Recombinant human granulocyte colony-stimulating factor increases circulating CD34-positive cells in patients with AIDS

 In a gene therapy-based treatment of AIDS, it would be desirable to have as many transduced target cells as possible. A limiting factor is the number of target cells. In this study, we investigated whether it was possible to increase the absolute number of one possible target cell, i.e., the circulating hematopoietic progenitor cells (CD34 cells) in patients with AIDS, using the recombinant human granulocyte colony-stimulating factor (G-CSF). Eight patients with AIDS were treated with G-CSF for neutropenia (<1.0×10⁹/l). Treatment consisted of daily subcutaneous injections with 300 μg G-CSF for 3–5 consecutive days. Within 5 days of initiation of G-CSF therapy, an increase in the absolute neutrophil count (ANC) was seen in all patients. There was a median increase in ANC from 0.4 to 3.4×10⁹/l. In addition, G-CSF treatment significantly increased the absolute number of CD34 cells. The median increase in CD34 cells was from 0.8 to 2.2×10⁶/l. Finally, using a highly sensitive HIV-1 RNA PCR, we found that treatment of AIDS patients with G-CSF did not lead to enhanced HIV replication. These observations indicate that G-CSF may be used to mobilize CD34 cells in patients with AIDS, e.g., for a gene therapy protocol. Received: 8 August 1996 / Accepted: 27 January 1997     

Combined administration of alpha-erythropoietin and filgrastim can improve the outcome and cost balance of autologous stem cell transplantation in patients with lymphoproliferative disorders

We compared the use of G-CSF plus EPO in a group of 32 multiple myeloma and lymphoma patients with historical controls receiving G-CSF alone. Haemopoietic reconstitution was significantly faster in patients receiving G-CSF+EPO (group B), with a median time of 10 days to achieve an ANC count >0.5 x 10(9)/l, compared to 11 days in the historical group (A). The median duration of severe neutropenia (ANC count <100/ml) was significantly shorter in group B compared to group A; platelet counts >20 x 10(9) and >50 x 10(9)/l were achieved at days + 13 and + 17, respectively in group B, compared to days + 14 and + 24, respectively, in group A (P = 0.015, 0.002) patients. The transfusion requirement was reduced in group B, with 0 (0-6) RBC units and 1 (0-5) platelet unit transfused in group B vs 2 RBC (0-9) and 2 platelet units (0-8) in group A. Median days of fever, antibiotic therapy and hospital stay were reduced in group B (9.5 days vs 22). The mean cost of autotransplantation per group A patient was 23,988 Euro, compared with 18,394 Euro for a group B patient. Our study suggests that the EPO + G-CSF combination not only accelerates engraftment kinetics, but can also improve the clinical course of ASCT.     

Recombinant human granulocyte colony-stimulating factor (rh-G-CSF) may accelerate hematopoietic recovery after HLA-identical sibling allogeneic peripheral blood stem cell transplantation

We studied the effects of recombinant human granulocyte colony-stimulating factor (G-CSF) on hematopoietic recovery and clinical outcome in patients undergoing allogeneic peripheral blood stem cell (PBSC) transplantation. Fifty-six patients with hematological malignancies who underwent allogeneic PBSC transplantation between 1995 and 1998 were entered into this study. Twenty-eight patients who received daily G-CSF from day +1 after allogeneic PBSC transplantation until the absolute neutrophil count (ANC) reached >0.5 x 10(9)/l for 3 consecutive days were compared with 28 patients (control group) who did not receive G-CSF in a non-randomized manner. The study group and the control group were comparable with respect to baseline patient and transplantation characteristics. Median times to ANC of >0.5 x 10(9)/l and 1 x 10(9)/l with or without G-CSF were 12 days (range 8-21), 13 days (10-32) (P = 0.04) and 13 days (9-21), 15 days (11-44) (P = 0.02), respectively. Median times to reach a platelet count of >20 x 10(9)/l with and without G-CSF were 11 days (0-20) and 13 days (9-26), respectively (P = 0.03). The incidence of febrile episodes was significantly lower with G-CSF, 75% vs 100% (P = 0.008). Patients receiving G-CSF had less grade III-IV mucositis than those who did not receive G-CSF (P = 0.01). There was also no increase in the incidence and severity of acute GVHD in patients using G-CSF (P = 0.22). Although the number of relapsing patients was greater in the G-CSF group (seven vs three patients), this was not statistically significant (P = 0.24). Disease-free and overall survival rates did not differ between the two groups (P = 0.58 and 0.53, respectively). The administration of G-CSF after allogeneic PBSC transplantation provided faster neutrophil and platelet engraftment associated with less severe mucositis and less febrile episodes.     

Increase of monocytes predicts mobilization of peripheral stem and progenitor cells after chemotherapy followed by G-CSF administration

Abstract: Mobilization of primitive haematopoietic cells to the peripheral blood was studied in 25 patients with haematological malignancies. The optimal level of peripheral stem cells (PSC), defined by their surface expression of CD34, was significantly higher after mobilization with G-CSF, either following chemotherapy or alone (median: 123 × 10⁶/l and 143 × 10⁶/l of CD34+ cells respectively) than without administration of G-CSF subsequent to chemotherapy (median: 27 × 10⁶/l of CD34+ cells). An individual variation in when optimal mobilization of CD34+ cells and myeloid progenitors occurs after chemotherapy and G-CSF administration was noted (median: day 12, range 7–24 days), which makes it difficult to predict when PSC collections in a given patient should be performed. In this study, chemotherapy followed by G-CSF administration resulted in a short lasting (2–3 days) peak appearance of CD34+ cells that could predicted by a 2-fold increase in absolute numbers of monocytes, as compared to the previous day. After the peak level of CD34+ cells in the blood was reached, no further increase in monocytes was seen. The identification of an increase in monocytes, to be used as a predictive variable for when optimal mobilization of PSC will occur in a given patient, may be particularly useful in the individual timing of PSC collections from non-hospitalized patients.     

Effects of G-CSF administration and peripheral blood progenitor cell collection in 20 healthy donors

 The effects of both daily G-CSF administration and subsequent peripheral blood progenitor cell collection (PBPCC) by apheresis on 20 healthy adult donors were studied. All received daily G-CSF (filgrastim) 10 μg/kg for 5–7 days by subcutaneous injection. G-CSF administration was well tolerated, except for moderate bone pain and headache. Peak values of CD34+ cells were observed on days 5 (n=12) or 6 (n=8). In all donors a significant increase in CD3+, CD4+, CD8+, CD19+, and NK cells was observed on day 5 in relation to the baseline values. CD4/CD8 lymphocyte ratio was unmodified by G-CSF. None of the donors required a central venous line for PBPCC. Immediately after PBPCC, a platelet count below 100×10⁹/l was observed in nine of 18 cases, although in all donors platelet counts were over 100×10⁹/l 7 days later. A lymphocytopenia on day 7 following PBPCC was observed, although there was a tendency to achieve baseline values 30–90 days after the procedure. Mean numbers (±SD) of collected cells ×10⁶/kg after a median of two (1–4) apheresis sessions and a median of 20 l (10–40) processed were: CD34+ 5.5 (±2.3), CD3+ 326 (±105), CD4+ 207 (±64), CD8+ 164 (±60), CD19+ 88 (±32), and NK cells 32 (±14). We conclude that G-CSF administration to healthy donors is a well-tolerated procedure which is associated with (a) obtaining a high number of hematopoietic progenitor cells, and (b) a significant increase in T, B, and NK cells in donors' blood. In addition, PBPCC by apheresis results in a moderate, rapidly reversible, and clinically irrelevant thrombocytopenia and a moderate lymphocytopenia, which tends to resolve within 3 months following the procedure. Received: 28 December 1995/Accepted: 22 January 1996     

Optimal timing of G-CSF administration after CD34+ immunoselected peripheral blood progenitor cell transplantation.

G-CSF accelerates neutrophil recovery after autologous peripheral blood progenitor cell transplantation (aPBPCT), although the optimal timing for its administration is currently unknown. In order to establish the role and the optimal timing of administration of G-CSF after immunoselected CD34+ aPBPCT, we analyzed the data from 21 consecutive patients affected by haematological malignancies. Patients were randomized into three groups according to G-CSF administration after transplantation: day +1 (group B); day +7 (group C) or no G-CSF (group A). Serum G-CSF level was evaluated until engraftment. The CD34+ cell dose reinfused was similar (P = 0.48). G-CSF significantly reduced time to recovery of PMN >0.5 x 10(9)/l (11 vs 14 vs 20.5 days) (P= 0.00046); >1.0 x 10(9)/l (12 vs 15 vs 22) (P = 0.001). No difference was observed in the number of days with PMN <0.1 x 10(9)/l (5.5 vs 7 vs 8 days). Platelet count >50 x 10(9)/l and >100 x 10(9)/l, reticulocytes >1%, length of hospitalization, non-prophylactic antibiotic therapy, fever, incidence of sepsis and transfusion support did not differ. Early or delayed G-CSF after immunoselected CD34+ aPBPCT significantly accelerated PMN recovery but did not reduce the amount of supportive treatment or the duration of hospitalization. Delaying the initiation of G-CSF did not reduce the length of treatment (11.5 vs 12 days). Early or delayed G-CSF administration resulted in G-CSF peak serum levels 7 (early)-12 (delayed)-fold greater than an endogenous response to neutropenia.     

Peripheral blood stem cell mobilization by granulocyte colony-stimulating factor alone and engraftment kinetics following autologous transplantation in children and adolescents with solid tumor

In 56 pediatric and adolescent patients (median age 7 years, range 1-21) with various solid tumors, peripheral blood stem cells (PBSC) were mobilized with granulocyte colony-stimulating factor (G-CSF) alone, and the yields of PBSC and engraftment kinetics following autologous peripheral blood stem cell transplantation (PBSCT) were evaluated retrospectively. Granulocyte colony-stimulating factor (10 microg/kg) was injected subcutaneously for mobilization when patients showed no influence of previous chemotherapy, and administration was continued for 5 days. The peaks of CD34+ cells and colony-forming units-granulocyte/macrophage in the blood were observed on days 4 through 6 of G-CSF administration in all patients. Peripheral blood stem cell harvest was commenced on day 5 of G-CSF treatment. Compared to the results in patients mobilized by chemotherapy plus G-CSF (N=18), the progenitor cell yields were lower in patients mobilized with G-CSF alone. However, there were no significant differences in WBC and ANC engraftment compared to the chemotherapy plus G-CSF mobilization group. Platelet recovery following autologous PBSCT was delayed in patients mobilized with G-CSF alone. The median time taken for ANC and platelet counts to reach 0.5 x 10(9) and 20 x 10(9)/l was 12 days (range: 9-28) and 15 days (8-55), respectively, in all patients who received PBSC mobilized by G-CSF alone. In summary, mobilization with G-CSF alone can mobilize sufficient CD34+ cells for successful autografting and sustained hematological reconstitution in pediatric and adolescent patients with solid tumors, and even in heavily pre-treated patients.     

Individually determined dosing of filgrastim after autologous peripheral stem cell transplantation in patients with malignant lymphoma--results of a prospective multicentre controlled trial

OBJECTIVES: To explore the safety and effectiveness of the individually determined application granulocyte-colony stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (ASCT). METHODS: The administration of G-CSF from day +5 (arm A) was compared in a randomised, controlled trial with delayed, individually determined administration (G-CSF started when WBC >or= 0.5 x 10(9)/L and ANC >or= 0.1 x 10(9)/L or at day +10; arm B), and with placebo (arm C). RESULTS: One hundred and six patients, median age 45 (range 21-64), all with malignant lymphoma treated with BEAM chemotherapy were analysed. A significant difference in the time to neutrophil engraftment and in the duration of neutropenia <0.5 x 10(9)/L and <1.0 x 10(9)/L was observed between the arms (P = 0.04-<0.0001) with a 1-d prolongation of the median durations in arm B in comparison with arm A but a 2-4-d prolongation in the placebo arm C in comparison with arm B. The median number and range of days to neutrophil engraftment >0.5 x 10(9)/L after graft re-infusion was 10 (9-14) in arm A; 11 (9-19) in arm B; and 14 (10-30) in arm C (P < 0.0001). Engraftment of platelets to >20 x 10(9)/L and >50 x 10(9)/L was significantly delayed in the arms using G-CSF in comparison with placebo (P = 0.04-0.002) without any increase in bleeding or in transfusion requirement. There was no difference in the incidence and duration of transplant-related complications and their treatment between the arms. CONCLUSIONS: Our study has confirmed the safety of individually determined administration of G-CSF. The optimal timing of G-CSF application after ASCT in patients with good-quality grafts is shortly before expected spontaneous engraftment.     

A comparative effectiveness study of lipegfilgrastim in multiple myeloma patients after high dose melphalan and autologous stem cell transplant

G-CSF administration after high-dose chemotherapy and autologous stem cell transplantation (ASCT) has been shown to expedite neutrophil recovery. Several studies comparing filgrastim and pegfilgrastim in the post-ASCT setting concluded that the two are at least equally effective. Lipegfilgrastim (LIP) is a new long-acting, once-per-cycle G-CSF. This multicentric, prospective study aimed to describe the use of LIP in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation (ASCT) and compare LIP with historic controls of patients who received short-acting agent (filgrastim [FIL]). Overall, 125 patients with a median age of 60 years received G-CSF after ASCT (80 patients LIP on day 1 post-ASCT and 45 patients FIL on day 5 post-ASCT). The median duration of grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 10 [9]/L) was 5 days in both LIP and FIL groups, whereas the median number of days to reach ANC ≥ 0.5 × 10 [9]/L was 10% lower in the LIP than in the FIL group (10 vs 11 days), respectively. Male sex was significantly associated with a faster ANC ≥ 0.5 × 10 [9] L response (p = 0.015). The incidence of FN was significantly lower in the LIP than in the FIL group (29% vs 49%, respectively, p = 0.024). The days to discharge after ASCT infusion were greater in patients with FN (p < 0.001). The study indicates that LIP had a shorter time to ANC recovery and is more effective than FIL for the prevention of FN in the ASCT setting.     

Assessment of the value of treatment with granulocyte colony-stimulating factor in children with acute lymphoblastic leukemia: a randomized clinical trial

Abstract: The present trial was designed to test the effects of G-CSF on the duration of the second phase of induction chemotherapy in children with newly diagnosed acute lymphoblastic leukemia (ALL). A total of 32 patients were assigned randomly to a group that received (14 patients; group A) or a group that did not receive (18 patients; group B) G-CSF (10 g/kg/day subcutaneously and daily) throughout of the second phase of induction therapy. One of 14 (7.1%) patients in group A and 2 of 18 (11.1%) patients in group B completed the course of chemotherapy within the planned time. The median length of this phase was 37 days (range, 29 to 65; mean, 40; SD, 8.6) for patients in group A and 36 days (range, from 29 to 55; mean, 38; SD, 7.4) for those in group B, and the difference was not statistically significant. The number of days during which patients had granulocyte counts of less than 2 × 10⁹/l, the number of febrile episodes of unknown origin, the number of bacterial and fungal infections and the number of days of hospitalization did not differ in a statistically significant manner between the two groups. Our data suggest that G-CSF supportive therapy may be unnecessary in children with neutropenia of short duration, for whom the risk of infection is low.     

Randomized comparison of two different schedules of granulocyte colony-stimulating factor administration after allogeneic bone marrow transplantation.

We performed a randomized trial to determine whether there are differential effects of G-CSF when it is either started on the day (day 0 group) or on the 6th day of marrow infusion (day 5 group) in the allogeneic BMT setting. G-CSF 450 microg was given intravenously daily until the peripheral blood ANC was over 3000/microl. Between May 1995 and April 1998, 60 patients were enrolled (30 in each group). Median number of days of G-CSF administration was significantly longer for the day 0 group (18.5 vs 14.0 days, P < 0. 001). Median days to an ANC over 500/microl were the same in both groups (16 days). Median days to an unsupported platelet count of 20 000/microl did not show significant differences (29.5 vs 28 days, P = 0.202). The frequency of hepatic VOD was higher for the day 0 group (66.7 vs 40.0%, P = 0.038). Mean plasma antithrombin III level was significantly lower in the day 0 group on post-transplant day 7 (83.6 vs 93.9%, P = 0.009). Patients in the day 0 group showed significantly worse 100-day survival (25/30 vs 30/30 surviving respectively, P = 0.019). In conclusion, early initiation of G-CSF after allogeneic BMT did not facilitate marrow engraftment. In addition, early administration of G-CSF was associated with a higher frequency of VOD and a significant fall in plasma antithrombin III level.     

Recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for malignant lymphoma: a British National Lymphoma Investigation double-blind, placebo-controlled trial

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is active in enhancing the production of mature myeloid cells in vitro and several phase I/II clinical trials have suggested that its administration may accelerate neutrophil recovery after autologous bone marrow transplantation (ABMT). We have conducted a multicentre randomized double-blind placebo controlled trial in patients with poor prognosis malignant lymphoma receiving an identical high-dose combination chemotherapy regimen with ABMT. 61 patients were entered and 29 in each arm of the trial were evaluated. Treatment with GM-CSF did not affect the period of severe neutropenia (absolute neutrophil count (ANC) of < 0.1 x 10(9)/l) but accelerated recovery to an ANC of 0.5 x 10(9)/l (median 14 d v 20 d in controls, P = 0.001). There was no significant difference in platelet recovery between the groups (GM-CSF group platelet dependent for 25 d v control 19 d, P = NS). The number of positive blood cultures was similar in both groups (GM-CSF 14 v placebo 13) and there were no differences in days of fever > 37.5 degrees C (median 8 v 6) or days on parenteral antibiotics (11 v 10). Patients receiving GM-CSF had a median period of hospitalization following BMT of 24 d (control 25). No significant major toxicity attributable to GM-CSF administration was detected. We have confirmed in a randomized trial that GM-CSF accelerates neutrophil but not platelet recovery following ABMT. We were unable to demonstrate any accompanying changes in clinical outcome and believe that further trials are necessary to assess the clinical value of GM-CSF in BMT.     

Flow cytometric reticulocyte quantification in the evaluation of hematologic recover

Abstract: The role of flow cytometric reticulocyte (RET) counting and the immature RET fractions (IRF) in the evaluation of hematopoietic recovery following chemoradiotherapy-induced aplasia was studied. RET counts and IRF were studied using an automated flow cytometric reticulocyte counter (Sysmex R-2000) in three groups of patients: 58 patients undergoing an autologous bone marrow transplantation (ABMT group), 28 of whom received granulocyte colony-stimulating factor (G-CSF); 28 patients undergoing an allogeneic bone marrow transplantation (BMT group); and 28 patients receiving remission-induction chemotherapy for acute leukemia (CHEMO group). To evaluate the IRF the percentages of RET fractions with middle and high fluorescence reticulocyte (MFR and HFR, respectively) were used. A rising IRF (expressed as the percentage of MFR ± HFR) was the first sign of hematopoietic recovery (ABMT group, IRF 9 days versus 18 days for the absolute neutrophil count (ANC); BMT group, 15 versus 18 days; CHEMO group, 9 versus 11 days). When recovery of the ANC (>0.5 times 109/1) was compared with that of the IRF (MFR ± HFR > 5%), statistically significant differences were found in all three groups. Additionally, 93.1% of the ABMT, 92% of the BMT and 91.2% of the CHEMO recovered the IRF before the ANC. In conclusion, an elevation in the percentage of IRF is the first sign of hematologic recovery in the majority of patients receiving remission-induction chemotherapy and the first sign of engraftment in those submitted to ABMT or BMT. Serial automated flow cytometric quantitative reticulocyte counting provides a useful and early measure of erythropoiesis indicative of hematopoietic reconstitution or successful bone marrow engraftment following marrow transplantation.     

Successful autologous bone marrow rescue in patients who failed peripheral blood stem cell mobilization

 We assessed autologous bone marrow (BM) harvest and hematologic recovery after high-dose chemotherapy (HDCT) in patients who failed to achieve peripheral blood stem cell (PBSC) mobilization. One hundred and ninety-three patients with germ cell tumor, malignant lymphoma, sarcoma or medulloblastoma were scheduled for HDCT. In 123 patients, PBSC were mobilized by disease-specific chemotherapy plus granulocyte colony-stimulating factor (G-CSF). In 110/123 patients (89%) with circulating CD34+ cell counts ≥10/μl, sufficient hematopoietic autografts were collected (group A). In 13/123 patients (11%) with peripheral CD34+ cell counts <10/μl, PBSC harvesting was not performed (group B). These latter patients were classified as "poor mobilizers" and underwent second-line BM harvest at a median of 46 (range 10–99) days after mobilization failure. Seventy patients with first-line BM harvest (group C) acted as historical controls. Ten patients from group B proceeded to HDCT and nine were evaluable for hematopoietic reconstitution. Recovery to neutrophils >0.5×10⁹/l was comparable with group C patients: 16 (range 9–34) days vs 13 (range 8–98) days. However, platelet (PLT) reconstitution >20×10⁹/l was significantly slower, with a median of 35 (range 13–50) days as compared with 19 (range 9–148) days (P=0.0106) for control patients. Supportive care requirements, febrile days and length of hospital stay were not significantly different between the two groups of patients. We conclude that patients who fail to mobilize PBSC should be evaluated for second-line BM harvest. This approach may preserve the therapeutic option of HDCT for these patients. Received: 7 March 2000 / Accepted: 4 May 2000     

Late G-CSF after allogeneic bone marrow or peripheral blood stem cell transplantation: a prospective controlled trial

Granulocyte colony-stimulating factor (G-CSF) is widely used to accelerate neutrophil recovery after allogeneic BMT or PBSC transplantation. The optimal time to start G-CSF treatment is not known. Forty-two patients undergoing allogeneic BMT or PBSC transplantation for hematological malignancies received G-CSF either on day 6 or on day 9 post transplant. The time to hematological recovery was monitored and the two groups were compared with respect to peritransplant morbidity and mortality. Recovery of the neutrophil counts to >0.1 x 10(9)/l, > 0.5 x 10(9)/l and >1.0 x 10(9)/l were not significantly different in either group. There was no difference in recovery of red blood cell and platelet counts and no difference between the two groups with respect to the number of febrile days or number of days on antibiotic treatment. Documented bacterial, viral or fungal infections did not occur more often when G-CSF treatment was started on day 9. Delaying treatment with G-CSF resulted in a significant reduction in the length of treatment from 13 to 10 days (23.1% reduction). Reducing the length of the treatment by 3 days lowered the costs by 395.40 Euro per patient. Delaying G-CSF treatment and starting on day 9 after BMT or PBSC transplantation is safe and results in a clear economic benefit.     

A BCNU-containing Regimen,Mini-BEAM,with GM-CSF is a Safe and Effective Mobilizing Regimen Pre-stem Cell Transplantation in Lymphoma Patients

Concern has been raised regarding the quality and engraftment potential of peripheral stem cells obtained from mobilizing regimens containing BCNU. We compared the mononuclear cell (MNC) yields and engraftment times of neutrophils and platelets in twenty-nine patients who received autologous peripheral blood stem cell transplants at our institution. Sixteen patients with either refractory or resistant Hodgkin's disease or non-Hodgkin's lymphoma, were mobilized with a BCNU-containing regimen, mini-BEAM (BCNU 60 mg/m² on day 1, etoposide 100 mg/m² on days 1–3, cytarabine 150 mg/m²q12h on days 1–3, and melphalan 30 mg/m² on day 3). Thirteen patients with various malignancies were mobilized with non-BCNU containing priming regimens. All patients received rhGM-CSF (Leukine, Immunex, Seattle, WA) 250μg/m² subcutaneously daily from 24 hours after completion of mobilizing chemotherapy through the completion of leukapheresis. The mean mononuclear cell yields in the BCNU versus non-BCNU containing regimens were 2.15 and 1.97 × 10⁸ MNC/kg [95% CI -.32 to.68] after a median of 3 and 3 leukaphereses respectively. The median time post-stem cell infusion to an absolute neutrophil count (ANC) of ≥0.5 × 10⁹/1 were 11 days and 13 days [mean 11.7 and 12.2, p = 0.99, 95% CI -2.5, 1.6], days to an ANC of ≥1.0 x 10⁹/1 were 13 and 13 [mean 13.8 and 13.1, p = 0.47, 95% CI-1.8, 3.3], days to a platelet count of ≥20 × 10⁹/1 were 9 and 9 days [mean 11.4 and 9.8, p = 0.10, CI -0.6, 4.0], and days to a platelet count of ≥50 × 10⁹/1 were 14 and 15 days (p = 0.14) respectively. Mini-BEAM, as a mobilizing regimen, is easily administered as an outpatient. Stem cells mobilized with this regimen produces similar mononuclear cell yields as compared to non-BCNU containing regimens. There was no difference in the engraftment times for ANC or platelets from stem cells mobilized with BCNU versus non-BCNU containing regimens.     

Studies of oral neutrophil levels in patients receiving G-CSF after autologous marrow transplantation

Patients are at risk of mucositis and infections in the oral cavity during the neutropenic period after chemotherapy, which are significant causes of morbidity. In phase I/II studies with the haemopoietic growth factor granulocyte colony stimulating factor (G-CSF), a reduction in post-chemotherapy mucositis has been observed in addition to haematologic effects. To understand this phenomenon better in patients receiving G-CSF following high-dose chemotherapy with autologous bone marrow transplantation (ABMT), we studied the effects of G-CSF on levels of neutrophils recoverable from the oral cavity using a quantitative mouthrinse assay. In normal subjects, mouthrinses contained 472 +/- 329 x 10(3) neutrophils/mouthrinse. After chemotherapy followed by ABMT, mouthrinse neutrophil levels decreased to undetectable levels during the neutropenic period, but recovered 1-2 and 3-9 d before circulating neutrophil levels reached 0.1 and 1 x 10(9)/l respectively, whether or not patients received G-CSF. In patients who received G-CSF, the mean cumulative mucositis score was reduced from 35 +/- 9 to 21 +/- 12 (P < 0.05), and the maximum mean daily mucositis score was reduced from 2.8 +/- 0.5 to 1.7 +/- 0.9 (P < 0.01), compared to patients who did not receive G-CSF after ABMT. These studies provide in vivo evidence that neutrophils produced during G-CSF therapy are available to leave the circulation and enter tissues where their function is required for host defence. Since the usual temporal relationship between oral and peripheral blood neutrophil recovery was preserved during G-CSF administration after ABMT, these data support the hypothesis that the reduction in post-ABMT mucositis observed with G-CSF therapy may reflect a beneficial effect of G-CSF on the kinetics of oral mucosal neutrophil recovery in addition to the effect of G-CSF to accelerate peripheral blood neutrophil recovery.     

A phase 1 study to address the safety and efficacy of granulocyte colony-stimulating factor for the mobilization of hematopoietic progenitor cells in active rheumatoid arthritis

Objective. To examine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) alone for the mobilization of peripheral blood progenitor cells in patients with resistant active rheumatoid arthritis (RA). Methods. Five patients with resistant active RA were studied. A dose of 5 μg/kg of G-CSF (Filgrastim) was given subcutaneously each day for 5 days, and the number of stem cells mobilized into the peripheral blood was assessed by daily CD34 counts. RA disease activity was assessed by standard clinical methods. Results. The absolute numbers of peripheral blood CD34+ cells peaked on day 4, with a mean value of 0.025 × 10⁹/liter (range 0.013–0.048 × 10⁹/liter). There was no significant change in disease activity during the study or in the month following therapy. Conclusion. Using G-CSF alone, CD34+ progenitor peripheral blood cells were mobilized in numbers suitable for leukopheresis. G-CSF therapy was welltolerated in patients with active RA, and was not associated with a flare during treatment or in the month following treatment.     

Sequential peripheral blood progenitor cell transplantation after mobilization with salvage chemotherapy and G-CSF in patients with resistant lymphoma

We enrolled 18 patients affected by refractory or relapsed lymphoma (HD, NHL) in a two-step protocol that included salvage chemotherapy with mitoxantrone, carboplatinum, methylprednisolone, and cytosine arabinoside (MICMA) plus G-CSF (5 μg/kg/day), peripheral blood progenitor cell (PBPC) collection, and subsequent transplantation after BUCY2 regimen. After MiCMA chemotherapy, four patients (22%) achieved complete response, eight patients (44%) obtained a partial response, and six showed progression of disease (PD). Fourteen out of 18 patients (78%) were considered eligible for PBPC transplantation. Three patients with complete response refused PBPCT; they are currently in continuous complete remission (CCR) at 15, 13, and 15 months, respectively. One patient has been recently transplanted but is too early to be evaluated. Ten patients so far completed the study, eight of whom are currently alive in CR, with a median follow-up of 7.5 months (range 2–13). Hematologic reconstitution was very rapid with a median time to achieve WBC > 1 × 10⁹/L, PMN > 0.5 × 10⁹/L, platelets > 50 × 10⁹ /L and > 100 × 10⁹/L of 13 (range 9–15), 12(range 9–14), 10(range 0–22), and 14 (range 5–49) days, respectively. Our protocol is highly effective as a salvage treatment, while permitting PBPC collection after G-CSF administration. Hemopoietic reconstitution after transplantation of PBPCs collected with this procedure is complete, rapid, and sustained. © 1994 Wiley-Liss, Inc.     

Recombinant human granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in non-Hodgkin's lymphoma: a double-blind placebo-controlled trial.

The toxicity of autologous bone marrow transplantation (ABMT) is correlated to neutropenia. Although recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) seems to hold promise in accelerating neutrophil recovery, few analyses from randomized studies are presently available. Ninety-one patients with non-Hodgkin's lymphoma receiving high-dose ablative chemotherapy followed by ABMT with unpurged or purged marrow were included in a randomized, double-blind, placebo-controlled trial. Forty-four patients received 250 micrograms rhu GM-CSF (Escherichia coli)/m2 and 47 patients received placebo. Treatment was administered daily as continuous infusion from day of ABMT until the absolute neutrophil count (ANC) reached 0.5 x 10(9)/L for 7 days or until day 30, whichever was first. With rhu GM-CSF, 50% of the patients reached an ANC count greater than 0.5 x 10(9)/L at day 14 as opposed to day 21 with placebo (P less than .0001). Patients transplanted with marrow purged by mafosfamide also recovered earlier when treated with rhu GM-CSF (16 v 20.5 days, P = .013). The hospitalization duration was shorter in the rhu GM-CSF group (median, 23 v 28 days, P less than .05). No difference was observed in fever, number of infections, and antibiotic administration between the two groups. The major adverse event ascribed to rhu GM-CSF was a capillary leak syndrome in three patients graded as severe in two patients, moderate in one, and reversible in all three patients. In addition, one patient in the rhu GM-CSF group died suddenly with no explanation. In long term follow-up, the relapse rate was identical in both groups and there was no significant difference in the number of deaths at 1 year (12 with rhu GM-CSF v 9 with placebo), although deaths seemed to occur slightly earlier in the rhu GM-CSF group. We conclude that after ABMT with purged or unpurged marrow, rhu GM-CSF (E coli) significantly reduces neutropenia duration and hospitalization stay. A positive causative relation between the study drug and/or its mode of application with an increased toxicity as compared with GM-CSF from other sources and/or other modes of application cannot be deduced from the experiences in this study. Additional randomized trials would be necessary for an appropriate answer.