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Biomedical subjects

A C Stern

Publications and source records attributed to A C Stern.

At least 19 recordsLinked to original sources
PubMed1993

Short-term administration of granulocyte-macrophage colony stimulating factor decreases hematopoietic toxicity of cytostatic drugs.

BACKGROUND: Administration of granulocyte-macrophage colony stimulating factor (GM-CSF) is followed by a rapid increase in the proliferative activity of the hematopoietic precursors. Within 72 hours after its suspension, however, establishment of a negative feedback results in a reduction of the proliferative activity of the hyperplastic marrow to values below the baseline, suggesting refractoriness of hematopoietic progenitors to the action of cell-cycle-specific cytostatic agents. METHODS: The hypothesis that short treatment with GM-CSF before chemotherapy could reduce the hematopoietic toxicity of cytostatics was investigated by administering GM-CSF glycosylate (Sandoz, Basel, Switzerland/Schering-Plough, Kenilworth, NJ) subcutaneously with a 5.5 micrograms/kg protein dosage per day from day-6-day-4 before each course of adjuvant chemotherapy (cyclophosphamide, epirubicin, 5-fluorouracil/cyclophosphamide, methotrexate, 5-fluorouracil alternate) in patients with node-positive breast cancer. Twelve patients were randomized to receive GM-CSF before chemotherapy or only at chemotherapy. The hematologic picture and dose intensity of chemotherapy were compared in the two groups of patients. RESULTS: In the group of patients receiving chemotherapy only, 22% of the cycles had to be postponed because of leukopenia, with a consequent reduction of the dose intensity, whereas in the GM-CSF group, the neutrophil counts remained at significantly (P < 0.001) higher levels, and there were no delays in chemotherapy administration. No substantial systemic toxicity was associated with this brief GM-CSF schedule. Moreover, GM-CSF treatment did not result in delayed depletion of the hematopoietic pool. CONCLUSIONS: Short treatment with GM-CSF can enable the dose intensity of conventional protocols of proven efficacy to be increased.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Intervention treatment of established neutropenia with human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in patients undergoing cancer chemotherapy.

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was given to 60 patients, in a double-blind, non-prophylactic study of already established chemotherapy-induced leucopenia, for 5 days by continuous intravenous infusion and twice or once daily by subcutaneous injection. Four patients were randomized to rhGM-CSF (3) or placebo (1) at each dose (1.3, 1.7, 5.5, 11, or 22 micrograms of protein/kg). Leucocyte recovery was significantly enhanced compared with controls, in a dose-dependent manner except for 22 micrograms/kg which was ineffective with a worse experience of side effects in some patients. Most adverse events occurred in equal proportions in the treated and placebo cases. Fourteen patients developed infection and were treated with antibiotics in addition to rhGM-CSF. They were joined by a further 18 febrile patients and treated with rhGM-CSF in a subsequent open-label trial. The survival from infection was related to white blood cell (WBC) count: 19 of 32 responded with increased numbers of leucocytes (WBC count above 1.5 x 10(9)/1) after 5 days of GM-CSF. Sixteen of the 19 leucocyte 'responders' recovered from infection, two died from the underlying disease and one from persistent infection. Six of the 13 patients who did not have a leucocyte response died with persistent infection. These data indicate that rhGM-CSF enhances the leucocyte count following chemotherapy and in this way saves critically ill neutropenic patients from fatal infections.

Adult↗
PubMed1993

Clinical experience with Escherichia coli rHuGM-CSF.

The use of rHuGM-CSF has resulted in patient benefit as shown by reduced infections (MDS and AA), reduced days in intensive care (ABM transplant), better adherence to cancer chemotherapy protocols, and the ability to use full doses of antiviral drugs in AIDS and cytomegalovirus retinitis. The adverse reactions are significant when high doses are used, therefore high doses should be avoided (there is a plateau in the dose-effective biological responses). At recommended doses, GM-CSF is well tolerated and is a valuable adjunctive therapy in the management of patients with conditions of dysmyelopoiesis and myeloid hypoplasia associated with myelotoxic therapy, or after bone marrow transplantation.

Antineoplastic Agents↗
PubMed1992

Recombinant human granulocyte-macrophage colony-stimulating factor accelerates neutrophil and monocyte recovery after allogeneic T-cell-depleted bone marrow transplantation.

In a prospective randomized study, five European transplant centers compared recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; mammalian glycosylated) with placebo. rhGM-CSF was administered in a dose of 8 micrograms glycoprotein (5.5 micrograms protein)/kg/d, as a continuous intravenous (IV) infusion for 14 days, starting 3 hours after bone marrow infusion. Fifty-seven patients entered and completed the study. Median age of the recipients was 34 years (range, 17 to 51 y). All donors were HLA-identical, MLC-nonreactive siblings. Marrow grafts were depleted of T lymphocytes either by counterflow centrifugation (n = 42) or by immunological methods (n = 15). Twenty-nine patients received rhGM-CSF and 28 patients placebo. The leukocyte count and the absolute neutrophil count were significantly higher in the rhGM-CSF-treated group from day +9 to day +14 after bone marrow transplantation (BMT). This was also true for the monocyte count from day +12 to day +21. Early neutrophil (greater than 0.1 and greater than 0.3 x 10(9)/L) and early leukocyte (greater than 0.3 and greater than 0.5 x 10(9)/L) recovery was significantly faster for the patients given GM-CSF. The incidences of graft-versus-host disease (GVHD) and transplant-related mortality were not different in both groups. However, the number of bronchopneumonias was significantly lower in the rhGM-CSF-treated group (P = .03). Long-term follow-up showed a trend to better overall disease-free survival at 2 years and a trend to a lower relapse risk in patients treated with rhGM-CSF. This study shows that rhGM-CSF significantly increases neutrophil and monocyte counts during periods of 6 to 10 days in the second and third week after BMT. This shortened period until myeloid cell recovery after transplantation resulted in a decreased number of pneumonias, without an increase in incidence of GVHD or relapse.

Adolescent↗
PubMed1992

The side-effect profile of GM-CSF.

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic molecule which displays a broad range of haematopoietic activities, has become available for clinical evaluation in various patient groups. It has been shown to be effective in preventing or reversing neutropenia. Adverse effects of GM-CSF, however, are dose related. Appropriate dose, route and schedules for GM-CSF in various clinical settings have recently been defined, the usual range being 5-10 micrograms/kg/day either by 4-6 h intravenous infusion or by subcutaneous injection. At such doses, adverse effects are predominantly mild-to-moderate in nature, occur in 20-30% of patients and usually comprise fever, myalgia, malaise, rash and injection site reaction. Early trials using very high doses of GM-CSF were often associated with marked adverse effects, which in rare cases proved severe (pericarditis and thrombosis). Similarly, a so-called "first-dose reaction", defined as a syndrome of hypoxia and hypotension after the initial but not subsequent doses of GM-CSF, was observed in certain predisposed patients following doses above 10 micrograms/kg/day. Subsequent trials have established that intravenous bolus or short infusions of GM-CSF are more likely to promote adverse effects. Certain patient groups, for example those with myelodysplastic syndrome, acute myeloid leukaemia, inflammatory disease, autoimmune thrombocytopenia or malfunctional immunological responsiveness, require careful clinical monitoring in order to avoid potential complications following the administration of GM-CSF. With the current appropriate administration and doses of GM-CSF, the benefit:risk ratio has been greatly improved.

Dose-Response Relationship, Drug↗
PubMed1991

Flow cytometry for clinical estimation of circulating hematopoietic progenitors for autologous transplantation in cancer patients.

Optimum methods of harvesting circulating hematopoietic progenitors for autologous transplantation to support myeloablative cancer therapy are still uncertain, mostly because of the lack of an assay for marrow-repopulating stem cells. The CFU-GM assay, the commonly used indirect indicator of the quality of the graft, is poorly standardized and provides results evaluable only retrospectively. Based on the knowledge that hematopoietic progenitors express CD34 and CD33 differentiation antigens, we developed a dual-color direct immunofluorescence flow cytometry assay with the aim of replacing the CFU-GM assay advantageously. For this purpose, we applied both assays to 157 blood samples obtained daily throughout 20 different recoveries from pancytopenia induced by high-dose cyclophosphamide or etoposide cancer therapy with or without recombinant human GM colony-stimulating factor (rhGM-CSF). The appearance of CD34+ cells in the circulation indicated that hematopoietic progenitors had increased to more than 500 CFU-GM/mL, a level clinically adequate for large-scale harvest by leukapheresis. Total CD34+ cells correlated well with CFU-GM (r = .89), and data could be fitted by a linear regression line described by the equation y = 388.3 + 64.0x, where y = CFU-GM/mL and x = CD34+ cells per microliter. Moreover, in a series of six patients treated with myeloablative chemoradiotherapy, early hematopoietic recovery of marrow functions was predicted more accurately by the number of transplanted CD34+/CD33+ cells than by either total nucleated cells, CFU-GM, CD34+/CD33- cells, or CD34-/CD33+ cells. Data presented in this article favor clinical use of the CD34/CD33 flow cytometry assay to guide harvesting of circulating hematopoietic progenitors for autologous transplantation and contribute to better understanding of the role played by circulating hematopoietic progenitor cell subsets in marrow recovery after myeloablative cancer therapy.

Antigens, CD↗
PubMed1991

A double-blind placebo-controlled study with granulocyte-macrophage colony-stimulating factor during chemotherapy for ovarian carcinoma.

In a placebo-controlled double-blind dose-finding trial, 15 patients with ovarian cancer stage III or IV received daily s.c. 1.5, 3, or 6 micrograms/kg recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). At each dose step three patients received recombinant human GM-CSF, and two received placebo. Chemotherapy comprised 6 cycles of carboplatin, 300 mg/m2, and cyclophosphamide, 750 mg/m2, by i.v. bolus on day 1 every 4 weeks. GM-CSF, given on days 6-12 on an outpatient basis, raised the mean leukocyte count on days 7, 10, and 15 and the mean neutrophil count on days 7 and 10 at all dose levels as compared with the control group. Neutrophil counts of less than 0.5 x 10(9)/liter occurred in 20 of 22 cycles in the control group and in 5 of 17 cycles at the 6-micrograms/kg/day GM-CSF dose level (P less than 0.0005). In comparison with the control group, the mean eosinophil count was higher on days 10 and 15 at all GM-CSF doses, as was the mean monocyte count on day 15. The mean platelet count was raised at the 3- and 6-micrograms GM-CSF doses on days 15 and 22. Chemotherapy dose reduction or postponement due to myelotoxicity occurred in 9 of 28 cycles in the placebo groups versus 5 of 44 cycles in the GM-CSF group (not significant). Local skin infiltrates at the GM-CSF injection sites occurred in 8/9 patients, leading to premature removal of two patients from the study. Capillary leakage of 131I-albumin was increased in all patients 5 days after the first chemotherapy course but was not significantly affected by 4 days of GM-CSF treatment. Tumor necrosis factor alpha and C-reactive protein serum levels increased during GM-CSF administration at the 6-micrograms dose level, but interleukin 6 serum levels were not affected. We conclude that a dose of 3 and 6 micrograms/kg/day GM-CSF reduces the severity of neutropenia and thrombocytopenia after carboplatin-cyclophosphamide. This GM-CSF dose does not induce additional capillary leakage.

Adult↗
PubMed1991

Correction of neutropenia associated with chronic lymphocytic leukaemia following treatment with granulocyte-macrophage colony-stimulating factor.

A patient with chronic lymphocytic leukaemia (CLL) and severe persisting neutropenia due to marrow infiltration of his leukaemia, developed bilateral Legionella pneumophila pneumonia for which he was treated with erythromycin, rifampin and ciprofloxacin. To increase the number of circulating polymorphonuclear neutrophils, the patient was treated with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) at a dose of 2 micrograms protein/kg bodyweight s.c./12 h. GM-CSF therapy resulted in a sustained rise of the neutrophil count from the fifth day of treatment onwards, without showing an effect on the number of circulating leukemic cells. The patient completely recovered from his pneumonia. It is suggested that the rise of the neutrophil count, due to GM-CSF, contributed to the improvement of the infection of this patient. Our observation illustrates that GM-CSF can be given safely to CLL-patients and that it can be used effectively in CLL patients with severe bacterial infections to restore neutropenia.

Granulocyte-Macrophage Colony-Stimulating Factor↗
PubMed1991

Human monoclonal antibodies neutralizing cytomegalovirus (CMV) for prophylaxis of CMV disease: report of a phase I trial in bone marrow transplant recipients.

The safety and pharmacokinetics of the two neutralizing human IgG1 monoclonal antibodies to cytomegalovirus (CMV) SDZ 89-104 and 89-109 in bone marrow transplant (BMT) recipients was assessed in an open phase I trial. Thirteen patients, 8 seropositive and 5 seronegative for CMV, were treated with allogeneic or autologous bone marrow transplantation. SDZ 89-104 was given to 5 and SDZ 89-109 to 8 patients. Patients were divided into high- and low-dose groups. A fixed prestudy dose of 0.1 mg/kg was given 4 days before BMT. On days 3, 17, 31, 45, 59, and 73, patients were treated with either 0.5 or 2 mg/kg of the respective antibody. Results indicate that doses of 2 mg/kg of SDZ 89-104 or SDZ 89-109 in alternating weeks can be safely administered to BMT patients. Serum trough levels measured by antiidiotype ELISA were approximately 10 micrograms/ml after administration of 0.5 mg/kg and approximately 50 micrograms/ml after treatment with 2 mg/kg of SDZ 89-104 or SDZ 89-109. High serum levels defined by antiidiotype ELISA techniques closely paralleled increased neutralizing activity. Serum half-lives calculated from these data were approximately 6 days.

Adolescent↗
PubMed1991

In vivo effect of granulocyte-macrophage colony-stimulating factor on the kinetics of human acute myeloid leukemia cells.

Granulocyte-macrophage colony-stimulating factor, (GM-CSF) was given at 8 micrograms/kg daily by continuous i.v. infusion for 72 h to six patients with acute myeloid leukemia (AML) in expansion and one with chronic myeloid leukemia in blastic crisis to determine whether it was possible to augment the proliferative activity of the neoplastic population. The percentage of marrow blasts in S phase (labeling index, LI) was increased in five patients (1.3-, 1.5-, 1.9-, 2.3- and 3.2-fold change). The increase in LI was similar 24 and 48 h after beginning GM-CSF. The RNA Index also increased in patients who showed an increased LI, suggesting that GM-CSF had recruited quiescent neoplastic cells into the cell cycle. Forty eight hours after beginning GM-CSF, chemotherapy was started. The fate of S phase cells, labeled in vivo with bromodeoxyuridine (BrdU) immediately before cytostatic treatment, was monitored. BrdU positive cells were identified by fluorescent antibody for up to 28 days. A preferential killing of BrdU (S phase) cells was observed in 5/7 patients who obtained a complete remission, whereas this was not apparent in the two patients who achieved only a partial remission. Chemotherapy induced a rapid and profound aplasia; its duration, however, was not significantly different from that observed in historical controls. GM-CSF may have a potential role in the treatment of AML, as this study shows that it recruits leukemic cells into the cell cycle without adversely prolonging aplasia after cycle-specific therapy.

Adolescent↗
PubMed1990

Efficacy and tolerability of recombinant human granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related leukopenia and fever.

30 patients with chemotherapy-related leukopenia (white cells 1.0 x 10(9)/l or lower) and fever (temperature 38.5 degrees C or higher) were treated in a double-blind randomised trial with standard antibiotics and 7 days of intravenously administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 2.8 micrograms/kg per day) or placebo. GM-CSF administration resulted in a faster percentage increase of peripheral neutrophil count after 2 and 3 days of treatment, except in patients treated with ablative chemotherapy and autologous bone-marrow transplantation. However, GM-CSF did not shorten the period of fever or antibiotic administration. No side-effects were observed; in particular tumour necrosis factor alpha and interleukin-6 did not increase in the 5 GM-CSF patients tested. These data suggest that a subgroup of patients with chemotherapy-related leukopenia and fever may benefit from GM-CSF treatment in view of the observed effects on neutrophil count.

Adolescent↗
PubMed1990

In vivo priming of human normal neutrophils by granulocyte-macrophage colony stimulating factor: effect on the production of platelet activating factor.

The effect of granulocyte-macrophage colony stimulating factor (GM-CSF) (recombinant, mammalian, glycosylated, Sandoz, Schering Plough; 4 micrograms/kg every 12 h for 3 d, s.c.) on platelet activating factor (PAF, 1-O-alkyl-2-acetyl-sn glycero-3 phosphorylcholine) production from neutrophils was studied in five cancer patients with normal haemopoiesis. Peripheral blood counts, PAF production and lyso-PAF: acetyl transferase (EC 2.3.1.67) (AT) activity in neutrophils were evaluated before treatment, during treatment and 3 d after treatment had been discontinued. GM-CSF induced a three-fold increase in the number of circulating neutrophils. Neutrophils obtained during treatment produced about twice as much PAF than before treatment in response to a variety of stimuli (N-formyl-methionyl-leucyl-phenylalanine, tumour necrosis factor-alpha, phagocytosis of baker's yeast spores opsonized with C3b). This increased PAF synthesis and release is concomitant with a 2-3-fold increase in AT activity. Moreover, lower concentrations of stimuli are sufficient to induce PAF synthesis from neutrophils obtained during GM-CSF treatment. Three days after treatment had been discontinued, stimulus induced PAF production had returned to baseline levels. Since GM-CSF induces a marked shift to the left in the Arneth score, the increased PAF release might have been due to the presence of younger granulocytes. This was, however, ruled out by experiments showing that normal neutrophils primed in vitro with GM-CSF produce more PAF when challenged with the same stimuli. The potential relevance of this effect of GM-CSF treatment lies on the crucial role of PAF in inflammatory reactions and its intervention in some immune reactions, including delayed hypersensitivity, and in endotoxic shock. Lastly, increased PAF production from neutrophils may explain some toxicities observed during treatment with high doses of GM-CSF.

Acetyltransferases↗
PubMed1990

Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma.

High-dose administration of anticancer agents is attractive both on theoretic and clinical grounds. Yet, high-dose regimens are usually used as salvage treatments, mainly as a consequence of their considerable hematologic toxicity. One pertinent example is represented by cyclophosphamide, an alkylating agent with a wide spectrum of marked antitumor activity. When used at doses up to 7 g/m2 (190 to 200 mg/kg) this drug does not cause myeloablation, but induces a severe, albeit transient, myelosuppression, which requires platelet transfusions in approximately 50% of treated patients, and is frequently complicated by infectious episodes, occasionally lethal. To accelerate hematopoietic recovery, we continuously infused for 14 consecutive days 5.5 micrograms/kg/d of the glycosylated human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) into 15 patients with breast cancer and non-Hodgkin's lymphoma treated with 7 g/m2 cyclophosphamide. This schedule was chosen having obtained the fastest hematopoietic recovery among four different options during an initial schedule-finding phase on 12 overall patients. Twenty-one comparable subjects with solid tumors served as controls. We report here that this relatively low, well-tolerated dose of rhGM-CSF reduces from 20 to 14 (median) and from 24 to 14, the number of days required to recover circulating granulocyte counts over 1,000 and 2,500/microL, respectively. The stimulatory effect was associated with a remarkable clinical benefit. In fact, treated patients experienced less infectious complications (7% v 24%) were eligible to receive chemotherapy earlier (median, by day +14 v day +20 for controls), and fewer required prophylactic platelet transfusions (13% v 43%). Our results show that even very high doses of cyclophosphamide can be administered with improved hematologic toxicity, tolerable morbidity, and reduced supportive care requirements. The increase in the therapeutic index made possible by rhGM-CSF infusion prompts the use of high-dose cyclophosphamide, and possibly of other agents with similar myelotoxic activity, early in the clinical course of chemotherapy-sensitive tumors.

Adolescent↗