A randomised study of 10 microg/kg/day (single dose) vs 2 x 5 microg/kg/day (split dose) G-CSF as stem cell mobilisation regimen in high-risk breast cancer patients

A randomised trial in breast cancer patients was designed to compare the number of peripheral blood progenitor cells collected after mobilisation with a single dose of 10 microg/kg/day granulocyte colony-stimulating factor (G-CSF) (n=14) or a split dose of 5 microg/kg twice daily (n=14). Both groups were well balanced. No significant differences were observed between groups regarding aphereses parameters. The total number of CD34+ cells collected was higher in the split-dose group (mean of 7.1 and median of 7.4 x 10(6)/kg) than in the single-dose group (5.6 and 5.8 x 10(6)/kg, respectively) (P=0.26). The mean of CD34+ cells collected after the first apheresis procedure was 3.9 x 10(6)/kg for the split dose group and 3.1 x 10(6)/kg for the single-dose group (P=0.24). Circulating CD34+ cells before the first apheresis were higher for the split-dose group (mean 79.7 vs 59.2 x 10(6)/l) (P=0.14). All bone pain scores applied were significantly higher for the split-dose group. Our primary end point of improving the mean of total CD34+ cells collected to 2.5 x 10(6)/kg was not achieved with twice-daily G-CSF administration. Further studies evaluating different mobilisation schedules with G-CSF are needed to determine the optimal regimen.     

Stem cell mobilisation with 16 microg/kg vs 10 microg/kg of G-CSF for allogeneic transplantation in healthy donors

We compared two doses of recombinant human granulocyte-stimulating factor (G-CSF) for stem cell mobilisation in 90 healthy donors for allogeneic stem cell transplantation in a retrospective analysis. Group I (n = 46) received 10 microg/kg G-CSF (filgrastim) given as 5 microg/kg twice daily, and group II (n = 44) received 16 microg/kg, given as 8 microg/kg twice daily with a 12-h interval. The groups were well-balanced for age and body-weight. G-CSF application was performed on an out-patient basis, and leukapheresis was started in all donors on day 5. The most frequent side-effects of G-CSF were grade I/II, bone pain, headache and fatigue in both groups, whereas grade III of bone pain, headache and fatigue occurred in the 2 x 8 microg/kg group only. One serious non-fatal event with non-traumatic spleen rupture occurred in the 2 x 5 microg/kg group. The CD34(+)cell count in the first apheresis of all donors was 5.1 x 10(6)/kg donor weight (range, 1.5-19.3). The CD34(+) cell harvest was higher in the 2 x 8 microg/kg group than in the 2 x 5 microg/kg group (7.1 x 10(6)/kg vs 4.9 x 10(6)/kg; P = 0.09). The target of collecting >5.0 x 10(6) CD34(+) cells/kg donor weight with one apheresis procedure was achieved in 45% of group I and in 61% of group II, respectively. Administering G-CSF at a dosage of 8 microg/kg twice daily leads to a higher CD34(+) cell yield than a dosage of 2 x 5 microg/kg, but is associated with increased toxicity and higher cost.     

A randomized comparison of once versus twice daily recombinant human granulocyte colony-stimulating factor (filgrastim) for stem cell mobilization in healthy donors for allogeneic transplantation

To evaluate the schedule dependency of granulocyte colony-stimulating factor (G-CSF) (filgrastim) for stem cell mobilization, we conducted a randomized comparison in 50 healthy donors, with one subcutaneous daily injection of 10 microg/kg G-CSF (n = 25) compared with twice injections daily of 5 microg/kg G-CSF (n = 25). The two groups were well balanced for age, body weight and sex. G-CSF application was performed on an out-patient basis and leukapheresis was started in all donors on day 5. The most frequent side-effects of G-CSF were mild to moderate bone pain (88%), mild headache (72%), mild fatigue (48-60%) and nausea (8%) without differences between the two groups. The CD34(+) cell count in the first apheresis was 5.4 x 10(6)/kg donor weight (range 2.8-13.3) in the 2 x 5 microg/kg group compared with 4.0 x 10(6)/kg (range 0.4-8.8) in the 1 x 10 microg/kg group (P = 0.007). The target of collecting > 3.0 x 10(6) CD34(+) cells/kg donor weight with one apheresis procedure was achieved in 24/25 (96%) donors in the 2 x 5 microg/kg group and in 17/25 (68%) donors in the 1 x 10 microg/kg group. The target of collecting > 5.0 x 10(6) CD34(+) cells/kg in the first apheresis was achieved in 64% in the 2 x 5 microg/kg group, but in only 36% in the 1 x 10 microg/kg group. The progenitor cell assay for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) was higher in the 2 x 5 microg/kg group than in the 1 x 10 microg/kg group (7.0 vs. 3.5 x 10(5)/kg, P = 0.01; 6.6 vs. 5.0 x 10(5)/kg; P = 0.1). Administering G-CSF (filgrastim) at a dosage of 5 microg/kg twice daily rather than 10 microg/kg once daily is recommended; this leads to a higher CD34(+) cell yield and requires fewer apheresis procedures without increasing toxicity or cost.     

Low doses of GM-CSF (molgramostim) and G-CSF (filgrastim) after cyclophosphamide (4 g/m2) enhance the peripheral blood progenitor cell harvest: results of two randomized studies including 120 patients

The use of a combination of G-CSF and GM-CSF versus G-CSF alone, after cyclophosphamide (4 g/m2) was compared in two randomized phase III studies, including 120 patients. In study A, 60 patients received 5 x 2 microg/kg/day of G-CSF and GM-CSF compared to 5 mug/kg/day of G-CSF. In study B, 60 patients received 2.5 x 2 microg/kg/day G-CSF and GM-CSF compared to G-CSF alone (5 microg/kg/day). With the aim to collect at least 5 x 10(6)/kg CD34 cells in a maximum of three large volume leukapherises (LK), 123 LK were performed in study A, showing a significantly higher number of patients reaching 10 x 10(6)/kg CD34 cells (21/29 in G+GM-CSF arm vs 11/27 in G-CSF arm, P=0.00006). In study B, 109 LK were performed, with similar results (10/27 vs 15/26, P=0.003). In both the study, the total harvest of CD34 cells/kg was twofold higher in G-CSF plus GM-CSF group (18.3 x 10(6) in study A and 15.85 x 10(6) in study B) than in G-CSF group (9 x 10(6) in study A and 8.1 x 10(6) in study B), a significant difference only seen in multiple myeloma, with no significant difference in terms of mobilized myeloma cells between G-CSF and GM-CSF groups.     

The VAD chemotherapy regimen plus a G-CSF dose of 10 microg/kg is as effective and less toxic than high-dose cyclophosphamide plus a G-CSF dose of 5 microg/kg for progenitor cell mobilization: results from a monocentric study of 82 patients

A study was conducted to compare the efficiency and toxicity of two peripheral blood stem cell (PBSC) mobilization procedures for newly diagnosed patients with multiple myeloma. Patients from group 1 (n=51) were treated by high-dose cyclophosphamide (HD-CY) plus G-CSF (5 microg/kg/day), and the second group (n=31) by VAD regimen plus G-CSF administration (10 microg/kg/day). Successful mobilization, defined by a minimal count of 2.5 x 10(6) CD34(+) cells/kg collected, was achieved in 96 and 90% of patients in groups 1 and 2, respectively (P=0.15). The mean peripheral blood CD34(+) cells concentration and the mean CD34(+) cells/kg collected were higher in group 2 than in the group 1 (P=0.05). The mean number of leukaphereses necessary to collect a count of 2.5 x 10(6) CD34(+) cells/kg was reduced in group 2 compared to group 1. Adverse events, blood products consumption and time spent in the hospital were significantly greater after HD-CY. In conclusion, VAD plus a G-CSF dose of 10 microg/kg administration seems preferential to HD-CY plus a G-CSF dose of 5 microg/kg for PBSC collection because of equivalent or better efficiency in stem cell mobilization, strong favorable toxicity profile and reduced cost.     

A randomized,multicenter study of G-CSF starting on day +1 vs day +5 after autologous peripheral blood progenitor cell transplantation

In order to assess the effect of delaying G-CSF administration after autologous peripheral blood progenitor cell (PBPC) transplantation on the duration of neutropenia, 87 patients were randomized to receive G-CSF 5 microg/kg/day starting on day +1 (n = 45) or +5 (n = 42) following PBPC transplantation, until recovery of the neutrophils. The duration of neutropenia (<0.5 x 10(9)/l) was shorter in the day +1 group (7 vs 8 days; P = 0.02), especially in patients receiving melphalan 200 mg/m(2) and CD34(+) cell doses >3.0 x 10(6)/kg. These patients had a later onset of neutropenia after transplant. There were no differences in time to neutrophil and platelet engraftment, or in the incidence of fever and documentation of infection. Although the duration of antibiotic therapy (7 vs 10.5 days; P = 0.01) and time to hospital discharge (13 vs 15 days; P = 0.02) were shorter in the day +1 group, these differences could not be predicted by the day of G-CSF initiation in multivariate analysis. Starting G-CSF on day +1 does not result in faster neutrophil engraftment but in later onset and consequently, slightly shorter duration of neutropenia in patients who receive melphalan 200 mg/m(2) and CD34(+) cell doses >3.0 x 10(6)/kg.     

A randomised study comparing peripheral blood progenitor mobilisation using intermediate-dose cyclophosphamide plus lenograstim with lenograstim alone

We conducted a prospective randomised study to compare the efficiency of out-patient progenitor cell mobilisation using either intermediate-dose cyclophosphamide (2 g/m(2)) and lenograstim at 5 micrograms/kg (Cyclo-G-CSF group, n=39) or lenograstim alone at 10 micrograms/kg (G-CSF group, n=40). The end points were to compare the impact of the two regimens on mobilisation efficiency, morbidity, time spent in hospital, the number of apheresis procedures required and engraftment kinetics. Successful mobilisation was achieved in 28/40 (70%) in the G-CSF group vs 22/39 (56.4%) for Cyclo-G-CSF (P=0.21). The median number of CD34+ cells mobilised was 2.3 x 10(6)/kg and 2.2 x 10(6)/kg for G-CSF and cyclo-G-CSF arms following a median of two apheresis procedures. Nausea and vomiting and total time spent in the hospital during mobilisation were significantly greater after Cyclo-G-CSF (P<0.05). Rapid neutrophil and platelet engraftment was achieved in all transplanted patients in both groups. In conclusion, G-CSF at 10 micrograms/kg was as efficient at mobilising progenitor cells as a combination of cyclophosphamide and G-CSF with reduced hospitalisation and side effects and prompt engraftment. When aggressive in-patient cytoreductive regimens are not required to both control disease and generate progenitor cells, the use of G-CSF alone appears preferable to combination with intermediate-dose cyclophosphamide.     

Etoposide (VP-16) plus G-CSF mobilizes different dendritic cell subsets than does G-CSF alone

Dendritic cells (DCs) are antigen-presenting cells that are critical to the generation of immunologic tumor responses. Myeloid DCs (DC1) express myeloid antigen CD11c; lymphoid DCs (DC2) express CD123(+) and are CD11c(-). Analysis of DC subsets from peripheral blood progenitor cells (PBPC) collected from normal donors mobilized with G-CSF shows a predominance of DC2 cells. Whether PBPCs mobilization by chemotherapy yields different subsets of DCs has not been studied. We analyzed DC subsets in apheresis products from 44 patients undergoing autologous stem cell transplantation from 6/00 to 5/01. Patients received either G-CSF alone (10 microg/kg per day, n=11) or etoposide (2 g/m(2)) plus G-CSF (n=33) for progenitor cell mobilization. The patients were apheresed for 2-10 days (median 3) to reach a minimum of 2.0 x 10(6) CD34(+) cells/kg. Patients receiving G-CSF alone mobilized significantly more total DC2s than did those receiving etoposide plus G-CSF (median 6.2 x 10(6)/kg vs 2.9 x 10(6)/kg, P=0.001). The DC2/DC1 ratio was also significantly different in the two groups, with the G-CSF group having a higher ratio (median 1.2 vs 0.4, P<0.001). We conclude that the combination of chemotherapy plus G-CSF yields different mobilized dendritic cell subsets than does G-CSF alone.     

Myelopoietin, a chimeric agonist of human interleukin 3 and granulocyte colony-stimulating factor receptors, mobilizes CD34+ cells that rapidly engraft lethally x-irradiated nonhuman primates.

Myelopoietin (MPO), a multifunctional agonist of interleukin 3 and granulocyte colony-stimulating factor (G-CSF) receptors, was evaluated for its ability to mobilize hematopoietic colony-forming cells (CFC) and CD34+ cells relative to control cytokines in normal nonhuman primates. Additionally, the engraftment potential of MPO-mobilized CD34+ cells was assessed in lethally irradiated rhesus monkeys. Normal rhesus monkeys were administered either MPO (200 microg/kg/day), daniplestim (a high-affinity interleukin 3 receptor agonist) (100 microg/kg/day), G-CSF (100 microg/kg/day), or daniplestim coadministered with G-CSF (100 microg/kg/day each), subcutaneously for 10 consecutive days. The mobilization kinetics were characterized by peripheral blood (PB) complete blood counts, hematopoietic CFC [granulocyte-macrophage CFC (GM-CFC), megakaryocyte CFC (MK-CFC)], and the immunophenotype (CD34+ cells) of PB nucleated cells prior to and on day 3 to days 7, 10, 12, and 14, and at intervals up to day 28 following initiation of cytokine administration. A single large-volume leukapheresis was conducted on day 5 in an additional cohort (n = 10) of MPO-mobilized animals. Eight of these animals were transplanted with two doses of CD34+ cells/kg. A maximum 10-fold increase in PB leukocytes (white blood cells) (from baseline 7.8-12.3 x 10(3)/microL to approximately 90 x 10(3)/microL) was observed over day 7 to day 10 in the MPO, G-CSF, or daniplestim+G-CSF cohorts, whereas daniplestim alone stimulated a less than onefold increase. A sustained, maximal rise in PB-derived GM-CFC/mL was observed over day 4 to day 10 for the MPO-treated cohort, whereas the daniplestim+G-CSF, G-CSF alone, and daniplestim alone treated cohorts were characterized by a mean peak value on days 7, 6, and 18, respectively. Mean peak values for PB-derived GM-CFC/mL were greater for MPO (5,427/mL) than for daniplestim+G-CSF (3,534/mL), G-CSF alone (3,437/mL), or daniplestim alone (155/mL) treated cohorts. Mean peak values for CD34+ cells/mL were noted within day 4 to day 5 of cytokine administration: MPO (255/microL, day 5), daniplestim+G-CSF (47/microL, day 5), G-CSF (182/microL, day 4), and daniplestim (96/microL, day 5). Analysis of the mobilization data as area under the curve indicated that for total CFCs, GM-CFC, MK-CFC, or CD34+ cells, the MPO-treated areas under the curve were greater than those for all other experimental cohorts. A single, large-volume (3.0 x blood volume) leukapheresis at day 5 of MPO administration (PB: CD34+ cell/microL = 438 +/- 140, CFC/mL = 5,170 +/- 140) resulted in collection of sufficient CD34+ cells (4.31 x 10(6)/kg +/- 1.08) and/or total CFCs (33.8 x 10(4)/kg +/- 8.34) for autologous transplantation of the lethally irradiated host. The immunoselected CD34+ cells were transfused into autologous recipients (n = 8) at cell doses of 2 x 10(6)/kg (n = 5), and 4 x 10(6)/kg (n = 3) on the day of apheresis. Successful engraftment occurred with each cell dose. The data demonstrated that MPO is an effective and efficient mobilizer of PB progenitor cells and CD34+ cells, such that a single leukapheresis procedure results in collection of sufficient stem cells for transplantation and long term engraftment of lethally irradiated hosts.     

Mobilization of peripheral blood progenitor cells (PBPC) in patients undergoing chemotherapy followed by autologous peripheral blood stem cell transplant (SCT) for high risk breast cancer (HRBC).

We have determined the effect of delayed addition of G-CSF after chemotherapy on PBPC mobilization in a group of 30 patients with high risk breast cancer (HRBC) undergoing standard chemotherapy followed by high-dose chemotherapy (HDCT) and autologous SCT. Patients received FAC chemotherapy every 21 days followed by G-CSF at doses of 5 microg/kg/day starting on day +15 (groups 1 and 2) or +8 (group 3) after chemotherapy. PBPC collections were performed daily starting after 4 doses of G-CSF and continued until more than 2.5 x 10(6) CD34+ cells had been collected. In group 1, steady-state BM progenitors were also harvested and used for SCT. Groups 2 and 3 received PBPC only. The median number of collections was three in each group. Significantly more PB CD34+ cells were collected in patients receiving G-CSF starting on day 8 vs day 15 (9.43 x 10(6)/kg and 6.2 x 10(6)/kg, respectively) (P < 0.05). After conditioning chemotherapy all harvested cells including BM and PBPC were reinfused. Neutrophil and platelet engraftment was significantly faster in patients transplanted with day 8 G-CSF-mobilized PBPC (P < 0.05) and was associated with lower transplant related morbidity as reflected by days of fever, antibiotics or hospitalization (P < 0.05). Both schedules of mobilization provided successful long-term engraftment with 1 year post-transplant counts above 80% of pretransplant values. In conclusion, we demonstrate that delayed addition of G-CSF results in successful mobilization and collection of PBPC with significant advantage of day 8 G-CSF vs day 15. PBPC collections can be scheduled on a fixed day instead of being guided by the PB counts which provides a practical advantage. Transplantation of such progenitors results in rapid short-term and long-term trilineage engraftment.     

Using at least 5x10(6)/kg CD34+ cells for autologous stem cell transplantation significantly reduces febrile complications and use of antibiotics after transplantation.

For autologous stem cell transplantation, it is common practice to infuse at least 2 x 10(6)/kg CD34+ cells to ensure rapid engraftment. However it was recently claimed that increasing the threshold to 5 x 10(6)/kg leads to a faster platelet engraftment. To evaluate these threshold values in our patient population we undertook a retrospective analysis of 127 autologous transplants performed at our institution between 1992 and 1998. Diagnoses included Hodgkin's and non-Hodgkin's lymphoma, myeloma, acute leukaemias and solid tumours. The transplant was peripheral blood stem cells in 107 cases and CD34-selected peripheral blood stem cells in 20 cases. The median number of transplanted CD34+ cells was 3.2 x 10(6)/kg (range 0.64-25.9 x 10(6)/kg). Haematopoietic recovery to a neutrophil count >0.5 x 10(9)/l took a median of 10 (range 5-16) days from transplant. When comparing patients receiving at least 5 x 10(6)/kg and 2-5 x 10(6)/kg CD34+ cells we found a significant reduction in the median number of days with fever (1 vs 3.5 days, P = 0.0025), incidence of fever (78.8 vs 92.1%, P = 0.032) as well as duration of antibiotic treatment (7 vs 10 days, P = 0.038). This was paralleled by a faster neutrophil recovery to 0.5 x 10(9)/l (9 vs 10 days, P = 0.047). There was no significant difference in the number of platelet or red cell transfusions between the two groups. We conclude that transplantation with a stem cell dose of at least 5 x 10(6)/kg CD34+ cells reduces infectious complications and should thereby increase the safety of this type of therapy while reducing duration (and cost) of antibiotic therapy. The transplantation threshold should thus not remain at 2 x 10(6)/kg particularly in patients with a good stem cell mobilisation capacity.     

Mobilisation of peripheral blood stem cells with IVE and G-CSF improves CD34+ cell yields and engraftment in patients with non-Hodgkin's lymphomas and Hodgkin's disease.

The transplantation of mobilised peripheral blood stem cells is associated with more rapid engraftment than marrow transplantation. We have previously reported that G-IVE (G-CSF, ifosphamide, VP-16, epirubicin) improves the yield of CD34+ cells mobilised in patients with lymphoproliferative disorders compared with cyclophosphamide 3 g/m2 and G-CSF (G/CYCLO). In this study we have extended these observations to a larger series of patients including different lymphoma subtypes. Ninety-seven patients undergoing stem cell mobilisation were studied. Forty-two patients with lymphoproliferative disorders received G-IVE for mobilisation and 55 patients G/CYCLO. The median number of mobilised CD34+cells per leucapheresis was significantly higher for those patients receiving G-IVE: 5.82 x 106/kg (0.19-36) compared with 1.2 x 106/kg (0.04-17), P < 0.001 which resulted in a significantly reduced number of leucapheresis procedures performed in the G-IVE group. When patients were analysed dependent on underlying disease G-IVE mobilised significantly more CD34+cells per leucapheresis for all lymphoma types reaching 8.41 x 10(6)/kg (0.2-32) compared to 1.32 x 10(6)/kg (0. 06-17) for patients with high-grade NHL mobilised with G-IVE and C-GCSF respectively (P = 0.012). For patients with low-grade NHL 3. 12 x 10(6)/kg (0.10-24.39) compared to 1.08 x 10(6)/kg (0.04-9.74) were collected (P = 0.04) and for patients with Hodgkin's disease 3.02 x 10(6)/kg (1.48-36) and 1.04 x 10(6)/kg (0.1-12.3) (P = 0.001). Mobilisation with G-IVE resulted in the achievement of clinically significant CD34+ cell thresholds in a significantly higher proportion of patients compared to cyclophosphamide and G-CSF reaching >2.5 x 10(6)/kg CD34+ cells in 88% vs 62% (P = 0.004), >5 x 10(6)/kg in 67% vs18% (P = 0.001) and >10 x 10(6)/kg in 31% vs 14.5% (P = 0.05). Furthermore, an analysis of engraftment demonstrated that there was a significant reduction in the time to achieve platelet counts of >20 and >50 x 10(9)/l in patients receiving each incremental dose of CD34+ cells. We conclude that G-IVE mobilizes significantly more CD34+cells than G/CYCLO in patients with lymphoproliferative disorders. This effect is consistent in patients with high-grade NHL, low-grade NHL and HD and results in fewer failed stem collections and increased CD34+ cells available for transplantation which results in significantly accelerated platelet engraftment post transplant.     

Single vs twice daily G-CSF dose for peripheral blood stem cells harvest in normal donors and children with non-malignant diseases

The optimal dose and schedule of G-CSF for mobilization of peripheral blood stem cells (PBSC) is not well defined. G-CSF mobilization was performed in a group of healthy donors and paediatric patients for autologous back-up before receiving allogeneic stem cell transplant. Seventeen consecutive subjects who received G-CSF at 5 microg/kg/dose twice daily (group A) were compared with a historical control group of 25 subjects who received a single daily dose of 10 microg/kg/day G-CSF (group B). Double blood volume apheresis for PBSC collection was started on day 5. G-CSF was continued and apheresis repeated until the targeted CD34+ cell dose was achieved. Both groups were comparable for sex, age, body weight and reason for PBSC collection. Over two-thirds of the subjects in both groups were less than 16 years of age. The G-CSF priming and apheresis were well tolerated. When the first day apheresis products were analyzed, group A resulted in significantly higher yield of total nucleated cells (5.91 vs 3.92 x 108/kg, P = 0. 013), mononuclear cells (5.73 vs 3.92 x 108/kg, P = 0.017), CD34+ cells (2.80 vs 1.69 x 106/kg, P = 0.049) and colony-forming units (107 vs 54 x 104/kg, P = 0.010) as compared with group B. We conclude that the two dose schedule is more efficient in mobilizing PBSC in normal donors and children with non-malignant diseases. This approach may reduce the number of aphereses required and thus reduce the transplant cost.     

Repeated peripheral stem cell mobilization in healthy donors: time-dependent changes in mobilization efficiency

Mobilization of peripheral blood stem cells was analysed in 10 consecutive healthy donors undergoing repeated stem cell mobilization for allogeneic transplantation. Donors received recombinant G-CSF at a dose of 10 microg/kg/d for both mobilizations. Collection of stem cells was started on day 5 of G-CSF administration. To compare the efficiency of first and second mobilization, we determined the leucocyte and CD34+ cell counts in peripheral blood, and the yield of nucleated cells and CD34+ cell counts in the apheresis product. CD34+ cell numbers in peripheral blood were (median) 81.2 x 10(6)/l during the first and 50.4 x 10(6)/l during the second mobilization (P = 0.007). Likewise, CD34+ cells in the apheresis product decreased from 319.8 x 10(6) to 275.7 x 10(6) (P = 0.02). Decrease in CD34+ cell counts in peripheral blood and in the apheresis product was associated with the time interval between first and second mobilization. In a regression analysis there was a correlation between the ratios of CD34+ cell counts of first and second mobilization and the inverse of time interval between procedures (r2 = 0.51 peripheral blood; r2 = 0.74 apheresis product). Thus, stem cell yield is reduced when healthy donors receive repeated mobilization within a short time. Nevertheless, an adequate number of stem cells may repeatedly be mobilized within 2 months.     

A randomized phase 2 study of PBPC mobilization by stem cell factor and filgrastim in heavily pretreated patients with Hodgkin's disease or non-Hodgkin's lymphoma

This randomized, controlled study compared the ability to mobilize and collect an optimal target yield of 5 x 10(6) CD34+ cells/kg using stem cell factor (SCF; 20 microg/kg/day) plus filgrastim (G-CSF; 10 microg/kg/day) vs filgrastim alone (10 microg/kg/day) in 102 patients diagnosed with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD), who were prospectively defined as being heavily pretreated. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield was reached, or until a maximum of five leukaphereses had been performed. Compared with the filgrastim-alone group (n = 54), the SCF plus filgrastim group (n = 48) showed an increase in the proportion of patients reaching the target yield within five leukaphereses (44% vs 17%, P = 0.002); reduction in the number of leukaphereses required to reach the target yield (P = 0.003); reduction in the proportion of patients failing to reach a minimum yield of 1 x 10(6) CD34+ cells/kg to proceed to transplant (16% vs 26%, P = NS); increase in the median yield of CD34+ cells per leukapheresis (0.73 x 10(6)/kg vs 0.48 x 10(6)/kg, P = 0.04); and an increase in the median total CD34+ cells collected within five leukaphereses (3.6 x 10(6)/kg vs 2.4 x 10(6)/kg, P = 0.05). All patients receiving SCF were premedicated (antihistamines and albuterol), and treatment was generally well tolerated. Five patients experienced severe mast cell-mediated reactions, none of which were life-threatening. In this study of heavily pretreated lymphoma patients, SCF plus filgrastim was more effective than filgrastim alone for mobilizing PBPC for harvesting and transplantation after high-dose chemotherapy.     

Reduced dose of lenograstim is as efficacious as standard dose of filgrastim for peripheral blood stem cell mobilization and transplantation: a randomized study in patients undergoing autologous peripheral stem cell transplantation

In vitro studies have demonstrated a 27% increased efficacy of lenograstim over filgrastim. However, equal doses of 10 microg/kg/day of filgrastim and lenograstim have been recommended for mobilization of CD34+ cells without associated chemotherapy. In this study, we investigated whether a 25% reduced dose of lenograstim at 7.5 microg/kg/day is equavalent to 10 microg/kg/day filgrastim for autologous peripheral blood stem cell (PBSC) mobilization and transplantation. A total of 40 consecutive patients were randomized to either filgrastim (n = 20) or lenograstim (n = 20). The two cohorts were similar in regard to disease, sex, body weight, body surface area, conditioning regimens, previous chemotherapy cycles and radiotherapy. Each growth factor was administered for 4 consecutive days. The first PBSC apheresis was done on the 5th day. In the posttransplant period, the same G-CSF was given at 5 microg/kg/day until leukocyte engraftment. Successful mobilization was achieved in 95% of patients. Successful mobilization with the first apheresis, was achieved in 10/20 (50%) patients in the filgrastim group versus 9/20 (46%) patients in the lenograstim group. No significant difference was seen in the median number of CD34+cells mobilized, as well as the median number of apheresis, median volume of apheresis, percentage of CD34+ cells, and CD34+ cell number. Leukocyte and platelet engraftments, the number of days requiring G-CSF and parenteral antibiotics, the number of transfusions were similar in both groups in the posttransplant period. Lenograstim 7.5 microg/kg/day is as efficious as filgrastim 10 microg/kg/day for autologous PBSC mobilization and transplantation.     

Long-term hematopoietic engraftment after autologous peripheral blood progenitor cell transplantation in pediatric patients: effect of the CD34+ cell dose

BACKGROUND AND OBJECTIVES: We analyzed the relationship between long-term hematopoietic recovery and the number of CD34+ cells infused in order to determine the optimal dose of CD34+ cells for rapid and stable engraftment. PATIENTS AND METHODS: Between November 1993 and December 1998, 96 consecutive autologous transplantations were performed in 92 pediatric patients with different malignancies. Peripheral blood progenitor cells (PBPC) were mobilized by G-CSF alone (12 microg/kg/day s.c., Neupogen((R)); Amgen, Thousand Oaks, Calif., USA) and collected using a Cobe Spectra blood cell separator (Cobe, Denver, Colo., USA) through a central venous catheter with double lumen. The CD34+ cell contents of apheresis products were assessed by means of flow-cytometric analysis using an Epics Elite flow cytometer (Coulter, USA). RESULTS: The median number of CD34+ cells infused was 3.2 x 10(6)/kg (range 0.17-44.4). The median times for short-term engraftment (neutrophil count >0.5 x 10(9)/l and platelet count >20 x 10(9)/l) was 9 (range: 7-16) and 13 days (range: 7-91), respectively. The median times for long-term engraftment (platelet count >50 x 10(9)/l and >100 x 10(9)/l) was 21 (range: 10-249) and 45 days (range: 12-288). When the infused CD34+ cell dose was >/=5 x 10(6)/kg (median 7.99, range 5.01-44.4), there was a statistically significant increase in the rate of short- and long-term hematopoietic recovery compared to patients transplanted with a lower number of CD34+ cells (p < 0.0001). The earlier recovery in the high CD34+ cell group resulted in less transfusional support, fewer days on intravenous antibiotics and shorter hospitalization. CONCLUSIONS: This study confirms that G-CSF-mobilized PBPC provide rapid short- and long-term hematopoietic engraftment in pediatric patients undergoing autologous transplantation if a CD34+ cell dose >/=5.0 x 10(6)/kg is infused. As this PBPC dose seems to have clinical and potentially economic implications, it should be considered the optimal dose for apheresis.     

Analysis of stem cell apheresis products using intermediate-dose filgrastim plus large volume apheresis for allogeneic transplantation

Previously, a dose-dependent influence of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on CD34+ mobilization was demonstrated. In this single-center prospective analysis, 52 healthy donors were investigated to determine the efficacy of intermediate-dose rhG-CSF 2x8 microg/kg donor body weight (bw) and intermediate large volume apheresis (LVA, median 12 l) to mobilize peripheral blood progenitor cells (PBPC) for allogeneic transplantation. The median number of CD34+ cells in apheresis products was 0.45% and 2.2x10(6)/kg recipient bw per single apheresis. A total of 5.4x10(6)/kg CD34+ cells were collected with two (range: one to three) LVA. In the analysis of donor subgroups, higher peripheral blood (PB) and apheresis results were obtained in male vs female donors; however, donor weight significantly differed in both groups. Heavier donors displayed higher PB and apheresis CD34+ counts; however, when CD34+ cells/kg were adjusted to a constant bw, similar harvest results were calculated in males and females, demonstrating that gender per se does not, whereas bw does affect apheresis results. Younger donors had significantly higher PB CD34+ counts, higher CD34+ numbers per single apheresis, increased CFU, more T, B, and CD61+, comparable NK, and less CD14+ cells. A correlation analysis of donor age and apheresis results displayed an age-related decline of 0.46x10(6)/kg CD34 cells per decade of donor aging. Cell subsets in apheresis products were CD14 (49%), CD3 (22%), CD4 (13%), CD8 (7%), CD61 (20%), CD19 (5%), and CD16/56+ (3%) cells, with increasing CD14+ cells and decreasing CD3, CD4, CD8, CD61, CD19, and CD16/56+ cells on subsequent days of apheresis. Compared to our previous analysis using high- (2x12 microg) and low-dose (1x10 microg) rhG-CSF for allogeneic PBPC mobilization, the intermediate-dose showed a similar CD34+ mobilization potential to 1x10 microg rhG-CSF; however, with use of LVA, two instead of three (p<0.05) aphereses were sufficient to mobilize > or =4x10(6)/kg bw CD34+ cells in most donors. Taken together, our results demonstrate that intermediate-dose rhG-CSF sufficiently mobilizes > or =4x10(6)/kg x bw CD34+ cells with use of LVA and that especially younger donors display increased CD34+ cell numbers.     

ESHAP plus G-CSF as an effective peripheral blood progenitor cell mobilization regimen in pretreated non-Hodgkin's lymphoma: comparison with high-dose cyclophosphamide plus G-CSF

The ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) regimen has been shown to be effective as an active salvage therapy for lymphoma. Mobilizing stem cells following ESHAP should decrease time to transplantation by making separate mobilizing chemotherapy (MC) unnecessary, while controlling a patient's lymphoma. We therefore assessed the mobilization potential of ESHAP plus G-CSF in 26 patients (ESHAP group) with non-Hodgkin's lymphoma (NHL) and compared these results with those of 24 patients with NHL who received high-dose (4 g/m2l) cyclophosphamide (HDCY) as MC (HDCY group). The age, sex, and radiotherapy to the axial skeleton were well matched between groups, but the number of patients with poor mobilization predictors was higher in the ESHAP group. Significantly higher numbers of CD34+ cells (x 10(6)/kg) (17.1+/-18.8 vs 5.8+/-5.0, P=0.03) and apheresis day 1 CD34+ cells (x 10(6)/kg) (5.5+/-6.6 vs 1.7+/-2.0, P=0.014) were collected from the ESHAP group than from the HDCY group, and the number of patients who achieved an optimal CD34+ cell target of 5 x 10(6)/kg was higher in the ESHAP group (81 vs 50%, P=0.022). Log-rank test revealed that time to target peripheral blood progenitor cell collection (> or =5 x 10(6)/kg) was shorter in the ESHAP group (P=0.007). These results indicate that ESHAP plus G-CSF is an excellent mobilization regimen in patients with relapsed and poor-risk aggressive NHL.     

CD34+ cell dose and hematologic recovery in allogeneic peripheral blood stem cell transplantation

Allogeneic peripheral blood stem cell transplantation (Allo-PBSCT) has been performed as an alternative to bone marrow transplantation (BMT). Here we report poor mobilization with granulocyte-colony stimulating factor (G-CSF) and engraftment kinetics in Allo-PBSCT. Sixteen patients (aged 6-61 yr, median 34 yr) received allogeneic peripheral blood stem cells from related donors (aged 15-68 yr, median 37 yr) after myeloablative therapy. Nine of the patients had standard-risk disease and 7 had high-risk disease. The donors received G-CSF at a dose of 10 micrograms/kg/day by subcutaneous injection for 4 to 6 days. Peripheral blood stem cells were subsequently collected in 1 to 3 aphereses and infused immediately. All patients received G-CSF after transplantation. Fifteen patients underwent Allo-PBSCT and one underwent Allo-PBSCT plus BMT. The mean number of CD34+ cells infused in the 15 Allo-PBSCT patients was 6.32 x 10(6)/kg (range 1.28-14.20). The outcomes were compared with 9 identically treated patients who underwent Allo-BMT. The median times until engraftment for neutrophils > 500/microliter and platelets > 20,000/microliter were 14 (range 10-17) and 15 (range 11-50) days in the Allo-PBSCT group and 17 (range 13-29) and 20 (range 16-160) days in the Allo-BMT group, respectively (p = 0.0177 and p = 0.003). Three donors were considered to have poor mobilization (< 2 x 10(6) CD34+ cells/kg of the recipient); two of them yielded 1.28 and 1.78 x 10(6) CD34+ cells/kg in 3 apheresis procedures. The patients who received cells from these donors showed prompt neutrophil engraftment, but one showed delayed platelet engraftment and another died of grade IV acute GVHD before reaching 20,000 platelets/microliter. An additional bone marrow harvest was necessary from one donor because of poor mobilization(0.17 x 10(6) CD34+ cells/kg). Thus, Allo-PBSCT results in more rapid engraftment. It will be necessary to clarify the minimum CD34+ cell dose for complete engraftment in a larger series of trials.