ALBERT

Beschreibung: Ten dogs were given 9.2 Gy of total body irradiation and autologous bone marrow infusion followed by ten daily transfusions of leukocytes for a total of 11.5 to 36.2 (median, 18.8) x 10(8)/kg obtained via leukapheresis from histoincompatible unrelated donors. Four dogs were given unirradiated leukocytes, and all developed graft-versus-host disease (GVHD). In contrast, only two of three dogs given leukocytes irradiated with 20 mJ/cm2 of ultraviolet (UV) light (200 to 300 nm), and none of three dogs given leukocytes irradiated with 1,000 mJ/cm2 developed GVHD. These data indicate that UV irradiation abrogates the alloreactive potential of transfused leukocytes, and suggest that UV irradiation can be used to prevent the development of transfusion- induced GVHD.

Beschreibung: A animal model was developed whereby reticulocyte-rich blood was introduced into normal rats by exchange transfusion. Measurements of plasma iron turnover was made at similar plasma iron concentrations before and after exchange transfusions. High reticulocyte blood obtained from animals rendered iron deficient by diet or by treatment with phenylhydrazine resulted in a mean increase of 86% in internal iron exchange, while the plasma iron turnover was unaffected by exchange with normal red cells. Since iron input from reticuloendothelial cells could have increased due to breakdown of transfused cells, iron absorption was also measured. Within 1 hr and for a least 6 hr after exchange with high reticulocyte blood, mean absorption in six groups of animals was increased over control animals by 50%-130%. The increased plasma iron turnover and absorption was not mediated by a decrease in plasma iron or an increase in unsaturated iron-binding capacity. Indeed, a higher plasma iron and transferrin saturation augmented the movement of iron into the plasma from iron- donating tissues. It is proposed that the donation of iron by transferrin in some way immediately facilitates the procurement of more iron by transferrin.

Beschreibung: A animal model was developed whereby reticulocyte-rich blood was introduced into normal rats by exchange transfusion. Measurements of plasma iron turnover was made at similar plasma iron concentrations before and after exchange transfusions. High reticulocyte blood obtained from animals rendered iron deficient by diet or by treatment with phenylhydrazine resulted in a mean increase of 86% in internal iron exchange, while the plasma iron turnover was unaffected by exchange with normal red cells. Since iron input from reticuloendothelial cells could have increased due to breakdown of transfused cells, iron absorption was also measured. Within 1 hr and for a least 6 hr after exchange with high reticulocyte blood, mean absorption in six groups of animals was increased over control animals by 50%-130%. The increased plasma iron turnover and absorption was not mediated by a decrease in plasma iron or an increase in unsaturated iron-binding capacity. Indeed, a higher plasma iron and transferrin saturation augmented the movement of iron into the plasma from iron- donating tissues. It is proposed that the donation of iron by transferrin in some way immediately facilitates the procurement of more iron by transferrin.

Beschreibung: Cumulative thrombocytopenia is a dose-limiting toxicity of dose-intensive chemotherapy for advanced breast cancer. In this phase I study, we have studied the hematologic toxicity associated with sequential interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF; molgramostim) administration after multiple cycles of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that after concurrent cytokine administration or to each cytokine administered alone. Ninety- three patients with advanced breast cancer were treated with five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15 days. Cohorts of patients were treated with one of four dose levels of IL-3 (1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 micrograms/kg/day. Sequential IL-3 and GM- CSF (schedule B) was associated with higher platelet nadirs, shorter durations of platelet counts less than 50,000/microL, and the need for fewer platelet transfusions over five cycles of FLAC chemotherapy compared with concurrent cytokines, sequential IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated with unexpected platelet toxicity. The duration of granulocytopenia after FLAC chemotherapy was significantly worse with IL-3 alone compared with each of the GM-CSF-containing cytokine regimens. Although no cycle 1 maximum tolerated dose for IL-3 was defined in this study, 5 micrograms/kg was well tolerated over multiple cycles of therapy and is recommended for future studies. The data from this phase I study suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days before beginning GM-CSF may be superior to shorter durations of IL- 3 administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either colony-stimulating factor alone in ameliorating the cumulative hematologic toxicity associated with multiple cycles of FLAC chemotherapy. Additional studies of sequential IL-3 and GM-CSF are warranted.

Beschreibung: Hematopoietic growth factors have been used to accelerate engraftment after bone marrow transplantation and to “mobilize” peripheral blood progenitor cells (PBPC). We report on the data in 85 consecutive patients with Hodgkin's disease who were treated in a single institution using different methods to obtain PB progenitor cells. Use of granulocyte colony-stimulating factor for mobilization resulted in a significantly accelerated time to recovery of granulocytes (10 days v 12 days, P 〈 .01) when compared with “nonmobilized” PBPC recipients. Similarly, use of mobilized PBPC resulted in a significantly accelerated time to platelet engraftment (13 days v 30 days, P 〈 .001) when compared with “nonmobilized” recipients. Moreover, there was a statistically significant difference in total costs in favor of the group receiving “mobilized” PBPC.

Beschreibung: Cumulative thrombocytopenia is a dose-limiting toxicity of dose-intensive chemotherapy for advanced breast cancer. In this phase I study, we have studied the hematologic toxicity associated with sequential interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF; molgramostim) administration after multiple cycles of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that after concurrent cytokine administration or to each cytokine administered alone. Ninety- three patients with advanced breast cancer were treated with five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15 days. Cohorts of patients were treated with one of four dose levels of IL-3 (1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 micrograms/kg/day. Sequential IL-3 and GM- CSF (schedule B) was associated with higher platelet nadirs, shorter durations of platelet counts less than 50,000/microL, and the need for fewer platelet transfusions over five cycles of FLAC chemotherapy compared with concurrent cytokines, sequential IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated with unexpected platelet toxicity. The duration of granulocytopenia after FLAC chemotherapy was significantly worse with IL-3 alone compared with each of the GM-CSF-containing cytokine regimens. Although no cycle 1 maximum tolerated dose for IL-3 was defined in this study, 5 micrograms/kg was well tolerated over multiple cycles of therapy and is recommended for future studies. The data from this phase I study suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days before beginning GM-CSF may be superior to shorter durations of IL- 3 administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either colony-stimulating factor alone in ameliorating the cumulative hematologic toxicity associated with multiple cycles of FLAC chemotherapy. Additional studies of sequential IL-3 and GM-CSF are warranted.

Beschreibung: Of 496 consecutive patients with multiple myeloma (MM) enrolled in clinical trials of tandem transplants with peripheral blood stem cells support, 470 (95%) completed the first autotransplant with melphalan 200 mg/m2 (MEL 200) and 363 (73%) completed the second transplant with either MEL 200 (40%), MEL 140 mg/m2 (MEL 140) with total-body irradiation (17%), or a combination of alkylating agents (16%), depending on the response status prior to the second transplant; 31 patients up to age 60 years received an allograft as the second transplant. The median interval from first to second transplant was 5 months. Treatment-related mortality during the first year after transplantation was 7%, and complete remission (CR) was obtained in 36%; the median durations of event-free survival (EFS) and overall survival (OS) after transplant were 26 and 41 months, respectively. Low beta 2-microglobulin ([B2M] 〈 or = 2.5 mg/L) and C-reactive protein ([CRP] 〈 or = 0.4 mg/dL) were the most significant standard parameters associated with both prolonged EFS and OS. Median OS exceeded 5.5 years in the one third of patients with both low B2M and CRP. When cytogenetics were included in the analysis, the presence of 11q abnormalities and/or complete or partial deletion of chromosome 13 (“unfavorable karyotype”) became a dominant negative feature for both EFS and OS. In addition to these pretransplant parameters, attainment of CR and application of two transplants within 6 months both significantly extended EFS and OS. The group of patients (7%) with high B2M and CRP with either IgA isotype or unfavorable karyotype had the worst prognosis (EFS, 〈 or = 10 months; median OS, 〈 or = 12 months) and will require novel therapy. We conclude that tandem transplants are feasible in the majority of patients up to age 70 years, effecting CR in one third of all patients. Median OS was greater than 5.5 years, regardless of pretransplant features, if the first transplant was applied within 12 months of initial treatment and the second transplant no more than 6 months later.

Beschreibung: Ten dogs were given 9.2 Gy of total body irradiation and autologous bone marrow infusion followed by ten daily transfusions of leukocytes for a total of 11.5 to 36.2 (median, 18.8) x 10(8)/kg obtained via leukapheresis from histoincompatible unrelated donors. Four dogs were given unirradiated leukocytes, and all developed graft-versus-host disease (GVHD). In contrast, only two of three dogs given leukocytes irradiated with 20 mJ/cm2 of ultraviolet (UV) light (200 to 300 nm), and none of three dogs given leukocytes irradiated with 1,000 mJ/cm2 developed GVHD. These data indicate that UV irradiation abrogates the alloreactive potential of transfused leukocytes, and suggest that UV irradiation can be used to prevent the development of transfusion- induced GVHD.

Beschreibung: Of 496 consecutive patients with multiple myeloma (MM) enrolled in clinical trials of tandem transplants with peripheral blood stem cells support, 470 (95%) completed the first autotransplant with melphalan 200 mg/m2 (MEL 200) and 363 (73%) completed the second transplant with either MEL 200 (40%), MEL 140 mg/m2 (MEL 140) with total-body irradiation (17%), or a combination of alkylating agents (16%), depending on the response status prior to the second transplant; 31 patients up to age 60 years received an allograft as the second transplant. The median interval from first to second transplant was 5 months. Treatment-related mortality during the first year after transplantation was 7%, and complete remission (CR) was obtained in 36%; the median durations of event-free survival (EFS) and overall survival (OS) after transplant were 26 and 41 months, respectively. Low beta 2-microglobulin ([B2M] 〈 or = 2.5 mg/L) and C-reactive protein ([CRP] 〈 or = 0.4 mg/dL) were the most significant standard parameters associated with both prolonged EFS and OS. Median OS exceeded 5.5 years in the one third of patients with both low B2M and CRP. When cytogenetics were included in the analysis, the presence of 11q abnormalities and/or complete or partial deletion of chromosome 13 (“unfavorable karyotype”) became a dominant negative feature for both EFS and OS. In addition to these pretransplant parameters, attainment of CR and application of two transplants within 6 months both significantly extended EFS and OS. The group of patients (7%) with high B2M and CRP with either IgA isotype or unfavorable karyotype had the worst prognosis (EFS, 〈 or = 10 months; median OS, 〈 or = 12 months) and will require novel therapy. We conclude that tandem transplants are feasible in the majority of patients up to age 70 years, effecting CR in one third of all patients. Median OS was greater than 5.5 years, regardless of pretransplant features, if the first transplant was applied within 12 months of initial treatment and the second transplant no more than 6 months later.

Beschreibung: Transfusion of autologous peripheral blood stem cells (PBSCs) of good quality ensures fast hematopoietic engraftment after myeloablative therapy with a decrease in procedure-related morbidity and mortality. We have analyzed variables influencing the kinetics of engraftment, and therefore reflecting the quality of PBSC collections, in 225 patients with newly diagnosed or refractory multiple myeloma (MM) who received an autotransplant in support of high dose melphalan (200 mg/m2); 132 of these patients also completed a second transplant. All PBSCs were collected before the first transplant after high-dose cyclophosphamide (6 g/m2) and hematopoietic growth factors, mainly granulocyte- macrophage colony-stimulating factor. PBSCs were administered either alone (91 patients) or with bone marrow (134 patients). A highly significant correlation was observed between the number of CD34+ cells per kilogram infused and prompt recovery of both granulocytes (P = .0001) and platelets (P = .0001). After correction for the proportion of patients with 〉 or = 2 x 10(6)/kg CD34 PBSCs infused and with 〈 or = 12 months of prior therapy, no difference in engraftment kinetics was seen between patients receiving PBSCs only and those also receiving bone marrow. Exposure to chemotherapy, even to 〈 or = 6 months of alkylating agents, significantly delayed hematopoietic recovery posttransplantation. The threshold dose of CD34 cells necessary for prompt engraftment was 〉 or = 2.0 x 10(6)/kg for patients with 〈 or = 24 months of chemotherapy before the first transplant, whereas greater than 5 x 10(6)/kg CD34 cells were required to assure rapid recovery also in those with longer exposure. Such quantities, easily collected in the large majority of patients with shorter exposure (91%), were obtained in only 28% of patients with more than 24 months of prior chemotherapy. Rapid platelet recovery within a narrow range of time (before day 14) was almost invariably seen (94%) when greater than 5 x 10(6)/kg CD34 cells were infused, irrespective of the duration of prior therapy, whereas the range widened progressively when less CD34 cells were infused. In the absence of CD34 measurements, fast recovery of platelets to greater than 50 x 10(9)/L within 14 days after high-dose cyclophosphamide and 〈 or = 12 months of prior chemotherapy were the best predictors of early engraftment. Prudent use of stem cell-damaging agents, such as melphalan and nitrosoureas, is recommended in MM patients who might be candidates for autotransplantation. Alternatively, PBSCs should be collected early after diagnosis.