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This study compares the immune properties of peripheral blood stem cell (PSC) products mobilized with different hematopoietic growth factors (HGFs) as well as apheresis products and peripheral blood leukocytes (PBL) from normal individuals. We found that monocytes in mobilized PSC products appear to inhibit T cell function independent of whether granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was used for mobilization. In addition, the GF used to mobilize the stem cell product may be less important to the CD4:CD8 ratio than the extent of prior chemotherapy, as we found an inverse correlation between chemotherapy and the CD4:CD8 ratio. In other observations, all apheresis products, whether mobilized or unmobilized, contained significantly more monocytes compared to normal PBL. The mononuclear cells (MNC) from G-CSF or GM-CSF mobilized PSC products had a similar T cell phytohemagglutinin (PHA) mitogenic response that was significantly lower (P = 0.001 and P = 0.005, respectively) than non-mobilized apheresis products. We also examined the T cell inhibitor (TI) activity of the MNC from the PSC products for allogeneic lymphocyte proliferation and found that PSC products significantly reduced the proliferation of allogeneic PBL to PHA. A significant correlation (P = 0.001, r = 0.517) between the frequency of monocytes and TI activity also was observed.

Purpose: A phase III trial to compare PIXY321 with granulocyte-macrophage colony-stimulating factor (GM-CSF) following high-dose therapy and autologous bone marrow transplant (ABMT) was conducted to evaluate the time to hematopoietic recovery., Patients and Methods: One hundred seventy-seven patients with non-Hodgkin's lymphoma (NHL) receiving ABMT were randomized to receive either PIXY321 750 micrograms/m2/d divided into two subcutaneous (SC) doses or GM-CSF 250 micrograms/m2/d as a 2-hour intravenous (IV) infusion starting on day 0 post-ABMT for a maximum of 28 days., Results: The median time to reach an absolute neutrophil count (ANC) > or = 500/microL in the PIXY321 group was 17 days versus 19 days in the GM-CSF group (P = .07) and the median time to reach platelet transfusion independence in the PIXY321 group was 25 days versus 23 days in the GM-CSF group (P = .30). The toxicity profiles of the two agents appeared to be equivalent with the exception of more patients in the PIXY321 group with a rash (64%) compared with the GM-CSF group (48%) (P = .028). A logistic regression model identified the use of a non-total-body irradiation (TBI) regimen and/or receipt of unpurged marrow and a body-surface area greater than 2.0 m2 as predictive of faster neutrophil engraftment, and those three factors, as well as the receipt of < or = two prior chemotherapy regimens as predictive for rapid platelet engraftment., Conclusion: There was a trend toward a slight improvement in neutrophil engraftment post-ABMT with the PIXY321 administered by an SC route compared with GM-CSF administered by an IV route. However, no differences could be identified between the two agents with respect to the time to platelet transfusion independence. Patient, regimen, and graft characteristics were most predictive of the engraftment tempo.

Purpose: Mobilization of peripheral-blood cells (PBC) with cytokines alone results in rapid hematopoietic recovery and avoids the potential morbidity associated with mobilization by chemotherapy. PIXY321, a fusion protein that consists of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), has enhanced hematopoietic colony-forming activity as compared with individual or equimolar combinations of the two cytokines. A phase I trial of PIXY321 for mobilization of PBC in patients with malignant lymphoma was performed., Patients and Methods: Thirteen patients with malignant lymphoma who were eligible for high-dose therapy (HDT) were enrolled onto the trial. All patients were ineligible for autologous bone marrow transplantation due to overt metastatic disease in the marrow or to severe marrow hypocellularity. PIXY321 was administered at three dose levels of 250, 500, and 750 micrograms/m2/d by continuous infusion until completion of PBC collections. Collections were initiated when the WBC count was greater than 10 x 10(9)/L or 4 days after the initiation of PIXY321, whichever came first. Collections were continued until a minimum of 6.5 x 10(8) mononuclear cells (MNC)/kg patient weight were obtained., Results: PIXY321 was generally well tolerated. Side effects associated with PIXY321 administration did not exceed grade 2 and included fever (85%), chills/sweats (54%), myalgias (38%), fatigue (31%), nausea/vomiting (31%), headache (31%), edema (23%), and rhinorrhea (23%). The median numbers of colony-forming units-granulocyte/macrophage (CFU-GM) in the graft products for the three dose levels were 0.31, 2.94, and 2.88 x 10(4)/kg, respectively; the median numbers of burst-forming units-erythroid (BFU-e) were 0.20, 6.94, and 12.78 x 10(4)/kg, and the median numbers of CD34+ cells were 2.30, 0.74, and 0.39 x 10(6)/kg. Following transplantation, the median times to an absolute neutrophil count (ANC) > 0.5 x 10(9)/L were 12, 15, and 12 days, respectively, and the median times to platelet transfusion independence were 30, 19, and 15 days., Conclusion: PIXY321 can be safely administered and effectively mobilizes PBC in patients with bone marrow defects. PIXY321-mobilized PBC autotransplants result in rapid and sustained hematopoietic recovery.

We evaluated the differences in engraftment and toxicities post-autologous transplant using granulocyte-macrophage colony stimulating factor (GM-CSF) as a continuous infusion either alone or in a sequential manner with granulocyte colony-stimulating factor (G-CSF). Patients receiving high-dose chemotherapy and autologous bone marrow transplantation (ABMT) for lymphoid malignancies participated in two phase II trials evaluating either continuous infusion GM-CSF (GM-CSF (CI)) or continuous infusion GM-CSF followed by sequential G-CSF (GM-CSF/G-CSF) administered post-ABMT. These patients were compared to similar historical control patients receiving GM-CSF administered as a 2-h intravenous (i.v.) infusion (GM-CSF (2-h)). Patients receiving GM-CSF (CI) and GM-CSF/G-CSF had a median day to reach an absolute neutrophil count of 500/microliter post-ABMT of 12 and 11 days, respectively. This compared to a median day of 22 in the GM-CSF (2-h) historical control patients. The median day to platelet independence was 18, 18 and 30 days, respectively. The incidence of toxicities such as incidence of infection, pleural effusions, and rash did not differ greatly between the groups. We conclude that the use of continuous infusion GM-CSF either alone or sequentially with G-CSF produced improved engraftment times compared to historical control patients treated with GM-CSF as a 2-h i.v. infusion. The toxicities at a reduced dose of 125 micrograms/m2 given as a continuous infusion appear to be similar to those seen in patients receiving GM-CSF as a 2-h infusion.

Purpose: A phase I/II study of PIXY321 following high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) was conducted to evaluate the safety and clinical potential of this agent., Patients and Methods: Fifty patients with Hodgkin's disease or non-Hodgkin's lymphoma (NHL) undergoing HDT and ABMT received PIXY321 post-ABMT in doses that ranged from 50 to 1,000 micrograms/m2/d either as intravenous (i.v.) or subcutaneous (SC) dosing until engraftment was reached., Results: If all doses are considered together, the median time to reach an absolute neutrophil count (ANC) > or = 500/microL was 18 days and the median time to platelet transfusion independence was 21 days. At the estimated optimum dose of 750 micrograms/m2/d by SC injection once daily, the median time to reach an ANC > or = 500/microL was 15 days and the median time to platelet transfusion independence was 16 days. Historical control patients who received granulocyte-macrophage colony-stimulating factor (GM-CSF) had a median time to an ANC > or = 500/microL of 19 days and a median time to platelet independence of 26 days., Conclusion: The administration of PIXY321 post-ABMT was generally well tolerated and resulted in prompt engraftment in the majority of patients who underwent HDT and ABMT for lymphoid malignancies. The optimum dose and route of administration of PIXY321 suggested by this trial was 750 micrograms/m2/d by once-daily SC injection. Compared with historical control patients who received 2-hour i.v. GM-CSF, patients who received PIXY321 at 750 micrograms/m2/d by SC injection once daily had an improvement in the median days to neutrophil and platelet engraftment by 4 and 10 days, respectively.

In an effort to determine whether subcutaneous or continuous intravenous infusion administration of rhGM-CSF results in better hematopoietic progenitor mobilization, the findings of two sequential clinical trials were reviewed. Patients who had received prior chemotherapy for leukemia, lymphoma, multiple myeloma, breast cancer, or other solid tumors and were candidates for high-dose therapy received rhGM-CSF, 250 micrograms/m2/day, either as a continuous intravenous infusion (trial 1) or subcutaneously (trial 2) for stem cell mobilization. At least five apheresis collection procedures were performed to collect a target number of 6.5 x 10(8) mononuclear cells (MNC)/kg. For the 37 patients in trial 1, the collections contained a median of 7.99 x 10(8) MNC/L (range 6.42-21.36) and a median of 5.27 x 10(4) CFU-GM/kg (range 0.28-19.35). In trial 1, 25 patients were autografted with their cells and recovered 0.5 x 10(9) granulocytes/L at a median of 12 days (range 6-16). For the 33 patients in trial 2, the autograft product contained a median of 7.63 x 10(8) MNC/kg (range 6.51-22.66) and 6.31 x 10(4) CFU-GM/kg (range 0.06-60.4). In trial 2, 25 patients were autografted. The median time to reach 0.5 x 10(9) granulocytes/L was 11 days (range 9-26). All patients received rhGM-CSF after peripheral stem cell transplant. No significant differences in the collected products or the time to hematopoietic recovery was found between the two trials (p > 0.05). The mobilization effects of subcutaneous rhGM-CSF in these pretreated patients were similar to those of intravenous rhGM-CSF.

Between June 1989 and June 1992, 144 patients participated in sequential clinical trials using peripheral blood progenitor cells (PBC) as their sole source of hematopoietic rescue following high-dose chemotherapy. All patients had received prior extensive combination chemotherapy and had marrow defects that precluded autologous bone marrow transplantation (ABMT). PBC were collected according to a single apheresis protocol. The initial 86 patients (group 1) had PBC collected without mobilization. Beginning in April 1991, PBC were mobilized solely with recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF). Thirty-four patients (group 2) received rHuGM-CSF at a dose of 125 micrograms/m2/d by continuous intravenous infusion, and 24 patients (group 3) received rHuGM-CSF at a dose of 250 micrograms/m2/d by continuous intravenous infusion. Patients underwent at least six aphereses and had a minimum of 6.5 x 10(8) mononuclear cells (MNC)/kg collected. Cytokines were not routinely administered immediately after transplantation. A median of nine aphereses were required to collect PBC in group 1 and seven aphereses for groups 2 and 3 (P = .03). The time required to recover 0.5 x 10(9)/L granulocytes after transplant was significantly shorter (P = .0004) for the mobilized groups; the median time to recovery was 26 days for group 1, 23 days for group 2, and 18 days for group 3. Transplantation of PBC mobilized with rHuGM-CSF resulted in a shorter time to platelet (P = .04) and red blood cell (P = .01) transfusion independence. Mobilization with rHuGM-CSF alone resulted in efficient collection of PBC, that provided rapid and sustained restoration of hematopoietic function following high-dose chemotherapy. Mobilization of PBC with rHuGM-CSF alone is an effective method for patients who have received prior chemotherapy and have bone marrow abnormalities.

One hundred and twenty-eight patients with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), and acute lymphoblastic leukemia (ALL) previously reported from a phase III trial of rhGM-CSF or placebo following autologous bone marrow transplantation (ABMT) were investigated for the development of late toxicities. Median follow-up is 36 months. No apparent long-term deleterious effects on BM function were observed. Moreover, disease-free survival and overall survival were similar for patients on both treatment arms, arguing for the long-term safety of recombinant human granulocyte macrophage-colony-stimulating factor (rhGM-CSF). The only factors predictive for both a high risk of relapse over time and mortality were having the diagnosis of ALL and/or undergoing ABMT in resistant relapse. We attempted to identify clinical variables before BM harvest, at the time of marrow infusion, or events within the first 100 days posttransplant, which might predict speed of neutrophil recovery in the setting of placebo or rhGM-CSF administration after ABMT. Only previous exposure to agents that deplete stem cells led to a significant delay in neutrophil recovery, suggesting their avoidance in patients who may undergo ABMT. Nevertheless, even those patients benefited from rhGM-CSF. For all patients, rhGM-CSF and agents that deplete stem cells were the strongest independent predictors for neutrophil engraftment. With the increasing use of newer hematopoietic growth factors both alone and in combination, long-term follow-up is essential to confirm the same safety that we report with rhGM-CSF.

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.

To test the value of recombinant human granulocyte-macrophage colony stimulating factor for the treatment of delayed engraftment following high dose therapy and autologous hematopoietic stem cell transplantation, we enrolled 12 patients with recurrent non-Hodgkin's lymphoma or Hodgkin's disease having an absolute granulocyte count less than 150 x 10(6)/l on day 30 after autologous hematopoietic stem cell infusion in an open-label, nonrandomized study. These patients were compared to 21 similar historical control patients who were not treated with colony stimulating factor. Overall, the patients treated with granulocyte-macrophage colony stimulating factor had a mean absolute granulocyte count of 704 x 10(6)/l on day 44 after stem cell infusion compared to a mean absolute granulocyte count of 408 x 10(6)/l in historical controls (p = 0.008). The number of documented bacterial and fungal infections occurring after day 30 (9 vs 0, p = 0.01) was significantly reduced in the study group. The toxicity attributed to the granulocyte-macrophage colony stimulating factor was minimal with only one patient experiencing chills. Recombinant human granulocyte-macrophage colony stimulating factor appears to be effective for the treatment of delayed engraftment following high-dose therapy and autologous hematopoietic transplantation for lymphoid malignancies, with most patients having accelerated granulocytic recovery and a reduced incidence of infections.