Therapy decisions in leukemia.

Complex factors determine how physicians select between alternative therapies. We conducted a survey of 352 leukemia experts to determine consensus regarding optimal treatment for leukemia and to identify factors correlated with therapy decisions. The study evaluated both general treatment policies and recommendations for specific clinical situations. Responses of chemotherapy, allotransplant and autotransplant experts were compared. Although responses of these groups were similar for general treatment policies, recommendations for specific cases differed substantially. Interestingly, responses of the three groups to some clinical situations also differed from conclusions of several published studies examining these issues. These data suggest that experts may discount published results in favor of personal experiences, perceptions of the best treatment strategy (based on published data or not) or available resources.

Prospective randomised double-blind trial of the in vivo use of recombinant human erythropoietin in bone marrow transplantation from HLA-identical sibling donors. The Australian Bone Marrow Transplant Study Group.

Ninety one patients between the ages of 17 and 58 years undergoing histocompatible allogeneic transplants from sibling donors were entered into a double-blind randomised trial to evaluate the effect of human erythropoietin (rhu EPO) at a dose of 300 units per kg/day given thrice weekly by intravenous injection on erythropoiesis and on erythrocyte and platelet transfusion requirements. Dose was ceased when the haemoglobin exceeded 12g/dL and recommenced if the haemoglobin fell below 12 g/dL, at 150 units/kg/day. If the haemoglobin exceeded 12 g/dL on a further occasion, the dose of rhu EPO was not given. Patients received two units of erythrocytes when the haemoglobin dropped below 8.5g/dL and received platelet transfusions when the count dropped below 20 x 10(9)/L. Univariate analysis revealed a significantly higher reticulocyte count, haemoglobin concentration and bone marrow erythropoiesis after day 14 in the group receiving rhu EPO but this was not reflected in decreased erythrocyte transfusion (7 +/- 5 in controls versus 6 +/- 5 in rhu EPO group) or in platelet transfusions (11 +/- 7 in controls versus 11 +/- 9 in rhu EPO group). Hospitalisation in each group was the same (29 +/- 8 in the control group and 28 +/- 8 in the rhu EPO group). However, in the multivariate analysis, the administration of rhu EPO was associated with an 18% reduction in erythrocyte transfusion requirement when other variables were taken into account. No side-effects due to rhu EPO were detected in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia.

Various isolation strategies are used to prevent infections during bone marrow transplantation; data on their efficacy are lacking. We studied whether use of high efficiency particulate air filtration (HEPA) and/or laminar airflow (LAF) units affect transplant-related mortality (TRM) or survival in the first year after allogeneic transplantation. 5065 patients with leukemia receiving bone marrow transplants from an HLA identical sibling (n = 3982) or alternative related or unrelated donors (n = 1083) between 1988 and 1992 were reported to the International Bone Marrow Transplant Registry by 222 teams. Two types of isolation were considered: (1) conventional protective isolation with single patient room and any combination of hand-washing, gloves, mask and gown; and (2) HEPA and/or LAF. Cox proportional hazards regression models were used to determine the relative risks (RRs) of transplant-related mortality (TRM) and of deaths from any cause in patients treated in HEPA/LAF units compared to patients treated in conventional isolation. HLA-identical sibling and alternative donor transplants were analyzed separately. Risks of TRM and overall mortality in the first 100 days post-transplant were significantly lower among patients treated in HEPA/LAF units than in those treated conventionally. RRs of TRM were 0.76 (P = 0.009) for recipients of HLA-identical sibling transplants and 0.65 (P = 0.003) for recipients of alternative donor transplants. Correspondingly RRs of overall mortality were 0.80 (P = 0.02) and 0.65 (P = 0.0006). Decreased risks of TRM and of death in the first 100 days post-transplant resulted in significantly higher 1-year survival rates in patients treated in HEPA/LAF rather than in conventional isolation units. Use of HEPA and/or LAF to prevent infections decreases TRM and increases survival after allogeneic bone marrow transplants for leukemia.

The potential usefulness of a differentiating teratocarcinoma cell line in in vitro toxicity testing.

A number of in vitro systems have been put forward as potential alternative methods for testing chemicals for teratogenic potential. The most promising of these systems, for example mammalian whole embryo culture and the micromass technique, are currently undergoing further interlaboratory validation. However, such tests involve the use of a considerable number of animals. It was therefore decided to investigate the possible use of a permanent cell line that possessed many of the properties of embryonic cells, that is a differentiating cell line, F9 (derived from a mouse teratocarcinoma), in the development of an in vitro teratogenicity test. In a preliminary study, six chemicals were tested for their modulating effects on differentiation in undifferentiated, differentiating and differentiated F9 cells. These effects were assessed morphologically and by measuring the production of laminin (a biochemial marker of F9 differentiation). The use of the F9 cell line in in vitro teratogenicity testing shows promise, but further work is necessary before its potential can be fully evaluated.

Development of a fixed-dose approach for the fluorescein leakage test.

To answer the question, "How toxic is this material?", rather than the question more usually asked in in vitro toxicology, "At what concentration does this material produce a given degree of toxicity?", a fixed-dose approach has been developed with the FRAME fluorescein leakage (FL) test. Recovery from the initial cytotoxic effect was also noted sometimes, after the cells had been maintained in fresh medium for a further 72 hr. Chemicals rated R41 or R36 in vivo gave a level of FL above 20% immediately, and 66% or more 72 hr later (i.e. there was further deterioration, rather than recovery). Acetaldehyde, when duplicated and tested either in Hanks' balanced salt solution or oil, showed greater toxicity in the oil because of its high volatility. The chemicals classified as no-label gave FL values below 12% immediately after exposure, except Brij-35, which showed no further deterioration during the 72-hr period in fresh medium.

Intravenous cyclosporine for severe attacks of ulcerative colitis: a survey of Canadian gastroenterologists.

UNLABELLED: A single randomized trial evaluated the use of intravenous cyclosporine treatment for severe attacks of ulcerative colitis. The perceived efficacy and safety of this intervention were measured through a survey of the membership of the Canadian Association of Gastroenterology (CAG). METHODS: All CAG members were mailed a survey with questions regarding their familiarity with the data supporting the use of cyclosporine, their perception of the efficacy and toxicity of the drug, and whether patients who fail conventional treatment should receive this therapy. The proportion of respondents who had used cyclosporine to treat severe ulcerative colitis was determined. RESULTS: One hundred and sixty-one responses were received (34% response rate). Sixty-four per cent of respondents were academic faculty members and 82% treated patients with severe colitis. Using multivariate analyses, positive associations were found between the respondents' age (P = 0.004) and subspecialty training in gastroenterology (P = 0.001), and whether respondents treat patients with severe ulcerative colitis. Twenty-six per cent of individuals had prescribed cyclosporine for this indication, of whom 88% were in academic practice (P = 0.007). Over 90% of respondents believe that further clinical trials are needed before cyclosporine becomes accepted as standard therapy. CONCLUSIONS: Although the use of cyclosporine is measurable among Canadian gastroenterologists, the majority believe that further clinical trials are necessary before the drug is accepted as a standard therapy.

Alternatives to ocular irritation testing in animals.

The preliminary conclusions of a survey of possible non-animal alternatives to the Draize rabbit eye irritancy test, recently conducted for the Commission of the European Communities, are presented. The various types of alternatives to animal tests are reviewed in terms of their current state of development and validation, and also their potential in relation to the type of exposure, level of testing, type of testing, type of effect, location of effect, and type of test material. Various problems concerning the availability and quality of in vivo eye irritation data, and the use of this data in in vitro/in vivo comparisons, are highlighted. Finally, the use of step-wise and integrated animal/non-animal and non-animal/non-animal test systems and strategies are discussed.

T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities.

T-cell depletion of donor marrow decreases graft-versus-host disease resulting from transplants from unrelated and human leukocyte antigen (HLA)-mismatched related donors. However, there are diverse strategies for T-cell-depleted transplantation, and it is uncertain whether any improve leukemia-free survival (LFS). To compare strategies for T-cell-depleted alternative donor transplants and to compare T-cell depleted with non-T-cell-depleted transplants, we studied 870 patients with leukemia who received T-cell-depleted transplants from unrelated or HLA-mismatched related donors from 1982 to 1994. Outcomes were compared with those of 998 non-T-cell-depleted transplants. We compared LFS using different strategies for T-cell-depleted transplantation considering T-cell depletion technique, intensity of pretransplant conditioning, and posttransplant immune suppression using proportional hazards regression to adjust for other prognostic variables. Five categories of T-cell depletion techniques were considered: narrow-specificity antibodies, broad-specificity antibodies, Campath antibodies, elutriation, and lectins. Strategies resulting in similar LFS were pooled to compare T-cell-depleted with non-T-cell-depleted transplants. Recipients of transplants T-cell depleted by narrow-specificity antibodies had lower treatment failure risk (higher LFS) than recipients of transplants T-cell depleted by other techniques. Compared with non-T-cell-depleted transplants (5-year probability +/- 95% confidence interval [CI] of LFS, 31% +/- 4%), 5-year LFS was 29% +/- 5% (P = NS) after transplants T-cell depleted by narrow-specificity antibodies and 16% +/- 4% (P <.0001) after transplants T-cell depleted by other techniques. After alternative donor transplantation, T-cell depletion of donor marrow by narrow-specificity antibodies resulted in LFS rates that were higher than those for transplants T-cell depleted using other techniques but similar to those for non-T-cell-depleted transplants. (Blood. 2000;95:3996-4003)