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Biomedical subjects

R Champlin

Publications and source records attributed to R Champlin.

At least 127 records · Page 7Linked to original sources
PubMed1997

Phase I/II study of dose-intense doxorubicin/paclitaxel/cyclophosphamide with peripheral blood progenitor cells and cytokine support in patients with metastatic breast cancer.

Relapse following complete remission achieved with a single course of high-dose chemotherapy continues to be the main cause of treatment failure in patients with metastatic breast cancer. A phase I/II trial was initiated that combined the two most active drugs against breast cancer, doxorubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), with cyclophosphamide, and delivered four cycles of these drugs with peripheral blood progenitor cells (PBPCs) and granulocyte colony-stimulating factor support in an outpatient setting. Patients with untreated metastatic breast cancer received two cycles of doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2. During recovery from the second cycle, PBPCs were harvested. Responding patients were then admitted for a day to receive escalating-dose doxorubicin, paclitaxel, and cyclophosphamide followed by PBPC reinfusion on day 3 as outpatients. Seventeen patients have been enrolled to date. Ten patients completed treatment and received 34 cycles of high-dose chemotherapy every 21 days (range, 21 to 28 days). The median age was 47 years (range, 26 to 56 years) and the median number of metastatic sites was two (range, one to three). Five patients had received adjuvant chemotherapy (four cyclophosphamide/methotrexate/5-fluorouracil and one mitoxantrone-based). The most common toxic reactions were nausea and vomiting (75% of courses) and neurosensory (50% of courses). No patients had a decreased ejection fraction or overt congestive heart failure. Ten patients underwent cardiac biopsy (median doxorubicin, 253 mg/m2; range, 120 to 312 mg/m2); only one showed grade 1 cytotoxic changes with doxorubicin 240 mg/ m2. Six patients were admitted for neutropenic fever. Eight of 10 patients responded (two pathologically confirmed complete remissions in liver). At these doses, four cycles of doxorubicin, paclitaxel, and cyclophosphamide with PBPC and granulocyte colony-stimulating factor support every 21 days was well tolerated and showed evidence of activity. Enrollment at higher dose levels continues so that maximum tolerated dose can be defined.

Adult↗
PubMed1997

Remission of refractory gestational trophoblastic disease in the brain with ifosfamide, carboplatin, and etoposide (ICE): first report and review of literature.

Gestational trophoblastic disease (GTD) metastatic to the brain has a very poor prognosis with a survival rate of less than 25%, especially for patients in whom brain metastases develop while on or after chemotherapy. Cure can be achieved by chemotherapy alone. The regimen of etoposide, methotrexate, actinomycin-D, vincristine, and cyclophosphamide has shown encouraging results and is considered to be standard first-line treatment for high risk patients. For patients in whom this regimen fails, a salvage chemotherapy regimen is used. The combination of ifosfamide, carboplatin, and etoposide (ICE) has synergistic activity in preclinical studies. This regimen has shown activity in metastatic breast cancer and non-small-cell lung cancer as well as platinum-resistant germ-cell tumors and metastatic GTD. This is the first report of a patient with a highly refractory GTD in whom brain metastasis developed while on chemotherapy, and whose brain metastasis went into remission with a low dose ICE regimen. Accordingly, ICE may be considered for patients with chemotherapy refractory GTD metastatic to the brain.

Adult↗
PubMed1997

Activity of interleukin-2 in non-Hodgkin's lymphoma following transplantation of interleukin-2-activated autologous bone marrow or stem cells.

PURPOSE: Disease recurrence constitutes the major cause of treatment failure following autologous transplantation for non-Hodgkin's lymphoma (NHL). Preclinical models indicate that bone marrow or stem cells that have been exposed to recombinant interleukin-2 (rIL-2) can be immunologically purged of chemotherapy-resistant malignant cells while retaining their proliferative potential. Continued treatment with rIL-2 in the posttransplantation period may further enhance the antitumor effect. We review here a phase I clinical study conducted to address the feasibility of this immunotherapeutic approach for reducing the relapse rate following autologous transplantation. PATIENTS AND METHODS: We have performed a phase I clinical trial of rIL-2-treated autologous bone marrow or stem cell transplantation for patients who had hematologic malignancies with poor prognoses. Conditioning for lymphoma patients consisted of thiotepa (250 mg/m2/day x 3 days), busulfan (1 mg/kg orally every 6 hours for 3 days), and cyclophosphamide (60 mg/kg/day x 2 days). Autologous bone marrow or granulocyte colony-stimulating factor (G-CSF) -mobilized autologous stem cells were thawed and exposed for 24 hours to rIL-2 (6000 IU/mL). Posttransplantation rIL-2 therapy (1-2 MIU/m2/day) was administered by continuous infusion from day 1 for a minimum of 21 days. Subsequently, all patients were to receive six cycles of maintenance rIL-2 (6 MIU/m2/day) for 5 days per week in weeks 1 and 2 every 28 days. Patients also received G-CSF (5 micrograms/kg) from day 1 until neutrophil recovery. Twenty-eight patients were accrued, of whom 19 had recurrent or refractory NHL. The median age of NHL patients was 33 years (range, 17-48 years). Seventeen patients had intermediate-grade lymphoma and two had high-grade lymphoma. Five patients received bone marrow, 10 patients received peripheral blood stem cells (PBSC), and four patients received a combination of PBSC and bone marrow. RESULTS: All patients engrafted. The median time to reach a granulocyte count of 0.5 x 10(9) cells/L was 11 days (range, 8-41 days). The median time to reach a platelet count of 50 x 10(9) cells/L was 34 days (range, 9-242 days). The most common dose-limiting toxicities associated with posttransplantation and maintenance rIL-2 therapy were fever, fatigue, and nausea. Among 19 NHL patients, eight patients have developed progressive disease and two patients have died from bilateral pneumonia or radiation-induced cardiomyopathy. Nine patients (47%) remain disease free with a median follow-up of 225 days (range, 150-948 days). CONCLUSION: These data indicate the feasibility of transplanting rIL-2-activated bone marrow or stem cells followed by posttransplantation immunotherapy in patients with advanced NHL. The potential antitumor efficacy of this approach is undergoing further evaluation in a prospective phase II trial.

Adult↗
PubMed1996

Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus.

We have evaluated the use of blood stem cell grafts for rapid hematopoietic recovery and tacrolimus (FK506) as GVHD prophylaxis to reduce early mortality after allogeneic transplantation. Eighty-five adults with advanced leukemia received high-dose thiotepa, busulfan, and cyclophosphamide as a preparative regimen in a prospective Phase II study. All donors were HLA-matched and related. Marrow (BMT) was used for 44 patients and filgrastim-mobilized blood stem cells (SCT) for 41 patients. GVHD prophylaxis consisted of cyclosporine (CsA) or FK506 with methotrexate (MTX) or methylprednisolone (MP). The median time to neutrophil recovery was earlier after SCT than after BMT (day 10 vs. 17, P<0.001), but this was due to the selective use of MTX only in the BMT patients. The risk of grades 2-4 GVHD was lower with FK506 than with CsA (16% vs. 45%, P=0.02) and was the same for SCT recipients as for BMT recipients (33% vs. 34%). Regimen-related toxicity was significantly lower after SCT than after BMT but did not differ between the FK506 and CsA patients. In comparison with those receiving the standard transplant (BMT with CsA and MTX), only the SCT recipients using FK506 and MP had a significantly higher survival at day 180 posttransplant (84% vs. 53%, P=0.014). In multivariate analyses, use of FK506 was associated with a lower risk of treatment-related mortality and a higher survival at day 180, while the diagnosis of acute lymphoblastic leukemia was associated with a higher risk of treatment-related mortality. These data suggest that the use of blood stem cell grafts and FK506 can reduce the early mortality after allogeneic transplantation for advanced leukemia.

Adolescent↗
PubMed1996

Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation.

Thirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (i.v.) by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3-4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last i.v. dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.

Actuarial Analysis↗
PubMed1996

A clinical phase I/II study of recombinant human interleukin-1 receptor in glucocorticoid-resistant graft-versus-host disease.

Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation. GVHD is accompanied by the release of inflammatory cytokines, including interleukin (IL)-1, and previous work has demonstrated that IL-1 participates in the pathogenesis of GVHD. The recombinant human IL-1 receptor (rhuIL-1R) is the soluble form of the type I IL-1 receptor that can bind to IL-1 and prevent cellular activation. We report a phase I/II trial utilizing the rhuIL-1R in the treatment of allogeneic bone narrow transplant patients not improving with glucocorticoid therapy. RhuIL-R was given at four dose levels for 21 days to 14 patients with progressive or persistent acute GVHD. The study drug had no clinical or persistent hematopoiesis and the treatment was tolerated by patients without toxicity at all dose levels. Eight of 14 patients (57%) had an improvement of GVHD after rhuIL-1R therapy. Improvement in GVHD was noted at each dose level, although a dose-response effect for rhuIL-1R treatment was not observed. This work supports the concept that IL-1 plays a role in the inflammation associated with acute GVHD. A controlled study of the rhuIL-1R for treatment of prophylaxis of GVHD is warranted.

Adult↗
PubMed1996

Peripheral blood progenitor cell transplantation: a replacement for marrow auto- or allografts.

Circulating hematopoietic progenitor cells include pluripotent stem cells expressing indefinite self-renewal capacity and, therefore, can be used for restoring hematopoiesis following myeloablative treatment. A transient shifting of progenitor cells from extravascular sites into the circulation by chemopriming and/or cytokine treatment enables the collection by apheresis of a sufficient number of progenitor cells to guarantee engraftment. The addition of new cytokines (e.g., thrombopoietin) and large volume apheresis will increase peripheral blood progenitor cell (PBPC) procurement efficiency, whereas the risk of concurrently mobilizing clonogenic tumor cells in patients with solid tumors and hematologic malignancies remains to be carefully evaluated. As compared with bone marrow (BM) progenitor cells, the use of PBPCs significantly shortens the recovery of WBC and platelets following transplantation. Most recently, successful allogeneic transplantation of PBPCs has been reported without increasing the incidence and severity of acute graft-versus-host-disease. Due to the more than one log higher number of lymphoid subsets contained in a PBPC allograft, one might expect a more pronounced graft-versus-leukemia effect in the transplant patient. Similar to BM cells, ex vivo manipulation of mobilized apheresis products is used or being developed (ultralight density percoll gradient, CD8 depletion, selection of graft facilitating cells, CD34+ cell purification and others). The transduction and long-term expression of marker genes and, most recently, therapeutic genes (e.g., MDR-1) in PBPCs have been successfully demonstrated by several groups in patients with hematologic malignancies and selected solid tumors. It is expected that, based on the easier procurement of hematopoietic stem cells and advantageous engraftment characteristics, PBPCs in both autologous and allogeneic transplant situations will eventually replace BM-derived progenitor cells.

Animals↗
PubMed1996

Allogeneic bone marrow transplantation for poor-prognosis lymphoma: response, toxicity and survival depend on disease histology.

PURPOSE: To evaluate outcomes and identify prognostic factors in allogeneic bone marrow transplantation in patients with end-stage lymphoma. PATIENTS AND METHODS: Data were retrospectively analyzed of 64 patients (42 men and 22 women) 18 to 48 years of age with recurrent or refractory lymphoma who underwent allogeneic bone marrow transplantation from matched sibling donors (or in 1 case from a one antigen-mismatched relative) between May 1981 and July 1994. RESULTS: Twelve patients survived free of disease. They were 8 of 15 with low-grade lymphoma (disease-free survival at 2 years 59% +/- 13%); 3 of 25 with lymphoblastic lymphoma (disease-free survival 17% +/- 8%); and 1 of 10 with diffuse small non-cleaved cell lymphoma (disease-free (10% +/- 9%). Survival and disease-free survival of patients with low-grade lymphoma were significantly superior compared to any other subgroup of patients (P <0.01). Only 2 patients with low-grade lymphoma had disease progression (9% +/- 9% actuarial risk at 2 years) as opposed to 5 of 15 with intermediate-grade lymphoma (39% +/- 14%), 9 of 25 with lymphoblastic lymphoma (28% +/- 9%), and 8 of 10 (80% +/- 13%) with diffuse small non-cleaved lymphoma. The actuarial risk for disease progression was significantly lower for patients with low-grade lymphoma than for any other histologic subgroup (P <0.02). It was significantly higher for those with diffuse small non-cleaved cell lymphoma than for other histologic subgroups (P < or = 0.003). CONCLUSIONS: Allogeneic bone marrow transplantation is an effective procedure in patients with refractory low-grade lymphoma. It results in long-term remissions and should be considered in younger patients with recurrent disease who have a matched sibling donor. The late recurrence in 1 patient indicates the necessity of continued follow-up. A small fraction of patients with end-stage intermediate- and high-grade lymphoma can obtain prolonged disease-free survival, but recurrence and regimen-related toxicity remain major problems. The results could be improved by the development of conditioning regimens with less toxicity and by the use of bone marrow transplantation earlier in the course of the disease.

Adolescent↗
PubMed1996

Use of minors as bone marrow donors: current attitude and management. A survey of 56 pediatric transplantation centers.

OBJECTIVE: To determine the current attitude about the use of minors as bone marrow donors in pediatric bone marrow transplantation (BMT) centers in North America. STUDY DESIGN: A questionnaire was mailed to 70 North American BMT centers. The questionnaire asked for opinions on a number of ethical and clinical issues pertaining to the use of minors as marrow donors. A case history was included and respondents were asked to check all appropriate answers listed in the survey. RESULTS: Fifty-six (80%) of 70 centers responded. There was general consensus on many issues. Pediatricians endorse the validity of parental consent, even in potentially controversial situations. Most are prepared to extract marrow from young (about 6 months of age) infants and are willing to use the same donor more than once. There is general approval of performing BMT with experimental protocols, and the projected outcome of BMT does not affect the decision to use a minor as a marrow donor. There is less consensus regarding the optimal management of minors donating a large volume of bone marrow. CONCLUSION: This survey shows a fairly consistent attitude among pediatric BMT centers about the use of minors as marrow donors. The actual management of such donors was not evaluated in detail and requires further study.

Adolescent↗
PubMed1996

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.

Adult↗
PubMed1996

Transient neutropenia in normal donors after G-CSF mobilization and stem cell apheresis.

Thirteen normal adult donors underwent daily leukapheresis for peripheral blood progenitor cell collection for allografting beginning on day 4 or 5 of G-CSF mobilization (12 micrograms/kg/d). They had complete blood counts performed 7-10 d after the completion of the procedure. A reduction in the total leucocyte count below baseline levels, accounted for by a decrease in the absolute neutrophil (ANC) and lymphocyte counts, was noted. Neutropenia (ANC < 1.5 x 10(9)/l) occurred in two (15%) of the donors. The lowest ANC observed was 0.6 x 10(9)/l. The neutropenia was asymptomatic and resolved on follow-up evaluation.

Adolescent↗
PubMed1996

Clinical toxicity and laboratory effects of granulocyte-colony-stimulating factor (filgrastim) mobilization and blood stem cell apheresis from normal donors, and analysis of charges for the procedures.

BACKGROUND: Apheresis of granulocyte-colony-stimulating factor (filgrastim)-mobilized blood stem cells from normal donors is now being used in place of a marrow harvest in transplantation. How the adverse effects of and charges for this procedure compare with those of the standard marrow harvest is not known. STUDY DESIGN AND METHODS: Forty consecutive normal subjects who received filgrastim 96 micrograms/kg) subcutaneously twice daily for 4 to 6 days in preparation for apheresis were monitored prospectively by clinical and laboratory evaluation. RESULTS: Sixty-two percent of the subjects required oral analgesics. None discontinued filgrastim prematurely. Bone pain (82%), headache (70%), fatigue (20%), and nausea (10%) were reported. Filgrastim caused a mean eightfold increase in neutrophil counts, a mean twofold increase in lymphocyte counts, a mean twofold rise in alkaline phosphatase and lactate dehydrogenase levels, and minor changes in serum potassium, magnesium, and uric acid. Adverse events and laboratory effects resolved within 7 days after apheresis. No apheresis stem cell donor required transfusion or hospitalization, and only one required an additional clinic visit after completion of apheresis. By comparison, a retrospective analysis of 33 normal marrow donors demonstrated that all received transfusion(s), 3 were hospitalized, 3 required additional clinic visits after the marrow harvest. The median total charges related to the two procedures were comparable (p = 0.43), although the charges were significantly lower for donors requiring only one apheresis procedure (p = 0.002). CONCLUSION: Filgrastim mobilization and apheresis of blood stem cells constitute a safe, well-tolerated, and comparable or less expensive alternative to the traditional marrow harvest.

Adolescent↗
PubMed1996

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).

Antigens, CD34↗