For many anticancer agents, dose–response curves are steep and tumor response is dose dependent, but optimal dosing is often hindered by toxicities such as myelosuppression. Hematopoietic rescue by autologous peripheral blood stem cell transplantation (APBSCT) is an important method employed to circumvent this dose limitation, allowing high-dose chemotherapy (HDC) to be widely used to attain tumor response, which would otherwise be myeloablative. 1–3 This process involves the use of priming agents such as granulocyte colony-stimulating factor (G-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF) either alone or in combination with chemotherapy to increase the number of peripheral stem cells available for harvest and later infusion. 4,5 After stem cell harvest, a pretransplant conditioning regimen consisting of HDC allows maximal tumor destruction. Subsequent infusion of the harvested peripheral stem cells results in eventual bone marrow reconstitution. After such treatment, there is a period of profound pancytopenia responsible for most of the treatment-related morbidity and mortality. Anemia and thrombocytopenia are treated with transfusions, but neutropenia, not generally correctable by transfusion, is associated with life-threatening infections. A great deal of research has addressed methods of shortening the length of neutropenia following myeloablative HDC.
Several hematopoietic growth factors, including stem cell factor and interleukin-6, as well as the colony-stimulating factors, interleukin-3, G-CSF, and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been demonstrated to promote granulopoiesis. 6–11 The two most specific for granulocytes, G-CSF and GM-CSF, 7 have been used to reduce neutropenia and its associated conditions (fever, infection, and oropharyngeal ulcerations) with varying degrees of success in a variety of clinical situations, such as after myeloablative chemotherapy, 12–15 in acquired immune deficiency syndrome–associated neutropenia, 16 in severe chronic neutropenia associated with congenital agranulocytosis, 17 and in myelodysplastic syndromes. 18–20 They have also been used to reduce neutropenia and its sequelae after autologous bone marrow transplantation. 21–26 Finally, G-CSF has been used with excellent results to mobilize hematopoietic progenitor cells into peripheral blood for collection by leukopheresis 4–5 and to accelerate neutrophil recovery after HDC/APBSCT. 27,28
Studies have demonstrated that all of these cytokines, primarily in synergy with each other, have the capacity to promote myeloid progenitor cell proliferation by shortening the G0 period of dormant stem cells. 6–11,29,30 G-CSF, as a single agent, is a very weak stimulus for progenitor cell proliferation, 7,10 but appears to be one of the primary inducers of differentiation and the terminal maturation of more advanced myeloid precursor cells to functional granulocytes. 10,31 From these data, it follows that the ability of G-CSF to shorten engraftment time after HDC/APBSCT may be dependent on its ability to induce terminal maturation and not on its weaker ability to contribute to the early proliferation of stem cells. If this is the case, administration of G-CSF beginning immediately after transplant may represent an unnecessary expense.
By reviewing our experience at Hahnemann University Hospital, we sought to demonstrate that starting the administration of G-CSF 8 days after HDC/APBSCT would not delay time for neutrophil recovery or hospital discharge when compared with initiating infusions starting on day 0.
PATIENTS AND METHODS
Patients and Inclusion Criteria
All charts for patients (bone marrow transplant records + patient’s inpatient and outpatient records) admitted to the Bone Marrow Transplant Unit at the Hahnemann University Hospital between 1994 and 1998 were reviewed. All patients with nonmyeloid malignancies (specifically, either breast cancer or non-Hodgkin’s lymphoma) who underwent priming with either G-CSF alone or G-CSF in combination with chemotherapy (paclitaxel 135–250 mg/m2 for patients with breast cancer, cyclophosphamide 3 g/m2 or mitoxantrone, ifosfamide, mesna, etoposide combination chemotherapy for patients with non-Hodgkin’s lymphoma), followed by peripheral stem cell harvest and HDC/APBSCT, who received initial G-CSF infusions on either day 0 or day 8 were enrolled in the study (Fig. 1). Only patients with complete chart information in the specified study design were enrolled.
The patients who received G-CSF support on the eighth day after peripheral stem cell transplant were designated as the day 8 group (group 1 = late G-CSF). Patients in the day 0 group (group 2 = early G-CSF) started G-CSF support on the same day as APBSCT. As illustrated in Table 1, there were no statistically significant differences in patient characteristics between the two groups, except in two parameters where designated. In addition, prior chemotherapy received and disease stage at the time of HDC/APBSCT were also similar in the two groups.
Peripheral Blood Stem Cell Harvesting
All the patients included in our study had been treated in a uniform manner regarding priming and peripheral blood stem cell harvesting (PBSCH). Specifically, all had been noted to have chemotherapy-sensitive tumors in the past, and thus were offered and accepted the option of HDC/ABBSCT. Informed consent was obtained, and the patients underwent PBSCH after a priming regimen consisting of either G-CSF or G-CSF and chemotherapy (paclitaxel 135–250 mg/m2 for patients with breast cancer, cyclophosphamide 3 g/m2 or mitoxantrone, ifosfamide, mesna, etoposide combination chemotherapy for patients with non-Hodgkin’s lymphoma where designated). The priming dose of G-CSF was approximately 10 μg/kg except in 2 patients in each group (as designated in Table 1). In the day 8 group, 2 patients received 5 and 6 μg/kg G-CSF doses, respectively, whereas in the day 0 group, 2 patients received 5 and 8 to 16 μg/kg G-CSF doses, respectively. Stem cells were collected with leukopheresis using a Cobe Spectra apheresis machine (Lakewood, CO) and then cryopreserved. By this uniform administration of pre-HDC/APBSCT growth factors (G-CSF), we eliminate any confounding influence of possible G-CSF receptor downregulation between the two groups, which may affect G-CSF’s activity after transplant.
Pretransplant Conditioning Regimen (High-Dose Chemotherapy)
All patients were hospitalized in single rooms with air filtration systems (laminar airflow or high-efficiency particulate air filtration) in the Bone Marrow Transplant Unit. An indwelling central venous catheter/access was present in all cases. All patients received prophylactic antimicrobial therapy as per standard protocol in our Bone Marrow Transplant Unit at that time (either ciprofloxacin or trimethoprim-sulfamethoxazole, acyclovir, and fluconazole).
The pretransplant conditioning HDC regimen for patients with breast cancer started 6 days before APBSCT (day −6) and continued until 2 days before APBSCT (day −2) with day −1 being the rest day.
The pretransplant conditioning regimen for patients with breast cancer consisted of cyclophosphamide 1,500 mg/m2/d × 4 days IV, thiotepa 125 mg/m2/d × 4 days IV, carboplatin 200 mg/m2/d × 4 days IV.
The pretransplant conditioning HDC regimen for patients with non-Hodgkin’s lymphoma started 8 days before APBSCT (day −8) and continued until 2 days before APBSCT (day −2) with day −1 being the rest day.
The pretransplant conditioning regimen for patients with non-Hodgkin’s lymphoma consisted of busulfan 4 mg/kg/d × 4 days, VP-16 40 mg/kg × 1 day, and cyclophosphamide 60 mg/kg/d × 2 days.
Autologous Peripheral Blood Stem Cell Transplantation
Patients were given their own harvested peripheral stem cells through IV infusion on day 0, which was the day of the transplant.
After conditioning with HDC, patients in whom fever of 38°C or higher developed were treated with additional appropriate broad-spectrum antibiotics. Packed erythrocytes were given as required to maintain a hemoglobin level 80 g/l or more, and prophylactic platelet transfusions were given to patients to maintain platelet count 20 × 109/l or more. Both groups received G-CSF approximately 5 μg/kg IV over 30 minutes infusion as supportive therapy until the neutrophil count recovery, with the day 0 group receiving the first infusion on the day of APBSCT, and the day 8 group receiving their first G-CSF 8 days later. (One patient in group 2 was given GM-CSF 250 μg IV on day −1 additionally.)
Main Outcome Measures
The mean time to reach absolute neutrophil count (ANC) 0.5 × 109/l or more, the posttransplant duration of hospitalization, and total days in the hospital were compared between the two groups.
The data are given as the mean, SD, and the range. The differences between the values were evaluated for statistical significance. The two groups (day 8 and day 0) were compared on numerical variables using unpaired two-tailed Student t test. For other variables (i.e., sex, diagnosis), chi-square test was used for comparison. p values less than or equal to 0.05 are considered to be significant.
The mean time to reach neutrophil count recovery (ANC ≥ 0.5 × 109/l) was 10.56 days in day 8 patients versus 9.68 in day 0 patients (p = 0.48, not statistically significant). In addition, posttransplant hospital days (12.81 versus 13.62, p = 0.39) and the total days in hospital (20.25 versus 20.25, p = 1.00) were not significantly different between the patients who received early versus late administration of G-CSF, respectively (Table 2). Although the mean total mononuclear cells and mononuclear cells/kg included in the peripheral blood stem cell infusion bags given to the day 0 group was significantly higher than that given to the day 8 group, a factor usually favoring earlier engraftment, 32 this did not translate into statistically significant enhancement of neutrophil recovery (Although neutrophil recovery was slightly shorter in the day 0 group, this was not statistically significant.) All patients in group 1 recovered (ANC ≥ 0.5 × 109/l) their counts within the next subsequent 4 days after G-CSF started, whereas the earliest recovery seen in group 2 was at day 8 (Table 3). This points out that there may be multiple factors playing a role in the neutrophil recovery in addition to the role of G-CSF receptor sensitivity and distribution in different steps of hematopoiesis in which G-CSF and other factors may act in synergy. Finally, there was a substantial cost saving with the late administration of G-CSF (US$200 × 8 ≅ US$1,600 per patient) at our institution.
It should also be noted that there was a large variation in the range of posttransplant discharge time and total hospital days in both groups, suggesting that there may be multiple factors predicting these outcomes in addition to neutrophil recovery.
It is well established that the administration of both G-CSF and GM-CSF accelerate neutrophil recovery after bone marrow transplantation, 21–26 and after a conditioning regimen with high-dose chemotherapy and subsequent APBSCT. 27,28 Studies have shown that G-CSF is a unique granulopoietic growth factor in that, as a single agent, it primarily serves to promote terminal differentiation rather than to induce progenitor proliferation, 10,31 with the latter function greatly dependent on the presence and likely synergy with other cytokines. 7,8,10,29–30 This concept has been supported by tissue culture studies in which human marrow progenitors enriched for a relatively primitive population expressing CD34+/CD33− show minimal response to G-CSF in terms of neutrophil colony formation, whereas it can effectively stimulate colony formation from a somewhat more mature marrow progenitor cell population committed to myeloid differentiation that expresses CD34+/CD33+. 31 Our results suggest that after myeloablative HDC/APBSCT, a set amount of time is needed for stem cells to engraft and begin hematopoiesis in the bone marrow that cannot be shortened by earlier administration of G-CSF. It is likely that this period corresponds to the time when early progenitor cells, which are relatively insensitive to G-CSF (One other important point should also be remembered that the biologic activity of G-CSF is mediated by specific receptors on the surface of responsive cells and the receptor number on granulocyte progenitor cells increase with neutrophilic differentiation), are the only cells present in the marrow.
Early administration of G-CSF along with the other factors shown to greatly enhance G-CSF’s ability to stimulate proliferation of the earliest stem cells may show a benefit beyond administration of G-CSF alone. For now, we conclude that G-CSF infusion after HDC/APBSCT can be delayed without affecting the overall amount of time to production of mature granulocytes.
Although very few other studies have addressed the issue of timing of G-CSF administration after HDC/APBSCT, the timing of G-CSF infusion after autologous bone marrow transplant (BMT) has been studied. Two studies compared time with ANC greater than or equal to 0.5 × 109/L after administration of G-CSF on posttransplant day 7 (n = 17) and posttransplant day 8 (n = 17), with historical controls who did not receive G-CSF. Both studies demonstrated a significant benefit with the use of G-CSF after autologous bone marrow transplant, but could draw no conclusions regarding early versus late administration. 33,34 In 1994, Clark et al. 35 performed a study comparing differential timing of G-CSF administration after autologous bone marrow transplant; they gave one group (n = 13) G-CSF on post–bone marrow transplant day 10 and G-CSF to the other group (n = 6) on day 7. The day 7 patients and day 10 patients were compared with historical controls (n = 18) who did not receive G-CSF. Both day 7 and day 10 groups showed a shorter reconstitution time than historical controls. 35 A prospective randomized study by Torres Gomez et al. 36 was conducted in 1995 that demonstrated no significant difference in time to reach ANC greater than or equal to 0.5 × 109/l between posttransplant day 0 G-CSF infusion (n = 36) and day 7 infusion (n = 39) after allogeneic and autologous bone marrow transplantations, and noted considerable cost savings in the day 7 group.
In 1994, Vey et al. 37 studied 49 patients, 25 receiving G-CSF on day 1 after autologous bone marrow transplant and 24 receiving G-CSF starting posttransplant day 6, and compared them with the 29 historical controls who did not receive G-CSF. Their study demonstrated that although there was no statistically significant difference in the time to neutrophil recovery 37 between the day 1 and day 6 groups, there was a significantly shorter time to neutrophil recovery in these groups when compared with historical controls.
A few small studies have addressed the optimal timing of G-CSF after HDC/APBSCT. A French study by Faucher et al. failed to demonstrate a significant difference in hospital stay or neutrophil recovery between patients who received G-CSF starting day 1 (n = 19) and day 6 (n = 16) after APBSCT. 38 Cetkovsky et al. compared time with neutrophil reconstitution and total hospital days between patients who received G-CSF on day 1 after APBSCT (n = 35) with patients who received G-CSF infusions starting when their ANC decreased to less than 0.5 × 109/l (n = 35 patients), which was approximately 4 days after APBSCT. They found no significant differences between groups for either endpoint, and noted significant cost savings in the latter group. 39
Finally, in an attempt to determine more accurately the optimal timing of G-CSF infusion, Uhr et al. designed a study with 3 groups: G-CSF infusion starting day 1 after APBSCT (n = 7), starting 6 days after transplant (n = 4) and day 10 after transplant (n = 6), which demonstrated a significantly shorter time to ANC recovery in the first two groups (9 days versus 8.5, no significant difference) than the day 10 group (12.5 days), 40 suggesting that the window for optimal timing of G-CSF administration lies between 6 and 10 days after APBSCT. However, the limited size of the study calls in question the precision of its results.
Given the small amount of data regarding optimal timing of G-CSF administration after HDC/APBSCT and the potential for substantial cost savings with delayed administration, we felt that it would be useful to examine our outcomes with day 8 posttransplant infusions versus infusions beginning day 0. Our results have confirmed that G-CSF can hasten neutrophil recovery and that there is no difference in efficacy or patient outcome whether G-CSF is administered immediately after APBSCT or starting 8 days later. This was observed despite the fact that the total mononuclear cells and mononuclear cells per kilogram included in the peripheral blood stem cell infusion were higher in the infusions given to the day 0 group, a factor usually favoring early engraftment. 32 Finally, in our institution, we estimated the cost savings of day 8 posttransplant G-CSF administration to be approximately US$1,600 per patient without any effect on clinical outcome in this perspective.
In our study, patients were treated only with Filgrastim (r-met HU G-CSF) (Amgen, Thousand Oaks, CA, U.S.A.) before and after transplant so that the activity related to the molecular structure was considered to be the same in the two groups. In addition, possible G-CSF receptor downregulation by prior use of growth factors (G-CSF, GM-CSF, or others) may have affected our study outcomes, but this was also balanced in the two groups because both received similar doses of growth factor with or without chemotherapy priming before peripheral blood stem cell harvesting procedure before HDC/APBSCT. Whether a different outcome would have occurred had GM-CSF been used remains uncertain.
There are several limitations of our study. First, this was a retrospective chart review analysis, and it is possible that the charts did not include all pertinent details. Also, the patients were not randomized, so there may have been bias present in the assignment of patients to receive G-CSF on day 8 rather than day 0, which was not addressed in the charts and was overlooked in our analysis of patient characteristics. Finally, we were unable to determine the several predictors of bone marrow health and subsequent ability to engraft, including the past radiation dose received by each patient and results of any bone marrow studies that may have shown fibrosis or myelophthisis.
More studies are needed to determine whether further delay in G-CSF administration (especially to day 9) would be efficacious or detrimental, as the neutrophil recovery time appears to be most optimal with G-CSF administration between day 8 and day 10 after transplant. 40 Also, it would be interesting to determine whether the efficacy of day 0 administered G-CSF would be enhanced by the concurrent administration of other growth factors shown to enhance G-CSF’s affect on the proliferation of early progenitor cells.
The authors thank Rasih Suha Ener, M.D. for his thoughtful review and substantial contribution to this article. The authors also thank Regina Mullaney, B.S.; Linda Cathay, bone marrow transplant coordinator; Marylin Difeliciantonio, P.A.-C.; Frances T. McManus, medical receptionist; and Dee Valley, medical transcriptionist for their help in data collection.
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