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Biomedical subjects

G L Phillips

Publications and source records attributed to G L Phillips.

At least 109 records · Page 6Linked to original sources
PubMed1991

The use of unrelated donors (UD) for allogeneic bone marrow transplantation (BMT): a pilot study of the Canadian BMT Group.

Thirty-five patients underwent allogeneic bone marrow transplantation (BMT) from unrelated donors (UD), in a pilot study of the Canadian Bone Marrow Transplant Group with techniques routinely used in BMT from HLA-identical related donors. Thirty-two of the patients had hematologic malignancies and 3 had aplastic anemia. Donors and patients were matched at all HLA loci tested serologically in 29 cases; 19 of these patients had mutually non-reactive mixed leukocyte cultures (MLC's). Six patients had some degree of serologic mismatch. Stable engraftment occurred in all but 3 evaluable patients. Acute graft-versus-host disease (GVHD) developed in greater than 80% and fatal BMT-related deaths occurred in a total of 55% of all patients. Conversely, only two relapses have occurred, and the 1-year actuarial event-free survival for all patients is 40% (95% confidence intervals [CI], 24-55%) with a follow-up of 0.8 to 2.7 years. All survivors are out of the hospital and all save 1 have a normal performance status. Our study has confirmed the utility of unrelated donors for allogeneic BMT. Although more complications are seen than with HLA-matched sibling donors, these patients did not have such donors available and virtually all were incurable without transplants. Further studies, especially those using new methods to prevent transplant-related complications, are needed.

Adolescent↗
PubMed1991

Human hematopoietic stem cells in long-term culture: quantitation and manipulation.

These results suggest a potentially important role for the LTC system, not only in the development of a quantitative assay for hematopoietic cells, but also clinically as a procedure for manipulating autologous marrow in culture in a variety of ways for therapeutic advantage. These include strategies for immune modulation, gene marking and gene therapy, and perhaps eventually for stem cell amplification.

Bone Marrow Transplantation↗
PubMed1990

Detection of breakpoint cluster region- negative and nonclonal hematopoiesis in vitro and in vivo after transplantation of cells selected in cultures of chronic myeloid leukemia marrow.

Philadelphia (Ph1) chromosome-positive clonogenic progenitors usually disappear within 4 to 6 weeks in long-term cultures established from the marrow of patients with chronic myeloid leukemia (CML). In contrast, coexisting chromosomally normal hematopoietic cells are relatively well maintained. Thus, even though normal cells are initially undetectable, they may become the predominant population. Recently, we have begun to explore the potential of such cultures as a strategy for preparing CML marrow for autografting, and based on cytogenetic studies of the differential kinetics of Ph1-positive and Ph1-negative clonogenic cells, have chosen a 10-day period in culture to obtain maximal numbers of selectively enriched normal stem cells. Here we present the results of molecular analyses of the cells regenerated in vivo for the initial three CML patients to be treated using this approach by comparison with the differentiated cells generated by continued maintenance of an aliquot of the autograft in vitro (using a slightly modified culture feeding procedure to enhance the production and release of cells into the nonadherent fraction after 4 weeks) for the one patient whose genotype made molecular analysis of clonality status also possible. These analyses showed that cells with a rearranged breakpoint cluster region (BCR) gene were not detectable by Southern blotting in either in vitro or in vivo populations of mature cells that might be assumed to represent the progeny of primitive cells present at the end of the initial 10 days in culture. Production of BCR-negative cells was also shown to be temporally correlated with the appearance of nonclonal hematopoietic cells both in culture and in vivo. These findings provide support for the view that prolonged maintenance of CML marrow cells in long-term culture may allow molecular characterization of both the BCR-genotype and clonality status of cells with in vivo regenerative potential.

Bone Marrow↗
PubMed1990

An overview of bone marrow transplantation for chronic myeloid leukemia.

The use of intensive therapy together with transplantation of marrow from a suitable donor is the only established curative treatment for patients with chronic myeloid leukemia (CML). However, marrow transplantation is hazardous, costly and applicable to relatively few patients. Therefore, we evaluated the results and limitations of marrow transplantation for CML and discussed new treatment strategies. We decided to select a limited number of papers that focused on the relevant issues rather than to undertake an exhaustive comparison of treatment results from different centres. Patients with CML in the chronic phase who receive marrow from a sibling with the same human leukocyte antigen type can expect to have a long-term disease-free survival rate of 50%. However, the procedure is associated with a mortality rate of 30%, mainly because of graft-versus-host disease (GVHD) and interstitial pneumonitis. Moreover, because of the requirements for age and histocompatibility only 10% of patients with chronic-phase CML are currently eligible. Transplantation earlier in the chronic phase (within 1 year after diagnosis), the use of marrow from matched, unrelated donors and the development of improved methods for reducing the incidence of GVHD all hold promise. In addition, the preliminary results of intensive therapy followed by transplantation with cultured autologous marrow have been encouraging. If further progress is to be made, continued optimism coupled with carefully developed and executed studies will be necessary.

Bone Marrow Transplantation↗
PubMed1990

Use of an anti-pan T-lymphocyte ricin a chain immunotoxin in steroid-resistant acute graft-versus-host disease.

Acute steroid-resistant graft-versus-host disease (AGVHD) after allogeneic bone marrow transplantation is frequently fatal. A new treatment for this T-lymphocyte-mediated condition uses an immunotoxin, H65-RTA, comprised of a monoclonal antibody that recognizes the CD5 lymphocyte differentiation antigen coupled to ricin A chain, a cytotoxic enzyme that inhibits protein synthesis. The safety and efficacy of this lymphocyte-targeted immunotoxin was evaluated in patients with severe AGVHD in a phase I-II dose escalation study with group expansion at the two middle doses. Thirty-four patients received up to 14 daily intravenous infusions of the immunotoxin. The principal side effects were constitutional symptoms such as fatigue and myalgias, and hypoalbuminemia with weight gain was seen at all doses. Thirty-two patients were evaluated for improvement or resolution of disease. Durable complete or partial responses were not dose-related and were seen in 16 patients. Skin GVHD had the highest incidence of response (73%), although improvement or resolution in gastrointestinal tract (45%) and liver (28%) GVHD was also noted. Survival in responding patients was significantly prolonged at all times as compared with those with no response (P = .03). Treatment was associated with a rapid decrease in peripheral blood T lymphocytes, which persisted for greater than 1 month after therapy. Anti-immunotoxin antibodies were seen in 6 of the 23 patients tested; these were of low titer and did not block immunotoxin binding to T cells. Results of this study indicate that anti-T-lymphocyte immunotoxins may form a new class of immunosuppressive agents useful in T-lymphocyte-mediated diseases.

Adrenal Cortex Hormones↗
PubMed1990

The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation.

Intensive chemoradiotherapy, with or without additional local radiotherapy, and unpurged autologous marrow transplantation was given to 68 patients with progressive non-Hodgkin's lymphoma. Responses were attained in 44 patients (65%, 95% confidence intervals [CI], 52% to 76%), including 37 who achieved complete responses. Fifteen patients (22%, 95% C.I. 13% to 34%) remain free of disease (including 11 continuously) at a median of 5.3 (range 3.1 to 9.1) years later. Higher Karnofsky scores (P less than .01, Mann-Whitney U test) and the absence of a history of prior radiotherapy (P = .02, chi 2 test) were associated with achievement of complete plus partial responses. Higher Karnofsky scores (P less than .01, Mann-Whitney U test) and less resistant disease status at transplantation (P = .04, chi 2 test) were significant when calculations were limited to complete responses. Karnofsky scores were also associated with the probability of freedom from progression (P = .02, log-rank) for responding patients. Also, Karnofsky scores and the absence of prior radiotherapy (P less than .01 and P = .01, respectively, log-rank) were associated with improved survival. Progressive lymphoma was the chief cause of failure; progression usually occurred less than 6 months after transplantation, most often at the sites of active disease before the transplant. However, five patients (including four with high-grade non-Hodgkin's lymphoma) suffered hematogenous patterns of relapse; four of these five patients had no prior history of marrow involvement. Other causes of mortality included interstitial pneumonitis, sepsis, hemorrhage and renal failure. Intensive chemoradiotherapy and autologous marrow transplantation produces durable remissions in some patients with progressive non-Hodgkin's lymphoma. Since such therapy is more effective when given to patients with signs of less advanced disease, earlier treatment would be the simplest way to produce improved results. However, improved conditioning regimens will also be needed, and measures to reduce occult lymphoma stem cell contamination with the autograft may also be required to increase the likelihood of cure in some patients.

Adolescent↗
PubMed1990

Sudden neurologic death after intrathecal methotrexate.

Methotrexate leukoencephalopathy is a chronic syndrome of ataxia and confusion which may progress to seizures, coma, and death. We report a fatal case of this syndrome in a patient who displayed no evidence of the typical prodrome of neurologic symptoms or signs. This patient suffered brain death after receiving 11 doses of intrathecal methotrexate for leukemic meningitis. Since leukoencephalopathy was not clinically suspected, this case underscores the need for a test that would reliably monitor central nervous system toxicity due to intrathecal therapy.

Adult↗
PubMed1990

Intensive chemotherapy and autologous peripheral blood stem cell transplantation in a patient with persistent marrow involvement with Hodgkin's disease.

A patient with refractory Hodgkin's disease whose persistent, dense marrow infiltration precluded autologous marrow harvest underwent peripheral blood stem cell harvest followed by intensive chemotherapy and re-infusion of the peripheral blood stem cells. Complete remission was followed by relapse 6 months later and death 13 months post-transplant. However, at no time post-transplant was evidence of marrow recurrence demonstrated. This case indicates that remission can be achieved using peripheral blood stem cell transplants despite persistent marrow involvement with Hodgkin's disease.

Adult↗
PubMed1990

Current management of vulvar melanoma.

In the past, minimal recommended therapy for vulvar melanoma was radical vulvectomy with bilateral inguinal-femoral lymphadenectomy, regardless of lesion size, thickness, or depth of invasion. In the last decade, several authors and investigators have questioned the need for radical surgery in all patients and have used a variety of microstaging methods to delineate risk categories for patients with vulvar melanoma. The author discusses non-vulvar cutaneous melanoma as well as vulvar melanoma, and summarizes the current recommendations for management of the latter.

Female↗
PubMed1990

Recombinant GM-CSF in patients with poor graft function after bone marrow transplantation.

Poor graft function after bone marrow transplantation is an infrequent complication that is fatal for most patients secondary to severe infections or to bleeding. Even a second marrow infusion is usually not successful in restoring hematopoiesis. We treated nine patients with recombinant Escherichia coli derived human granulocyte-macrophage colony-stimulating factor (GM-CSF) for delayed engraftment or graft failure after autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). Six patients were given a dose of 10 micrograms/kg/d over 30 min; three patients received lower doses of 3-5 micrograms/kg/d. Seven patients lived longer than 3 days after commencing GM-CSF and could be evaluated for their response. Six of them had a marked rise in neutrophil counts; there was no effect on platelet and reticulocyte counts. Two patients died within the first 3 days after starting GM-CSF, although both seemed to have some response to GM-CSF (increasing blood neutrophils in one, and increasing macrophages in the bone marrow on autopsy in the other). Side effects most likely attributable to GM-CSF administration were mild and included diarrhea and abdominal pain, low grade fever and mild rash. Severity of graft-vs-host disease (GVHD) was not enhanced in the recipients of allogeneic marrow. We conclude that recombinant GM-CSF can be safely given to patients with poor graft function after marrow transplantation. In some patients, this may lead to a subsequently sustained neutrophil recovery.

Adolescent↗
PubMed1990

Autologous bone marrow transplantation for hematologic cancer.

In summary, autologous BMT is emerging as a way to deliver myeloablative therapy to patients with hematologic cancer ineligible for allogeneic BMT. Moreover, there are likely circumstances in which autologous is preferable to allogeneic BMT--most notably in Hodgkin's disease, but likely also in the older adult acute leukemia patient. Work is clearly required to produce upgraded conditioning regimens, and to define the need for and utility of marrow purification procedures. However, these pressing needs should not obscure the benefits of the current use of autologous BMT techniques for selected patients--nor prevent the realization that improved patient selection is the most immediate method to improve current results.

Bone Marrow Transplantation↗
PubMed1990

Use of an immunoglobulin preparation enriched for IgM (Pentaglobin) for the treatment of acute graft-versus-host disease.

Pentaglobin is a commercial immunoglobulin preparation which is enriched specifically for IgM and also contains antibodies that are capable of neutralizing endotoxins. Its potential use in treating patients with acute graft-versus-host disease (GVHD) was studied in a phase I/II study. Pentaglobin was administered at a dose of 8 ml/kg/day for 4 days as a continuous infusion to 10 patients after allogeneic marrow transplantation who had histologically documented moderate grade II (n = 8) or moderately severe acute GVHD grade III (n = 2), and who did not require immediate treatment with steroids. There were no side effects related to the infusion of Pentaglobin and in all cases the serum concentrations of IgA, IgG and IgM at least doubled. Improvement of GVHD was seen in five patients with grade II GVHD. Conversely, in three patients with grade II and two patients with grade III GVHD, the disease either progressed during Pentaglobin infusion and required steroid treatment or showed no change and required steroids later in the course. Pentaglobin, therefore, might have some effect on mild and moderate GVHD. Randomized trials should be able to determine whether Pentaglobin could be considered as part of the GVHD prophylaxis or as adjunct treatment for acute GVHD together with low doses of steroids.

Bone Marrow Transplantation↗
PubMed1989

Clonal hematopoiesis demonstrated by X-linked DNA polymorphisms after allogeneic bone marrow transplantation.

We analyzed DNA from peripheral-blood and marrow cells from 12 recipients of allogeneic bone marrow transplants to determine whether monoclonal but otherwise normal hematopoiesis occurs in such patients. All patients were being treated for various forms of leukemia or lymphoma. In 10 patients, granulocytes isolated from peripheral-blood samples obtained 28 to 159 days after transplantation were polyclonal. In some, circulating T cells were isolated and also found to be polyclonal. In contrast, two patients had donor-derived monoclonal or oligoclonal hematopoiesis after transplantation. In one, DNA from circulating mononuclear cells obtained 29 days after transplantation revealed a monoclonal pattern on analysis of a restriction-fragment-length polymorphism in the phosphoglycerate kinase gene. In the other, analysis of a restriction-fragment-length polymorphism in the hypoxanthine phosphoribosyltransferase gene suggested the presence of a dominant clone in the granulocytes sampled 36 days after transplantation. When the latter patient was reassessed on day 267, the same clone of donor hematopoietic cells was still predominant and was found to include circulating T cells as well as granulocytes. We conclude that monoclonal hematopoiesis of donor origin may be observed in recipients of allogeneic bone marrow transplants, indicating that stem cells in normal adult human marrow are able to repopulate both lymphoid and myeloid compartments after transplantation.

Adolescent↗
PubMed1989

Allogeneic marrow transplantation for refractory Hodgkin's disease.

Eight patients with refractory Hodgkin's disease received intensive combination chemotherapy conditioning with cyclophosphamide, carmustine (BCNU), and etoposide (VP 16-213), and allogeneic marrow transplants. All patients achieved complete responses. Three patients relapsed; two died of Hodgkin's disease and one of chronic graft-v-host disease (GVHD) and infection. In all, four patients died due to transplant-related toxicity. One patient developed a fatal B-cell lymphoproliferative disorder soon after transplantation, and died without evidence of Hodgkin's disease. One patient is alive and free of progression 29 months after transplantation. These data indicate that allogeneic marrow transplantation may be considered as therapy for selected patients with advanced Hodgkin's disease and, despite substantial toxicity, will occasionally result in long-term responses. Better patient selection would likely improve results.

Adolescent↗
PubMed1989

High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: long-term follow-up and results.

In an effort to increase the proportion of patients with acute myeloid leukemia (AML) remaining in continued complete remission (CCR), we administered intensive postremission consolidation therapy with high-dose cytarabine (Ara-C) and daunorubicin. Eighty-seven patients, with a median age of 38 years (range, 7 to 71), received consolidation therapy after first complete remission was obtained with standard induction chemotherapy that included conventional doses of Ara-C. Consolidation therapy consisted of from one to three cycles of high-dose Ara-C (3 g/m2 intravenously [IV] over 1 hour every 12 hours for 12 doses) followed by daunorubicin (30 mg/m2/d IV bolus for 3 days). After completion of the high-dose Ara-C and daunorubicin, no further therapy was administered. Myelosuppression encountered with consolidation resulted in a median duration of neutropenia and thrombocytopenia of 3 weeks. Four patients (5%) died during consolidation due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious or extramedullary organ toxicity. With a median follow-up of more than 3.5 years from diagnosis, the proportion of patients, by Kaplan-Meier product-limit estimate, remaining in CCR is 49% (95% confidence limits, 37% to 61%). In a Cox multivariate analysis, only age significantly (P less than .001) influenced the probability of remaining in CCR. The probability of remaining in CCR was 83%, 50%, and 23% for age groups of 25 or less, 26 to 45, and more than 45 years, respectively. These survival curves all have stable long-term plateaus, suggesting cure. In this study, the administration of brief, intensive nonmarrow ablative chemotherapy resulted in a large proportion of patients with AML remaining in CCR, results similar to those reported with allogeneic bone marrow transplantation. Relapse of acute leukemia was still the major reason for therapy failure, suggesting that more effective or additional postremission therapy will be required to further improve the likelihood of cure especially for older patients.

Adolescent↗