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.

Transplantation with low-density autologous PBSC prepared with BDS60 for women with Stage II, III and IV breast cancer.

BACKGROUND: DS60 is a novel buoyant density solution, whose density has been adjusted to enrich PBSC from subjects who have been mobilized with cytokines alone, or cytokines plus chemotherapy. This report describes the use of BDS60 to enrich autologous PBSC that were used for hematological reconstitution after myeloablative chemotherapy in women with breast cancer. METHODS: Fifty-one consecutive patients with high-risk Stage II or III breast cancer or chemotherapy-sensitive Stage IV breast cancer were enrolled. Forty-seven completed treatment and were evaluable. After mobilization with cyclophosphamide (4.0 g/m(2) i.v. once) and filgrastim (10 microg/kg/day), the patients underwent leukapheresis and the products were enriched with BDS60 using the DACS300 Kit. Myeloablative chemotherapy, given on Day -5 through Day -2, consisted of cyclophosphamide (1.5 g/m(2)/day), thiotepa (150 mg/m(2)/day) and carboplatin (200 mg/m(2)/day). RESULTS: Forty-one patients underwent a single leukapheresis procedure to achieve the target number of BDS60-enriched CD34+ cells for transplantation (> or = 2 x 10(6)/kg). Five of the other six patients had less than the target number of cells in the leukapheresis product and thus required 2-4 leukapheresis procedures. Median cell recovery was 76.8% for CD34+ cells, 39.1% for nucleated cells, and 17.7% for platelets. Erythrocyte contamination of the final product was negligible. The median time to sustained neutrophil count > 500/mm(3) was 9 days (range: 8-12) and the median time to platelet count > 20 000/mm(3), without transfusion support, was also 9 days (range: 6-15). There were no late graft failures. Infusion-related adverse events were mild and no adverse events were attributed to the use of BDS60 to enrich CD34+ cells. DISCUSSION: BDS60 is an effective, rapid method for enrichment of CD34+ cells by buoyant density centrifugation and the resulting cell product is safe and effective for engraftment after myeloablative therapy.

Timing of platelet recovery is associated with adequacy of leukapheresis product yield after cyclophosphamide and G-CSF in patients with lymphoma.

A subgroup of patients with refractory Hodgkin's (HD) or non-Hodgkin's (NHL) lymphoma may be cured with high-dose chemotherapy and peripheral blood progenitor cell rescue. To investigate the relationship of adequate leukapheresis yield and time course of platelet recovery after mobilization chemotherapy, we retrospectively analyzed the leukapheresis yields in seven patients with Hodgkin's disease and fifteen patients with non-Hodgkin's lymphoma undergoing high-dose chemotherapy. Our goal was to develop a rule to determine when to initiate leukapheresis and then to prospectively validate this rule. All patients were mobilized with cyclophosphamide and G-CSF (granulocyte-colony stimulating factor). A total of 144 leukaphereses were completed and analyzed. Based on the CD34 content in the initial harvest product, fifteen patients were defined as poor mobilizers (CD34 < 0.15 x 10(6)/kg) and seven were good mobilizers. The platelet count on the first day of harvesting was significantly associated with the poor mobilizers (P = .03). Age, sex, marrow involvement, disease (HD vs. NHL), prior radiation, time since last chemotherapy, and total number of cycles of prior chemotherapy were not predictive of poor mobilizers. By using a platelet count cut off of 35 x 10(9)/L, we retrospectively analyzed 144 individual leukapheresis products, to test whether CD34 yield was predicted by the peripheral blood platelet count on the day of leukapheresis. This rule had an excellent sensitivity, 91%, and a specificity of 67%. Subsequently, we validated this rule with the next twenty-four patients undergoing leukapheresis of which there were 143 leukaphereses. The prediction rule exhibited a sensitivity of 72% and a specificity of 68% in the validation set. There does appear to be utility in using the platelet count to guide the initiation of leukapheresis after chemotherapy and G-CSF mobilization.

A Phase I dose escalation trial of continuous infusion paclitaxel to augment high dose cyclophosphamide and thiotepa plus stem cell rescue for the treatment of patients with advanced breast carcinoma.

BACKGROUND: Paclitaxel, an effective chemotherapeutic agent in the management of breast carcinoma, may have activity in women whose disease has recurred after high dose chemotherapy. With this is mind the authors explored the addition of a 120-hour continuous infusion of paclitaxel to a previously reported regimen comprised of high dose cyclophosphamide and thiotepa. METHODS: Thirty-one women with advanced breast carcinoma (30 patients with Stage IV disease and 1 patient with Stage IIIB disease) underwent harvest and cryopreservation of bone marrow and/or peripheral blood progenitor cells. High dose cyclophosphamide (2.5 g/m2) and thiotepa (225 mg/m2) were administered intravenously on Days -7, -5, and -3. Paclitaxel was administered as a 120-hour continuous infusion starting on Day -7. RESULTS: Three patients were treated at the initial cohort dose of 50 mg/m2 (over 120 hours), 6 patients at 100 mg/m2, 6 patients at 125 mg/m2, 6 patients at 150 mg/m2, 6 patients at 180 mg/m2, and 4 patients at 210 mg/m2. All patients completed the treatment protocol as planned with no associated transplant-related deaths. Mucositis as evidenced by either stomatitis or noninfectious diarrhea was experienced by all patients and was determined to be the dose-limiting toxicity at the 210 mg/m2 dose level. One patient with dose-limiting mucositis required intubation for airway protection and also experienced Grade 3 (according to the Cancer and Leukemia Group B common toxicity grading scale) pulmonary and neurologic toxicity. Only one Grade 3 toxicity was encountered below the maximum tolerated dose in a patient who developed diffuse alveolar hemorrhage at a dose of 125 mg/m2. No allergic reactions or clinical evidence of peripheral neuropathies were encountered. Cardiac, hepatic, and renal toxicities were minimal. Response rates in this previously treated patient population were difficult to assess in light of the high incidence of bone metastases; an overall response rate of 24% was obtained. CONCLUSIONS: Paclitaxel at a dose of 180 mg/m2 as a 120-hour continuous infusion may be added safely to high dose cyclophosphamide and thiotepa with autologous stem cell rescue. Further studies are ongoing to evaluate the efficacy and further define the toxicity of this recommended Phase II dose.

High-dose chemotherapy consolidation with autologous stem cell rescue in metastatic breast cancer: a 10-year experience.

One hundred women with metastatic breast cancer (MBC) underwent high-dose chemotherapy with autologous stem cell rescue at our institution beginning in 1986. The patients underwent induction chemotherapy from June 1986 to December 1993. Patients who showed stable or responsive disease underwent HDC with cyclophosphamide (CY) at 7.5 g/m2 and thiotepa (TPA) at 675 mg/m2 or the same doses of CY and TPA with carmustine at 450 mg/m2. The source of stem cell rescue was either BM alone, BM and G-CSF-mobilized peripheral blood progenitor cells (PBPC) or PBPC alone if patients had BM involvement with MBC. With a median follow-up of 62 months (range 1-109 months), median survival from reinfusion was 16 months with a 5-year survival of 19+/-4%. The median event-free survival (EFS) was 8 months with a 5-year EFS of 11+/-3%. Patients achieving a complete response to induction therapy showed a higher 5-year EFS from reinfusion of 31+/-8% in contrast to 3+/-3% (P = 0.006) for patients who achieved a partial response to induction therapy prior to HDC. Marrow involvement or source of stem cell rescue did not affect outcome. Our mature results confirm that high-dose chemotherapy with autologous stem cell rescue can confer a prolonged DFS in a subset of women with MBC. However, the high rate of relapse remains a universally disturbing problem in this patient population.