Antiviral activity of the human immunodeficiency virus type 1-specific nonnucleoside reverse transcriptase inhibitor HBY 097 alone and in combination with zidovudine in a phase II study. HBY 097/2001 Study Group.

The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study. Mean maximum virus load decreases ranged from -1.31 log10 copies/mL of plasma at week 1 in the group receiving HBY 097 monotherapy (250 mg three times daily) to -2.19 log10 copies/mL at week 4 in the group receiving zidovudine plus HBY 097 (750 mg three times daily). After 12 weeks, these patients had viral RNA copy numbers 1.05 log10 below baseline. Genotypic analysis of resistance development revealed reverse transcriptase K103N variants in most patients, which was associated with less durable efficacy of HBY 097 treatment. Fewer patients receiving combination therapy with high-dose HBY 097 developed the K103N variant (P<.01). HBY 097 caused pronounced acute suppression of HIV-1 replication both in combination with zidovudine and alone. Therefore, sustained antiviral activity can be expected from multiple combination therapy regimens including a quinoxaline derivative.

Pentoxifylline therapy in human immunodeficiency virus-seropositive persons with tuberculosis: a randomized, controlled trial.

Macrophage activation and tumor necrosis factor-alpha (TNF-alpha) production are critical in tuberculosis immunity but may result in increased human immunodeficiency virus (HIV) expression and accelerated HIV disease progression in HIV-infected persons. Pentoxifylline inhibits expression of TNF-alpha and HIV. A double-blind, placebo-controlled study of adjunctive therapy with pentoxifylline (1800 mg/day) as a timed-release formulation was done in Ugandan HIV-infected patients with pulmonary tuberculosis. Subjects had early HIV disease (mean CD4 cell count, 380/microL) and did not receive other antiretroviral drugs. Pentoxifylline resulted in decreased plasma HIV RNA and serum beta 2-microglobulin and, in a subset of moderately anemic patients, improved blood hemoglobin levels. Trends were noted toward reduced TNF-alpha production in vitro and improved performance scores, but these did not reach statistical significance. No effect was noted on body mass, CD4 cell count, or survival. Additional studies of more potent TNF-alpha inhibitors in HIV-positive subjects with tuberculosis are warranted.

Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating-factor support for dose-intensive cyclophosphamide, etoposide, and cisplatin.

This is a double-blind randomized placebo-controlled trial to evaluate the efficacy and safety of granulocyte-macrophage colony-stimulating-factor (GM-CSF) after dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP). Fifty-six patients with lymphoma or breast carcinoma were randomized to receive GM-CSF 250 microg/m2 or placebo subcutaneously (SC) every 12 hr after each course of DICEP until recovery of absolute neutrophil count (ANC) of 1.5 x 10(9)/L. Each patient was to receive three courses of DICEP. There were 28 patients in each group. The median duration of ANC below 0.5 x 10(9)/L was 10 versus 12 days for Course 1 (P = 0.010), 10 versus 12 days for Course 2 (P = 0.248), and 16.5 versus 15 days for Course 3 (P = 0.126); platelet counts below 20 x 10(9)/L was 4 versus 4 days for Course 1 (P = 0.586), 8.5 versus 7 days for Course 2 (P = 0.013), and 23.5 versus 10.5 days for Course 3 (P = 0.104); hospitalization for patients readmitted with cytopenic fever were 4 versus 8 days for Course 1 (P = 0.035); 7 versus 6 days for Course 2 (P = 0.692); and 8 versus 12 days for Course 3 (P = 0.884) in the GM-CSF and placebo group, respectively. GM-CSF significantly shortens the duration of neutropenia and readmission only during the first course of DICEP. There was a delay in platelet recovery and an increase in transfusion requirement during subsequent courses in the GM-CSF group. The result cautions the routine use of lineage specific hematopoietic growth factors in supporting repeated cycles of dose-intensive chemotherapy.

A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490).

The treatment of adult patients greater than 55 to 70 years of age with acute myelogenous leukemia (AML) is associated with a treatment-related mortality of approximately 25%. This prospective, double-blind randomized study was designed to see if the use of granulocyte-macrophage colony stimulating factor (GM-CSF; yeast-derived) could shorten the period of neutropenia and to determine any effect this would have on therapy-related morbidity and mortality. A total of 124 patients entered this study. Induction consisted of standard daunorubicin and cytarabine. A day-10 bone marrow was examined; if this was aplastic without leukemia, patients received blinded placebo or GM-CSF from day 11 until neutrophil recovery. Patients who entered complete remission received the identical study medication (blinded GM-CSF or placebo) in consolidation that they had received during induction. The overall complete remission rate was 52%; 60% for the GM-CSF arm and 44% for the placebo arm (P = .08). Median times to neutrophil recovery were significantly shortened on the GM-CSF arm. The overall treatment-related toxicity from start of GM-CSF/placebo was reduced on the GM-CSF arm (P = .049). Similarly, the infectious toxicity was significantly reduced on the GM-CSF arm (P = .015). The median survival for all patients was 10.6 months in the GM-CSF group and 4.8 months in the placebo arm (P = .048). It appears that GM-CSF is safe and efficacious for adult patients greater than 55 to 70 years of age with AML; its major impact is in reducing the duration of neutropenia and therapy-related mortality and morbidity. This may result in a better response rate.

Dose escalation trial of cyclophosphamide with Sargramostim in the treatment of central nervous system (CNS) neoplasms.

We conducted a dose escalation trial of cyclophosphamide plus Sargramostim in the therapy of patients with newly diagnosed or recurrent central nervous system tumors. Cyclophosphamide was administered at doses ranging between 1.0 and 2.5 g/m2 daily for two doses. Sargramostim was administered at a fixed dose of 250 micrograms/m2 subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the absolute neutrophil count (ANC) was > 1,000 cells/microliters for two consecutive days. The MTD for patients who had not received any prior chemotherapy and who had received either no radiotherapy or radiotherapy confined to the cranium was 2.0 g/m2 daily for two doses. The MTD for patients previously treated with chemotherapy or neuraxis radiotherapy was also 2.0 g/m2 daily for two doses. Responses were seen in patients with medulloblastoma (8/9), glioblastoma multiforme (2/13), germinoma (1/1), and pineoblastoma (1/2).

A phase I trial of cyclosphosphamide and carboplatinum combined with interleukin-3 in women with advanced-stage ovarian cancer.

The hematopoietic growth factor, recombinant human interleukin-3 (rhu IL-3), stimulates production of both leukocytes and platelets, and thus potentially has greater utility than growth factors that solely stimulate leukocytes production when employed with dose-intensive chemotherapeutic regimens. To determine the optimal schedule for administration of rhu IL-3 in combination with cyclophosphamide and carboplatin, an aggressive regimen for the treatment of advanced ovarian cancer, a phase I trial was initiated by the New York Gynecologic Oncology Group. Following surgical debulking, all patients received cyclophosphamide and carboplatin for 6 cycles. rhu IL-3 was administered at 50, 250, or 500 microgram subcutaneously for 5 days either immediately prior to or after administration of chemotherapy. Cohorts of six patients were treated at each dose level (three pre- and three postchemotherapy). Eighteen patients received 91 cycles of treatment. The major toxicities attributable to rhu IL-3 included fevers, chills, malaise, nausea, and headache, but were not dose-limiting at the doses of rhu IL-3 employed. The major finding of this study was that rhu IL-3 administered after chemotherapy offered greater platelet protection than rhu IL-3 administered prior to chemotherapy as assessed by median platelet nadir and duration of platelet counts < 50,000/mm3. A second major finding was a dose-response relationship for rhu IL-3: the two higher doses employed, 250 and 500 micrograms, offered more effective platelet protection than the lower dose employed, 50 micrograms. rhu IL-3 had no significant effects on leukocyte nadirs or duration of nadirs at any schedule or dose employed. rhu IL-3 may reduced the thrombocytopenia associated with aggressive treatment with cyclophosphamide and carboplatin, although this remains to be confirmed in a randomized, placebo-controlled trial. The effects of rhu IL-3 are dose- and schedule-dependent.

Contrasting effects of recombinant human granulocyte-macrophage colony-stimulating factor (CSF) and granulocyte CSF treatment on the cycling of blood elements in childhood-onset cyclic neutropenia.

Recombinant human granulocyte colony-stimulating factor (G-CSF) treatment has been shown to increase average neutrophil counts substantially in patients with childhood-onset cyclic neutropenia (or "cyclic hematopoiesis"), but not to eliminate the cyclic oscillations of neutrophil counts or those of other blood elements (monocytes, platelets, eosinophils, and reticulocytes) that are characteristic of this hematopoietic disorder. Indeed, oscillations of neutrophil counts are amplified during G-CSF treatment. We have compared the effects of recombinant granulocyte-macrophage-CSF (GM-CSF) with those of G-CSF in three patients with this disease (2 men and 1 woman, 17, 30, and 32 years of age). These patients were treated with GM-CSF (2.1 micrograms/kg/day, subcutaneously) for 6 weeks, preceded and followed by 6 to 13 weeks of detailed observation to document changes in the cyclic oscillations of blood neutrophils and other blood elements; two of the patients were subsequently treated with G-CSF (5.0 micrograms/kg/d, subcutaneously) and observed for comparable periods of time. Unlike G-CSF treatment, which increased average neutrophil counts more than 20-fold, GM-CSF increased neutrophil counts only modestly, from 1.6- to 3.9-fold, although eosinophilia of varying prominence was induced in each patient. However, at the same time, GM-CSF treatment dampened or eliminated the multilineage oscillations of circulating blood elements (neutrophils, monocytes, platelets, and/or reticulocytes) in each of the patients. In contrast, G-CSF treatment of the same patients markedly amplified the oscillations of neutrophil counts and caused the cycling of other blood elements (monocytes in particular) to become more distinct. These findings support the conclusion that the distinctive cycling of blood cell production in childhood-onset cyclic neutropenia results from abnormalities in the coordinate regulation of both GM-CSF-responsive, multipotential progenitor cells and G-CSF-responsive, lineage-restricted, neutrophil progenitors.

Analysis of radiolabeled CHO cell-derived rHuGM-CSF pharmacokinetics and biodistribution in rhesus monkeys following intravenous and subcutaneous injection.

The purpose of these studies was to examine the biodistribution and pharmacokinetics of radiolabeled human CHO cell-derived rHuGM-CSF in normal Rhesus monkeys (Macaca mulatta) following intravenous (i.v.) and subcutaneous (s.c.) injection. A dual radioisotope tracer technique was utilized to monitor the behavior of rHuGM-CSF in vivo. Recombinant HuGM-CSF was radiolabeled with I-123 (a 13.2 h half-life, 140 KeV pure gamma emitting radionuclide detected using gamma scintigraphic imaging) using a mild chloramine T reaction. A separate preparation of rHuGM-CSF radiolabeled with S-35 methionine by bioincorporation in tissue culture was mixed with the I-123-labeled protein, permitting comparison of data obtained from the two radiolabels. Two dose levels of rHuGM-CSF were used for i.v. bolus (15 and 300 micrograms/kg) and s.c. (10 and 100 micrograms/kg) studies. The results of these studies demonstrated that the co-administered I-123 rHuGM-CSF and S-35 rHuGM-CSF followed similar blood elimination kinetics after i.v. or s.c. injection. Following i.v. bolus injection, rHuGM-CSF was found to rapidly distribute to all central body cavity high blood flow organs, followed by rapid uptake in the kidneys and elimination in the urine. There were no differences in the pharmacokinetic values obtained for I-123- and S-35-labeled rHuGM-CSF nor for the two dose levels examined. Following, s.c. injection, I-123- and S-35-labeled rHuGM-CSF were found to reach maximal plasma levels after approximately 16 h. The primary route of elimination was the urine. Monkeys previously exposed to rHuGM-CSF were found to have circulating antibodies to rHuGM-CSF. Studies in these animals revealed a significantly altered distribution and clearance of radiolabeled rHuGM-CSF, with the majority of the injected activity being cleared by the liver.

Effects of interleukin-3 and granulocyte-macrophage colony-stimulating factor on thrombopoiesis in congenital amegakaryocytic thrombocytopenia.

Amegakaryocytic thrombocytopenia (AMT) is a rare and often fatal disorder of infancy and childhood presenting with isolated thrombocytopenia that progresses to marrow failure. The defect in thrombopoiesis is not well understood nor is the etiology of the progressive marrow failure. No standard modality of treatment exists. Here, we evaluated the capacity of marrow cells isolated from five patients with AMT and progressive marrow failure to generate megakaryocyte progenitor cells (CFU-MK). These in vitro studies demonstrated assayable numbers of CFU-MK from all patient bone marrows that responded in vitro to the addition of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or the combination of both. These findings suggest that the defect in AMT might be partially correctable by the administration of these cytokines. A Phase I/II trial of in vivo administration of these same hematopoietins in the identical patients was conducted in which no significant toxicity was observed. IL-3 but not GM-CSF administration resulted in improved platelet counts in two patients and decreased bleeding and transfusion requirement in the remaining three. No clinical benefit was observed when GM-CSF was administered after IL-3 pretreatment. Prolonged IL-3 administration has resulted in platelet increases in an additional two patients. In vitro responsiveness of CFU-MK to either cytokine did not predict the degree of clinical response. Although the optimal dose and schedule of IL-3 either alone or in combination remains to be established, this study suggests that IL-3 may contribute to the treatment of patients with AMT.

Dosing regimen of granulocyte-macrophage colony-stimulating factor to support dose-intensive chemotherapy.

PURPOSE: This trial evaluated the optimum dosing regimen for recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) to support a dose-intensive chemotherapy regimen given without progenitor cell replacement. PATIENTS AND METHODS: Fifty-one patients with refractory malignancy received cyclophosphamide 2,500 mg/m2 on days 1 and 2, etoposide 500 mg/m2 on days 1, 2, and 3, and cisplatin 50 mg/m2 on days 1, 2, and 3. Patients were hospitalized from cycle days 1 to 4 for chemotherapy and readmitted for cytopenic temperatures above 38.5 degrees C. Cycles were repeated every 35 days in patients who responded to a total of three cycles. GM-CSF was given at doses of 250 to 1,000 micrograms/m2 by continuous intravenous infusion (CIV) or subcutaneously starting on cycle days 3 to 6. Two nonrandomized control groups are used. RESULTS: The optimum regimen of GM-CSF for shortening the duration of leukopenia (WBC count less than 300/microL) was 500 micrograms/m2 given CIV. Duration of leukopenia was 5.9 days compared with 13.2 and 10.2 days in the controls (P less than .05). The optimum regimens for shortening duration of hospitalization, however, were 500 and 750 micrograms/m2/d given as divided (twice daily) subcutaneous injections. Durations of hospitalization were 9.6 and 9.8 days compared with 15.7 and 22.2 days in the controls (P less than .08). At the higher GM-CSF dose, only 36% of patients required readmission for cytopenic fever. Toxicities of GM-CSF at clinically useful doses were minimal. Twelve patients had complete response (24%) and 22 partial response (43%). CONCLUSIONS: This dose-intensive regimen can be given safely without progenitor replacement. rhu GM-CSF decreases the duration of severe leukopenia and decreases the need for hospitalization and antibiotic therapy.

Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for relapsed non-Hodgkin's lymphoma: blood and bone marrow progenitor growth studies. A phase II Eastern Cooperative Oncology Group Trial.

Sixteen patients with relapsed non-Hodgkin's lymphoma underwent autologous bone marrow transplantation and infusion of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Treatment consisted of involved-field radiotherapy, cyclophosphamide 60 mg/kg/d intravenously (IV) for 2 days, and fractionated total body irradiation (1,200 cGy). Autologous bone marrow was thawed and infused IV, followed 3 hours later by the first infusion of IV rhGM-CSF 11 micrograms/kg/d over 4 hours. Infusions of rhGM-CSF were continued daily until either both neutrophil count exceeded 1,500/microL and platelet count exceeded 50,000/microL, or until 30 days after marrow re-infusion. Toxicities encountered were mild and included fever, chills, hypertension, alopecia, rash, diarrhea, stomatitis, myalgias, and synovial (knee) effusions. Neutrophil recovery greater than 500/microL occurred a median of 14 days (range, 9 to 30 days) after marrow infusion, significantly earlier than in a comparable group of historic controls who recovered counts at a median time of 20 days (range, 12 to 51 days) (P = .00002). Median time to self-sustaining platelet counts greater than 20,000/microL was 23.5 days (range, 12 to 100 days), comparable with the historic group (P = .38). One bacteremia (central venous catheter exit site infection with Staphylococcus epidermidis) and one local infection (Giardia lamblia in stool) occurred. Patients received a median of 11.4 (range, 4.4 to 20.2) x 10(4) colony-forming unit granulocyte-macrophage (CFU-GM) progenitors per kg. Stem cell progenitors CFU-GM, CFU-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM), and burst-forming unit-erythroid (BFU-E) were detected in the bone marrow as early as 7 days after marrow re-infusion, and increased in proportion to peripheral blood counts, but by 30 to 60 days still remained much lower than before transplant. Neutrophils transiently decreased in 13 of 16 patients (median decrease, 42%) within 24 to 72 hours of discontinuing rhGM-CSF infusions. These data suggest that rhGM-CSF therapy enhances neutrophil recovery by forcing stem cells to produce mature elements at an enhanced rate but may not affect marrow stem cell and early progenitor population sizes.

Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer.

BACKGROUND: The period of neutropenia after autologous bone marrow transplantation results in substantial morbidity and mortality. The results of previous phase I-II clinical trials suggest that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) may accelerate neutrophil recovery and thereby reduce complications in patients after autologous bone marrow transplantation. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at three institutions. The study design and treatment schedules were identical, and the results were pooled for analysis. One hundred twenty-eight patients were enrolled. Sixty-five patients received rhGM-CSF in a two-hour intravenous infusion daily for 21 days, starting within four hours of the marrow infusion, and 63 patients received placebo. RESULTS: No toxic effects specifically ascribed to rhGM-CSF were observed. The patients given rhGM-CSF had a recovery of the neutrophil count to 500 x 10(6) per liter 7 days earlier than the patients who received placebo (19 vs. 26 days, P less than 0.001), had fewer infections, required 3 fewer days of antibiotic administration (24 vs. 27 days, P = 0.009), and required 6 fewer days of initial hospitalization (median, 27 vs. 33 days; P = 0.01). There was no difference in the survival rate at day 100. CONCLUSIONS: In patients undergoing autologous bone marrow transplantation for lymphoid neoplasia, rhGM-CSF significantly lessens morbidity. Further studies will be required to establish its optimal dosage and schedule of administration.

A phase I/II trial of recombinant granulocyte-macrophage colony-stimulating factor for children with aplastic anemia.

Nine pediatric patients (median age, 8 years; range, 0.7 to 19 years), eight with refractory aplastic anemia and one with newly diagnosed aplasia, were enrolled in a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) administered via continuous intravenous infusion. Doses ranged from 8 to 32 micrograms/kg/d. Six of eight evaluable patients responded with a significant rise in neutrophil count (median fourfold increase; range, 2.5- to 31-fold) during the 28-day induction period. Five patients completed 2 further months of therapy (maintenance) with persistent or improved neutrophil responses. Three patients had bone marrow aspirates suggestive of increased erythropoiesis, although only one patient had improvement in peripheral hematocrit and platelet count. In the five patients completing maintenance, three experienced a rapid return to baseline counts after rhGM-CSF was discontinued, one maintained a neutrophil response for 2 months after drug discontinuation, and one has maintained a trilineage response for greater than 1 year off study. Drug therapy was well tolerated. Toxicity was minimal at doses from 8 to 16 micrograms/kg/d. Fever and rash were more commonly seen at 32 micrograms/kg/d. No patient developed an infection during the course of rhGM-CSF administration. These results demonstrate that rhGM-CSF increases peripheral neutrophil counts in children with refractory and newly diagnosed aplastic anemia and may be able to stimulate a multilineage response in a more limited number. Randomized, prospective trials are necessary to determine if rhGM-CSF administration will impact favorably on the morbidity and mortality of severe aplastic anemia.

Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection.

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) administered by the subcutaneous route, first alone and then alternating with azidothymidine (AZT), in leukopenic patients with severe human immunodeficiency virus (HIV) infection. Ten patients with acquired immunodeficiency syndrome (AIDS) or related disorders, five of whom could not tolerate conventional doses of AZT, were administered rGM-CSF subcutaneously for 12 days. They then were administered an alternating regimen using AZT for 1 week, followed by 5 days of subcutaneous rGM-CSF and 2 days without any medication. During the initial 12 days of GM-CSF administration, there was an increase in the mean white blood cell (WBC) value. In addition, rGM-CSF stimulated circulating monocytes as evidenced by an increase in superoxide anion production and expression of surface HLA-DR antigen. However, at the same time rGM-CSF increased the serum HIV p24 antigen in each of the six evaluable patients from 189 x/divided by 2.02 pg/mL (geometric mean x/divided by SEM) at entry to 375 x/divided by 2.11 pg/mL (P less than .05). During the subsequent period of alternating AZT and rGM-CSF treatment, serum HIV p24 antigen fell below the day 14 value in most patients, particularly after the weeks of AZT administration. The mean T4 cell value increased in patients who had not previously received AZT, but generally did not change in those who had prior AZT exposure. Hematologic toxicity appeared to be somewhat reduced compared with continuous full-dose AZT therapy, and two patients with previous AZT hematologic toxicity tolerated this alternating regimen for 25 weeks. Additional regimens simultaneously combining these two agents are worth exploring.

Treatment of refractory aplastic anemia with recombinant human granulocyte-macrophage-colony-stimulating factor.

Fifteen patients with refractory aplastic anemia or agranulocytosis received treatment with recombinant human granulocyte-macrophage-colony-stimulating factor (rhGM-CSF) in doses from 4 to 64 micrograms/kg/d by continuous intravenous (IV) infusion. Ten of 11 evaluable patients with aplastic anemia had substantial increments in granulocytes, monocytes, and eosinophils associated with myeloid and eosinophilic hyperplasia in the bone marrow. Patients with pretreatment granulocytes greater than 0.3 x 10(9)/L had greater increments in circulating myeloid cells than patients with more severe granulocytopenia. Only one patient had improvement in erythrocytes and platelets. Blood counts fell to baseline after rhGM-CSF treatment was discontinued. Doses up to 16 micrograms/kg/d were relatively well tolerated in the absence of extreme leukocytosis. Fatigue and myalgia were common. Three patients developed pulmonary infiltrates that resolved with discontinuation of treatment. Patients tended to have recurrent inflammation in previously diseased tissues. These data indicate that rhGM-CSF will increase circulating granulocytes, monocytes, and eosinophils in patients with refractory aplastic anemia. Further studies are necessary to determine if rhGM-CSF treatment will reduce morbidity or improve survival.

Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression.

An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.

Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation.

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) has been reported to increase the leukocyte count in subhuman primates subjected to total-body irradiation and in patients with the acquired immunodeficiency syndrome. We administered this substance to 19 patients with breast cancer or melanoma treated with high-dose combination chemotherapy and autologous bone marrow support. Groups of three or four patients were treated with 2.0, 4.0, 8.0, 16.0, or 32.0 micrograms per kilogram of body weight per day of glycosylated rHuGM-CSF by continuous intravenous infusion for 14 days, beginning three hours after bone marrow infusion. Total leukocyte and granulocyte recovery was accelerated in these patients as compared with 24 historical controls matched for age, diagnosis, and treatment. Leukocyte counts (mean +/- SD) obtained 14 days after transplantation were 1511 +/- 1003 per microliter in patients given 2 to 8 micrograms per kilogram per day, 2575 +/- 2304 in those given 16 micrograms, and 3120 +/- 1744 in those given 32 micrograms, as compared with 863 +/- 645 per microliter in the controls. No consistent effect on platelet counts was noted. Toxic effects were generally mild and not clearly dose-related in patients given 2 to 16 micrograms per kilogram per day. Edema, weight gain, or myalgias occurred in all patients given 32 micrograms per kilogram; marked weight gain, generalized edema, pleural effusions, and hypotension developed in two patients, one of whom also had acute renal failure. Our results indicate that rHuGM-CSF can accelerate myeloid recovery after high-dose chemotherapy and autologous bone marrow transplantation, over a range of doses that can be tolerated. In this setting the ability to increase the dose is limited by the development of myalgias and fluid retention.

Granulocyte-macrophage colony-stimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients.

We conducted a clinical trial of human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) in leukopenic patients with acquired immunodeficiency syndrome (AIDS) and analyzed neutrophil function before, during, and after in vivo administration of rGM-CSF. Prior to GM-CSF infusion, AIDS patients' neutrophil superoxide generation and neutrophil antibody-dependent cell-mediated cytotoxicity were enhanced normally by in vitro exposure to GM-CSF. Neutrophil phagocytosis and intracellular killing of Staphylococcus aureus were also normal in the majority of these patients. Two patients, however, had discrete neutrophil functional defects: one in phagocytosis and one in intracellular killing. During the period of GM-CSF infusion, these abnormalities were corrected. The number of circulating neutrophils increased in all patients treated with GM-CSF in a dose-dependent manner. Neutrophils produced in vivo in response to GM-CSF administration functioned normally and there was evidence for neutrophil priming and activation in vivo. We conclude that GM-CSF treatment of AIDS patients leads to the production of functionally active neutrophils, suggesting therapeutic potential for GM-CSF in the treatment of patients with impaired host defense.

Effect of recombinant human granulocyte-macrophage colony-stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome.

We administered recombinant (biosynthetic) human granulocyte-macrophage colony-stimulating factor (GM-CSF) to 16 patients with the acquired immunodeficiency syndrome (AIDS) and leukopenia (2225 +/- 614 cells per microliter [mean +/- SD]). Each patient first received a single intravenous dose; 48 hours later a 14-day continuous intravenous infusion of the agent was begun. The doses used were 1.3 X 10(3) (n = 4), 2.6 X 10(3) (n = 4), 5.2 X 10(3) (n = 4), 1.0 X 10(4) (n = 3), or 2.0 X 10(4) (n = 1) U per kilogram of body weight per day. Administration of recombinant GM-CSF resulted in dose-dependent increases in circulating leukocytes and in increases in circulating neutrophils, eosinophils, and monocytes. The peak leukocyte count ranged from 4575 +/- 2397 cells per microliter at the lowest dose, to 48,700 in the patient receiving the highest dose. Mild side effects--low-grade fever, myalgia, phlebitis, and flushing--were observed in some patients; there were no life-threatening toxic reactions. Our data demonstrate that recombinant human GM-CSF is well tolerated and biologically active in leukopenic patients with AIDS. Strategies to increase the number and function of circulating leukocytes may reduce the morbidity and mortality of infections in these and other patients with leukopenia.