role of CD133+ stem cells in hematopoietic reconstitution after transplantation.
AC133 Antigen↗