High-dose ifosfamide and etoposide with filgrastim for stem cell mobilization in patients with advanced ovarian cancer.

High-dose chemotherapy combined with autologous peripheral blood stem cell transplantation has shown promise as treatment for recurrent or persistent epithelial ovarian cancer. We evaluated the stem cell mobilization regimen of high-dose ifosfamide plus etoposide in 32 patients with epithelial ovarian cancer, who had a positive second-look laparatomy or recurrent disease. Ifosfamide was given at 10 g/m2 by continuous i.v. from days 1 to 3. Etoposide was given at 150 mg/m2 every 12 h for six doses on days 1-3. Filgrastim was given at 10 microg/kg/d s.c. from day 5 until the completion of peripheral blood stem cell harvest. Fourteen of 32 patients had measurable or evaluable disease before mobilization therapy and were assessed for response. In nine (64%) of the 14 patients, treatment response was demonstrated, and these patients received a second cycle of mobilization therapy. The target CD34+ cell dose (>8 x 106 cells/kg) was achieved with a median of one apheresis (range 1-5). A median of 25.1 (range 8.0-122.5) x 106 CD34+ cells/kg body weight was collected. Non-hematologic toxicity was limited to grade 2 renal dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was well tolerated, lead to successful stem cell harvest and had antitumor activity.

High CD34 cell doses do not worsen regimen-related toxicity or early mortality after autologous blood stem cell transplantation for breast cancer.

BACKGROUND: Some transplant-related complications, such as the engraftment syndrome, are thought to be mediated by cytokines released during expansion of hematopoietic progenitors at the time of neutrophil recovery. Since there is an inverse correlation between CD34(+) cell dose and time to neutrophil recovery, we sought to determine if peritransplant toxicity and early mortality were adversely affected by high CD34(+) cell doses. METHODS: The study group included 186 women with breast cancer who received high-dose cyclophosphamide, carmustine, thiotepa and an autologous PBSC transplant. The median CD34(+) cell dose was 5.9 x 10(6)/kg (1.0-154.7 x 10(6)/kg). Patients were categorized by CD34(+) cell dose (1.0-3.5, 3.6-5.9, 6.0-19.9, and 20.0-154.7 x 10(6)/kg) for assessment of outcomes. RESULTS: Grades 2-4 mucositis occurred in 49%, cardiac toxicity in 7%, pulmonary toxicity in 5%, cystitis in 4%, diarrhea in 3%, renal toxicity in 1%, and central nervous system toxicity in 1%. A Grade 2-4 regimen-related toxicity occurred in 109 patients (59%) and Grade 3-4 in eight patients (4%). Overall survival was 100% at Day 30, 96% at Day 90, and 89% at 1 year. Treatment-related mortality was 3.8%. In multivariate analyses that included prior chemotherapy, disease status, visceral metastases, prior chest radiation and age, CD34(+) cell dose group was not an independent risk factor for Grade 2-4 mucositis, Grade 2-4 maximum toxicity, Grade > or =3 cumulative toxicity, 90 day survival or 1 year survival. DISCUSSION: We conclude that CD34(+) cell doses >20 x 10(6)/kg do not affect transplant outcome in a negative or positive fashion.

Intensive dose ifosfamide and etoposide with G-CSF for stem cell mobilization in patients with non-Hodgkin's lymphoma.

We studied 36 patients with non-Hodgkin's lymphoma to evaluate the stem cell yield following recovery from intensive dose ifosfamide and etoposide given as mobilization chemotherapy. We also assessed the toxicity of the regimen and engraftment kinetics. All patients had intermediate grade lymphoma and had either failed to achieve a complete remission to induction chemotherapy or had relapsed. Patients received ifosfamide 10 g/m2 IV total dose given over 72 hours, etoposide 150 mg/m2 IV every 12 hours for 6 doses and G-CSF 10 microg/kg/d. Thirty-four patients went on to receive high-dose chemotherapy with BEAM or with CVP and BEAM. A median of 2 (1-10) apheresis was required to reach the target CD34+ count of >4 x 10(6)/kg. A median of 13.1 CD34+ cells/kg (4.1-148) was obtained. Toxicity was limited to mucositis in 3 patients, transient confusion and transient rise in liver function tests in 3 and 2 patients respectively. The median time to engraftment was 10 days (8-17) for all the patients undergoing high-dose chemotherapy. The regimen of intensive dose ifosfamide and etoposide along with G-CSF is well tolerated and in this group of patients has lead to successful stem cell harvests and sustained engraftment.

Collection of peripheral blood stem cells from normal donors 60 years of age or older.

We report 14 normal peripheral blood stem cell (PBSC) donors > or = 60 years of age who had cytokine mobilization followed by PBSC apheresis for allogeneic transplantation. Mobilization was achieved with filgrastim (6 microg/kg twice daily). Their median age was 63.5 years (range 60-77), and 43% had a positive medical history, mainly hypertension and/or cardiac problems. Their median pre-apheresis leucocyte count (x 10(9)/l) was 38.6 (range 29.6-63.4). The median apheresis yield (x 10(6) CD34+ cells/litre blood processed, first apheresis) was 27.9 (range 1.6-54.8). The target cell dose (> or = 4 x 10(6) CD34+ cells/kg recipient) was reached with one procedure in eight (57%) donors. Filgrastim-related adverse events were acceptable and apheresis was well tolerated. When compared to younger donors (< 60 years of age), a trend to a lower CD34+ apheresis yield and a requirement for more than one apheresis to achieve the collection target (> or = 4 x 10(6) CD34+ cells/kg) was evident. Although older (> or = 60 years) donors seem to mobilize less effectively, these data suggest that PBSC collection from them is feasible and has an acceptable short-term safety profile.

Factors affecting mobilization of CD34+ cells in normal donors treated with filgrastim.

BACKGROUND: Multiple days of apheresis are required for some normal peripheral blood progenitor cell (PBPC) donors, to ensure a sufficient collection of CD34+ cells for allografting. It would be of practical value to be able to identify the patients with poor mobilization on the basis of simple pretreatment clinical or hematologic variables. STUDY DESIGN AND METHODS: Clinical characteristics and laboratory data for 119 normal PBPC donors who underwent apheresis on Days 4 to 6 of treatment with granulocyte-colony-stimulating factor (filgrastim) were analyzed for correlations with CD34+ cell yield from the first day of apheresis. RESULTS: The CD34+ cell yield was significantly lower in donors who were more than 55 years of age, who underwent apheresis on Day 4 of filgrastim therapy, or who were not obese. There were weak direct correlations between CD34+ cell yield and the baseline white cell count, preapheresis white cell count, and preapheresis mononuclear cell count, and there was a weak inverse correlation with age. Twenty-one donors (18%) were considered to have poor mobilization (< 20 x 10(6) CD34+ cells/L blood processed). In the multivariate analysis, the only significant factor was age greater than 55 years, which conferred a 3.8 times greater risk (95% CI, 1.1-13.7) of poor mobilization (p = 0.04). However, poor mobilization occurred in all age groups, so the predictive value of the model was low. CONCLUSION: Donor variables correlated with CD34+ cell yield only weakly, so no particular clinical characteristic can be used to exclude an individual as a PBPC donor if he or she is otherwise suitable for the apheresis procedure.

Peripheral blood stem cell apheresis in normal donors: feasibility and yield of second collections.

We report 13 normal peripheral blood stem cell (PBSC) donors who had a second PBSC collection for allogeneic transplantation performed after the first. The median interval between the first and second collection was 5 months. Mobilization was achieved with filgrastim (12 microg/kg/d). No significant difference was found in the median pre-apheresis leucocyte count (x10(9)/l) between the two donations (40.2 v 38.5; P = 0.91). The median apheresis yield (x10(6) CD34+ cells/litre blood processed, first apheresis) was also similar (28 v 27.3; P = 0.91). Filgrastim-related adverse events were comparable. These data suggest that second PBSC collections are feasible, similarly tolerated and provide comparable apheresis yields.

Rapid debulking and CD34 enrichment of filgrastim-mobilized peripheral blood stem cells by semiautomated density gradient centrifugation in a closed system.

Filgrastim-mobilized peripheral blood progenitor cells (PBPC) are used for hematopoietic reconstitution after myeloablative therapy for malignancies, but the large number of cells collected in a single apheresis frequently presents a problem for storage or further processing. We have evaluated the use of CD34 Buoyant Density Solution-PBPC, an ultralight-density colloidal silica suspension, for debulking and enrichment of CD34+ cells in PBPC preparations in a semiautomated system. Cells were collected from four filgrastim-treated normal donors using the COBE Spectra. The separation procedure was carried out with Plasma-Lyte A and DNase 5 U/ml using the COBE 2991. Following processing and washing, there was a 26% recovery of nucleated cells, 2.6-fold enrichment of CD34+ cells, 68% recovery of CD34+ cells, 88% recovery of CFU-GM, 73% recovery of BFU-E, 1 log depletion of CD3+ cells, 0.5 log depletion of CD56+ cells, and 1 log depletion of CD19+ cells. These results were not significantly different from those obtained when PBPC were separated over CD34 Buoyant Density Solution-PBPC by centrifugation in tubes. Using CD34 Buoyant Density Solution-PBPC, mononuclear preparations of PBPC can be enriched rapidly for CD34+ cells and depleted of lymphocytes in a semiautomated closed system using reagents produced according to good manufacturing practice (GMP).

Duration of filgrastim mobilization and apheresis yield of CD34+ progenitor cells and lymphoid subsets in normal donors for allogeneic transplantation.

Seventy-seven normal donors underwent leukapheresis for peripheral blood progenitor cell collection beginning on day 4 (n = 45) or day 5 (n = 32) of filgrastim mobilization (12 micrograms/kg/d). The two groups were comparable for age, weight, blood volumes processed during leukapheresis and target CD34+ cell dose to be collected. The day 5 schedule allowed a more consistent achievement of the target cell dose with one apheresis (P = 0.005) and resulted in the initial collection of a significantly larger number of CD34+ cells (P = 0.009). There was no statistically significant difference in the leukapheresis yield of lymphoid subsets and natural killer cells.