Biomedical subjects

S F Williams

Publications and source records attributed to S F Williams.

At least 19 recordsLinked to original sources

PubMed2006

Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially?

Sixty three patients aged 27-66 years (median 52) were allografted from HLA-matched sibling (n=47), 10 of 10 allele-matched unrelated (n=19), or one-antigen/allele-mismatched (n=7) donors aged 24-69 years (median 46) after a conditioning regimen comprising 100 mg/m(2) melphalan. Cyclophosphamide (50 mg/kg) was also administered to patients who had not been autografted previously. Cyclosporine or tacrolimus, and mycophenolate mofetil were administered to prevent graft-versus-host disease (GVHD). The 2-year cumulative incidences of relapse and TRM were 55 and 24% respectively, and 2-year probabilities of overall survival (OS) and disease-free survival (DFS) were 36 and 21%, respectively. Poor performance status, donor age >45 years and elevated lactate dehydrogenase (LDH) increased the risk of treatment-related mortality (TRM), refractory disease and donor age >45 years increased the risk of relapse, and OS and DFS were adversely influenced by refractory disease, poor performance status, increased LDH, and donor age >45 years. Our data suggest that younger donor age is associated with better outcome after sub-myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies due to lower TRM and relapse. This finding raises the question of whether a young 10-allele-matched unrelated donor is superior to an older matched sibling donor in patients where the clinical situation permits a choice between such donors.

Adult↗

PubMed2006

Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARgamma fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARgamma, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARgamma agonist (RS5444) that is dependent upon PPARgamma for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC50 for growth inhibition is approximately 0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited three- to fourfold in nude mice. siRNA against PPARgamma and a pharmacological antagonist demonstrated that functional PPARgamma was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21WAF1/CIP1. Silencing p21WAF1/CIP1 rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARgamma is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.

Angiogenesis Inhibitors↗

PubMed2006

Ideal rather than actual body weight should be used to calculate cell dose in allogeneic hematopoietic stem cell transplantation.

Whether the CD34+ and CD3+ cell doses in allogeneic HSCT should be estimated using actual (ABW) or ideal (IBW) body weight has never been definitively determined. We have shown that CD34+ cell doses based upon IBW are better predictive of engraftment after autologous and allogeneic HSCT. Sixty-three patients undergoing reduced-intensity HSCT after a uniform preparative regimen were evaluated to determine the effect of cell dose. ABW and IBW were 45-147 kg (median 79) and 52-85 kg (median 67) respectively. The ABW-IBW difference was -24% to +133% (median +16%); nine patients were >5% underweight and 41 were >5% overweight. The CD34+ cell dose (10(6)/kg) was 1.4-11.8 (median 5) by IBW and 1.2-9.3 (median 4.5) by ABW. The CD3+ cell dose (10(8)/kg) was 0.9-14.9 (median 3) by IBW and 0.7-19.7 (median 2.7) by ABW. While CD34+ and CD3+ cell doses based upon IBW were found to affect transplant-related mortality, and disease-free and overall survival significantly, those based on ABW were either not predictive of outcome or the differences were of borderline significance. We suggest using IBW rather than ABW to calculate cell doses for HSCT; for statistical analyses and for clinical practice if a specific cell dose is being targeted.

Adult↗

PubMed2003

Ideal or actual body weight to calculate CD34+ cell doses for autologous hematopoietic stem cell transplantation?

The number of CD34+ cells infused influences the speed of hematologic recovery post-transplant. There are limited data on whether ideal (IBW) or actual (ABW) body weight should be used to calculate CD34+ cell dose. We compared the correlation between recovery to 0.5 x 10(9)/l neutrophils and the CD34+ cell dose based upon ABW as well as IBW in 87 patients autografted for cancer. ABW was >or=25% over IBW in 43% of patients. The median number of CD34+ cells administered was 3.6 x 10(6)/kg ABW and 4.2 x 10(6)/kg IBW. The time to neutrophil recovery was 8-15 days (median 10). There was a stronger inverse correlation between CD34+ cell dose/IBW and neutrophil recovery (r(2)=0.308; P<0.0001) than between CD34+ cell dose/ABW and neutrophil recovery (r(2)=0.267; P<0.0001). The median time to neutrophil recovery was comparable for those receiving >or=2 x 10(6)/kg CD34+ cells/kg IBW as well as ABW (10 days) and those receiving >or=2 x 10(6)/kg CD34+ cells/kg IBW but <2/kg ABW (10 days), but was significantly slower for those receiving <2 x 10(6)/kg CD34+ cells/kg IBW (12 days). These data show that the CD34+ cell dose based on IBW is a better predictor of neutrophil recovery after autotransplantation.

Adolescent↗

PubMed2001

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↗

PubMed2001

Optimization of culture conditions to enhance transfection of human CD34+ cells by electroporation.

The ability to culture CD34+ stem cells, while maintaining their pluripotency, is essential for manipulations such as gene transfection for therapeutic trials. Human peripheral blood (PB) CD34+ cells (> or = 90% purity) were cultured for up to 4 days in serum-free culture medium supplemented with thrombopoietin (TPO), stem cell factor (SCF), Flt-3 ligand (Flt-3L), with or without PIXY321 (IL-3/GM-CSF fusion protein) and human serum. The CD34 mean fluorescence intensity (MFI) and cell cycle status were evaluated daily using flow cytometry and hypotonic propidium iodide. Prior to culture (day 0), 97.0 +/- 0.9%, 1.9 +/- 0.3% and 1.0 +/- 0.6% of the selected CD34+ cells were in G0-G1, S-phase, or G2-M, respectively. After 2-4 days in culture with TPO/SCF/Flt-3L, there was an increase in the percent of cells in S-phase to 26.4 +/- 0.1% without significant loss of CD34 MFI. The addition of PIXY321 increased.the percentage of CD34+ cells in S-phase to 36.3 +/- 4.0%, but the CD34 MFI and numbers of CFU (colony-forming units) were significantly decreased at day 3 when cultured with PIXY321 or various recombinant cytokine combinations that included IL-3 and IL-6. There is an increase from day 0 to day 4 in the percentages of CD34+ with CD38-, HLA-DR-, and c-kit(low), but not Thy-1+ cells. Electroporation with EGFP reporter gene showed that 1-2 days of pre-stimulation in X-VIVO 10 supplemented with TPO/SCF/Flt-3L was necessary and sufficient for efficient transfection. Flow cytometry analysis demonstrated that 22% of the viable cells are CD34+/EGFP+ 48 h post electroporation. The introduced reporter gene appears to be stable as determined by EGFP+/LTC-IC (long-term colony-initiating cells), at 30-40 positive colonies (16 +/- 7%) per 1 x 10(5) electroporated CD34+ cells.

Antigens, CD34↗

PubMed2001

Efficient expression of foreign genes in human CD34(+) hematopoietic precursor cells using electroporation.

Introduction of foreign genes into human CD34(+) hematopoietic precursor cells offers a means to correct inborn errors or to protect human stem cells from chemotherapeutic damage. Electroporation is a non-chemical, nonviral, highly reproducible means to introduce foreign genes into mammalian cells that has been used primarily for rapidly dividing cells. CD34(+) cells isolated from mobilized peripheral blood of patients were cultured for 48 h in serum-free culture medium supplemented with Flt-3 ligand, stem cell factor and thrombopoietin. Cell cycle analysis showed an increase in % S-phase from 2% on day 0 to 28% on day 2 without significant loss of mean fluorescence intensity (MFI). Optimal electroporation conditions for CD34(+) cells were 550 V/cm, 38 ms, 30 microg DNA/500 microl at cell densities between 0.2 x 10(6) and 10 x 10(6) cells/ml resulting in transient EGFP gene expression in 21% (+/- 1%) of CD34(+) precursor cells, as determined by flow cytometry 48 h after electroporation. The more primitive cells were also found to be EGFP(+) as determined by subset analysis using Thy1, CD38, AC133 and c-kit conjugated monoclonal antibodies. Methylcellulose assays on electroporated CD34(+) cells yielded 20% (+/- 7%) EGFP(+) colonies (CFU-GM, BFU-E and CFU-mix) and 22% (+/- 5%) EGFP(+) long-term colony-initiating cells (LTC-IC). The reporter gene was found to be integrated into the LTC-IC genomic DNA as determined by inverse PCR and DNA sequencing. These results suggest that electroporation has the potential to effectively and stably deliver exogenous genes into human hematopoietic precursor cells.

Antigens, CD34↗

PubMed2000

Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors.

We sought to define risk factors predisposing breast cancer and lymphoma patients to cardiac and pulmonary toxicity when undergoing high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR). Additionally, we evaluated in depth the predictive value of the ejection fraction measured prior to HDC in determining cardiac toxicity. In this retrospective analysis, 24 variables were examined in 138 patients undergoing HDC and ASCR from 1990 until 1995. Logistic regression models were used to model the probability of experiencing cardiac and pulmonary toxicity as a function of the 24 prognostic covariates. Cardiac toxicity occurred in 12% of patients and pulmonary toxicity in 24% of patients. Bivariate analyses showed that patients with lymphoma (as opposed to breast cancer) and those with a higher cardiac risk factor score were more likely to experience cardiac toxicity. Multivariate logistic regression models predicted lymphoma and older age to be risk factors for cardiac toxicity. History of an abnormal ejection fraction and higher doses of anthracyclines prior to HDC may also contribute to cardiac toxicity. Pulmonary toxicity occurred more commonly in lymphoma than breast cancer patients, likely due to the busulfan used in the HDC regimen. No other risk factors for pulmonary toxicity were identified. We conclude that older patients with lymphoma should be carefully evaluated prior to being accepted for HDC programs. Older patients with breast cancer may tolerate this procedure well. There is a trend towards cardiac toxicity in patients with a past history of low ejection fraction, although seemingly poor cardiac risk patients may fare well with HDC if carefully selected with the aid of a thorough cardiac evaluation.

Adult↗

PubMed2000

Clinical impact of ex vivo differentiated myeloid precursors after high-dose chemotherapy and peripheral blood progenitor cell rescue.

The infusion of ex vivo differentiated myeloid precursors may be able to shorten the period of obligatory neutropenia after high-dose chemotherapy and peripheral blood progenitor cell rescue by providing cells capable of differentiating to mature neutrophils within days of infusion. To test this hypothesis, 21 female patients with metastatic breast cancer underwent progenitor cell mobilization with cyclophosphamide, etoposide and G-CSF. CD34+ cells from one to two leukapheresis products were isolated and placed in suspension culture with a serum-free growth medium supplemented with PIXY321. The cultures were maintained for 12 days with subcultures initiated on day 7. The remaining leukapheresis products were cryopreserved in an unmanipulated state. Forty-eight hours after completing high-dose cyclophosphamide, thiotepa and carboplatin, the cryopreserved progenitors were infused, followed 1 to 24 h later by infusion of the differentiated myeloid precursors. In one patient, the cultured cells were labeled with Indium-111 with nuclear imaging performed up to 48 h post infusion. The differentiated myeloid precursors were suitable for infusion in 17 of the patients with a median 13-fold expansion of total nucleated cells. A range of 5.6 to 1066 x 10(7) nucleated cells were infused. Morphologically the cells were predominantly of myeloid lineage (63%) with a median 41% of the cells expressing CD15. No untoward effects were noted with the infusion of the cultured cells. The median days to neutrophil and platelet recovery were 8 and 10 days, respectively. There was a significant relationship (r = 0.67, P = 0.007) between the dose of differentiated myeloid precursors (CD15+ cells) and the depth and duration of neutropenia; a similar relationship, however, was also observed with the dose of cryopreserved CD34+ cells. After infusion of the radiolabeled myeloid precursors, a pattern of distribution similar to radio-labeled granulocytes was noted with uptake detected initially in the lungs and subsequently the reticulo-endothelial system. The impact of differentiated myeloid precursors on neutropenia as an adjunct to high-dose chemotherapy and peripheral blood progenitor cell rescue remains unclear from this study. Further study with controlled doses of cryopreserved progenitors and escalating doses of differentiated myeloid precursors is required.

Adult↗

PubMed2000

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.

Adult↗

PubMed2000

Antineoplastic drugs administered during pregnancy.

Cancer is the second leading cause of death in women during their reproductive years. Thus, antineoplastic drugs may be administered to pregnant women. The effects these agents have on the developing fetus depend on the type of agent and the timing of exposure during embryogenesis. In particular, antifolate antimetabolites should be avoided. However, the literature contains many reports of successful fetal outcomes after exposure to other types of agents. The decision to begin antineoplastic therapy must be carefully considered by all physicians and the patient involved.

Antineoplastic Agents↗

PubMed1999

Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer.

CONTEXT: Women with breast cancer are the most frequent recipients of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autotransplants) in North America. Despite widespread use, controversy exists about the benefits of and appropriate patients for this therapy. OBJECTIVE: To determine factors associated with disease progression or death after autotransplantation in women with metastatic breast cancer. DESIGN: Analysis of data collected retrospectively (January 1989 to 1992) and prospectively (1992 through January 1995) for the Autologous Blood and Marrow Transplant Registry. SETTING: Sixty-three hospitals in North America, Brazil, and Russia. PARTICIPANTS: A total of 1188 consecutive women aged 18 to 70 years receiving autotransplants for metastatic or locally recurrent breast cancer, with a median follow-up of 291/2 months. MAIN OUTCOME MEASURE: Time to treatment failure (disease progression, disease recurrence, or death) after autotransplantation. RESULTS: Factors associated with significantly (P<.05) increased risk of treatment failure in a Cox multivariate analysis included age older than 45 years (relative hazard, 1.17; 95% confidence interval [CI], 1.02-1.33), Karnofsky performance score less than 90% (1.27; 95% CI, 1.07-1.51), absence of hormone receptors (1.31; 95% CI, 1.15-1.51), prior use of adjuvant chemotherapy (1.31; 95% CI, 1.10-1.56), initial disease-free survival interval after adjuvant treatment of no more than 18 months (1.99; 95% CI, 1.62-2.43), metastases in the liver (1.47; 95% CI, 1.20-1.80) or central nervous system (1.56; 95% CI, 0.99-2.46 [approaches significance]) vs soft tissue, bone, or lung, 3 or more sites of metastatic disease (1.32; 95% CI, 1.13-1.54), and incomplete response vs complete response to standard-dose chemotherapy (1.65; 95% CI, 1.36-1.99). Receiving tamoxifen posttransplantation was associated with a reduced risk of treatment failure in women with hormone receptor-positive tumors (relative hazard, 0.60; 95% CI, 0.47-0.87). Women with no risk factors (n = 38) had a 3-year probability of progression-free survival of 43% (95% CI, 27%-61 %) vs 4% (95% CI, 2%-8%) for women with more than 3 risk factors (n = 343). CONCLUSION: These data indicate that some women are unlikely to benefit from autotransplantation and should receive this treatment only after being provided with prognostic information and in the context of clinical trials attempting to improve outcome.

Adult↗

PubMed1999

A randomized phase 3 study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients.

This randomized study compared the number of leukaphereses required to collect an optimal target yield of 5 x 10(6) CD34(+) peripheral blood progenitor cells/kg, using either stem cell factor (SCF) at 20 micrograms/kg/d in combination with Filgrastim at 10 micrograms/kg/d or Filgrastim alone at 10 micrograms/kg/d, from 203 patients with high-risk stage II, III, or IV breast cancer. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield of CD34(+) cells had been reached or a maximum of 5 leukaphereses performed. By day 5 of leukapheresis, 63% of the patients treated with SCF plus Filgrastim (n = 100) compared with 47% of those receiving Filgrastim alone (n = 103) reached the CD34(+) cell target yield. There was a clinically and statistically significant reduction (P <.05) in the number of leukaphereses required to reach the target yield for the patients receiving SCF plus Filgrastim (median, 4 leukaphereses) compared with patients receiving Filgrastim alone (median, 6 or more leukapherses; ie, <50% of patients reached the target in 5 leukaphereses). All patients receiving SCF were premedicated with antihistamines, albuterol, and pseudoephedrine. Treatment was safe, generally well tolerated, and not associated with life-threatening or fatal toxicity. In conclusion, SCF plus Filgrastim is a more effective peripheral blood progenitor cell (PBPC)-mobilization regimen than Filgrastim alone. In addition to the potential for reduced leukapheresis-related morbidity and costs, SCF offers additional options for obtaining cells for further graft manipulation.

Adult↗

PubMed1999

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.

Adult↗

PubMed1999

Myelodysplasia and acute leukemia following high-dose chemotherapy and autologous bone marrow or peripheral blood stem cell transplantation.

Therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML) has been reported after autologous bone marrow or peripheral blood stem cell transplantation (ABMT/PBSCT) for various malignancies. We retrospectively reviewed all adult ABMT/PBSCT cases performed at the University of Chicago Medical Center from 1985 to 1997 in order to determine the incidence of therapy-related leukemia. Among 649 patients, seven (1.1%) developed therapy-related acute lymphoblastic leukemia (one patient) or t-MDS/t-AML (six patients). Of these seven, primary malignancies included one case of breast carcinoma, five cases of Hodgkin's disease (HD) and one case of non-Hodgkin's lymphoma (NHL). Disease-specific incidences for therapy-related leukemia occurring after ABMT/PBSCT were one in 354 (0.3%) for breast carcinoma, five in 79 (6.3%) for HD and one in 103 (1%) for NHL. The median latency periods for the development of therapy-related leukemia from the time of initial diagnosis and of ABMT/PBSCT were 5.5 and 1.5 years, respectively, for the combined HD and NHL group of patients and 4.4 and 2.8 years, respectively, for the one breast carcinoma patient. All seven patients had clonal cytogenetic abnormalities, and five had recurring abnormalities typical of myeloid disorders. Given the similar latency period observed in patients treated with conventional chemotherapy alone, our findings support the hypothesis that therapy-related leukemia after ABMT/PBSCT likely results from pre-transplant therapy. Early detection of therapy-related leukemia is therefore critical to exclude these patients from undergoing ABMT/PBSCT.

Adult↗

PubMed1998

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.

Adult↗

PubMed1998

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.

Adult↗

PubMed1998

Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis.

Randomized, prospective studies comparing BUCY to TBI conditioning regimens for allogeneic bone marrow transplantation have yielded conflicting results. We investigated the overall survival, the disease-free survival and the toxicities of BUCY vs TBI-based regimens by conducting a meta-analysis of all published, randomized, prospective trials comparing these regimens. Five studies were analyzed. We evaluated six endpoints: survival, disease-free survival, veno-occlusive disease (VOD) of the liver, acute GVHD, chronic GVHD, and interstitial pneumonitis. We combined individual study results using a random effects model. Survival and disease-free survival were better with TBI-based regimens than with BUCY, but these differences were not statistically significant (survival odds ratio 1.4, 95% confidence interval 0.9-2.2, P = 0.09; disease-free survival odds ratio 1.2, 95% confidence interval 0.7-2.1, P = 0.44). A power analysis indicated that BUCY was unlikely to have a clinically relevant survival or disease-free survival advantage. The power analysis could not exclude the possibility of such an advantage for TBI-based regimens. A significantly greater incidence of VOD occurred with BUCY (odds ratio 2.5, 95% confidence interval 1.2-5.2, P = 0.02). For the other side-effects, there were no significant differences. We concluded that TBI-based regimens cause less VOD than BUCY and are at least as good for survival and disease-free survival.

Adult↗