Biomedical subjects

G L Phillips

Publications and source records attributed to G L Phillips.

At least 37 records · Page 2Linked to original sources

PubMed1999

Granulocyte-colony stimulating factor (G-CSF)-primed, delayed marrow harvests as a source of hematopoietic stem and progenitor cells for allogeneic transplantation.

We evaluated the ability of G-CSF to increase the number of hematopoietic stem cells obtained by "delayed" BM harvest for allogeneic transplantation. Five normal donors received G-CSF @ 10 mcg/kg/day x 5 followed by repeat PB and BM assays at day 6 and 16, and BM harvest at day 16. Stem cells were not increased in the BM at day 16. Five patients underwent BMT and engrafted at +10 to +19 days. While the tested strategy offers no intrinsic advantages, its potential cannot be evaluated fully without alternative timing and/or additional, "early acting" growth factors.

Blood Donors↗

PubMed1998

A phase II study of BTI-322, a monoclonal anti-CD2 antibody, for treatment of steroid-resistant acute graft-versus-host disease.

BTI-322, a rat monoclonal IgG2b directed against the CD2 antigen on T cells and natural killer (NK) cells, blocks primary and memory alloantigen proliferative responses in vitro. We have evaluated the pharmacokinetics and safety of BTI-322 during treatment of 20 transplant recipients with steroid-refractory acute graft-versus-host disease (GVHD). Treatment consisted of BTI-322 by intravenous (IV) bolus or 30-minute infusion at approximately 0.1 mg/kg/d for 10 days in addition to continuing high-dose steroids and tacrolimus or cyclosporine. Pharmacokinetic sampling was performed in 10 patients; the t1/2 +/- SE was 9.1 +/- 1.3 hours, the Cmax was 2,549 +/- 291 ng/mL, the Vd was 3.97 +/- 0.95 L, and the Vd/kg was 0. 05 +/- 0.01 L/kg. Ten patients experienced transient dyspnea sometimes accompanied by nausea, vomiting, diarrhea, and tachycardia shortly after the initial bolus dose of drug, but serious drug-related adverse events were not seen during the remainder of the infusions. At the end of treatment (day 11), there were six patients with complete responses and five with a reduction in grade of GVHD for a total response rate of 55% (95% confidence interval [CI], 32% to 77%). Antibodies targeting CD2 may be active in the treatment of acute GVHD, and evaluation of a humanized form of BTI-322 is warranted.

Adult↗

PubMed1998

Allogeneic bone marrow transplantation for low-grade lymphoma.

Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS >/=90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare.

Adolescent↗

PubMed1998

Autologous CD34+ cell transplantation for patients with advanced lymphoma: effects of overnight storage on peripheral blood progenitor cell enrichment and engraftment.

In order to demonstrate the feasibility of mobilization, enrichment and engraftment of autologous peripheral blood CD34+ cells in patients with relapsed lymphoma, 59 peripheral blood progenitor cell (PBPC) collections from 21 patients were enriched for CD34+ cells using CEPRATE SC (CellPro, Bothell, WA, USA) immunoaffinity column. Following high-dose chemotherapy, a mean of 17 x 10(8) (range, 3-34) nucleated cells/kg containing 8.7 x 10(6) (0.3-26) CD34+ cells/kg were re-infused. Blood cell recovery in these patients was compared to engraftment capacity of unenriched PBPCs in a cohort of lymphoma patients treated with an identical high-dose chemotherapy regimen. Neutrophil and platelet engraftment was rapid in both groups including five patients who received < or = 1 x 10(6) CD34+ cells/kg. After infusion of CD34+ enriched cells, neutrophils exceeded 0.5 x 10(9)/l in 11 (8-14) days and platelets exceeded 20 x 10(9)/l (untransfused) in 15 (9-39) days. In order to optimize the immunoaffinity column utilization we stored the first PBPC collections overnight at 4 degrees C and combined them with the next day's collection prior to the CD34+ enrichment procedure in 11 patients. This maneuver resulted in a significant decrease in the CD34+ cell recovery (resulting in reinfusion of a mean of 42% less CD34+ cells). Although overnight storage did not affect neutrophil engraftment, platelet engraftment was prolonged in this group of patients even when > 2.0 x 10(6) CD34+ cells/kg were re-infused. The overnight storage procedure should be further evaluated for its effects on the CD34+ immunoaffinity enrichment procedure, megakaryocyte progenitors and platelet engraftment. We conclude that CD34+ cells enriched from peripheral blood result in rapid engraftment after high-dose chemotherapy in patients with advanced lymphoma that is comparable to that of patients receiving unenriched PBPCs.

Adult↗

PubMed1998

Admission of bone marrow transplant recipients to the intensive care unit: outcome, survival and prognostic factors.

The role of ICU support in BMT patients is controversial. In an era of constrained resources, the use of prognostic factors predicting outcome may be helpful in identifying patients who are most likely (or unlikely) to benefit from this intervention. We attempted to define the survival of patients admitted to ICU following autologous or allogeneic BMT and to identify those factors important in determining patient outcome. A retrospective study of all adult BMT recipients admitted to intensive care over a 6 year study period was performed to determine overall and prognostic indicators of poor outcome. Pre-treatment, pre-ICU admission and ICU admission data were analyzed to identify factors predicting long-term survival. 116 patients were admitted to ICU on 135 separate occasions with the primary reasons for admission being respiratory failure (66%), sepsis associated with hypotension (10%), and cardiorespiratory failure (8%). No pre-ICU characteristics were predictive of survival. Univariate analysis identified the number of support measures required, the need for ventilation or hemodynamic support, the APACHE II score, the year of ICU admission and the serum bilirubin as significant predictors of post-discharge survival. On multivariate analysis the year of ICU admission, the need for hemodynamic support and the serum bilirubin remained significant. The APACHE II score significantly underestimated survival in the 46% of patients with scores less than 35, and could only be used to predict 100% mortality when it exceeded 45. Twenty-three percent of all BMT patients admitted to the ICU and 17% of ventilated patients survived to hospital discharge. Of the 27 patients surviving to leave hospital, 16 remain alive with a median follow-up of 4.2 years and a mean Karnofsky performance status of 90. Although mortality in BMT recipients admitted to ICU is high our results indicate that intensive care support can be lifesaving and that the outcome in patients requiring ventilation and ICU support may not be as poor as has been previously reported. No single variable was identified which could be used to predict futility but patients requiring both hemodynamic support and mechanical ventilation, and those with an APACHE II score greater than 45 have a very poor prognosis and are unlikely to benefit from lengthy ICU support.

Adolescent↗

PubMed1998

Delphi-panel analysis of appropriateness of high-dose chemotherapy and blood cell or bone marrow autotransplants in diffuse large-cell lymphoma.

Although high-dose chemotherapy and a blood cell or bone marrow autotransplant are commonly used to treat people with diffuse large-cell lymphoma, there is controversy whether this is better than conventional-dose chemotherapy. Subject-selection and time-to-treatment biases preclude comparison of data from uncontrolled trials and there are few date from randomized trials. We used a Delphi-panel group judgment process to determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow transplant. Results were compared to those of randomized trials. Nine lymphoma experts from diverse geographic sites and practice settings were panelists. Boolean MEDLINE searches of lymphoma and chemotherapy and an autotransplant formed the dataset. Panelists were asked to rate appropriateness of high-dose chemotherapy and an autotransplant compared to conventional-dose chemotherapy. Clinical variables were permuted to define 80 clinical settings rated by the panelists on a 9-point ordinal scale. Results were used to determine an appropriateness index reflecting the mean and distribution of ratings. The relationship of appropriateness indices to permuted clinical variables was considered by analysis of variance and recursive partitioning. In people with initial diffuse large-cell lymphoma, autotransplants were never rated appropriate. They were rated uncertain in all settings except in people never receiving chemotherapy and in those with a complete response to chemotherapy and an international prognostic index < 3, where they were rated inappropriate. In people with recurrent lymphoma, autotransplants were rated appropriate in those with a complete or partial response to chemotherapy, uncertain in those with a less than partial response and in those not receiving re-induction chemotherapy and inappropriate in people with CNS lymphoma. These conclusions agree with results of randomized trials.

Aged↗

PubMed1997

Treatment of leukemia with partially matched related bone marrow transplantation.

The results of partially matched related donor (PMRD) marrow transplantation for 82 patients with leukemia are reported, including 45 who received two antigen disparate grafts. Following intensive radiochemotherapy, patients received grafts which were partially depleted of T cells by the monoclonal antibody T10B9 and complement. Actuarial probability of engraftment was 86% (95% CI = 78-93%). The median day to engraftment was similar among recipients of grafts disparate at one, two or three antigen loci. The incidence of severe (grades III and IV) acute graft-versus-host disease and extensive chronic graft-versus-host disease was 13% and 6%, respectively. The probability of disease-free survival for the entire cohort of patients is 31% at 3 years. Age < or = 30 years, early or intermediate stage disease and a graft disparate at one or two loci predicted longer disease-free survival in multivariant analysis. Moreover, 47% of patients receiving PMRD grafts disparate at two loci who had both these favorable pretransplant characteristics were alive and free of disease 3 years after transplantation. We believe that the utilization of PMRDs, especially those with two antigen disparate grafts, can extend allogeneic transplantation to additional leukemic patients lacking a histocompatible donor, with acceptable results.

Acute Disease↗

PubMed1997

A randomized phase II study of BB-10010: a variant of human macrophage inflammatory protein-1alpha for patients receiving high-dose etoposide and cyclophosphamide for malignant lymphoma and breast cancer.

Macrophage inflammatory protein-1alpha (MIP-1alpha) is a chemokine that can inhibit the cell cycle progression of both primitive haemopoietic and epidermal progenitor cells. This property could potentially be exploited to attenuate both the myelosuppressive effects of chemotherapy as well as mucositis. We evaluated both the biological and clinical effects of BB-10010, a genetically engineered variant of MIP-1alpha, in patients with malignant lymphoma or breast cancer receiving high-dose etoposide (VP 3.6 g/m2) and cyclophosphamide (Cy 200 mg/kg). 52 patients were randomized to one of three cohorts. Cohort A received no BB-10010; cohorts B and C received 10 microg/kg and 100 microg/kg of BB-10010, respectively. All patients received post-chemotherapy G-CSE BB-10010 was well tolerated. There were no significant differences between groups in recovery to an ANC > 0.5 x 10(9)/l, 1 x 10(9)/l or 1.5 x 10(9)/l, the number of days with an ANC < 0.5 x 10(9)/l, days to a platelet count > 50 x 10(9)/l or 100 x 10(9)/l, or the incidence and severity of mucositis. There was no evidence of any effect of BB-10010 on colony-forming cell (CFC) or long-term culture-initiating cell (LTC-IC) mobilization, cycling activity in the marrow or on chemotherapy-induced changes in CFC or LTC-IC number both of which were in the normal range by 22 d after completion of the chemotherapy. To our knowledge this is the first report of a myelointensive regimen having no apparent long-term effect on the LTC-IC compartment. In summary, BB-10010 is safe when used in patients receiving high-dose therapy but has no effect on reducing the toxicity of such therapy.

Adolescent↗

PubMed1997

The use of conventional salvage chemotherapy before dose-intensive cytotoxic therapy and autologous transplantation for aggressive-histology lymphoma: a case for re-evaluation.

The use of CSCT to judge suitability for DIT and AHSCT in patients with aggressive-histology lymphoma who recur after primary chemotherapy is a widespread practice that excludes many NHL patients from this potentially curative therapy. Surprisingly, little direct evidence exists to suggest that CSCT used in this way is a useful strategy. On the other hand, it is clear that many of these patients undergoing DIT and AHSCT will not be cured using any currently available strategy or technique, and a method to identify such patients would be most helpful. CSCT may or may not be the best way to do so. This is an important question, but currently there are insufficient data to give us a definitive answer. Clinical trials are needed to resolve the issue. If the utility of CSCT is not validated, it should be abandoned. If it is validated, however, we may begin to address ways in which CSCT may be given more effectively.

Antineoplastic Agents↗

PubMed1997

Induction failure in de novo acute myelogenous leukemia is associated with expression of high levels of CD34 antigen by the leukemic blasts.

The prognostic significance of CD34 antigen expression in acute myelogenous leukemia (AML) is controversial. Most studies to date have reported on CD34 positivity and not the level of antigen present. In this study of 62 patients with de novo AML, 48 (77%) patients were CD34+ in varying levels (0-85 mean channels of fluorescence (MCF)). Forty seven of 62 were treated with combination chemotherapy and 39 (83%) of them achieved complete remission (CR). Patients with CD34- blasts were more likely to achieve CR; however, this trend was not statistically significant (p = .11). On the other hand, patients with higher levels of CD34 antigen on the blasts were less likely to attain CR (p < 0.001, multivariate analysis). The patients who achieved CR expressed lower levels of CD34 (0-57; median 9 MCF) as compared to those who did not achieve CR (15-85; median 30 MCF). Of the other antigens tested, partial or complete absence of CD33 (CD33 absent in > or =25% blasts) correlated with failure to achieve CR (p = 0.0029). These results are in keeping with the hypothesis that more primitive AML blasts with high levels of CD34 are chemoresistant.

Adult↗

PubMed1996

Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease.

PURPOSE: To determine the outcome of HLA-identical sibling bone marrow transplants in advanced Hodgkin's disease. PATIENTS AND METHODS: We reviewed the data on 100 consecutive patients with Hodgkin's disease who received HLA-identical sibling bone marrow transplants between April 1, 1982 and August 12, 1992, reported to the International Bone Marrow Transplant Registry (IBMTR). The median interval from diagnosis to transplant was 2.5 years (range, < 1 to 14). All had advanced disease. Eighty-nine of 100 patients were not in remission at the time of transplant. Fifty had pretransplant Karnofsky scores less than 90% and 27 had active infection in the week before transplant. Patients received a variety of conditioning regimens; 45 received total-body radiation. RESULTS: The 100-day probability of acute graft-versus-host disease (GVHD) was 35% (95% confidence interval [CI], 26% to 46%); the 3-year probability of chronic GVHD was 45% (95% CI, 31% to 59%). The 3-year probability of relapse was 65% (95% CI, 50% to 78%). The 3-year probability of survival was 21% (95% CI, 14% to 30%). The 3-year disease-free survival rate was 15% (95% CI, 9% to 24%). CONCLUSION: HLA-identical sibling bone marrow transplants have a limited role in advanced Hodgkin's disease.

Adolescent↗

PubMed1996

Intensive therapy and autologous stem cell transplantation for Hodgkin's disease in first relapse after combination chemotherapy.

Data from a number of transplant centers has shown that several intensive therapy regimens, supported by autologous stem cell transplantation, have the capability to produce durable responses in a proportion of patients with Hodgkin's disease progressive after combination chemotherapy. Although many questions regarding the optimal use of autotransplantation remain unanswered, the issue of the preferred timing at which to apply transplantation is of critical importance in planning therapeutic strategies for patients with this disease. This paper will focus on the timing options for autotransplantation in Hodgkin's disease. In the absence of a formal Phase III study comparing conventional salvage therapy versus autotransplantation in first relapse patients, the encouraging results from our center and others support the use of transplantation at the time of first relapse after combination chemotherapy. Non-relapse mortality is low in this setting, and the primary problem has been recurrent disease despite transplantation. Risk factors for both disease recurrence, as well as for the probability of progression-free survival, can be defined based on biologic features present at the time of first relapse after chemotherapy, and may provide a basis for improving the current transplant results for first relapse patients. Prolonged follow-up will be important to define the incidence and risk of late toxicities in autografted patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Criteria for marrow engraftment: comparison of reticulocyte maturity index with conventional parameters.

Reticulocyte maturity index (RMI) has recently been proposed as an early indicator of marrow engraftment. We compared the RMI with conventional bone marrow engraftment criteria including total leukocyte count (WBC), absolute neutrophil count (ANC), reticulocyte count (RC) and the day of last platelet transfusion required to maintain the platelet count (PC) > or = 20 x 10(9)/l in 37 patients undergoing allo- or autologous BMT. There was no discrepancy in predicting engraftment between RMI, ANC, WBC and RC. RMI indicated engraftment earlier (median day 17, range 10-63 days) than the ANC (median day 19, range 8-63 days), WBC (median day 19, 9-71), RC (median day 19, 11-125) or PC (median day 29, 11-237). RMI heralded engraftment preceded ANC, WBC, RC or PC in 22, 21, 34 and 32 patients, respectively. RMI signal occurred 6 days prior to the rise in ANC in patients who engrafted later than 25 days (n = 7). Trend analysis showed that ANC fluctuated more frequently (6/37 patients) than RMI (1/37). Combined use of ANC and RMI (whichever increased first) predicted engraftment earlier (median 15 days) and more confidently (no false starts) than either used alone.

Bone Marrow Transplantation↗

PubMed1996

Successful paternity of twins following bone marrow transplantation with busulfan, melphalan and cyclophosphamide conditioning.

A 33-year-old man who had received previous chemotherapy with cytarabine, daunorubicin and mitoxantrone followed by an autologous marrow transplant after conditioning with busulfan, melphalan and cyclophosphamide, fathered sex-mismatched fraternal twins approximately 6 years post-transplant. HLA and DNA analyses showed the probability of paternity to be in excess of 99% for each twin. To our knowledge this represents the first documented case of paternity following conditioning with this combination of marrow ablative agents and the first report of twin paternity following autologous marrow transplantation.

Adult↗

PubMed1996

Utility of DRB1 subtyping: a case report.

The purpose of presenting this case is to illustrate the importance of high-resolution DNA Class 2 typing when assignment of MHC antigens is of extreme importance (i.e. bone marrow transplantation); suggest this test as a substitute for the mixed lymphocyte culture (MLC), and provide evidence that DRB1 subtype mismatches may be clinically significant. Initial serological and monoclonal HLA Class 1 and low-resolution DNA-SSP Class 2 typing of a potential bone marrow transplant patient and two sisters revealed all to be HLA identical with apparent homozygosity for DRB1 x 04. High-resolution DNA-SSP Class 2 typing was then performed and revealed electrophoretic banding patterns which were not specific for any DRB1 x 04 subtype. One sister and the patient had identical patterns, while the other sister had a different pattern. Complete HLA Class 1 and high-resolution DNA-SSP Class 2 typing of the parents was performed. The mother was found to be heterozygous for Class 1 and Class 2 antigens and possess the DRB1 x 0404, 0405 subtypes. In contrast, the father was found to be homozygous for Class 1 antigens, heterozygous for Class 2 antigens and possess the DRB1 x 0404, 0407 subtypes. This led to the initial false assumption of HLA identity for the patient and her two sisters. However, assignment of haplotypes revealed one sister to be HLA identical with the patient and the other sister to be a one-haplotype five-antigen match with the patient, mismatching for one DRB1 allele. Bone-marrow transplantation was performed utilizing the latter sister, which resulted in intractable acute graft vs. host disease that resulted in the patient's demise.

Acute Disease↗

PubMed1995

Lymphocytosis of large granular lymphocytes in patients with Hodgkin's disease.

Clonal disorders of large granular lymphocytes (LGL) of either CD3- (NK cell) or CD 3+ (T-cell) phenotype have been described. B-cell malignancies such as hairy cell leukemia and non-Hodgkin's lymphoma have been observed in association with the T-cell type of LGL leukemia. Here we report the occurrence of LGL lymphocytosis in four patients with Hodgkin's disease. Immunophenotyping studies showed that these LGL were CD 3- in three patients and CD3+ in the other. LGL were polyclonally expanded in both patients in whom clonality could be assessed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Quantitation, mobilization, and clinical use of long-term culture-initiating cells in blood cell autografts.

Mobilized peripheral blood is increasingly used as a source of cells to provide hematopoietic reconstitution in marrow ablated patients. There is controversy as to how the engraftment potential of these preparations should be evaluated. The long-term culture-initiating cell is a very primitive hematopoietic with unique phenotypic feature. The potential role and significance of these cells in peripheral blood cell autografts is discussed.

Animals↗

PubMed1995

Is there a place for immunotherapy with interleukin-2 to prevent relapse after autologous stem cell transplantation for acute leukemia?

Chemotherapy-resistant cells cause disease recurrence in a significant proportion of patients with acute leukemia treated with autologous stem cell transplantation due to the lack of immune-mediated effects which contribute significantly to the prevention of post-treatment disease recurrence. This conclusion is based on the observation that relapse after high dose chemotherapy supported by a stem cell transplant from a twin donor is 3-4 times higher than after transplant from an allogeneic donor. This anti-leukemic mechanism of transplanted donor cells has been termed graft-versus-leukemia (GVL) effect, and efforts are being directed toward utilizing such an immune-mechanism after autologous transplantation. Since interleukin-2 (IL-2) can induce remissions in selected patients with advanced leukemia, it has become a candidate cytokine to be used in attempts to introduce GVL after autologous stem cell transplantation. Here we review the available clinical data with IL-2 and critically evaluate whether IL-2 has a place as adjunct treatment to prevent relapse after autologous transplantation for acute leukemia.

Actuarial Analysis↗